Fourier optics analysis of grating sensors with tilt errors.
Dynamic diffraction gratings can be microfabricated with precision and offer extremely sensitive displacement measurements and light intensity modulation. The effect of pure translation of the moving part of the grating on diffracted order intensities is well known. This study focuses on the parameters that limit the intensity and the contrast of the interference. The effects of grating duty cycle, mirror reflectivities, sensor tilt and detector size are investigated using Fourier optics theory and Gaussian beam optics. Analytical findings reveal that fringe visibility becomes <0.3 when the optical path variation exceeds half the wavelength within the grating interferometer. The fringe visibility can be compensated by monitoring the interfering portion of the diffracted order light only through detector size reduction in the expense of optical power. Experiments were conducted with a grating interferometer that resulted in an eightfold increase in fringe visibility with reduced detector size, which is in agreement with theory. Findings show that diffraction grating readout principle is not limited to translating sensors but also can be used for sensors with tilt or other deflection modes.


Prediction of cancer drug sensitivity using high-dimensional omic features.
A large number of cancer drugs have been developed to target particular genes/pathways that are crucial for cancer growth. Drugs that share a molecular target may also have some common predictive omic features, e.g., somatic mutations or gene expression. Therefore, it is desirable to analyze these drugs as a group to identify the associated omic features, which may provide biological insights into the underlying drug response. Furthermore, these omic features may be robust predictors for any drug sharing the same target. The high dimensionality and the strong correlations among the omic features are the main challenges of this task. Motivated by this problem, we develop a new method for high-dimensional bilevel feature selection using a group of response variables that may share a common set of predictors in addition to their individual predictors. Simulation results show that our method has a substantially higher sensitivity and specificity than existing methods. We apply our method to two large-scale drug sensitivity studies in cancer cell lines. Both within-study and between-study validation demonstrate the good efficacy of our method.


Membrane orientation and subcellular localization of transmembrane protein 106B (TMEM106B), a major risk factor for frontotemporal lobar degeneration.
TMEM106B was identified as a major risk factor in a genome-wide association study for frontotemporal lobar degeneration (FTLD) with TAR DNA-binding protein (TDP)-43 pathology. The most significant association of TMEM106B single nucleotide polymorphisms with risk of FTLD-TDP was observed in patients with progranulin (GRN) mutations. Subsequent studies suggested an inverse correlation between TMEM106B expression and GRN levels in patient serum. However, in this study, this was not confirmed as we failed to detect a significant alteration of GRN levels upon knockdown or exogenous expression of TMEM106B in heterologous cells. To provide a basis for understanding TMEM106B function in health and disease, we investigated the membrane orientation and subcellular localization of this completely uncharacterized protein. By differential membrane extraction and sequential mutagenesis of potential N-glycosylation sites, we identified TMEM106B as a type 2 integral membrane protein with a highly glycosylated luminal domain. Glycosylation is partially required for the transport of TMEM106B beyond the endoplasmic reticulum to late cellular compartments. Endogenous as well as overexpressed TMEM106B localizes to late endosomes and lysosomes. Interestingly, the inhibition of vacuolar H(+)-ATPases significantly increased the levels of TMEM106B, a finding that may provide an unexpected biochemical link to GRN, because this protein is also strongly increased under the same conditions. Our findings provide a biochemical and cell biological basis for the understanding of the pathological role of TMEM106B in FTLD, an incurable neurodegenerative disorder.


Neurocognitive test performance and symptom reporting in cheerleaders with concussions.
To evaluate neurocognitive test results and symptom reporting after sports-related concussion in a group of female cheerleaders. Junior and senior high school female cheerleaders (n = 138) underwent preparticipation baseline testing and repeated the ImPACT (Immediate Postconcussion Assessment and Cognitive Testing) evaluation within 7 days of concussive injury (range, 0-7 days; mean, 3.9 days). Postinjury neurocognitive and symptom scores were compared with preinjury (baseline) scores. "Abnormal" test performance was determined statistically using Reliable Change Index scores and self-reported symptoms. Main outcome variables included the composite scores indices from the ImPACT test, as well as symptoms reported by participants. Preinjury baseline and postinjury test results were compared using MANOVA. As a group, cheerleaders with concussion evaluated within 7 days of injury performed poorly on the ImPACT test battery relative to their own baseline (F = 6.5; P = .00). In addition, 61% of the cheerleaders with concussions reported an increase in symptoms compared with baseline. The groups did not differ significantly by position on the squad (F = 0.37; P = .96). Of the group of cheerleaders who did not report increased symptoms at the time of postinjury evaluation, 37% had at least 1 abnormal ImPACT composite score result, suggesting some residual cognitive decline compared with baseline. The diagnosis and management of concussion in cheerleaders should not consist solely of self-reported symptoms. Neurocognitive test results represent an important component of the evaluation process and may identify athletes with residual neurocognitive deficits who report being clinically asymptomatic.


Role of astroglia in Down's syndrome revealed by patient-derived human-induced pluripotent stem cells.
Down's syndrome (DS), caused by trisomy of human chromosome 21, is the most common genetic cause of intellectual disability. Here we use induced pluripotent stem cells (iPSCs) derived from DS patients to identify a role for astrocytes in DS pathogenesis. DS astroglia exhibit higher levels of reactive oxygen species and lower levels of synaptogenic molecules. Astrocyte-conditioned medium collected from DS astroglia causes toxicity to neurons, and fails to promote neuronal ion channel maturation and synapse formation. Transplantation studies show that DS astroglia do not promote neurogenesis of endogenous neural stem cells in vivo. We also observed abnormal gene expression profiles from DS astroglia. Finally, we show that the FDA-approved antibiotic drug, minocycline, partially corrects the pathological phenotypes of DS astroglia by specifically modulating the expression of S100B, GFAP, inducible nitric oxide synthase, and thrombospondins 1 and 2 in DS astroglia. Our studies shed light on the pathogenesis and possible treatment of DS by targeting astrocytes with a clinically available drug.


Restoring native fish assemblages to a regulated California stream using the natural flow regime concept.
We examined the response of fishes to establishment of a new flow regime in lower Putah Creek, a regulated stream in California, U.S.A. The new flow regime was designed to mimic the seasonal timing of natural increases and decreases in stream flow. We monitored fish assemblages annually at six sample sites distributed over approximately 30 km of stream for eight years before and nine years after the new flow regime was implemented. Our purpose was to determine whether more natural stream flow patterns would reestablish native fishes and reduce the abundances of alien (nonnative) fishes. At the onset of our study, native fishes were constrained to habitat immediately (<1 km) below the diversion dam, and alien species were numerically dominant at all downstream sample sites. Following implementation of the new flow regime, native fishes regained dominance across more than 20 km of lower Putah Creek. We propose that the expansion of native fishes was facilitated by creation of favorable spawning and rearing conditions (e.g., elevated springtime flows), cooler water temperatures, maintenance of lotic (flowing) conditions over the length of the creek, and displacement of alien species by naturally occurring high-discharge events. Importantly, restoration of native fishes was achieved by manipulating stream flows at biologically important times of the year and only required a small increase in the total volume of water delivered downstream (i.e., water that was not diverted for other uses) during most water years. Our results validate that natural flow regimes can be used to effectively manipulate and manage fish assemblages in regulated rivers.


