Treatment recommendations for psoriatic arthritis.
To develop comprehensive recommendations for the treatment of the various clinical manifestations of psoriatic arthritis (PsA) based on evidence obtained from a systematic review of the literature and from consensus opinion. Formal literature reviews of treatment for the most significant discrete clinical manifestations of PsA (skin and nails, peripheral arthritis, axial disease, dactylitis and enthesitis) were performed and published by members of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA). Treatment recommendations were drafted for each of the clinical manifestations by rheumatologists, dermatologists and PsA patients based on the literature reviews and consensus opinion. The level of agreement for the individual treatment recommendations among GRAPPA members was assessed with an online questionnaire. Treatment recommendations were developed for peripheral arthritis, axial disease, psoriasis, nail disease, dactylitis and enthesitis in the setting of PsA. In rotal, 19 recommendations were drafted, and over 80% agreement was obtained on 16 of them. In addition, a grid that factors disease severity into each of the different disease manifestations was developed to help the clinician with treatment decisions for the individual patient from an evidenced-based perspective. Treatment recommendations for the cardinal physical manifestations of PsA were developed based on a literature review and consensus between rheumatologists and dermatologists. In addition, a grid was established to assist in therapeutic reasoning and decision making for individual patients. It is anticipated that periodic updates will take place using this framework as new data become available.


The legal ethics of pediatric research.
Since the mid- to late 1990s, the scientific and medical research community has sought to increase its access to healthy children for research protocols that involve harm or a risk of harm. This move reverses longstanding policy within that community generally to exclude healthy children from such protocols on the grounds that the research as to them is non-therapeutic, that they are particularly vulnerable to research-related abuses, and that they are unable themselves to give informed consent to their participation. The research community's new posture has been supported by prominent pediatric bioethicists who have argued that unless healthy children are included as research subjects in harmful or risky research, the pediatric population will continue to suffer relative to the adult population in the extent to which it benefits from modern advances in science and medicine. In their view, it is possible for the research community to self-administer a rule that strikes a balance between protecting healthy children from research-related abuses and allowing their inclusion in cutting-edge pediatric research. In this scheme, parental consent is central to the research community's claims about child protection. This Article explores the flaws inherent in this ethics of pediatric research. Specifically, it challenges the view from ethics that the law permits parents to consent to their children's inclusion in harmful or risky research to the extent that related invasions would meet legal maltreatment standards. More broadly, it challenges the movement to increase access to healthy children for harmful and risky research on the ground that it risks two important regressions: First, in its willingness to risk harm to individual children in the interests of the group, it threatens the progress the law has made in its development of the concept of the child as an individual worthy of respect in his or her own right, a concept that imagines parents as fiduciaries and that includes strong protections against invasions of bodily integrity. Second, in its failure to assure that the burdens of non-therapeutic research are not placed disproportionately on children of lower socioeconomic and minority status, it violates the antidiscrimination principle, which has only begun to make good on its promise of equal treatment for all children. Ultimately, this Article argues that harmonization of the rules governing pediatric research with the law of child protection and parents' consent authority is the best way to assure that children are protected in the research setting in these respects and to the same extent they are otherwise in the society.


Multimodal surface matching: fast and generalisable cortical registration using discrete optimisation.
Group neuroimaging studies of the cerebral cortex benefit from accurate, surface-based, cross-subject alignment for investigating brain architecture, function and connectivity. There is an increasing amount of high quality data available. However, establishing how different modalities correlate across groups remains an open research question. One reason for this is that the current methods for registration, based on cortical folding, provide sub-optimal alignment of some functional subregions of the brain. A more flexible framework is needed that will allow robust alignment of multiple modalities. We adapt the Fast Primal-Dual (Fast-PD) approach for discrete Markov Random Field (MRF) optimisation to spherical registration by reframing the deformation labels as a discrete set of rotations and propose a novel regularisation term, derived from the geodesic distance between rotation matrices. This formulation allows significant flexibility in the choice of similarity metric. To this end we propose a new multivariate cost function based on the discretisation of a graph-based mutual information measure. Results are presented for alignment driven by scalar metrics of curvature and myelination, and multivariate features derived from functional task performance. These experiments demonstrate the potential of this approach for improving the integration of complementary brain data sets in the future.


Spontaneously remitting insulin autoimmune syndrome in a patient taking alpha-lipoic acid.
Insulin autoimmune syndrome (IAS), or Hirata disease, is a rare hypoglycaemic disorder caused by the presence of high titer of insulin autoantibodies (IAA) in patients without previous exposure to exogenous insulin. Even though its pathogenesis is not fully understood, striking evidences link IAS to previous exposure to sulphydryl-containing medications, like alpha-lipoic acid, a widely used nutritional supplement. Although challenging, a careful differential diagnosis from other causes of hyperinsulinaemic hypoglycaemia (such as insulinoma) is mandatory, since these conditions require different therapeutic approaches. In the present study, we report a 35-year-old woman originally from Sri Lanka who was referred to our University Hospital on suspicion of occult insulinoma. Her medical history was positive for endometriosis, treated with estroprogestins and alpha-lipoic acid. The latter supplement was begun 2 weeks before the first hypoglycaemic episode. Our tests confirmed the presence of hypoglycaemia associated with high insulin and C-peptide concentrations. When insulin concentrations were compared using different assays, the results were significantly different. Moreover, insulin values significantly decreased after precipitation with polyethylene glycol. An assay for IAA proved positive (530 U/mL). A genetic analysis revealed the presence of HLA-DRB1*04,15, an immunogenetic determinant associated with IAS. On the basis of clinical data we avoided a first-line approach with immunosuppressive treatments, and the patient was advised to modify her diet, with the introduction of frequent low-caloric meals. During follow-up evaluations, glucose levels (registered trough a flash glucose monitoring system) resulted progressively more stable. IAA titer progressively decreased, being undetectable by the fifteenth month, thus indicating the remission of the IAS. Learning points: Insulin autoimmune syndrome (IAS) is a rare cause of hyperinsulinaemic hypoglycaemia, whose prevalence is higher in East Asian populations due to the higher prevalence of specific immunogenetic determinants. Nevertheless, an increasing number of IAS cases is being reported worldwide, due to the wide diffusion of medications such as alpha-lipoic acid. Differential diagnosis of IAS from other causes of hyperinsulinemic hypoglycaemia is challenging. Even though many tests can be suggestive of IAS, the gold standard remains the detection of IAAs, despite that dedicated commercial kits are not widely available. The therapeutic approach to IAS is problematic. As a matter of fact IAS is often a self-remitting disease, but sometimes needs aggressive immunosuppression. The benefits and risks of any therapeutic choice should be carefully weighted and tailored on the single patient.


Three-dimensional histology: tools and application to quantitative assessment of cell-type distribution in rabbit heart.
Cardiac histo-anatomical organization is a major determinant of function. Changes in tissue structure are a relevant factor in normal and disease development, and form targets of therapeutic interventions. The purpose of this study was to test tools aimed to allow quantitative assessment of cell-type distribution from large histology and magnetic resonance imaging- (MRI) based datasets. Rabbit heart fixation during cardioplegic arrest and MRI were followed by serial sectioning of the whole heart and light-microscopic imaging of trichrome-stained tissue. Segmentation techniques developed specifically for this project were applied to segment myocardial tissue in the MRI and histology datasets. In addition, histology slices were segmented into myocytes, connective tissue, and undefined. A bounding surface, containing the whole heart, was established for both MRI and histology. Volumes contained in the bounding surface (called 'anatomical volume'), as well as that identified as containing any of the above tissue categories (called 'morphological volume'), were calculated. The anatomical volume was 7.8 cm(3) in MRI, and this reduced to 4.9 cm(3) after histological processing, representing an 'anatomical' shrinkage by 37.2%. The morphological volume decreased by 48% between MRI and histology, highlighting the presence of additional tissue-level shrinkage (e.g. an increase in interstitial cleft space). The ratio of pixels classified as containing myocytes to pixels identified as non-myocytes was roughly 6:1 (61.6 vs. 9.8%; the remaining fraction of 28.6% was 'undefined'). Qualitative and quantitative differentiation between myocytes and connective tissue, using state-of-the-art high-resolution serial histology techniques, allows identification of cell-type distribution in whole-heart datasets. Comparison with MRI illustrates a pronounced reduction in anatomical and morphological volumes during histology processing.


Constrained linear basis sets for HRF modelling using Variational Bayes.
FMRI modelling requires flexible haemodynamic response function (HRF) modelling, with the HRF being allowed to vary spatially and between subjects. To achieve this flexibility, voxelwise parameterised HRFs have been proposed; however, inference on such models is very slow. An alternative approach is to use basis functions allowing inference to proceed in the more manageable General Linear Model (GLM) framework. However, a large amount of the subspace spanned by the basis functions produces nonsensical HRF shapes. In this work we propose a technique for choosing a basis set, and then the means to constrain the subspace spanned by the basis set to only include sensible HRF shapes. Penny et al. showed how Variational Bayes can be used to infer on the GLM for FMRI. Here we extend the work of Penny et al. to give inference on the GLM with constrained HRF basis functions and with spatial Markov Random Fields on the autoregressive noise parameters. Constraining the subspace spanned by the basis set allows for far superior separation of activating voxels from nonactivating voxels in FMRI data. We use spatial mixture modelling to produce final probabilities of activation and demonstrate increased sensitivity on an FMRI dataset.


Resilience and MRI correlates of cognitive impairment in community-dwelling elders.
The contribution of education and intelligence to resilience against age-related cognitive decline is not clear, particularly in the presence of 'normal for age' minor brain abnormalities. Participants (n = 208, mean age 69.2 years, s.d. = 5.4) in the Whitehall II imaging substudy attended for neuropsychological testing and multisequence 3T brain magnetic resonance imaging. Images were independently rated by three trained clinicians for global and hippocampal atrophy, periventricular and deep white matter changes. Although none of the participants qualified for a clinical diagnosis of dementia, a screen for cognitive impairment (Montreal Cognitive Assessment (MoCA) <26) was abnormal in 22%. Hippocampal atrophy, in contrast to other brain measures, was associated with a reduced MoCA score even after controlling for age, gender, socioeconomic status, years of education and premorbid IQ. Premorbid IQ and socioeconomic status were associated with resilience in the presence of hippocampal atrophy. Independent contributions from a priori risk (age, hippocampal atrophy) and resilience (premorbid function, socioeconomic status) combine to predict measured cognitive impairment.