Human syndromes of immunodeficiency and dysregulation are characterized by distinct defects in T-cell receptor repertoire development.
Human immunodeficiencies characterized by hypomorphic mutations in critical developmental and signaling pathway genes allow for the dissection of the role of these genes in the development of the T-cell receptor (TCR) repertoire and the correlation of alterations of the TCR repertoire with diverse clinical phenotypes. The presence of T cells in patients with Omenn syndrome (OS) and patients with atypical presentations of severe combined immunodeficiency gene mutations presents an opportunity to study the effects of the causal genes on TCR repertoires and provides a window into the clinical heterogeneity observed. We performed deep sequencing of TCRβ complementarity-determining region 3 (CDR3) regions in subjects with a series of immune dysregulatory conditions caused by mutations in recombination activating gene 1/2 (RAG 1/2), IL-2 receptor γ (IL2RG), and ζ chain-associated protein kinase 70 (ZAP70); a patient with atypical DiGeorge syndrome; and healthy control subjects. We found that patients with OS had marked reductions in TCRβ diversity compared with control subjects, as expected. Patients with atypical presentations of RAG or IL2RG mutations associated with autoimmunity and granulomatous disease did not have altered overall diversity but instead had skewed V-J pairing and skewed CDR3 amino acid use. Although germline TCRs were more abundant and clonally expanded in patients with OS, nongermline sequences were expanded as well. TCRβ from patients with RAG mutations had less junctional diversity and smaller CDR3s than patients with OS caused by other gene mutations and healthy control subjects but relatively similar CDR3 amino acid use. High-throughput TCR sequencing of rare immune disorders has demonstrated that quantitative TCR diversity can appear normal despite qualitative changes in repertoire and strongly suggests that in human subjects RAG enzymatic function might be necessary for normal CDR3 junctional diversity.


CYP2D6 polymorphisms and codeine analgesia in postpartum pain management: a pilot study.
Codeine, a common opiate prescribed for pain postcesarean section (c-section), is biotransformed by the highly polymorphic Cytochrome P450 enzyme 2D6 (CYP2D6). Ultrarapid metabolizers (UMs), individuals with multiple active copies of CYP2D6, can biotranform up to 50% more codeine into morphine than normal individuals can. In contrast, poor metabolizers (PMs), individuals who have no active CYP2D6 genes, convert almost no codeine into morphine and as a result may take multiple doses of codeine without attaining analgesia. The aim was to study the relationship between CYP2D6 genotype and codeine analgesia among women recovering from c-section. Forty-five mothers prescribed codeine provided a blood sample for CYP2D6 genotyping and recorded their pain level 4 times a day for 3 days immediately after a c-section. Codeine was used on an as-needed basis; doses and times were recorded. The relationship between CYP2D6 genotype, pain scores, need for codeine, and adverse events was studied. Theoretical morphine dose, based on CYP2D6 genotype, was estimated. Women at the genotypic extremes reported codeine effects consistent with their genotype: the 2 PMs of codeine reported no analgesia as a result of taking codeine, whereas 2 of the 3 UMs reported immediate pain relief from codeine but stopped taking it due to dizziness and constipation. Much larger numbers are needed to study similar correlations among extensive and intermediate metabolizers. In this pilot study, the extreme CYP2D6 genotypes (PMs and UMs) seemed to predict pain response and adverse events. Larger sample sizes are needed to correlate the range of genotypes with pain response.


Validation of group B borderline resectable pancreatic cancer: retrospective analysis.
Among borderline resectable pancreatic cancer (BRPC), group B BRPC patients have findings that are suggestive but not diagnostic of metastasis. In this study, we attempted to validate whether group B could truly be categorized as a borderline resectable group. We placed the BRPC patients into group A or group B. The survival outcomes were compared between the groups. A total of 53 patients with pancreatic adenocarcinoma was classified as either group A or B borderline resectable. In group A, 23 (60.5%) of 38 patients underwent pancreatectomy after concurrent chemoradiotherapy or chemotherapy, but in group B, only five (33.3%) of 15 patients underwent pancreatectomy, mainly because of the progression of suspected distant metastasis. There was a significant difference in overall survival (OS) between group A and B patients (median OS, 21.2 months vs 10.2 months, respectively; p=0.007). Of the patients who underwent pancreatectomy, group B had a higher recurrence rate compared to group A (recurrence rate: 11 of 23 patients [47.8%] vs five of five patients [100%], respectively; p=0.033). This report is the first to validate the definition of BPRC. Group B had much worse outcomes, and whether group B BRPC can be categorized as BRPC together with group A is questionable.


Retinal findings in carriers of monoallelic ABCC6 mutations.
Biallelic ABCC6 mutations cause pseudoxanthoma elasticum, a systemic disease characterised by calcification of elastic tissue and a specific retinal phenotype. In this study, we investigated if monoallelic ABCC6 mutations are also associated with retinal alterations. In this prospective, cross-sectional, monocentre case-control study, carriers of monoallelic ABCC6 mutations were investigated and compared with age-matched controls. The retinal phenotype was characterised using fundus photography, fundus autofluorescence, confocal near-infrared reflectance imaging, spectral domain optical coherence tomography and in selected cases late-phase indocyanine green angiography. Thirty-eight subjects carrying monoallelic ABCC6 mutations (mean age 70.2 years, range 50-90, 26 female) were examined and compared with 77 age-matched controls (mean age 69.9 years, range 50-93, 43 female). Retinal alterations were more frequently found in carriers of monoallelic ABCC6 mutations compared with controls (50% vs 33.8%, p=0.107) with increasing prevalence at older age. Typical findings were peripapillary atrophy (37% vs 23%, p=0.184), pattern dystrophy-like changes (24% vs 12%, p=0.109), reticular pseudodrusen (21% vs 5%, p=0.019), small angioid streaks (8% vs 1%, p=0.105), choroidal neovascularisations and atrophic lesions (both 8% vs 0%, p=0.034). Late-phase indocyanine green angiography showed a reduced cyanescence centred to the posterior pole in 11 of 14 examined subjects with monoallelic ABCC6 mutations. The findings of this study indicate a possible ocular ABCC6 haploinsufficiency phenotype. Due to its late-onset and phenotypic similarities, misinterpretation as age-related macular degeneration is possible.


Morbidity and oncologic outcome after saphenous vein-sparing inguinal lymphadenectomy in melanoma patients.
Inguinal lymph node dissection (LND) is a surgical procedure with a high morbidity rate. Variations in surgical procedure, such as sparing of the saphenous vein, have been proposed to reduce surgical morbidity. While sparing of the saphenous vein has shown promising results in earlier studies, data for this procedure in melanoma patients are rare. In this retrospective study, we report 10-year findings on the effects of saphenous vein-sparing LND on surgical morbidity and oncologic outcomes in melanoma patients. A retrospective analysis of melanoma patients receiving inguinal LND in our facility between 2003 and 2013 was performed. Patients were divided into two groups: the saphenous vein resection group and the vein sparing group. Surgical morbidity, including wound infection, lymphatic fistula, severe bleeding, neurological complications, and chronic lymphedema, as well as regional recurrence-free survival were investigated. A total of 106 patients were included in this study; of these, the saphenous vein was spared in 41 patients (38.7%). The rate of lymphatic fistula was 51.6 vs. 48.8%, wound infection occurred in 31.3 vs. 24.4%, and patients suffered from chronic lymphedema in 30.0 vs. 26.5% in V. saphena magna resection vs. sparing group. Differences observed, however, were not significant. No difference in regional recurrence-free survival between the two study groups was detected. The results of our retrospective analysis could not confirm the promising results reported in earlier studies. Thus, sparing of the saphenous vein appears to be optional.


Investigation of the Structure of Atomically Dispersed NiNx Sites in Ni and N-Doped Carbon Electrocatalysts by 61Ni Mössbauer Spectroscopy and Simulations.
Ni and nitrogen-doped carbons are selective catalysts for CO2 reduction to CO (CO2R), but the hypothesized NiNx active sites are challenging to probe with traditional characterization methods. Here, we synthesize 61Ni-enriched model catalysts, termed 61NiPACN, in order to apply 61Ni Mössbauer spectroscopy using synchrotron radiation (61Ni-SR-MS) to characterize the structure of these atomically dispersed NiNx sites. First, we demonstrate that the CO2R results and standard characterization techniques (SEM, PXRD, XPS, XANES, EXAFS) point to the existence of dispersed Ni active sites. Then, 61Ni-SR-MS reveal significant internal magnetic fields of ∼5.4 T, which is characteristic of paramagnetic, high-spin Ni2+, in the 61NiPACN samples. Finally, theoretical calculations for a variety of Ni-Nx moieties confirm that high-spin Ni2+ is stable in non-planar, tetrahedrally distorted geometries, which results in calculated isotropic hyperfine coupling that is consistent with 61Ni-SR-MS measurements.


Flow cytometry reveals subpopulations of murine epidermal cells that are refractory to induction of cytochrome P-4501A1 by beta-naphthoflavone.
Topical application of beta-naphthoflavone to CD-1 mice induced an 87-fold increase in epidermal 7-ethoxyresorufin O-dealkylation activity per cell and a many-fold increase in epidermal cytochrome P-4501A1 (CYP1A1) concentration. Flow cytometric analysis of individual epidermal cells from acetone-treated and beta-naphthoflavone-treated mice using a monoclonal antibody for CYP1A1 indicated that 50% to 60% of the isolated epidermal cells were refractory to beta-naphthoflavone induction of CYP1A1. Examination of the differences between responsive and nonresponsive epidermal cells from beta-naphthoflavone-treated mice revealed that 70% of the low CYP1A1-containing cells (noninduced) separated by flow cytometry were basal cells and only 12% were suprabasal differentiated cells. In contrast, about 50% of the high CYP1A1-containing induced cells separated by flow cytometry from the epidermis of mice treated with beta-naphthoflavone were suprabasal cells and 35% were basal cells. These results indicate that topical application of beta-naphthoflavone increased the level of CYP1A1 in about 80% of the separated suprabasal cells and in about 35% of the separated basal cells.


Alcohol abstainers: a low-risk group for cancer--a cohort study of Norwegian teetotalers.
Groups with assumed health-protective life-styles have been studied for several decades, in search of causes for cancer. We have analyzed cancer incidence, total mortality, and cause-specific mortality in Norwegian teetotalers to assess the possible health gains from an alcohol-abstaining life-style. A cohort of 5332 members of the International Organization of Good Templars was followed for 10 years from 1980. The cancer incidence and the cause-specific mortality of the cohort has been compared to that of the total Norwegian population. The standardized incidence ratio (SIR) for all cancer sites was 74 [95% confidence interval (CI), 64-80] for men and 72 (95% CI, 61-84) for women. For possible alcohol-associated cancers, such as cancer of the oral cavity, pharynx, esophagus, liver, and larynx, the SIR was 43 (95% CI, 17-88) for both sexes combined. For lung cancer the SIR was 57 (95% CI, 37-90) for men and 10 (95% CI, 0-57) for women. When all alcohol- and tobacco-associated cancers were excluded, the SIR for both sexes combined was 79 (95% CI, 69-87). The standardized mortality ratio for total mortality was 81 (95% CI, 65-74). This significant decrease in total mortality was caused by reduced risks for all major causes of death. The study indicates that members of the Norwegian chapter of the International Organization of Good Templars are a low-risk group not only regarding alcohol- and tobacco-associated cancers, but also regarding all other cancers.


Meta-analysis of real-time fMRI neurofeedback studies using individual participant data: How is brain regulation mediated?
An increasing number of studies using real-time fMRI neurofeedback have demonstrated that successful regulation of neural activity is possible in various brain regions. Since these studies focused on the regulated region(s), little is known about the target-independent mechanisms associated with neurofeedback-guided control of brain activation, i.e. the regulating network. While the specificity of the activation during self-regulation is an important factor, no study has effectively determined the network involved in self-regulation in general. In an effort to detect regions that are responsible for the act of brain regulation, we performed a post-hoc analysis of data involving different target regions based on studies from different research groups. We included twelve suitable studies that examined nine different target regions amounting to a total of 175 subjects and 899 neurofeedback runs. Data analysis included a standard first- (single subject, extracting main paradigm) and second-level (single subject, all runs) general linear model (GLM) analysis of all participants taking into account the individual timing. Subsequently, at the third level, a random effects model GLM included all subjects of all studies, resulting in an overall mixed effects model. Since four of the twelve studies had a reduced field of view (FoV), we repeated the same analysis in a subsample of eight studies that had a well-overlapping FoV to obtain a more global picture of self-regulation. The GLM analysis revealed that the anterior insula as well as the basal ganglia, notably the striatum, were consistently active during the regulation of brain activation across the studies. The anterior insula has been implicated in interoceptive awareness of the body and cognitive control. Basal ganglia are involved in procedural learning, visuomotor integration and other higher cognitive processes including motivation. The larger FoV analysis yielded additional activations in the anterior cingulate cortex, the dorsolateral and ventrolateral prefrontal cortex, the temporo-parietal area and the visual association areas including the temporo-occipital junction. In conclusion, we demonstrate that several key regions, such as the anterior insula and the basal ganglia, are consistently activated during self-regulation in real-time fMRI neurofeedback independent of the targeted region-of-interest. Our results imply that if the real-time fMRI neurofeedback studies target regions of this regulation network, such as the anterior insula, care should be given whether activation changes are related to successful regulation, or related to the regulation process per se. Furthermore, future research is needed to determine how activation within this regulation network is related to neurofeedback success.


Do Sebacinales commonly associate with plant roots as endophytes?
Sebacinales are basal Hymenomycetes with diverse mycorrhizal abilities, ranging from ectomycorrhizae to ericoid and orchid mycorrhizae. Several previous PCR or isolation works raised the possibility that Sebacinales are endophytes in plant roots. We tested this hypothesis in an isolation-independent approach by using specific PCR primers for ribosomal DNA of Sebacinales on AM mycorrhizal or non-mycorrhizal roots. Thirty-nine plant species were sampled on a Caribbean and two European sites (3 repetition per species and site), covering 25 families in monocots and eudicots. PCR signals were obtained from 40 samples (28.9%) from 27 species (69.2%) and all sites. Whenever sequencing was successful, a sequence belonging to Sebacinales was recovered. A phylogenetic approach revealed that 13 of them belonged to clade B (encompassing ericoid and orchid mycorrhizal species) and 4 to clade A (usually encompassing only ectomycorrhizal species). These data suggest that Sebacinales may be endophytic in many angiosperm roots, and that this condition is plesiomorphic in Sebacinales. They bridge the gap between physiological studies, inoculating Sebacinales (Piriformospora indica or Sebacina vermifera) on diverse plants and molecular ecology, hitherto restricting Sebacinales to mycorrhizal interactions. Structural and functional aspects of the interaction deserve further studies.


Changes in American Adults' Sexual Behavior and Attitudes, 1972-2012.
In the nationally representative General Social Survey, U.S. Adults (N = 33,380) in 2000-2012 (vs. the 1970s and 1980s) had more sexual partners, were more likely to have had sex with a casual date or pickup or an acquaintance, and were more accepting of most non-marital sex (premarital sex, teen sex, and same-sex sexual activity, but not extramarital sex). The percentage who believed premarital sex among adults was "not wrong at all" was 29 % in the early 1970s, 42 % in the 1980s and 1990s, 49 % in the 2000s, and 58 % between 2010 and 2012. Mixed effects (hierarchical linear modeling) analyses separating time period, generation/birth cohort, and age showed that the trend toward greater sexual permissiveness was primarily due to generation. Acceptance of non-marital sex rose steadily between the G.I. generation (born 1901-1924) and Boomers (born 1946-1964), dipped slightly among early Generation X'ers (born 1965-1981), and then rose so that Millennials (also known as Gen Y or Generation Me, born 1982-1999) were the most accepting of non-marital sex. Number of sexual partners increased steadily between the G.I.s and 1960s-born GenX'ers and then dipped among Millennials to return to Boomer levels. The largest changes appeared among White men, with few changes among Black Americans. The results were discussed in the context of growing cultural individualism and rejection of traditional social rules in the U.S.


HindSight: Encouraging Exploration through Direct Encoding of Personal Interaction History.
Physical and digital objects often leave markers of our use. Website links turn purple after we visit them, for example, showing us information we have yet to explore. These "footprints" of interaction offer substantial benefits in information saturated environments - they enable us to easily revisit old information, systematically explore new information, and quickly resume tasks after interruption. While applying these design principles have been successful in HCI contexts, direct encodings of personal interaction history have received scarce attention in data visualization. One reason is that there is little guidance for integrating history into visualizations where many visual channels are already occupied by data. More importantly, there is not firm evidence that making users aware of their interaction history results in benefits with regards to exploration or insights. Following these observations, we propose HindSight - an umbrella term for the design space of representing interaction history directly in existing data visualizations. In this paper, we examine the value of HindSight principles by augmenting existing visualizations with visual indicators of user interaction history (e.g. How the Recession Shaped the Economy in 255 Charts, NYTimes). In controlled experiments of over 400 participants, we found that HindSight designs generally encouraged people to visit more data and recall different insights after interaction. The results of our experiments suggest that simple additions to visualizations can make users aware of their interaction history, and that these additions significantly impact users' exploration and insights.