Mixed behaviors in dementia: the need for a paradigm shift.
This research was an examination of two specific types of behaviors, apathy and agitation, that commonly occur in older adults with dementia. In a retrospective analysis of existing data from two intervention projects, the authors explored the times and the types of behaviors occurring in 141 older adults living in the community, assisted living, and nursing home settings. The occurrence of apathetic and agitated behaviors was monitored throughout the day for a 2-week period. The result of the analysis suggests that in all stages and settings, a combination of apathy and agitation is the most common phenomenon, and that the predominant behavior actually fluctuates during the course of the day. The use of individualized interventions based on carefully monitored behavior patterns may provide a more sensitive approach to the overall treatment needs of individuals with dementia in the future.


Thyrotoxicosis induced by excessive 3,5,3'-triiodothyronine in a dog.
CASE DESCRIPTION A 7-year-old castrated male Havanese was evaluated at a veterinary teaching hospital because of a 12-week history of hyperactivity, aggression, and progressive weight loss despite a healthy appetite. CLINICAL FINDINGS Tachycardia was the only remarkable finding during physical examination. Serum 3,5,3'-triiodothyronine (T3) and free T3 concentrations were markedly increased, and thyroxine (T4), free T4, and thyroid-stimulating hormone concentrations were at or decreased from the respective reference ranges. Thyroid scintigraphy revealed suppressed uptake of sodium pertechnetate Tc 99m by the thyroid gland but no ectopic thyroid tissue, which was indicative of thyrotoxicosis induced by an exogenous source of T3. TREATMENT AND OUTCOME The dog was hospitalized for 24 hours, and its diet was changed, after which the clinical signs rapidly resolved and serum T3 and free T3 concentrations returned to within the respective reference ranges. This raised suspicion of an exogenous source of T3 in the dog's home environment. Analysis of the commercial beef-based canned food the dog was being fed revealed a high concentration of T3 (1.39 μg/g) and an iodine (82.44 μg/g) concentration that exceeded industry recommendations. No other source of T3 was identified in the dog's environment. CLINICAL RELEVANCE To our knowledge, this is the first report of clinical thyrotoxicosis in a dog induced by exogenous T3, although the source of exogenous T3 was not identified. This case highlights the importance of measuring serum T3 and thyroid-stimulating hormone concentrations in addition to T4 and free T4 concentrations when there is incongruity between clinical findings and thyroid function test results.


Oxford Lithium Trial (OxLith) of the early affective, cognitive, neural and biochemical effects of lithium carbonate in bipolar disorder: study protocol for a randomised controlled trial.
Despite lithium's being the most effective drug for bipolar disorder and in clinical use for decades, we still know very little about its early effects relevant to its mode of action. The Oxford Lithium Trial is a double-blind, randomised, placebo-controlled study of 6-week lithium treatment in participants with bipolar disorder and mood instability. Its aim is to identify early clinical, neurocognitive and biological effects. Participants (n = 40) will undergo an intensive battery of multi-modal investigations, including remote monitoring of mood, activity and physiology, as well as cognitive testing, fMRI and magnetoencephalography, together with biochemical and gene expression measurements to assess renal, inflammatory and circadian effects. The findings derived from this trial may be of value in predicting subsequent therapeutic response or side effects, not only relevant to the use of lithium but also providing a potential signature to help in more rapid evaluation of novel mood stabilisers. In this respect, OxLith is a step towards the development of a valid experimental medicine model for bipolar disorder. ISRCTN91624955 . Registered on 22 January 2015.


FOXO3A directs a protective autophagy program in haematopoietic stem cells.
Blood production is ensured by rare, self-renewing haematopoietic stem cells (HSCs). How HSCs accommodate the diverse cellular stresses associated with their life-long activity remains elusive. Here we identify autophagy as an essential mechanism protecting HSCs from metabolic stress. We show that mouse HSCs, in contrast to their short-lived myeloid progeny, robustly induce autophagy after ex vivo cytokine withdrawal and in vivo calorie restriction. We demonstrate that FOXO3A is critical to maintain a gene expression program that poises HSCs for rapid induction of autophagy upon starvation. Notably, we find that old HSCs retain an intact FOXO3A-driven pro-autophagy gene program, and that ongoing autophagy is needed to mitigate an energy crisis and allow their survival. Our results demonstrate that autophagy is essential for the life-long maintenance of the HSC compartment and for supporting an old, failing blood system.


Genome-wide association study of hepatitis C virus- and cryoglobulin-related vasculitis.
The host genetic basis of mixed cryoglobulin vasculitis is not well understood and has not been studied in large cohorts. A genome-wide association study was conducted among 356 hepatitis C virus (HCV) RNA-positive individuals with cryoglobulin-related vasculitis and 447 ethnically matched, HCV RNA-positive controls. All cases had both serum cryoglobulins and a vasculitis syndrome. A total of 899 641 markers from the Illumina HumanOmni1-Quad chip were analyzed using logistic regression adjusted for sex, as well as genetically determined ancestry. Replication of select single-nucleotide polymorphisms (SNPs) was conducted using 91 cases and 180 controls, adjusting for sex and country of origin. The most significant associations were identified on chromosome 6 near the NOTCH4 and MHC class II genes. A genome-wide significant association was detected on chromosome 6 at SNP rs9461776 (odds ratio=2.16, P=1.16E-07) between HLA-DRB1 and DQA1: this association was further replicated in additional independent samples (meta-analysis P=7.1 × 10(-9)). A genome-wide significant association with cryoglobulin-related vasculitis was identified with SNPs near NOTCH4 and MHC Class II genes. The two regions are correlated and it is difficult to disentangle which gene is responsible for the association with mixed cryoglobulinemia vasculitis in this extended major histocompatibility complex region.


ASPP2 links the apical lateral polarity complex to the regulation of YAP activity in epithelial cells.
The Hippo pathway, by tightly controlling the phosphorylation state and activity of the transcription cofactors YAP and TAZ is essential during development and tissue homeostasis whereas its deregulation may lead to cancer. Recent studies have linked the apicobasal polarity machinery in epithelial cells to components of the Hippo pathway and YAP and TAZ themselves. However the molecular mechanism by which the junctional pool of YAP proteins is released and activated in epithelial cells remains unknown. Here we report that the tumour suppressor ASPP2 forms an apical-lateral polarity complex at the level of tight junctions in polarised epithelial cells, acting as a scaffold for protein phosphatase 1 (PP1) and junctional YAP via dedicated binding domains. ASPP2 thereby directly induces the dephosphorylation and activation of junctional YAP. Collectively, this study unearths a novel mechanistic paradigm revealing the critical role of the apical-lateral polarity complex in activating this localised pool of YAP in vitro, in epithelial cells, and in vivo, in the murine colonic epithelium. We propose that this mechanism may commonly control YAP functions in epithelial tissues.


OmpW of Caulobacter crescentus Functions as an Outer Membrane Channel for Cations.
Caulobacter crescentus is an oligotrophic bacterium that lives in dilute organic environments such as soil and freshwater. This bacterium represents an interesting model for cellular differentiation and regulation because daughter cells after division have different forms: one is motile while the other is non-motile and can adhere to surfaces. Interestingly, the known genome of C. crescentus does not contain genes predicted to code for outer membrane porins of the OmpF/C general diffusion type present in enteric bacteria or those coding for specific porins selective for classes of substrates. Instead, genes coding for 67 TonB-dependent outer membrane receptors have been identified, suggesting that active transport of specific nutrients may be the norm. Here, we report that high channel-forming activity was observed with crude outer membrane extracts of C. crescentus in lipid bilayer experiments, indicating that the outer membrane of C. crescentus contained an ion-permeable channel with a single-channel conductance of about 120 pS in 1M KCl. The channel-forming protein with an apparent molecular mass of about 20 kDa was purified to homogeneity. Partial protein sequencing of the protein indicated it was a member of the OmpW family of outer membrane proteins from Gram-negative bacteria. This channel was not observed in reconstitution experiments with crude outer membrane extracts of an OmpW deficient C. crescentus mutant. Biophysical analysis of the C. crescentus OmpW suggested that it has features that are special for general diffusion porins of Gram-negative outer membranes because it was not a wide aqueous channel. Furthermore, OmpW of C. crescentus seems to be different to known OmpW porins and has a preference for ions, in particular cations. A putative model for OmpW of C. crescentus was built on the basis of the known 3D-structures of OmpW of Escherichia coli and OprG of Pseudomonas aeruginosa using homology modeling. A comparison of the two known structures with the model of OmpW of C. crescentus suggested that it has a more hydrophilic interior and possibly a larger diameter.


Effects of BRCA2 cis-regulation in normal breast and cancer risk amongst BRCA2 mutation carriers.
Cis-acting regulatory single nucleotide polymorphisms (SNPs) at specific loci may modulate penetrance of germline mutations at the same loci by introducing different levels of expression of the wild-type allele. We have previously reported that BRCA2 shows differential allelic expression and we hypothesize that the known variable penetrance of BRCA2 mutations might be associated with this mechanism. We combined haplotype analysis and differential allelic expression of BRCA2 in breast tissue to identify expression haplotypes and candidate cis-regulatory variants. These candidate variants underwent selection based on in silico predictions for regulatory potential and disruption of transcription factor binding, and were functionally analyzed in vitro and in vivo in normal and breast cancer cell lines. SNPs tagging the expression haplotypes were correlated with the total expression of several genes in breast tissue measured by Taqman and microarray technologies. The effect of the expression haplotypes on breast cancer risk in BRCA2 mutation carriers was investigated in 2,754 carriers. We identified common haplotypes associated with differences in the levels of BRCA2 expression in human breast cells. We characterized three cis-regulatory SNPs located at the promoter and two intronic regulatory elements which affect the binding of the transcription factors C/EBPα, HMGA1, D-binding protein (DBP) and ZF5. We showed that the expression haplotypes also correlated with changes in the expression of other genes in normal breast. Furthermore, there was suggestive evidence that the minor allele of SNP rs4942440, which is associated with higher BRCA2 expression, is also associated with a reduced risk of breast cancer (per-allele hazard ratio (HR) = 0.85, 95% confidence interval (CI) = 0.72 to 1.00, P-trend = 0.048). Our work provides further insights into the role of cis-regulatory variation in the penetrance of disease-causing mutations. We identified small-effect genetic variants associated with allelic expression differences in BRCA2 which could possibly affect the risk in mutation carriers through altering expression levels of the wild-type allele.