Editorial: Early detection of mental health and neurodevelopmental disorders: the ethical challenges of a field in its infancy.
The signs of many mental health and neurodevelopmental conditions first appear in childhood and diagnosis can reliably be made by school age for most. Such conditions can be chronically disabling and confer significant long-term impairment. Determining early risk signs and first emerging symptoms of disorder is imperative to enhance early detection and to identify targets and ideal time points for prevention and intervention efforts. This Special Issue of JCPP focuses on the prospect of earlier identification of conditions that are traditionally diagnosed later in childhood. Ten invited empirical articles cover topics related to the science of early detection. Several are focused on prediction of later diagnosis, of functional impairment, and of future service utilization, while others cover instrument development and topics related to screening. The papers span the conditions of ADHD, ASD, dyslexia, mood dysregulation, disruptive behavior disorders, and anxiety disorders. This Editorial provides an overview of the invited contributions and the perspectives they provide on the ethical challenges and choices of a field still in its infancy.


Thermodynamical approach to sympathetic cooling of neutral particles.
We present a "toy" classical model for sympathetic cooling of the neutral Brownian particle in the frame of robust thermodynamical approach. The cooling time is expressed with the parameters of the Brownian particle and the particles from the cooling reservoir. Qualitative and numerical estimations of the model confirm that the sympathetic cooling can be efficient for heavy neutral molecules and clusters.


Light-induced structural changes and the site of O=O bond formation in PSII caught by XFEL.
Photosystem II (PSII) is a huge membrane-protein complex consisting of 20 different subunits with a total molecular mass of 350 kDa for a monomer. It catalyses light-driven water oxidation at its catalytic centre, the oxygen-evolving complex (OEC). The structure of PSII has been analysed at 1.9 Å resolution by synchrotron radiation X-rays, which revealed that the OEC is a Mn4CaO5 cluster organized in an asymmetric, 'distorted-chair' form. This structure was further analysed with femtosecond X-ray free electron lasers (XFEL), providing the 'radiation damage-free' structure. The mechanism of O=O bond formation, however, remains obscure owing to the lack of intermediate-state structures. Here we describe the structural changes in PSII induced by two-flash illumination at room temperature at a resolution of 2.35 Å using time-resolved serial femtosecond crystallography with an XFEL provided by the SPring-8 ångström compact free-electron laser. An isomorphous difference Fourier map between the two-flash and dark-adapted states revealed two areas of apparent changes: around the QB/non-haem iron and the Mn4CaO5 cluster. The changes around the QB/non-haem iron region reflected the electron and proton transfers induced by the two-flash illumination. In the region around the OEC, a water molecule located 3.5 Å from the Mn4CaO5 cluster disappeared from the map upon two-flash illumination. This reduced the distance between another water molecule and the oxygen atom O4, suggesting that proton transfer also occurred. Importantly, the two-flash-minus-dark isomorphous difference Fourier map showed an apparent positive peak around O5, a unique μ4-oxo-bridge located in the quasi-centre of Mn1 and Mn4 (refs 4,5). This suggests the insertion of a new oxygen atom (O6) close to O5, providing an O=O distance of 1.5 Å between these two oxygen atoms. This provides a mechanism for the O=O bond formation consistent with that proposed previously.


Does disadvantage start at home? Racial and ethnic disparities in health-related early childhood home routines and safety practices.
Little is known about whether racial/ethnic differences exist in household family activities, safety practices, and educational opportunities known to impact young children's healthy development and school success. To examine whether racial/ethnic disparities exist in early childhood home routines, safety measures, and educational practices/resources. The 2000 National Survey of Early Childhood Health is a telephone survey of a nationwide sample of parents of 2608 children aged 4 to 35 months. Differences in family activities, safety measures, and educational practices/resources were examined for white, black, and Hispanic children. Minority children are less likely than white children to have consistent daily mealtimes and bedtimes, and more frequently never eat lunch or dinner with their family. Minority parents are less likely to install stair gates or cabinet safety locks and to turn down hot water settings. Minority parents less often read daily to their child, Hispanic parents more often never read to their child, and minority households average fewer children's books. Black children average more hours watching television daily. Disparities persisting in multivariate analyses included: minority children having increased odds of never eating lunch or dinner with their family, black children not having regular mealtimes (odds ratio, 1.8; 95% confidence interval, 1.2-2.7) and watching 1 more hour of television daily, black parents not installing cabinet locks, minority parents having twice the odds of not installing stair gates and not reading to their child daily, and minority homes having fewer children's books (black homes, -30; and Hispanic homes, -20). Children whose parents completed surveys in Spanish also experienced several disparities. Young minority children experience multiple disparities in home routines, safety measures, and educational practices/resources that have the potential to impede their healthy development and future school success. Such disparities might be reduced or eliminated through targeted education and intervention by pediatric providers.


Clinical course and interstage monitoring after the Norwood and hybrid procedures for hypoplastic left heart syndrome.
Infants with hypoplastic left heart syndrome (HLHS) are at risk for interstage morbidity and mortality, especially between the first and second surgical stages after the Norwood and hybrid procedures. This study compared the morbidity and mortality of patients treated by either the Norwood or the hybrid procedure for HLHS between the first and second stages who were undergoing interstage monitoring. Between October 2008 and December 2011, 26 infants (14 boys) with HLHS (n = 16) and other univentricular heart malformations with aortic arch anomaly (n = 10) were scheduled for interstage monitoring after Norwood I (n = 12) and hybrid (n = 14) procedures. Three infants (11.5 %) died after first-stage palliation (one hybrid patient and two Norwood patients), and three infants (11.5 %) died after second-stage palliation (two hybrid patients and one Norwood patient) (p = 0.83), all after early second-stage surgery (<90 days). The Norwood I and hybrid procedures did not differ in terms of overall mortality (23 %) (three hybrid and three Norwood patients; p = 1.00). Seven infants (26.9 %) could not be discharged from the hospital due to hemodynamic instability and were referred for early second-stage surgery (<90 days). After the first stage, the invasive reevaluation rate before discharge was high (53.8 %), with cardiac catheterizations for 8 of 14 patients after the hybrid procedure and for 6 of 12 patients after the Norwood procedure (p = 0.69). A total of 11 reinterventions were performed (eight by catheter and three by surgery). Of the eight catheter reinterventions, five were performed for hybrid patients (p = 0.22). For 14 infants, 89 days (range 10-177 days) of interstage monitoring were scheduled. One infant (3.9 %) died during the interstage monitoring. The findings showed a breach of the physiologic criteria for interstage monitoring in seven infants (50 %) after 10 days (range 4-68 days) (five hybrid and two Norwood patients), leading to rehospitalization and catheterization for six patients (four hybrid and two Norwood patients), requiring interventions for two patients (patent arterial duct stent dilation, and atrial septal defect stenting, all for hybrid patients). Overall, three of the seven patients with red flag events of interstage monitoring were candidates for early second-stage surgery. In conclusion, morbidity among infants treated for HLHS remains high, either before or after hospital discharge, emphasizing the need of interstage monitoring programs. Despite retrograde aortic flow in infants with HLHS after the hybrid procedure, the mortality rate was comparable between the two groups. Mortality occurs after early second-stage surgery (<90 days).