Finding people who will tell you their thoughts on genomics-recruitment strategies for social sciences research.
This paper offers a description of how social media, traditional media and direct invitation were used as tools for the recruitment of 6,944 research participants for a social sciences study on genomics. The remit was to gather the views of various stakeholders towards sharing incidental findings from whole genome studies. This involved recruiting members of the public, genetic health professionals, genomic researchers and non-genetic health professionals. A novel survey was designed that contained ten integrated films; this was made available online and open for completion by anyone worldwide. The recruitment methods are described together with the convenience and snowballing sampling framework. The most successful strategy involved the utilisation of social media; Facebook, Blogging, Twitter, LinkedIn and Google Ads led to the ascertainment of over 75 % of the final sample. We conclude that the strategies used were successful in recruiting in eclectic mix of appropriate participants. Design of the survey and results from the study are presented separately.


Human X-linked variable immunodeficiency caused by a hypomorphic mutation in XIAP in association with a rare polymorphism in CD40LG.
The present study focuses on a large family with an X-linked immunodeficiency in which there are variable clinical and laboratory phenotypes, including recurrent viral and bacterial infections, hypogammaglobulinemia, Epstein-Barr virus-driven lymphoproliferation, splenomegaly, colitis, and liver disease. Molecular and genetic analyses revealed that affected males were carriers of a hypomorphic hemizygous mutation in XIAP (XIAP(G466X)) that cosegregated with a rare polymorphism in CD40LG (CD40 ligand(G219R)). These genes are involved in the X-linked lymphoproliferative syndrome 2 and the X-linked hyper-IgM syndrome, respectively. Single expression of XIAP(G466X) or CD40L(G219R) had no or minimal effect in vivo, although in vitro, they lead to altered functional activities of their gene products, which suggests that the combination of XIAP and CD40LG mutations contributed to the expression of clinical manifestations observed in affected individuals. Our report of a primary X-linked immunodeficiency of oligogenic origin emphasizes that primary immunodeficiencies are not caused by a single defective gene, which leads to restricted manifestations, but are likely to be the result of an interplay between several genetic determinants, which leads to more variable clinical phenotypes.


Towards a Unified Testing Framework for Single-Sided Deafness Studies: A Consensus Paper.
While hearing aids for a contralateral routing of signals (CROS-HA) and bone conduction devices have been the traditional treatment for single-sided deafness (SSD) and asymmetric hearing loss (AHL), in recent years, cochlear implants (CIs) have increasingly become a viable treatment choice, particularly in countries where regulatory approval and reimbursement schemes are in place. Part of the reason for this shift is that the CI is the only device capable of restoring bilateral input to the auditory system and hence of possibly reinstating binaural hearing. Although several studies have independently shown that the CI is a safe and effective treatment for SSD and AHL, clinical outcome measures in those studies and across CI centers vary greatly. Only with a consistent use of defined and agreed-upon outcome measures across centers can high-level evidence be generated to assess the safety and efficacy of CIs and alternative treatments in recipients with SSD and AHL. This paper presents a comparative study design and minimum outcome measures for the assessment of current treatment options in patients with SSD/AHL. The protocol was developed, discussed, and eventually agreed upon by expert panels that convened at the 2015 APSCI conference in Beijing, China, and at the CI 2016 conference in Toronto, Canada. A longitudinal study design comparing CROS-HA, BCD, and CI treatments is proposed. The recommended outcome measures include (1) speech in noise testing, using the same set of 3 spatial configurations to compare binaural benefits such as summation, squelch, and head shadow across devices; (2) localization testing, using stimuli that rove in both level and spectral content; (3) questionnaires to collect quality of life measures and the frequency of device use; and (4) questionnaires for assessing the impact of tinnitus before and after treatment, if applicable. A protocol for the assessment of treatment options and outcomes in recipients with SSD and AHL is presented. The proposed set of minimum outcome measures aims at harmonizing assessment methods across centers and thus at generating a growing body of high-level evidence for those treatment options.


Systematic review of methodology used in ultrasound studies aimed at creating charts of fetal size.
Reliable ultrasound charts are necessary for the prenatal assessment of fetal size, yet there is a wide variation of methodologies for the creation of such charts. To evaluate the methodological quality of studies of fetal biometry using a set of predefined quality criteria of study design, statistical analysis and reporting methods. Electronic searches in MEDLINE, EMBASE and CINAHL, and references of retrieved articles. Observational studies whose primary aim was to create ultrasound size charts for bi-parietal diameter, head circumference, abdominal circumference and femur length in fetuses from singleton pregnancies. Studies were scored against a predefined set of independently agreed methodological criteria and an overall quality score was given to each study. Multiple regression analysis between quality scores and study characteristics was performed. Eighty-three studies met the inclusion criteria. The highest potential for bias was noted in the following fields: 'Inclusion/exclusion criteria', as none of the studies defined a rigorous set of antenatal or fetal conditions which should be excluded from analysis; 'Ultrasound quality control measures', as no study demonstrated a comprehensive quality assurance strategy; and 'Sample size calculation', which was apparent in six studies only. On multiple regression analysis, there was a positive correlation between quality scores and year of publication: quality has improved with time, yet considerable heterogeneity in study methodology is still observed today. There is considerable methodological heterogeneity in studies of fetal biometry. Standardisation of methodologies is necessary in order to make correct interpretations and comparisons between different charts. A checklist of recommended methodologies is proposed.


Serum-free culture alters the quantity and protein composition of neuroblastoma-derived extracellular vesicles.
Extracellular vesicles (EVs) play a significant role in cell-cell communication in numerous physiological processes and pathological conditions, and offer promise as novel biomarkers and therapeutic agents for genetic diseases. Many recent studies have described different molecular mechanisms that contribute to EV biogenesis and release from cells. However, little is known about how external stimuli such as cell culture conditions can affect the quantity and content of EVs. While N2a neuroblastoma cells cultured in serum-free (OptiMEM) conditions did not result in EVs with significant biophysical or size differences compared with cells cultured in serum-containing (pre-spun) conditions, the quantity of isolated EVs was greatly increased. Moreover, the expression levels of certain vesicular proteins (e.g. small GTPases, G-protein complexes, mRNA processing proteins and splicing factors), some of which were previously reported to be involved in EV biogenesis, were found to be differentially expressed in EVs under different culture conditions. These data, therefore, contribute to the understanding of how extracellular factors and intracellular molecular pathways affect the composition and release of EVs.


Body Fat Distribution and Systolic Blood Pressure in 10,000 Adults with Whole-Body Imaging: UK Biobank and Oxford BioBank.
This study aimed to quantify the associations of regional fat mass and fat-free mass with systolic blood pressure. This analysis combined individual participant data from two large-scale imaging studies: UK Biobank and Oxford BioBank. In both studies, participants were interviewed and measured, and they underwent dual-energy x-ray absorptiometry imaging. Linear regression was used to relate systolic blood pressure to anthropometric measures of adiposity (BMI, waist circumference, and waist to hip ratio) and dual-energy x-ray absorptiometry-derived measures of body composition (visceral android fat, subcutaneous android fat, subcutaneous gynoid fat, and fat-free mass). Among 10,260 participants (mean age 49; 96% white), systolic blood pressure was positively associated with visceral android fat (3.2 mmHg/SD in men; 2.8 mmHg/SD in women) and fat-free mass (1.92 mmHg/SD in men; 1.64 mmHg/SD in women), but there was no evidence of an association with subcutaneous android or gynoid fat. Associations of systolic blood pressure with BMI were slightly steeper than those with waist circumference or waist to hip ratio; these associations remained unchanged following adjustment for fat-free mass, but adjustment for visceral android fat eliminated associations with waist circumference and waist to hip ratio and more than halved associations with BMI. This analysis indicates that visceral fat is the primary etiological component of excess adiposity underlying the development of adiposity-related hypertension.


Perinatal and maternal outcomes by planned place of birth for healthy women with low risk pregnancies: the Birthplace in England national prospective cohort study.
To compare perinatal outcomes, maternal outcomes, and interventions in labour by planned place of birth at the start of care in labour for women with low risk pregnancies. Prospective cohort study. England: all NHS trusts providing intrapartum care at home, all freestanding midwifery units, all alongside midwifery units (midwife led units on a hospital site with an obstetric unit), and a stratified random sample of obstetric units. 64,538 eligible women with a singleton, term (≥37 weeks gestation), and "booked" pregnancy who gave birth between April 2008 and April 2010. Planned caesarean sections and caesarean sections before the onset of labour and unplanned home births were excluded. A composite primary outcome of perinatal mortality and intrapartum related neonatal morbidities (stillbirth after start of care in labour, early neonatal death, neonatal encephalopathy, meconium aspiration syndrome, brachial plexus injury, fractured humerus, or fractured clavicle) was used to compare outcomes by planned place of birth at the start of care in labour (at home, freestanding midwifery units, alongside midwifery units, and obstetric units). There were 250 primary outcome events and an overall weighted incidence of 4.3 per 1000 births (95% CI 3.3 to 5.5). Overall, there were no significant differences in the adjusted odds of the primary outcome for any of the non-obstetric unit settings compared with obstetric units. For nulliparous women, the odds of the primary outcome were higher for planned home births (adjusted odds ratio 1.75, 95% CI 1.07 to 2.86) but not for either midwifery unit setting. For multiparous women, there were no significant differences in the incidence of the primary outcome by planned place of birth. Interventions during labour were substantially lower in all non-obstetric unit settings. Transfers from non-obstetric unit settings were more frequent for nulliparous women (36% to 45%) than for multiparous women (9% to 13%). The results support a policy of offering healthy women with low risk pregnancies a choice of birth setting. Women planning birth in a midwifery unit and multiparous women planning birth at home experience fewer interventions than those planning birth in an obstetric unit with no impact on perinatal outcomes. For nulliparous women, planned home births also have fewer interventions but have poorer perinatal outcomes.