Metagenomic insights into diazotrophic communities across Arctic glacier forefields.
Microbial nitrogen fixation is crucial for building labile nitrogen stocks and facilitating higher plant colonisation in oligotrophic glacier forefield soils. Here, the diazotrophic bacterial community structure across four Arctic glacier forefields was investigated using metagenomic analysis. In total, 70 soil metagenomes were used for taxonomic interpretation based on 185 nitrogenase (nif) sequences, extracted from assembled contigs. The low number of recovered genes highlights the need for deeper sequencing in some diverse samples, to uncover the complete microbial populations. A key group of forefield diazotrophs, found throughout the forefields, was identified using a nifH phylogeny, associated with nifH Cluster I and III. Sequences related most closely to groups including Alphaproteobacteria, Betaproteobacteria, Cyanobacteria and Firmicutes. Using multiple nif genes in a Last Common Ancestor analysis revealed a diverse range of diazotrophs across the forefields. Key organisms identified across the forefields included Nostoc, Geobacter, Polaromonas and Frankia. Nitrogen fixers that are symbiotic with plants were also identified, through the presence of root associated diazotrophs, which fix nitrogen in return for reduced carbon. Additional nitrogen fixers identified in forefield soils were metabolically diverse, including fermentative and sulphur cycling bacteria, halophiles and anaerobes.


Experimental demonstration of parallel two-step phase-shifting digital holography.
Parallel two-step phase-shifting digital holography is a technique for single-shot implementation of phase-shifting interferometry and requires only the intensity distribution of the reference wave and spatial two phase-shifted holograms. We constructed a system of parallel two-step phase-shifting digital holography and experimentally demonstrated the technique, for the first time. The system uses an originally fabricated image sensor having an array of 2 × 1 micro polarizers. Each micro polarizer was attached on pixel by pixel. In the experiment, the unwanted images, the zero-order diffraction wave and the conjugate image, are removed from the reconstructed image of objects by the system, while the images superimpose on the image of objects reconstructed by Fresnel transform alone. Also the capability of single-shot and three-dimensional imaging is demonstrated by the system.


Bis(μ-2-carb-oxy-methyl-2-hy-droxy-butane-dioato)bis-[diaqua-manganese(II)]-1,2-bis-(pyridin-4-yl)ethene-water (1/1/2).
The asymmetric unit of the title compound, [Mn2(C6H6O7)2(H2O)4]·C12H10N2·2H2O, contains half of the centrosymmetric Mn complex dimer, half of a 1,2-bis-(pyridin-4-yl)ethene mol-ecule, which lies across an inversion center, and one water mol-ecule. Two citrate ligands bridge two Mn(II) ions, and each Mn(II) atom is coordinated by four O atoms from the citrate ligands (one from hy-droxy and three from carboxyl-ate groups) and two water O atoms, forming a distorted octa-hedral environment. In the crystal, O-H⋯O and O-H⋯N hydrogen bonds link the centrosymmetric dimers and lattice water mol-ecules into a three-dimensional structure which is further stabilized by inter-molecular π-π inter-actions [centroid-centroid distance = 3.959 (2) Å]. Weak C-H⋯O hydrogen bonding interactions are also observed.


Short-term immunological effects of induced emotion.
Twenty healthy volunteers (half male) recalled and relived maximally disturbing (NEG) and maximally pleasurable (POS) emotional experiences. Forty minutes of silence, then neutral conversation, preceded and followed 40 minutes of emotion elicitation (NEG and POS randomly rotated). They were under video, cardiovascular, and immunological monitoring. Subjects reported appropriate emotions and showed significant cardiovascular activation during the NEG condition. Speech alone had an independent cardiovascular activating effect. Emotion, particularly NEG, led to further activation. NEG emotion promoted significant declines in mitogenic lymphocyte reactivity, followed by return to pre-emotion levels. A similar though less extreme decline was seen in the POS condition. There was a weak trend for elevated natural killer cell activity under the NEG condition, possibly due in part to changed trafficking patterns. Correlational findings confirmed these group effects. The decline in mitogenic reactivity during POS emotion appeared to be due to subtle degrees of tension and excitement triggered by the experimental experience regardless of the exact emotions recalled. Results suggest that immunologic processes are sensitive to influence by arousal of emotion.


Specificity Analysis of Genome Based on Statistically Identical K-Words With Same Base Combination.
Goal: Individual characteristics are determined through a genome consisting of a complex base combination. This base combination is reflected in the k-word profile, which represents the number of consecutive k bases. Therefore, it is important to analyze the genome-specific statistical specificity in the k-word profile to understand the characteristics of the genome. In this paper, we propose a new k-word-based method to analyze genome-specific properties. Methods: We define k-words consisting of the same number of bases as statistically identical k-words. The statistically identical k-words are estimated to appear at a similar frequency by statistical prediction. However, this may not be true in the genome because it is not a random list of bases. The ratio between frequencies of two statistically identical k-words can then be used to investigate the statistical specificity of the genome reflected in the k-word profile. In order to find important ratios representing genomic characteristics, a reference value is calculated that results in a minimum error when classifying data by ratio alone. Finally, we propose a genetic algorithm-based search algorithm to select a minimum set of ratios useful for classification. Results: The proposed method was applied to the full-length sequence of microorganisms for pathogenicity classification. The classification accuracy of the proposed algorithm was similar to that of conventional methods while using only a few features. Conclusions: We proposed a new method to investigate the genome-specific statistical specificity in the k-word profile which can be applied to find important properties of the genome and classify genome sequences.


Tests for determining in-use concentrations of antibiotics and disinfectants are based on entirely different concepts: "resistance" has different meanings.
There are concerns that more extensive application of disinfectants in the food industry could result in increased resistance of bacteria to antibiotics and that therapeutic failure could ensue. This paper highlights the differences in application and mode of action between antibiotics in human or animal medicine and disinfectants in the food industry. It describes the completely different methods used to determine in-use concentrations in the two contexts. It points out that the minimum inhibitory concentration (MIC) is never the concentration at which disinfectants should be applied. It also discusses erroneous conclusions that may be drawn when the failure of therapy or disinfection is attributed to intrinsic properties of the molecules rather than to misuse of antibiotics or disinfectants. The paper suggests that the intended meaning of the word "resistance" be carefully defined in scientific articles with due reference to the measurement mentioned in the abstract and possibly reflected in the title. It also suggests that in matters of disinfection the word "resistance" be preferred when the phenomenon being studied is killing and "tolerance" when it is the adaptation to inhibitory concentrations.


Telemedicine-based collaborative care for posttraumatic stress disorder: a randomized clinical trial.
Posttraumatic stress disorder (PTSD) is prevalent, persistent, and disabling. Although psychotherapy and pharmacotherapy have proven efficacious in randomized clinical trials, geographic barriers impede rural veterans from engaging in these evidence-based treatments. To test a telemedicine-based collaborative care model designed to improve engagement in evidence-based treatment of PTSD. The Telemedicine Outreach for PTSD (TOP) study used a pragmatic randomized effectiveness trial design with intention-to-treat analyses. Outpatients were recruited from 11 Department of Veterans Affairs (VA) community-based outpatient clinics serving predominantly rural veterans. Inclusion required meeting diagnostic criteria for current PTSD according to the Clinician-Administered PTSD Scale. Exclusion criteria included receiving PTSD treatment at a VA medical center or a current diagnosis of schizophrenia, bipolar disorder, or substance dependence. Two hundred sixty-five veterans were enrolled from November 23, 2009, through September 28, 2011, randomized to usual care (UC) or the TOP intervention, and followed up for 12 months. Off-site PTSD care teams located at VA medical centers supported on-site community-based outpatient clinic providers. Off-site PTSD care teams included telephone nurse care managers, telephone pharmacists, telepsychologists, and telepsychiatrists. Nurses conducted care management activities. Pharmacists reviewed medication histories. Psychologists delivered cognitive processing therapy via interactive video. Psychiatrists supervised the team and conducted interactive video psychiatric consultations. The primary outcome was PTSD severity as measured by the Posttraumatic Diagnostic Scale. Process-of-care outcomes included medication prescribing and regimen adherence and initiation of and adherence to cognitive processing therapy. During the 12-month follow-up period, 73 of the 133 patients randomized to TOP (54.9%) received cognitive processing therapy compared with 16 of 132 randomized to UC (12.1%) (odds ratio, 18.08 [95% CI, 7.96-41.06]; P < .001). Patients in the TOP arm had significantly larger decreases in Posttraumatic Diagnostic Scale scores (from 35.0 to 29.1) compared with those in the UC arm (from 33.5 to 32.1) at 6 months (β = -3.81; P = .002). Patients in the TOP arm also had significantly larger decreases in Posttraumatic Diagnostic Scale scores (from 35.0 to 30.1) compared with those in the UC arm (from 33.5 to 31.7) at 12 months (β = -2.49; P=.04). There were no significant group differences in the number of PTSD medications prescribed and adherence to medication regimens were not significant. Attendance at 8 or more sessions of cognitive processing therapy significantly predicted improvement in Posttraumatic Diagnostic Scale scores (β = -3.86 [95% CI, -7.19 to -0.54]; P = .02) and fully mediated the intervention effect at 12 months. Telemedicine-based collaborative care can successfully engage rural veterans in evidence-based psychotherapy to improve PTSD outcomes. clinicaltrials.gov Identifier: NCT00821678.


Male-typical visuospatial functioning in gynephilic girls with gender dysphoria - organizational and activational effects of testosterone.
Sex differences in performance and regional brain activity during mental rotation have been reported repeatedly and reflect organizational and activational effects of sex hormones. We investigated whether adolescent girls with gender dysphoria (GD), before and after 10 months of testosterone treatment, showed male-typical brain activity during a mental rotation task (MRT). Girls with GD underwent fMRI while performing the MRT twice: when receiving medication to suppress their endogenous sex hormones before onset of testosterone treatment, and 10 months later during testosterone treatment. Two age-matched control groups participated twice as well. We included 21 girls with GD, 20 male controls and 21 female controls in our study. In the absence of any group differences in performance, control girls showed significantly increased activation in frontal brain areas compared with control boys (pFWE = 0.012). Girls with GD before testosterone treatment differed significantly in frontal brain activation from the control girls (pFWE = 0.034), suggesting a masculinization of brain structures associated with visuospatial cognitive functions. After 10 months of testosterone treatment, girls with GD, similar to the control boys, showed increases in brain activation in areas implicated in mental rotation. Since all girls with GD identified as gynephilic, their resemblance in spatial cognition with the control boys, who were also gynephilic, may have been related to their shared sexual orientation rather than their shared gender identity. We did not account for menstrual cycle phase or contraceptive use in our analyses. Our findings suggest atypical sexual differentiation of the brain in natal girls with GD and provide new evidence for organizational and activational effects of testosterone on visuospatial cognitive functioning.


Use of eye shields and eye lubricants among oculoplastic and Mohs surgeons: a survey.
Eye shields and lubricants are recommended for use in the eye during periorbital surgery to prevent injury to the globe. Nonetheless, data regarding their use is sparse, and no study to date has examined the prevalence of their usage and complications. To investigate how commonly eye shields and lubricants are used during periorbital surgery and whether there are complications from their use. The authors conducted a survey of oculoplastic and Mohs surgery fellowship directors. The questionnaire investigated the prevalence of use of eye shields and lubricants, complications encountered, and whether the standard of care requires or prohibits their use. A majority of those surveyed at least sometimes use eye shields in periorbital surgery, particularly to prevent patient injury. Most surgeons believe there are more pros than cons to their use. However, corneal abrasions may be encountered and may be related to the type of lubricant chosen. Surgeons using fat-based lubricants tended to encounter more complications with eye shield use. Eye shield and lubricant use is common among oculoplastic and Mohs surgeons. However, most disagree as to whether the standard of care requires or forbids their use.


High-Sensitivity Troponin I and Incident Coronary Events, Stroke, Heart Failure Hospitalization, and Mortality in the ARIC Study.
We assessed whether plasma troponin I measured by a high-sensitivity assay (hs-TnI) is associated with incident cardiovascular disease (CVD) and mortality in a community-based sample without prior CVD. ARIC study (Atherosclerosis Risk in Communities) participants aged 54 to 74 years without baseline CVD were included in this study (n=8121). Cox proportional hazards models were constructed to determine associations between hs-TnI and incident coronary heart disease (CHD; myocardial infarction and fatal CHD), ischemic stroke, atherosclerotic CVD (CHD and stroke), heart failure hospitalization, global CVD (atherosclerotic CVD and heart failure), and all-cause mortality. The comparative association of hs-TnI and high-sensitivity troponin T with incident CVD events was also evaluated. Risk prediction models were constructed to assess prediction improvement when hs-TnI was added to traditional risk factors used in the Pooled Cohort Equation. The median follow-up period was ≈15 years. Detectable hs-TnI levels were observed in 85% of the study population. In adjusted models, in comparison to low hs-TnI (lowest quintile, hs-TnI ≤1.3 ng/L), elevated hs-TnI (highest quintile, hs-TnI ≥3.8 ng/L) was associated with greater incident CHD (hazard ratio [HR], 2.20; 95% CI, 1.64-2.95), ischemic stroke (HR, 2.99; 95% CI, 2.01-4.46), atherosclerotic CVD (HR, 2.36; 95% CI, 1.86-3.00), heart failure hospitalization (HR, 4.20; 95% CI, 3.28-5.37), global CVD (HR, 3.01; 95% CI, 2.50-3.63), and all-cause mortality (HR, 1.83; 95% CI, 1.56-2.14). hs-TnI was observed to have a stronger association with incident global CVD events in white than in black individuals and a stronger association with incident CHD in women than in men. hs-TnI and high-sensitivity troponin T were only modestly correlated ( r=0.47) and were complementary in prediction of incident CVD events, with elevation of both troponins conferring the highest risk in comparison with elevation in either one alone. The addition of hs-TnI to the Pooled Cohort Equation model improved risk prediction for atherosclerotic CVD, heart failure, and global CVD. Elevated hs-TnI is strongly associated with increased global CVD incidence in the general population independent of traditional risk factors. hs-TnI and high-sensitivity troponin T provide complementary rather than redundant information.


CD25+ CD4+ T cells regulate the expansion of peripheral CD4 T cells through the production of IL-10.
The mechanisms by which the immune system achieves constant T cell numbers throughout life, thereby controlling autoaggressive cell expansions, are to date not completely understood. Here, we show that the CD25(+) subpopulation of naturally activated (CD45RB(low)) CD4 T cells, but not CD25(-) CD45RB(low) CD4 T cells, inhibits the accumulation of cotransferred CD45RB(high) CD4 T cells in lymphocyte-deficient mice. However, both CD25(+) and CD25(-) CD45RB(low) CD4 T cell subpopulations contain regulatory cells, since they can prevent naive CD4 T cell-induced wasting disease. In the absence of a correlation between disease and the number of recovered CD4(+) cells, we conclude that expansion control and disease prevention are largely independent processes. CD25(+) CD45RB(low) CD4 T cells from IL-10-deficient mice do not protect from disease. They accumulate to a higher cell number and cannot prevent the expansion of CD45RB(high) CD4 T cells upon transfer compared with their wild-type counterparts. Although CD25(+) CD45RB(low) CD4 T cells are capable of expanding when transferred in vivo, they reach a homeostatic equilibrium at lower cell numbers than CD25(-) CD45RB(low) or CD45RB(high) CD4 T cells. We conclude that CD25(+) CD45RB(low) CD4 T cells from nonmanipulated mice control the number of peripheral CD4 T cells through a mechanism involving the production of IL-10 by regulatory T cells.