Biomimetics Linked to Classical Product Development: An Interdisciplinary Endeavor to Develop a Technical Standard.
Biomimetics is a well-known approach for technical innovation. However, most of its influence remains in the academic field. One option for increasing its application in the practice of technical design is to enhance the use of the biomimetic process with a step-by-step standard, building a bridge to common engineering procedures. This article presents the endeavor of an interdisciplinary expert panel from the fields of biology, engineering science, and industry to develop a standard that links biomimetics to the classical processes of product development and engineering design. This new standard, VDI 6220 Part 2, proposes a process description that is compatible and connectable to classical approaches in engineering design. The standard encompasses both the solution-based and the problem-driven process of biomimetics. It is intended to be used in any product development process for more biomimetic applications in the future.


The Bowen-Conradi syndrome protein Nep1 (Emg1) has a dual role in eukaryotic ribosome biogenesis, as an essential assembly factor and in the methylation of Ψ1191 in yeast 18S rRNA.
The Nep1 (Emg1) SPOUT-class methyltransferase is an essential ribosome assembly factor and the human Bowen-Conradi syndrome (BCS) is caused by a specific Nep1(D86G) mutation. We recently showed in vitro that Methanocaldococcus jannaschii Nep1 is a sequence-specific pseudouridine-N1-methyltransferase. Here, we show that in yeast the in vivo target site for Nep1-catalyzed methylation is located within loop 35 of the 18S rRNA that contains the unique hypermodification of U1191 to 1-methyl-3-(3-amino-3-carboxypropyl)-pseudouri-dine (m1acp3Ψ). Specific (14)C-methionine labelling of 18S rRNA in yeast mutants showed that Nep1 is not required for acp-modification but suggested a function in Ψ1191 methylation. ESI MS analysis of acp-modified Ψ-nucleosides in a Δnep1-mutant showed that Nep1 catalyzes the Ψ1191 methylation in vivo. Remarkably, the restored growth of a nep1-1(ts) mutant upon addition of S-adenosylmethionine was even observed after preventing U1191 methylation in a Δsnr35 mutant. This strongly suggests a dual Nep1 function, as Ψ1191-methyltransferase and ribosome assembly factor. Interestingly, the Nep1 methyltransferase activity is not affected upon introduction of the BCS mutation. Instead, the mutated protein shows enhanced dimerization propensity and increased affinity for its RNA-target in vitro. Furthermore, the BCS mutation prevents nucleolar accumulation of Nep1, which could be the reason for reduced growth in yeast and the Bowen-Conradi syndrome.


Exosome-mediated delivery of siRNA in vitro and in vivo.
The use of small interfering RNAs (siRNAs) to induce gene silencing has opened a new avenue in drug discovery. However, their therapeutic potential is hampered by inadequate tissue-specific delivery. Exosomes are promising tools for drug delivery across different biological barriers. Here we show how exosomes derived from cultured cells can be harnessed for delivery of siRNA in vitro and in vivo. This protocol first describes the generation of targeted exosomes through transfection of an expression vector, comprising an exosomal protein fused with a peptide ligand. Next, we explain how to purify and characterize exosomes from transfected cell supernatant. Next, we detail crucial steps for loading siRNA into exosomes. Finally, we outline how to use exosomes to efficiently deliver siRNA in vitro and in vivo in mouse brain. Examples of anticipated results in which exosome-mediated siRNA delivery is evaluated by functional assays and imaging are also provided. The entire protocol takes ~3 weeks.


Costly punishment across human societies.
Recent behavioral experiments aimed at understanding the evolutionary foundations of human cooperation have suggested that a willingness to engage in costly punishment, even in one-shot situations, may be part of human psychology and a key element in understanding our sociality. However, because most experiments have been confined to students in industrialized societies, generalizations of these insights to the species have necessarily been tentative. Here, experimental results from 15 diverse populations show that (i) all populations demonstrate some willingness to administer costly punishment as unequal behavior increases, (ii) the magnitude of this punishment varies substantially across populations, and (iii) costly punishment positively covaries with altruistic behavior across populations. These findings are consistent with models of the gene-culture coevolution of human altruism and further sharpen what any theory of human cooperation needs to explain.


Young, uninsured, and in debt: why young adults lack health insurance and how the Affordable Care Act is helping: findings from the Commonwealth Fund Health Insurance Tracking Survey of Young Adults, 2011.
The Commonwealth Fund Health Insurance Tracking Survey of Young Adults finds that between November 2010 and November 2011, an estimated 13.7 million young adults ages 19-25 stayed on or joined their parents' health plans, including 6.6 million who likely would not have been able to do so prior to the passage of the Affordable Care Act. The findings of the survey underscore the need for policymakers to implement the remaining coverage expansions in the law. Nearly two of five young adults ages 19-29 were without health insurance for all or part of 2011, with young adults in low- and moderate-income households the most at risk. The lack of insurance had significant health and financial implications for young adults: 60 percent said they did not get needed health care because of cost and half reported problems paying medical bills or said they were paying off medical debt over time.


Trunk Muscle Activity during Drop Jump Performance in Adolescent Athletes with Back Pain.
In the context of back pain, great emphasis has been placed on the importance of trunk stability, especially in situations requiring compensation of repetitive, intense loading induced during high-performance activities, e.g., jumping or landing. This study aims to evaluate trunk muscle activity during drop jump in adolescent athletes with back pain (BP) compared to athletes without back pain (NBP). Eleven adolescent athletes suffering back pain (BP: m/f: n = 4/7; 15.9 ± 1.3 y; 176 ± 11 cm; 68 ± 11 kg; 12.4 ± 10.5 h/we training) and 11 matched athletes without back pain (NBP: m/f: n = 4/7; 15.5 ± 1.3 y; 174 ± 7 cm; 67 ± 8 kg; 14.9 ± 9.5 h/we training) were evaluated. Subjects conducted 3 drop jumps onto a force plate (ground reaction force). Bilateral 12-lead SEMG (surface Electromyography) was applied to assess trunk muscle activity. Ground contact time [ms], maximum vertical jump force [N], jump time [ms] and the jump performance index [m/s] were calculated for drop jumps. SEMG amplitudes (RMS: root mean square [%]) for all 12 single muscles were normalized to MIVC (maximum isometric voluntary contraction) and analyzed in 4 time windows (100 ms pre- and 200 ms post-initial ground contact, 100 ms pre- and 200 ms post-landing) as outcome variables. In addition, muscles were grouped and analyzed in ventral and dorsal muscles, as well as straight and transverse trunk muscles. Drop jump ground reaction force variables did not differ between NBP and BP (p > 0.05). Mm obliquus externus and internus abdominis presented higher SEMG amplitudes (1.3-1.9-fold) for BP (p < 0.05). Mm rectus abdominis, erector spinae thoracic/lumbar and latissimus dorsi did not differ (p > 0.05). The muscle group analysis over the whole jumping cycle showed statistically significantly higher SEMG amplitudes for BP in the ventral (p = 0.031) and transverse muscles (p = 0.020) compared to NBP. Higher activity of transverse, but not straight, trunk muscles might indicate a specific compensation strategy to support trunk stability in athletes with back pain during drop jumps. Therefore, exercises favoring the transverse trunk muscles could be recommended for back pain treatment.


Cognitive correlates of a functional COMT polymorphism in children with 22q11.2 deletion syndrome.
Chromosome 22q11.2 deletion syndrome (22q11DS) is a common microdeletion syndrome associated with a markedly elevated risk of schizophrenia in adulthood. Cognitive impairments such as a low IQ and deficits in attention and executive function are common in childhood. The catechol O-methyltransferase (COMT) gene maps within the deleted region and is involved in the degradation of dopamine, a neurotransmitter thought to be important in cognition and the development of schizophrenia. Thus, we examined the correlation between neurocognitive deficits and a common polymorphism Val(158)Met in the COMT gene in a cohort of children with 22q11DS. Our results show that children with 22q11DS who have the Met allele have higher IQ and achievement scores and perform better on measures of prefrontal cognition, such as the Continuous Performance Task, as compared with those with the Val allele. These results confirm that the hemizygous COMT Val(158)Met genotype impacts upon cognition in children with 22q11DS.


PROSPECTIV-a pilot trial of a nurse-led psychoeducational intervention delivered in primary care to prostate cancer survivors: study protocol for a randomised controlled trial.
Prostate cancer survivors can experience physical, sexual, psychological and emotional problems, and there is evidence that current follow-up practices fail to meet these men's needs. Studies show that secondary and primary care physicians see a greater role for primary care in delivering follow-up, and that primary care-led follow-up is acceptable to men with prostate cancer. A two-phase study with target population being men who are 9-24 months from diagnosis. Phase 1 questionnaire aims to recruit 300 men and measure prostate-related quality of life and unmet needs. Men experiencing problems with urinary, bowel, sexual or hormonal function will be eligible for phase 2, a pilot trial of a primary care nurse-led psychoeducational intervention. Consenting eligible participants will be randomised either to intervention plus usual care, or usual care alone (40 men in each arm). The intervention, based on a self-management approach, underpinned by Bandura's Social Cognitive Theory, will provide advice and support tailored to these men's needs and address any problems they are experiencing. Telephone follow-up will take place at 6 months. Study outcomes will be measured by a questionnaire at 7 months. Phase 1 will allow us to estimate the prevalence of urinary, sexual, bowel and hormone-related problems in prostate cancer survivors and the level of unmet needs. 'Usual care' will also be documented. Phase 2 will provide information on recruitment and retention, acceptability of the intervention/outcome measures, effect sizes of the intervention and cost-effectiveness data, which is required to inform development of a larger, phase 3 randomised controlled trial. The main outcome of interest is change in prostate-cancer-related quality of life. Methodological issues will also be addressed. Ethics approval has been gained (Oxford REC A 12/SC/0500). Findings will be disseminated in peer-reviewed journals, at conferences, through user networks and relevant clinical groups. ISRCTN 97242511.


Expression of 5-HT receptors and the 5-HT transporter in rat brain after electroconvulsive shock.
Modulation of central 5-HT receptor sensitivity is implicated in the therapeutic response to electroconvulsive shock (ECS). Altered 5-HT receptor expression may play a role in this process. We have measured the mRNAs encoding 5-HT1A, 5-HT2A, 5-HT2C and 5-HT7 receptors, and the 5-HT transporter, in rat brain after single ECS, repeated ECS, and 3 weeks after repeated ECS. Hippocampal 5-HT1A receptor mRNA was decreased in CA4 and increased in dentate gyrus by single or repeated ECS, with parallel alterations in [3H]8-OH-DPAT binding site densities. Repeated ECS increased cortical [3H]ketanserin binding and 5-HT2A receptor mRNA. The other mRNAs were unchanged. The results show that ECS has subtype specific, anatomically discrete, and temporally selective effects on 5-HT receptor expression.


Immune synapses between mast cells and γδ T cells limit viral infection.
Mast cells (MCs) are immune sentinels, but whether they also function as antigen-presenting cells (APCs) remains elusive. Using mouse models of MC deficiency, we report on MC-dependent recruitment and activation of multiple T cell subsets to the skin and draining lymph nodes (DLNs) during dengue virus (DENV) infection. Newly recruited and locally proliferating γδ T cells were the first T cell subset to respond to MC-driven inflammation, and their production of IFN-γ was MC dependent. MC-γδ T cell conjugates were observed consistently in infected peripheral tissues, suggesting a new role for MCs as nonconventional APCs for γδ T cells. MC-dependent γδ T cell activation and proliferation during DENV infection required T cell receptor (TCR) signaling and the nonconventional antigen presentation molecule endothelial cell protein C receptor (EPCR) on MCs. γδ T cells, not previously implicated in DENV host defense, killed infected targeted DCs and contributed to the clearance of DENV in vivo. We believe immune synapse formation between MCs and γδ T cells is a novel mechanism to induce specific and protective immunity at sites of viral infection.


Statins protect against fulminant pneumococcal infection and cytolysin toxicity in a mouse model of sickle cell disease.
Sickle cell disease (SCD) is characterized by intravascular hemolysis and inflammation coupled to a 400-fold greater incidence of invasive pneumococcal infection resulting in fulminant, lethal pneumococcal sepsis. Mechanistically, invasive infection is facilitated by a proinflammatory state that enhances receptor-mediated endocytosis of pneumococci into epithelial and endothelial cells. As statins reduce chronic inflammation, in addition to their serum cholesterol-lowering effects, we hypothesized that statin therapy might improve the outcome of pneumococcal infection in SCD. In this study, we tested this hypothesis in an experimental SCD mouse model and found that statin therapy prolonged survival following pneumococcal challenge. The protective effect resulted in part from decreased platelet-activating factor receptor expression on endothelia and epithelia, which led to reduced bacterial invasion. An additional protective effect resulted from inhibition of host cell lysis by pneumococcal cholesterol-dependent cytotoxins (CDCs), including pneumolysin. We conclude therefore that statins may be of prophylactic benefit against invasive pneumococcal disease in patients with SCD and, more broadly, in settings of bacterial pathogenesis driven by receptor-mediated endocytosis and the CDC class of toxins produced by Gram-positive invasive bacteria.


Characterization of reward and effort mechanisms in apathy.
Apathy is a common but poorly understood condition with a wide societal impact observed in several brain disorders as well as, to some extent, in the normal population. Hence the need for better characterization of the underlying mechanisms. The processes by which individuals decide to attribute physical effort to obtain rewards might be particularly relevant to relate to apathy traits. Here, we designed two paradigms to assess individual differences in physical effort production and effort-based decision-making and their relation to apathy in healthy people. Apathy scores were measured using a modified version of the Lille Apathy Rating Scale, suitable for use in a non-clinical population. In the first study, apathy scores were correlated with the degree to which stake (reward on offer) and difficulty level impacts on physical effort production. Individuals with relatively high apathy traits showed an increased modulation of effort while more motivated individuals generally exerted greater force across different levels of stake. To clarify the underlying mechanisms for this behavior, we designed a second task that allows independent titration of stake and effort levels for which subjects are willing to engage in an effortful response to obtain a reward. Our results suggest that apathy traits in the normal population are related to the way reward subjectively affects the estimation of effort costs, and more particularly manifest as decreased willingness to exert effort when rewards are small, or below threshold. The tasks we introduce here may provide useful tools to further investigate apathy in clinical populations.


3D Correlative Cryo-Structured Illumination Fluorescence and Soft X-ray Microscopy Elucidates Reovirus Intracellular Release Pathway.
Imaging of biological matter across resolution scales entails the challenge of preserving the direct and unambiguous correlation of subject features from the macroscopic to the microscopic level. Here, we present a correlative imaging platform developed specifically for imaging cells in 3D under cryogenic conditions by using X-rays and visible light. Rapid cryo-preservation of biological specimens is the current gold standard in sample preparation for ultrastructural analysis in X-ray imaging. However, cryogenic fluorescence localization methods are, in their majority, diffraction-limited and fail to deliver matching resolution. We addressed this technological gap by developing an integrated, user-friendly platform for 3D correlative imaging of cells in vitreous ice by using super-resolution structured illumination microscopy in conjunction with soft X-ray tomography. The power of this approach is demonstrated by studying the process of reovirus release from intracellular vesicles during the early stages of infection and identifying intracellular virus-induced structures.


Host adaptations reduce the reproductive success of Varroa destructor in two distinct European honey bee populations.
Honey bee societies (Apis mellifera), the ectoparasitic mite Varroa destructor, and honey bee viruses that are vectored by the mite, form a complex system of host-parasite interactions. Coevolution by natural selection in this system has been hindered for European honey bee hosts since apicultural practices remove the mite and consequently the selective pressures required for such a process. An increasing mite population means increasing transmission opportunities for viruses that can quickly develop into severe infections, killing a bee colony. Remarkably, a few subpopulations in Europe have survived mite infestation for extended periods of over 10 years without management by beekeepers and offer the possibility to study their natural host-parasite coevolution. Our study shows that two of these "natural" honey bee populations, in Avignon, France and Gotland, Sweden, have in fact evolved resistant traits that reduce the fitness of the mite (measured as the reproductive success), thereby reducing the parasitic load within the colony to evade the development of overt viral infections. Mite reproductive success was reduced by about 30% in both populations. Detailed examinations of mite reproductive parameters suggest these geographically and genetically distinct populations favor different mechanisms of resistance, even though they have experienced similar selection pressures of mite infestation. Compared to unrelated control colonies in the same location, mites in the Avignon population had high levels of infertility while in Gotland there was a higher proportions of mites that delayed initiation of egg-laying. Possible explanations for the observed rapid coevolution are discussed.


Can we rely on the best trial? A comparison of individual trials and systematic reviews.
The ideal evidence to answer a question about the effectiveness of treatment is a systematic review. However, for many clinical questions a systematic review will not be available, or may not be up to date. One option could be to use the evidence from an individual trial to answer the question? We assessed how often (a) the estimated effect and (b) the p-value in the most precise single trial in a meta-analysis agreed with the whole meta-analysis. For a random sample of 200 completed Cochrane Reviews (January, 2005) we identified a primary outcome and extracted: the number of trials, the statistical weight of the most precise trial, the estimate and confidence interval for both the highest weighted trial and the meta-analysis overall. We calculated the p-value for the most precise trial and meta-analysis. Of 200 reviews, only 132 provided a meta-analysis of 2 or more trials, with a further 35 effect estimates based on single trials. The average number of trials was 7.3, with the most precise trial contributing, on average, 51% of the statistical weight to the summary estimate from the whole meta-analysis. The estimates of effect from the most precise trial and the overall meta-analyses were highly correlated (rank correlation of 0.90).There was an 81% agreement in statistical conclusions. Results from the most precise trial were statistically significant in 60 of the 167 evaluable reviews, with 55 of the corresponding systematic reviews also being statistically significant. The five discrepant results were not strikingly different with respect to their estimates of effect, but showed considerable statistical heterogeneity between trials in these meta-analyses. However, among the 101 cases in which the most precise trial was not statistically significant, the corresponding meta-analyses yielded 31 statistically significant results. Single most precise trials provided similar estimates of effects to those of the meta-analyses to which they contributed, and statistically significant results are generally in agreement. However, "negative" results were less reliable, as may be expected from single underpowered trials. For systematic reviewers we suggest that: (1) key trial(s) in a review deserve greater attention (2) systematic reviewers should check agreement of the most precise trial and the meta analysis. For clinicians using trials we suggest that when a meta-analysis is not available, a focus on the most precise trial is reasonable provided it is adequately powered.


Phosphodiester content measured in human liver by in vivo 31 P MR spectroscopy at 7 tesla.
Phosphorus (31 P) metabolites are emerging liver disease biomarkers. Of particular interest are phosphomonoester and phosphodiester (PDE) "peaks" that comprise multiple overlapping resonances in 31 P spectra. This study investigates the effect of improved spectral resolution at 7 Tesla (T) on quantifying hepatic metabolites in cirrhosis. Five volunteers were scanned to determine metabolite T1 s. Ten volunteers and 11 patients with liver cirrhosis were scanned at 7T. Liver spectra were acquired in 28 min using a 16-channel 31 P array and 3D chemical shift imaging. Concentrations were calculated using γ-adenosine-triphosphate (γ-ATP) = 2.65 mmol/L wet tissue. T1 means ± standard deviations: phosphatidylcholine 1.05 ± 0.28 s, nicotinamide-adenine-dinucleotide (NAD+ ) 2.0 ± 1.0 s, uridine-diphosphoglucose (UDPG) 3.3 ± 1.4 s. Concentrations in healthy volunteers: α-ATP 2.74 ± 0.11 mmol/L wet tissue, inorganic phosphate 2.23 ± 0.20 mmol/L wet tissue, glycerophosphocholine 2.34 ± 0.46 mmol/L wet tissue, glycerophosphoethanolamine 1.50 ± 0.28 mmol/L wet tissue, phosphocholine 1.06 ± 0.16 mmol/L wet tissue, phosphoethanolamine 0.77 ± 0.14 mmol/L wet tissue, NAD+ 2.37 ± 0.14 mmol/L wet tissue, UDPG 2.00 ± 0.22 mmol/L wet tissue, phosphatidylcholine 1.38 ± 0.31 mmol/L wet tissue. Inorganic phosphate and phosphatidylcholine concentrations were significantly lower in patients; glycerophosphoethanolamine concentrations were significantly higher (P < 0.05). We report human in vivo hepatic T1 s for phosphatidylcholine, NAD+ , and UDPG for the first time at 7T. Our protocol allows high signal-to-noise, repeatable measurement of metabolite concentrations in human liver. The splitting of PDE into its constituent peaks at 7T may allow more insight into changes in metabolism. Magn Reson Med 78:2095-2105, 2017. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.