Reduced carbohydrate availability enhances exercise-induced p53 signaling in human skeletal muscle: implications for mitochondrial biogenesis.
The mechanisms that regulate the enhanced skeletal muscle oxidative capacity observed when training with reduced carbohydrate (CHO) availability are currently unknown. The aim of the present study was to test the hypothesis that reduced CHO availability enhances p53 signaling and expression of genes associated with regulation of mitochondrial biogenesis and substrate utilization in human skeletal muscle. In a repeated-measures design, muscle biopsies (vastus lateralis) were obtained from eight active males before and after performing an acute bout of high-intensity interval running with either high (HIGH) or low CHO availability (LOW). Resting muscle glycogen (HIGH, 467 ± 19; LOW, 103 ± 9 mmol/kg dry wt) was greater in HIGH compared with LOW (P < 0.05). Phosphorylation (P-) of ACC(Ser79) (HIGH, 1.4 ± 0.4; LOW, 2.9 ± 0.9) and p53(Ser15) (HIGH, 0.9 ± 0.4; LOW, 2.6 ± 0.8) was higher in LOW immediately postexercise and 3 h postexercise, respectively (P < 0.05). Before and 3 h postexercise, mRNA content of pyruvate dehydrogenase kinase 4, mitochondrial transcription factor A, cytochrome-c oxidase IV, and PGC-1α were greater in LOW compared with HIGH (P < 0.05), whereas carnitine palmitoyltransferase-1 showed a trend toward significance (P = 0.09). However, only PGC-1α expression was increased by exercise (P < 0.05), where three-fold increases occurred independently of CHO availability. We conclude that the exercise-induced increase in p53 phosphorylation is enhanced in conditions of reduced CHO availability, which may be related to upstream signaling through AMPK. Given the emergence of p53 as a molecular regulator of mitochondrial biogenesis, such nutritional modulation of contraction-induced p53 activation has implications for both athletic and clinical populations.


What works in practice: user and provider perspectives on the acceptability, affordability, implementation, and impact of a family-based intervention for child overweight and obesity delivered at scale.
As part of a study considering the impact of a child weight management programme when rolled out at scale following an RCT, this qualitative study focused on acceptability and implementation for providers and for families taking part. Participants were selected on the basis of a maximum variation sample providing a range of experiences and social contexts. Qualitative interviews were conducted with 29 professionals who commissioned or delivered the programme, and 64 individuals from 23 families in 3 English regions. Topic guides were used as a tool rather than a rule, enabling participants to construct a narrative about their experiences. Transcripts were analysed using framework analysis. Practical problems such as transport, work schedules and competing demands on family time were common barriers to participation. Delivery partners often put considerable efforts into recruiting, retaining and motivating families, which increased uptake but also increased cost. Parents and providers valued skilled delivery staff. Some providers made adaptations to meet local social and cultural needs. Both providers and parents expressed concerns about long term outcomes, and how this was compromised by an obesogenic environment. Concerns about funding together with barriers to uptake and engagement could translate into barriers to commissioning. Where these barriers were not experienced, commissioners were enthusiastic about continuing the programme. Most families felt that they had gained something from the programme, but few felt that it had 'worked' for them. The demands on families including time and emotional work were experienced as difficult. For commissioners, an RCT with positive results was an important driver, but family barriers, alongside concerns about recruitment and retention, a desire for local adaptability with qualified motivated staff, and funding changes discouraged some from planning to use the intervention in future.


Plantago lanceolata and Plantago rugelii Extracts are Toxic to Meloidogyne incognita but not to Certain Microbes.
Extracts from the plants Plantago lanceolata and P. rugelii were evaluated for toxicity to the root-knot nematode Meloidogyne incognita, the beneficial microbes Enterobacter cloacae, Pseudomonas fluorescens and Trichoderma virens, and the plant-pathogenic fungi Fusarium oxysporum f. sp. gladioli, Phytophthora capsici, Pythium ultimum, and Rhizoctonia solani. Wild plants were collected, roots were excised from shoots, and the plant parts were dried and ground to a powder. One set of extracts (10% w/v) was prepared in water and another in methanol. Treatments included extract concentrations of 25%, 50%, 75% and 100%, and water controls. Meloidogyne incognita egg hatch was recorded after 7-day exposure to the treatments, and second-stage juvenile (J2) activity after 48 hours. All extracts were toxic to eggs and J2, with P. lanceolata shoot extract tending to have the most activity against M. incognita. Numbers of active J2 remained the same or decreased in a 24-hour water rinse following the 48-hour extract treatment, indicating that the extracts were lethal. When data from water- and methanol-extracted roots and shoots of both plant species were combined for analysis, J2 tended to be more sensitive than eggs to the toxic compounds at lower concentrations, while the higher concentrations (75% and 100%) were equally toxic to both life stages. The effective concentrations causing 50% reduction (EC(50)) in egg hatch and in J2 viability were 44.4% and 43.7%, respectively. No extract was toxic to any of the bacteria or fungi in our assays.


Investigations on the efficiency of cardiac-gated methods for the acquisition of diffusion-weighted images.
Diffusion-weighted images are inherently very sensitive to motion. Pulsatile motion of the brain can give rise to artifactual signal attenuation leading to over-estimation of the apparent diffusion coefficients, even with snapshot echo planar imaging. Such miscalculations can result in erroneous estimates of the principal diffusion directions. Cardiac gating can be performed to confine acquisition to the quiet portion of the cycle. Although effective, this approach leads to significantly longer acquisition times. On the other hand, it has been demonstrated that pulsatile motion is not significant in regions above the corpus callosum. To reduce acquisition times and improve the efficiency of whole brain cardiac-gated acquisitions, the upper slices of the brain can be imaged during systole, reserving diastole for those slices most affected by pulsatile motion. The merits and disadvantages of this optimized approach are investigated here, in comparison to a more standard gating method and to the non-gated approach.


Interferon suppresses pinocytosis but stimulates phagocytosis in mouse peritoneal macrophages: related changes in cytoskeletal organization.
Treatment of thioglycolate-elicited macrophages with mouse beta-interferon markedly reduces pinocytosis of horseradish peroxidase and fluorescein isothiocyanate (FITC)-dextran but stimulates phagocytosis of IgG-coated sheep erythrocytes. Experiments with FITC-dextran have revealed that the overall decrease in pinocytosis is due to a nearly complete inhibition of pinocytosis in a large fraction of interferon-treated macrophages. In the remaining cells pinocytosis continues at a rate similar to that in untreated control cells. A considerable reduction in the number of cells pinocytosing FITC-dextran was observed within 12 h from the beginning of interferon treatment. Measurement of the overall level of pinocytic activity with horseradish peroxidase showed a progressive decline through 72 h of treatment. In the interferon-sensitive subpopulation, there were marked changes in cytoskeletal organization. Microtubules and 10-nm filaments were aggregated in the perinuclear region while most of the peripheral cytoplasm became devoid of these cytoskeletal structures as observed by fluorescence and electron microscopy. In addition, interferon treatment of macrophages appeared to disrupt the close topological association between bundles of 10-nm filaments and organelles such as mitochondria, lysosomes, and elements of the Golgi apparatus and endoplasmic reticulum. Such alterations in the distribution of microtubules and 10-nm filaments were not seen in the interferon-insensitive subpopulation. We have investigated the mechanism of the interferon-induced enhancement of phagocytic activity by binding IgG-coated sheep erythrocytes to mouse peritoneal macrophages at 4 degrees C and then initiating a synchronous round of ingestion by warming the cells to 37 degrees C. Thioglycolate-elicited macrophages that had been treated with mouse beta-interferon ingested IgG-coated erythrocytes faster and to a higher level than control cells in a single round of phagocytosis. In interferon-treated cultures, phagocytic cups became evident within 30 s of the shift of cultures from 4 degrees to 37 degrees C, whereas in control cultures, they appeared in 2 min. Cytochalasin D, an inhibitor of actin assembly and polymerization, abolished phagocytic activity in both control and beta-interferon-treated macrophages. However, to inhibit phagocytosis completely in thioglycolate-elicited interferon-treated macrophages, twice as much cytochalasin D was required in the treated as in control cultures.(ABSTRACT TRUNCATED AT 400 WORDS)


Effectiveness over time of a multimodal intervention to improve compliance with standard hygiene precautions in an intensive care unit of a large teaching hospital.
Standard hygiene precautions are an effective way of controlling healthcare-associated infections. Nevertheless, compliance with hand hygiene (HH) guidelines among healthcare workers (HCWs) is often poor, and evidence regarding appropriate use of gloves and gowns is limited and not encouraging. In this study, we evaluated the ability over time of a multimodal intervention to improve HCWs compliance with standard hygiene precautions. Trend analysis of direct observations of compliance with HH guidelines and proper glove or gown use was conducted in the medical/surgical intensive care unit (ICU) of Umberto I Teaching Hospital of Sapienza University of Rome. The study consisted of two phases: a six-month baseline phase and a 12-month post-intervention phase. The multimodal intervention was based on the World Health Organization strategy and included education and training of HCWs, together with performance feedback. A total of 12,853 observations were collected from November 2016 to April 2018. Overall compliance significantly improved from 41.9% at baseline to 62.1% (p < 0.001) after the intervention and this improvement was sustained over the following trimesters. Despite variability across job categories and over the study period, a similar trend was observed for most investigations. The main determinants of compliance were job category (with nurses having the highest compliance rates), being a member of ICU staff and whether delivering routine, as opposed to emergency, care. HH compliance was modified by glove use; unnecessary gloving negatively affected HH behaviour while appropriate gloving positively influenced it. The multimodal intervention resulted in a significant improvement in compliance with standard hygiene precautions. However, regular educational reinforcement and feedback is essential to maintain a high and uniform level of compliance.