Climate change mitigation through livestock system transitions.
Livestock are responsible for 12% of anthropogenic greenhouse gas emissions. Sustainable intensification of livestock production systems might become a key climate mitigation technology. However, livestock production systems vary substantially, making the implementation of climate mitigation policies a formidable challenge. Here, we provide results from an economic model using a detailed and high-resolution representation of livestock production systems. We project that by 2030 autonomous transitions toward more efficient systems would decrease emissions by 736 million metric tons of carbon dioxide equivalent per year (MtCO2e⋅y(-1)), mainly through avoided emissions from the conversion of 162 Mha of natural land. A moderate mitigation policy targeting emissions from both the agricultural and land-use change sectors with a carbon price of US$10 per tCO2e could lead to an abatement of 3,223 MtCO2e⋅y(-1). Livestock system transitions would contribute 21% of the total abatement, intra- and interregional relocation of livestock production another 40%, and all other mechanisms would add 39%. A comparable abatement of 3,068 MtCO2e⋅y(-1) could be achieved also with a policy targeting only emissions from land-use change. Stringent climate policies might lead to reductions in food availability of up to 200 kcal per capita per day globally. We find that mitigation policies targeting emissions from land-use change are 5 to 10 times more efficient--measured in "total abatement calorie cost"--than policies targeting emissions from livestock only. Thus, fostering transitions toward more productive livestock production systems in combination with climate policies targeting the land-use change appears to be the most efficient lever to deliver desirable climate and food availability outcomes.


Inherited polyglutamine spinocerebellar ataxias in South Africa.
To determine the frequency and distribution of polyglutamine spinocerebellar ataxias (SCAs) from referrals over a 24-year period to the National Health Laboratory Service (NHLS) in South Africa (SA). Paper-based clinical reports in the University of Cape Town laboratory and the NHLS electronic patient record database spanning a 24-year period were mined for information regarding the molecular diagnosis, ethnicity and CAG repeat length for individuals referred for molecular genetic testing for the polyglutamine SCAs. SCA1 and 7 are the most frequent types of polyglutamine SCA in the SA patient population, followed by SCA2, 3 and 6. SCA1 is the most common type in the coloured, white and Indian populations, whereas the majority of indigenous black African patients are affected with SCA7 and 2. Of individuals tested, 22% were found to be positive for one of the polyglutamine SCAs. Although trends in the frequency and distribution of the polyglutamine SCAs in SA have not changed significantly since our previous study in 2003, they differ remarkably from those reported elsewhere, and reflect the unique genetic and demographic background of SA. The provision of accurate and complete patient information and family history is crucial to the diagnostic process, to enable comprehensive epidemiological studies and assist in developing therapeutic and patient management strategies.


Six children with allergic contact dermatitis to methylisothiazolinone in wet wipes (baby wipes).
Methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) is a combination preservative used in personal care and household products and is a common cause of allergic contact dermatitis (ACD). Recently, MI alone, without MCI, has been increasingly used in consumer products in attempts to minimize allergic reactions. Wet wipes are extensively tested and traditionally believed to be innocuous. MI in wet wipes ("baby wipes") has not been previously reported to cause ACD in children in the United States. Only 1 previous report of ACD in a child in Belgium has been recently reported. We report 6 children with chronic, perianal/buttock, and facial eczematous dermatitis, refractory to multiple topical and oral antibiotics and corticosteroids. All tested positive to MCI/MI on patch testing. None wore diapers. All patients had been using wet wipes containing MI (without MCI) to affected areas. Discontinuation of wipes resulted in rapid and complete resolution. This is the first report of pediatric ACD to MI in wet wipes in the United States, and the largest series to date. ACD to MI in wet wipes is frequently misdiagnosed as eczema, impetigo, or psoriasis. Wet wipes are increasingly marketed in personal care products for all ages, and MI exposure and sensitization will likely increase. Dermatitis of the perianal, buttock, facial, and hand areas with a history of wet wipe use should raise suspicion of ACD to MI and prompt appropriate patch testing. Rapid resolution occurs after the allergen exposure is eliminated. All isothiozolinones should be avoided in personal care and household products for these patients.


State-of-the-art of 3D cultures (organs-on-a-chip) in safety testing and pathophysiology.
Integrated approaches using different in vitro methods in combination with bioinformatics can (i) increase the success rate and speed of drug development; (ii) improve the accuracy of toxicological risk assessment; and (iii) increase our understanding of disease. Three-dimensional (3D) cell culture models are important building blocks of this strategy which has emerged during the last years. The majority of these models are organotypic, i.e., they aim to reproduce major functions of an organ or organ system. This implies in many cases that more than one cell type forms the 3D structure, and often matrix elements play an important role. This review summarizes the state of the art concerning commonalities of the different models. For instance, the theory of mass transport/metabolite exchange in 3D systems and the special analytical requirements for test endpoints in organotypic cultures are discussed in detail. In the next part, 3D model systems for selected organs--liver, lung, skin, brain--are presented and characterized in dedicated chapters. Also, 3D approaches to the modeling of tumors are presented and discussed. All chapters give a historical background, illustrate the large variety of approaches, and highlight up- and downsides as well as specific requirements. Moreover, they refer to the application in disease modeling, drug discovery and safety assessment. Finally, consensus recommendations indicate a roadmap for the successful implementation of 3D models in routine screening. It is expected that the use of such models will accelerate progress by reducing error rates and wrong predictions from compound testing.


Reproducibility of dietary intakes of macronutrients, specific food groups, and dietary patterns in 211 050 adults in the UK Biobank study.
To detect modest associations of dietary intake with disease risk, observational studies need to be large and control for moderate measurement errors. The reproducibility of dietary intakes of macronutrients, food groups and dietary patterns (vegetarian and Mediterranean) was assessed in adults in the UK Biobank study on up to five occasions using a web-based 24-h dietary assessment (n 211 050), and using short FFQ recorded at baseline (n 502 655) and after 4 years (n 20 346). When the means of two 24-h assessments were used, the intra-class correlation coefficients (ICC) for macronutrients varied from 0·63 for alcohol to 0·36 for polyunsaturated fat. The ICC for food groups also varied from 0·68 for fruit to 0·18 for fish. The ICC for the FFQ varied from 0·66 for meat and fruit to 0·48 for bread and cereals. The reproducibility was higher for vegetarian status (κ > 0·80) than for the Mediterranean dietary pattern (ICC = 0·45). Overall, the reproducibility of pairs of 24-h dietary assessments and single FFQ used in the UK Biobank were comparable with results of previous prospective studies using conventional methods. Analyses of diet-disease relationships need to correct for both measurement error and within-person variability in dietary intake in order to reliably assess any such associations with disease in the UK Biobank.


Intractable hypercalcaemia during pregnancy and the postpartum secondary to pathogenic variants in CYP24A1.
Parathyroid-independent hypercalcaemia of pregnancy, due to biallelic loss of function of the P450 enzyme CYP24A1, the principal inactivator of 1,25(OH)2D results in hypervitaminosis D, hypercalcaemia and hypercalciuria. We report two cases of this disorder, with intractable hypercalcaemia, one occurring during gestation and into the postpartum, and the other in the postpartum period. Case 1, a 47-year-old woman with a twin pregnancy conceived by embryo transfer, presented with hypercalcaemia at 23 weeks gestation with subnormal serum parathyroid hormone (PTH) and normal serum 25-OH D levels. She was admitted to hospital at 31 weeks gestation with pregnancy-induced hypertension, gestational diabetes and increasing hypercalcaemia. Caesarean section at 34 weeks gestation delivered two healthy females weighing 2.13 kg and 2.51 kg. At delivery, the patient's serum calcium level was 2.90 mmol/L. Postpartum severe hypercalcaemia was treated successfully with Denosumab 60 mg SCI, given on two occasions. CYP24A1 testing revealed she was compound heterozygous for pathogenic variants c.427_429delGAA, (p.Glu143del) and c.1186C>T, (p.Arg396Trp). Case 2, a 36-year-old woman presented 4 days after the delivery of healthy twins with dyspnoea, bradycardia, severe headaches, hypertension and generalized tonic-clonic seizures after an uneventful pregnancy. She was hypercalcaemic with a suppressed PTH, normal 25(OH)D, and elevated 1,25(OH)2D levels. Her symptoms partially responded to i.v. saline and corticosteroids in the short term but bisphosphonates such as Pamidronate and Zoledronic acid did not result in sustained improvement. Denosumab 120 mg SCI successfully treated the hypercalcaemia which resolved completely 2 months post-partum. CYP24A1 testing revealed she was homozygous for the pathogenic variant c.427_429delGAA, (p.Glu143del). Hypercalcaemia in pregnancy can be associated with considerable morbidity with few options available for management. In non-PTH-related hypercalcaemia the diagnosis of CYP24A1 deficiency should be considered. Making a definitive diagnosis of CYP24A1 deficiency by genetic testing delays the diagnosis, while the availability of serum 24,25-dihydroxyvitamin D (24,25(OH)2D) will expedite a diagnosis. In pregnant women with CYP24A1 deficiency hypercalcaemia can worsen in the post-partum period and is more likely to occur with twin pregnancies but generally resolves within 2-3 months. Therapeutic alternatives are limited in pregnancy and their effectiveness is short-lived and mostly ineffective. Denosumab used in both our patients after delivery was the most effective agent normalizing calcium and may have benefit as a long-term therapeutic agent in preventing complications in patients with CYP24A1 deficiency.


A screen of chemical modifications identifies position-specific modification by UNA to most potently reduce siRNA off-target effects.
Small interfering RNAs (siRNAs) are now established as the preferred tool to inhibit gene function in mammalian cells yet trigger unintended gene silencing due to their inherent miRNA-like behavior. Such off-target effects are primarily mediated by the sequence-specific interaction between the siRNA seed regions (position 2-8 of either siRNA strand counting from the 5'-end) and complementary sequences in the 3'UTR of (off-) targets. It was previously shown that chemical modification of siRNAs can reduce off-targeting but only very few modifications have been tested leaving more to be identified. Here we developed a luciferase reporter-based assay suitable to monitor siRNA off-targeting in a high throughput manner using stable cell lines. We investigated the impact of chemically modifying single nucleotide positions within the siRNA seed on siRNA function and off-targeting using 10 different types of chemical modifications, three different target sequences and three siRNA concentrations. We found several differently modified siRNAs to exercise reduced off-targeting yet incorporation of the strongly destabilizing unlocked nucleic acid (UNA) modification into position 7 of the siRNA most potently reduced off-targeting for all tested sequences. Notably, such position-specific destabilization of siRNA-target interactions did not significantly reduce siRNA potency and is therefore well suited for future siRNA designs especially for applications in vivo where siRNA concentrations, expectedly, will be low.


Positive Selection on a Regulatory Insertion-Deletion Polymorphism in FADS2 Influences Apparent Endogenous Synthesis of Arachidonic Acid.
Long chain polyunsaturated fatty acids (LCPUFA) are bioactive components of membrane phospholipids and serve as substrates for signaling molecules. LCPUFA can be obtained directly from animal foods or synthesized endogenously from 18 carbon precursors via the FADS2 coded enzyme. Vegans rely almost exclusively on endogenous synthesis to generate LCPUFA and we hypothesized that an adaptive genetic polymorphism would confer advantage. The rs66698963 polymorphism, a 22-bp insertion-deletion within FADS2, is associated with basal FADS1 expression, and coordinated induction of FADS1 and FADS2 in vitro. Here, we determined rs66698963 genotype frequencies from 234 individuals of a primarily vegetarian Indian population and 311 individuals from the US. A much higher I/I genotype frequency was found in Indians (68%) than in the US (18%). Analysis using 1000 Genomes Project data confirmed our observation, revealing a global I/I genotype of 70% in South Asians, 53% in Africans, 29% in East Asians, and 17% in Europeans. Tests based on population divergence, site frequency spectrum, and long-range haplotype consistently point to positive selection encompassing rs66698963 in South Asian, African, and some East Asian populations. Basal plasma phospholipid arachidonic acid (ARA) status was 8% greater in I/I compared with D/D individuals. The biochemical pathway product-precursor difference, ARA minus linoleic acid, was 31% and 13% greater for I/I and I/D compared with D/D, respectively. This study is consistent with previous in vitro data suggesting that the insertion allele enhances n-6 LCPUFA synthesis and may confer an adaptive advantage in South Asians because of the traditional plant-based diet practice.


Real-time analysis of cAMP-mediated regulation of ciliary motility in single primary human airway epithelial cells.
Airway ciliary beat frequency regulation is complex but in part influenced by cyclic adenosine monophosphate (cAMP)-mediated changes in cAMP-dependent kinase activity, yet the cAMP concentration required for increases in ciliary beat frequency and the temporal relationship between ciliary beat frequency and cAMP changes are unknown. A lentiviral gene transfer system was developed to express a fluorescence resonance energy transfer (FRET)-based cAMP sensor in ciliated cells. Expression of fluorescently tagged cAMP-dependent kinase subunits from the ciliated-cell-specific foxj1 promoter enhanced expression in fully differentiated ciliated human airway epithelial cells, and permitted simultaneous measurements of ciliary beat frequency and cAMP (represented by the FRET ratio). Apical application of forskolin (1 microM, 10 microM, 20 microM) and, in permeabilized cells, basolateral cAMP (20 microM, 50 microM, 100 microM) caused dose-dependent, albeit similar and simultaneous-increases in cAMP and ciliary beat frequency. However, decreases in cAMP preceded decreases in ciliary beat frequency, suggesting that either cellular cAMP decreases before ciliary cAMP or the dephosphorylation of target proteins by phosphatases occur at a rate slower than the rate of cAMP hydrolysis.


Open Source Platform for Transperineal In-Bore MRI-Guided Targeted Prostate Biopsy.
Accurate biopsy sampling of the suspected lesions is critical for the diagnosis and clinical management of prostate cancer. Transperineal in-bore MRI-guided prostate biopsy (tpMRgBx) is a targeted biopsy technique that was shown to be safe, efficient, and accurate. Our goal was to develop an open source software platform to support evaluation, refinement, and translation of this biopsy approach. We developed SliceTracker, a 3D Slicer extension to support tpMRgBx. We followed modular design of the implementation to enable customization of the interface and interchange of image segmentation and registration components to assess their effect on the processing time, precision, and accuracy of the biopsy needle placement. The platform and supporting documentation were developed to enable the use of software by an operator with minimal technical training to facilitate translation. Retrospective evaluation studied registration accuracy, effect of the prostate segmentation approach, and re-identification time of biopsy targets. Prospective evaluation focused on the total procedure time and biopsy targeting error (BTE). Evaluation utilized data from 73 retrospective and ten prospective tpMRgBx cases. Mean landmark registration error for retrospective evaluation was 1.88 ± 2.63 mm, and was not sensitive to the approach used for prostate gland segmentation. Prospectively, we observed target re-identification time of 4.60 ± 2.40 min and BTE of 2.40 ± 0.98 mm. SliceTracker is modular and extensible open source platform for supporting image processing aspects of the tpMRgBx procedure. It has been successfully utilized to support clinical research procedures at our site.


Quality of asthma care: Western Cape province, South Africa.
Asthma is the eighth leading contributor to the burden of disease in South Africa, but has received less attention than other chronic diseases. The Asthma Guidelines Implementation Project (AGIP) was established to improve the impact of the South African guidelines for chronic asthma in adults and adolescents in the Western Cape. One strategy was an audit tool to assist with assessing and improving the quality of care. The audit of asthma care targeted all primary care facilities that managed adult patients with chronic asthma within all six districts of the Western Cape province. The usual steps in the quality improvement cycle were followed. Data were obtained from 957 patients from 46 primary care facilities. Only 80% of patients had a consistent diagnosis of asthma, 11.5% of visits assessed control and 23.2% recorded a peak expiratory flow (PEF), 14% of patients had their inhaler technique assessed and 11.2% were given a self-management plan; 81% of medication was in stock, and the controller/reliever dispensing ratio was 0.6. Only 31.5% of patients were well controlled, 16.3% of all visits were for exacerbations, and 17.6% of all patients had been hospitalised in the previous year. The availability of medication and prescription of inhaled steroids is reasonable, yet control is poor. Health workers do not adequately distinguish asthma from chronic obstructive pulmonary disease, do not assess control by questions or PEF, do not adequately demonstrate or assess the inhaler technique, and have no systematic approach to or resources for patient education. Ten recommendations are made to improve asthma care.


[Prevalence of smoking and second-hand smoke exposure: differences between Spanish and immigrant pregnant women].
To identify differences in the prevalence of smoking and second-hand smoke exposure between Spanish and immigrant pregnant women, as well as the factors associated with continued smoking during pregnancy. An epidemiologic cross-sectional study was carried out in women attended at delivery in Zaragoza (Spain). A smoking questionnaire was used to collect the following variables: the women's and partners' sociodemographic factors and smoking behavior, second-hand smoke exposure and perception of the risks of this exposure. We included 2440 women (35% immigrants). A total of 31.1% smoked before becoming pregnant and 18.2% during pregnancy, with significant differences between Spanish and immigrant women (21.9% versus 8.7%; p<0.001). Immigrant women lived with a greater number of smokers, smoked more inside the home, were exposed to second-hand smoke for a greater number of hours per day, avoided public places with second-hand smoke less, and more often worked in bars and restaurants. The following factors were associated with smoking during pregnancy: being Spanish, smoking a greater number of cigarettes before pregnancy, being exposed to second-hand smoke at home for a greater number of hours, having a low perception of risks and having a partner with lower educational attainment. The prevalence of smoking is higher among Spanish pregnant women than immigrant women, although the immigrant population is more exposed to second-hand smoke at home and at work. There are socio-cultural differences that should be taken into account when carrying out interventions in women of reproductive age.


Going with the flow: trafficking-dependent and -independent regulation of serotonin transport.
Antidepressant-, cocaine- and 3,4-methylenedioxymethamphetamine-sensitive serotonin (5-hydroxytryptamine, 5-HT) transporters (SERTs) are expressed on presynaptic membranes of 5-HT-secreting neurons to provide efficient uptake of the biogenic amine after release. SERTs also support 5-HT transport across platelet, placental, gastrointestinal and pulmonary membranes and thus play a critical role in central nervous system and peripheral nervous system 5-HT signaling. SERTs are subject to multiple levels of posttranslational regulation that can rapidly alter 5-HT uptake and clearance rates. Specific cell surface receptors are now known to regulate SERT trafficking and/or catalytic function, with pathways activating protein kinase C, protein kinase G and p38 mitogen-activated protein kinase receiving the greatest attention. Remarkably, disease-associated mutations in SERT not only impact basal SERT activity but also selectively impact one or more SERT regulatory pathway(s). In this review, we describe both trafficking-dependent and trafficking-independent modes of SERT regulation and also the suspected roles played in regulation by SERT-associated proteins. Elucidation of the SERT 'regulome' provides important depth to our understanding of the likely origins of 5-HT-associated disorders and may help orient research to develop novel therapeutics.


Exonic single nucleotide polymorphisms within TLR3 associated with infant responses to serogroup C meningococcal conjugate vaccine.
The introduction of the serogroup C meningococcal (MenC) conjugate vaccination has successfully controlled the burden of disease associated with this serogroup in many countries. However, considerable inter-individual variation is observed in immune responses to MenC vaccine, and little is understood of the determinants of this variability. Previously, we reported an association between single nucleotide polymorphisms (SNPs) in TLR3 and CD44 and the persistence of MenC vaccine immunity. Here we further examine polymorphisms within these two candidate genes and immune responses to MenC vaccine. MenC-specific IgG concentrations and serum bactericidal assay (SBA) titres were measured one month after a primary course of MenC vaccination in 318 human infants. Tagging SNPs (TagSNPs) within TLR3 and CD44 were genotyped and regional imputations carried out to screen these genes for variations associated with immunological responses to MenC vaccine. This study reports an association between an exonic variant (rs3775290, P=0.025) in TLR3 and MenC IgG concentrations, as well as an association between three SNPs in CD44 (rs3794109, P=0.021; rs3794110, P=0.022; rs112762, P=0.049) and MenC SBA titres. These data support our previous findings of an association between SNPs in TLR3 and CD44, and present novel findings implicating exonic variants in these genes with MenC vaccine responses.


[The "Bolsa Família" family grant scheme: the interface between professional practice and the human right to adequate food and nutrition].
The Human Right to Adequate Nutrition must be ensured through the public policies included in SAN, namely the Food and Nutritional Security campaign. Besides the income transfer geared to ensuring access to basic social rights, the "Bolsa Família" Program (PBF) is included in this context. This study seeks to analyze the operational aspects of the PBF and also ascertain whether or not the health professionals see the program as a core element of the SAN public policy. With this in mind, semi-structured interviews were conducted with primary healthcare workers involved directly both with the PBF and with the families who receive this benefit. By the end of the study, it was possible to perceive the importance of training health professionals who work in this area, because when one dissociates the social reality in which the beneficiaries live from the program objectives, this can lead to the simple mechanization of these practices. In this respect, it should be stressed that health professionals need to understand the proposals of the program as political and social strategies which, in addition to providing immediate relief, strive to overcome the problems related to poverty and hunger.


Body size and breast cancer risk: findings from the European Prospective Investigation into Cancer And Nutrition (EPIC).
The evidence for anthropometric factors influencing breast cancer risk is accumulating, but uncertainties remain concerning the role of fat distribution and potential effect modifiers. We used data from 73,542 premenopausal and 103,344 postmenopausal women from 9 European countries, taking part in the EPIC study. RRs from Cox regression models were calculated, using measured height, weight, BMI and waist and hip circumferences; categorized by cohort-wide quintiles; and expressed as continuous variables, adjusted for study center, age and other risk factors. During 4.7 years of follow-up, 1,879 incident invasive breast cancers were identified. In postmenopausal women, current HRT modified the body size-breast cancer association. Among nonusers, weight, BMI and hip circumference were positively associated with breast cancer risk (all ptrend < or = 0.002); obese women (BMI > 30) had a 31% excess risk compared to women with BMI < 25. Among HRT users, body measures were inversely but nonsignificantly associated with breast cancer. Excess breast cancer risk with HRT was particularly evident among lean women. Pooled RRs per height increment of 5 cm were 1.05 (95% CI 1.00-1.16) in premenopausal and 1.10 (95% CI 1.05-1.16) in postmenopausal women. Among premenopausal women, hip circumference was the only other measure significantly related to breast cancer (ptrend = 0.03), after accounting for BMI. In postmenopausal women not taking exogenous hormones, general obesity is a significant predictor of breast cancer, while abdominal fat assessed as waist-hip ratio or waist circumference was not related to excess risk when adjusted for BMI. Among premenopausal women, weight and BMI showed nonsignificant inverse associations with breast cancer.


IOC Consensus Statement: Dietary Supplements and the High-Performance Athlete.
Nutrition usually makes a small but potentially valuable contribution to successful performance in elite athletes, and dietary supplements can make a minor contribution to this nutrition program. Nonetheless, supplement use is widespread at all levels of sport. Products described as supplements target different issues, including the management of micronutrient deficiencies, supply of convenient forms of energy and macronutrients, and provision of direct benefits to performance or indirect benefits such as supporting intense training regimens. The appropriate use of some supplements can offer benefits to the athlete, but others may be harmful to the athlete's health, performance, and/or livelihood and reputation if an anti-doping rule violation results. A complete nutritional assessment should be undertaken before decisions regarding supplement use are made. Supplements claiming to directly or indirectly enhance performance are typically the largest group of products marketed to athletes, but only a few (including caffeine, creatine, specific buffering agents and nitrate) have good evidence of benefits. However, responses are affected by the scenario of use and may vary widely between individuals because of factors that include genetics, the microbiome, and habitual diet. Supplements intended to enhance performance should be thoroughly trialed in training or simulated competition before implementation in competition. Inadvertent ingestion of substances prohibited under the anti-doping codes that govern elite sport is a known risk of taking some supplements. Protection of the athlete's health and awareness of the potential for harm must be paramount, and expert professional opinion and assistance is strongly advised before embarking on supplement use.


Making fast photoswitches faster--using Hammett analysis to understand the limit of donor-acceptor approaches for faster hemithioindigo photoswitches.
Hemithioindigo (HTI) photoswitches have a tremendous potential for biological and supramolecular applications due to their absorptions in the visible-light region in conjunction with ultrafast photoisomerization and high thermal bistability. Rational tailoring of the photophysical properties for a specific application is the key to exploit the full potential of HTIs as photoswitching tools. Herein we use time-resolved absorption spectroscopy and Hammett analysis to discover an unexpected principal limit to the photoisomerization rate for donor-substituted HTIs. By using stationary absorption and fluorescence measurements in combination with theoretical investigations, we offer a detailed mechanistic explanation for the observed rate limit. An alternative way of approaching and possibly even exceeding the maximum rate by multiple donor substitution is demonstrated, which give access to the fastest HTI photoswitch reported to date.


Seeing voices of health disparity: evaluating arts projects as influence processes.
Arts-informed approaches are increasingly popular as vehicles for research, knowledge translation and for engaging key stakeholders on topics of health and health care. This paper describes an evaluation of a multimedia art installation intended to promote awareness of health disparities as experienced by homeless persons living in Toronto (Canada). The objective of the evaluation was to determine whether the installation had an impact on audience members, and if so, to understand its influence on viewers' perspectives on homelessness and the health concerns of homeless persons. Key themes were identified through the analysis of direct observational data of viewer interactions with the exhibit and qualitative interviews with different audience members after the exhibit. The four key themes were: (1) Promoting recognition of common humanity between viewers and viewed (challenging previously held assumptions and stereotypes, narrowing perceived social distance); (2) functions fulfilled (or potentially fulfilled) by the exhibit: raising awareness, educational applications, and potential pathways by which the exhibit could serve as a call to social action; (3) stories that prompt more stories: the stories within the exhibit (coupled with the interview questions) prompted further sharing of stories amongst the evaluation respondents, highlighting the iterative nature of such approaches. Respondents told of recognizing similarities in the experiences recounted in the exhibit with their own interactions with homeless persons; (4) strengths and weaknesses identified: including aesthetic features, issues of audience 'reach' and the importance of suitable venues for exhibition. Theoretically informed by narrative analysis and visual anthropology, this evaluation demonstrates that arts-informed 'interventions' are highly complex and work in subtle ways on viewers, allowing them to re-imagine the lives of others and identify points of common interest. It also problematizes our assumptions about which outcomes matter and why.


Effectiveness of academic detailing to optimize medication prescribing behaviour of family physicians.
To synthesize current knowledge about the effectiveness and the magnitude of the effect, of Academic Detailing (AD), as a stand-alone intervention, at modifying drug prescription behavior of Family Physicians (FPs) in primary care settings. A search of MEDLINE, EMBASE, CENTRAL, and Web of Science databases of all English language articles between January 1983 and July 2010 was conducted. We hand-searched the bibliographies of articles retrieved from the electronic search to identify additional studies. Inclusion criteria were: full-length articles describing original research; randomized controlled trial (RCT), or observational study design with a control group; studies of AD delivered to FPs; AD as a stand-alone intervention; drug prescription as the target behavior. Data extraction was done independently by two reviewers. Outcomes evaluated were: the difference in relative change in prescription rate between the intervention and control groups; the difference in absolute change in prescription rate between the intervention and control groups; and effect size, calculated as the standardized mean difference. 11 RCTs and 4 observational studies were included. Five RCTS described results showing effectiveness, while 2 RCTs reported a positive effect on some of the target drugs. Two observational studies found AD to be effective, while 2 did not. The median difference in relative change among the studies reviewed was 21% (interquartile range 43.75%) for RCTs, and 9% (interquartile range 8.5%) for observational studies. The median effect size among the studies reviewed was - 0.09 (interquartile range 2.73). This systematic review demonstrates that AD can be effective at optimizing prescription of medications by FPs. Although variable, the magnitude of the effect is moderate in the majority of studies. This systematic review also provides evidence supportive of the use of AD as a strategy to promote evidence based prescription of medications or incorporation of clinical guidelines into clinical practice. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.


Antimicrobial chitosan-lysozyme (CL) films and coatings for enhancing microbial safety of mozzarella cheese.
This study investigated the antimicrobial activities of chitosan-lysozyme (CL) composite films and coatings against tested microorganisms inoculated onto the surface of Mozzarella cheese. CL film-forming solutions (FFS) with a pH of 4.4 to 4.5 were prepared by incorporating 0% or 60% lysozyme (per dry weight of chitosan) into chitosan FFS with or without a pH adjustment to 5.2. Sliced cheese was subjected to 3 CL package applications: film, lamination on a multilayer coextruded film, and coating. Cheese was inoculated with Listeria monocytogenes, Escherichia coli, or Pseudomonas fluorescens at 10(4) CFU/g, or with mold and yeast at 10(2) CFU/g. Inoculated cheese was individually vacuum packaged and stored at 10 degrees C for sampling at 1, 7, and 14 d for bacteria, and at 10, 20, and 30 d for fungi. Inoculated bacteria survived but failed to multiply in untreated cheese during storage. Treated cheese received 0.43- to 1.25-, 0.40- to 1.40-, and 0.32- to 1.35-log reductions in E. coli, P. fluorescens, and L. monocytogenes, respectively. Incorporation of 60% lysozyme in chitosan FFS showed greater antimicrobial effect than chitosan alone on P. fluorescens and L. monocytogenes. The pH adjustment only affected the antimicrobial activity on L. monocytogenes, with lower pH (unadjusted) showing greater antimicrobial effect than pH 5.2. Mold and yeast increased to 10(5) CFU/g in untreated cheese after 30 d storage. Growth of mold was completely inhibited in cheese packaged with CL films, while 0.24- to 1.90- and 0.06- to 0.50-log reductions in mold populations were observed in cheese packaged with CL-laminated films and coatings, respectively. All CL packaging applications resulted in 0.01- to 0.64-log reduction in yeast populations.