Acceptance and commitment therapy for late-life treatment-resistant generalised anxiety disorder: a feasibility study.
Generalised anxiety disorder (GAD) is the most common anxiety disorder in older people. First-line management includes pharmacological and psychological therapies, but many do not find these effective or acceptable. Little is known about how to manage treatment-resistant generalised anxiety disorder (TR-GAD) in older people. To examine the acceptability, feasibility and preliminary estimates of the effectiveness of acceptance and commitment therapy (ACT) for older people with TR-GAD. People aged ≥65 years with TR-GAD (defined as not responding to GAD treatment, tolerate it or refused treatment) recruited from primary and secondary care services and the community. Participants received up to 16 one-to-one sessions of ACT, developed specifically for older people with TR-GAD, in addition to usual care. Co-primary outcomes were feasibility (defined as recruitment of ≥32 participants and retention of ≥60% at follow-up) and acceptability (defined as participants attending ≥10 sessions and scoring ≥21/30 on the satisfaction with therapy subscale). Secondary outcomes included measures of anxiety, worry, depression and psychological flexibility (assessed at 0 and 20 weeks). Thirty-seven participants were recruited, 30 (81%) were retained and 26 (70%) attended ≥10 sessions. A total of 18/30 (60%) participants scored ≥21/30 on the satisfaction with therapy subscale. There was preliminary evidence suggesting that ACT may improve anxiety, depression and psychological flexibility. There was evidence of good feasibility and acceptability, although satisfaction with therapy scores suggested that further refinement of the intervention may be necessary. Results indicate that a larger-scale randomised controlled trial of ACT for TR-GAD is feasible and warranted.


General Principles for the welfare of animals in production systems: the underlying science and its application.
In 2012, the World Organisation for Animal Health adopted 10 'General Principles for the Welfare of Animals in Livestock Production Systems' to guide the development of animal welfare standards. The General Principles draw on half a century of scientific research relevant to animal welfare: (1) how genetic selection affects animal health, behaviour and temperament; (2) how the environment influences injuries and the transmission of diseases and parasites; (3) how the environment affects resting, movement and the performance of natural behaviour; (4) the management of groups to minimize conflict and allow positive social contact; (5) the effects of air quality, temperature and humidity on animal health and comfort; (6) ensuring access to feed and water suited to the animals' needs and adaptations; (7) prevention and control of diseases and parasites, with humane euthanasia if treatment is not feasible or recovery is unlikely; (8) prevention and management of pain; (9) creation of positive human-animal relationships; and (10) ensuring adequate skill and knowledge among animal handlers. Research directed at animal welfare, drawing on animal behaviour, stress physiology, veterinary epidemiology and other fields, complements more established fields of animal and veterinary science and helps to create a more comprehensive scientific basis for animal care and management.


Sequential Digestion with Trypsin and Elastase in Cross-Linking Mass Spectrometry.
Cross-linking mass spectrometry has become an important approach for studying protein structures and protein-protein interactions. The amino acid compositions of some protein regions impede the detection of cross-linked residues, although it would yield invaluable information for protein modeling. Here, we report on a sequential-digestion strategy with trypsin and elastase to penetrate regions with a low density of trypsin-cleavage sites. We exploited intrinsic substrate-recognition properties of elastase to specifically target larger tryptic peptides. Our application of this protocol to the TAF4-12 complex allowed us to identify cross-links in previously inaccessible regions.


Design, synthesis and biological evaluation of novel inhibitors of Trypanosoma brucei pteridine reductase 1.
Genetic studies indicate that the enzyme pteridine reductase 1 (PTR1) is essential for the survival of the protozoan parasite Trypanosoma brucei. Herein, we describe the development and optimisation of a novel series of PTR1 inhibitors, based on benzo[d]imidazol-2-amine derivatives. Data are reported on 33 compounds. This series was initially discovered by a virtual screening campaign (J. Med. Chem., 2009, 52, 4454). The inhibitors adopted an alternative binding mode to those of the natural ligands, biopterin and dihydrobiopterin, and classical inhibitors, such as methotrexate. Using both rational medicinal chemistry and structure-based approaches, we were able to derive compounds with potent activity against T. brucei PTR1 (K(i)(app)=7 nM), which had high selectivity over both human and T. brucei dihydrofolate reductase. Unfortunately, these compounds displayed weak activity against the parasites. Kinetic studies and analysis indicate that the main reason for the lack of cell potency is due to the compounds having insufficient potency against the enzyme, which can be seen from the low K(m) to K(i) ratio (K(m)=25 nM and K(i)=2.3 nM, respectively).


Effects of Emollient Containing Bee Venom on Atopic Dermatitis: A Double-Blinded, Randomized, Base-Controlled, Multicenter Study of 136 Patients.
Atopic dermatitis (AD) is a common, complex disease that follows a chronic relapsing course and significantly affects the quality of life of patients. Skin barrier dysfunction and inflammatory processes induce and aggravate this skin condition. Proper use of an emollient for hydration is a keystone of AD treatment. Bee venom is known to have anti-inflammatory effects and has been widely used in traditional medicine to treat various inflammatory disorders. To find out the beneficial effect of an emollient containing bee venom in the treatment of patients with AD. This study included 136 patients with AD who were randomized to receive either an emollient containing bee venom and silk-protein or a vehicle that was identical except for the bee venom for 4 weeks. The patients were instructed to apply the emollient twice daily on their entire body and not to use other medications, including topicals, during the course of the study. The eczema area and severity index (EASI) score, transepidermal water loss, and visual analogue scale (VAS) score of itching were evaluated at the first visit and after 2 and 4 weeks. The investigator global assessment was evaluated at 2 and 4 weeks after the application of emollient containing bee venom or vehicle. Patients applying emollient containing bee venom showed significantly lower EASI score and VAS value compared to patients applying emollient without bee venom. Emollient containing bee venom is a safe and effective option for patients with AD.


Efficient learning and feature selection in high-dimensional regression.
We present a novel algorithm for efficient learning and feature selection in high-dimensional regression problems. We arrive at this model through a modification of the standard regression model, enabling us to derive a probabilistic version of the well-known statistical regression technique of backfitting. Using the expectation-maximization algorithm, along with variational approximation methods to overcome intractability, we extend our algorithm to include automatic relevance detection of the input features. This variational Bayesian least squares (VBLS) approach retains its simplicity as a linear model, but offers a novel statistically robust black-box approach to generalized linear regression with high-dimensional inputs. It can be easily extended to nonlinear regression and classification problems. In particular, we derive the framework of sparse Bayesian learning, the relevance vector machine, with VBLS at its core, offering significant computational and robustness advantages for this class of methods. The iterative nature of VBLS makes it most suitable for real-time incremental learning, which is crucial especially in the application domain of robotics, brain-machine interfaces, and neural prosthetics, where real-time learning of models for control is needed. We evaluate our algorithm on synthetic and neurophysiological data sets, as well as on standard regression and classification benchmark data sets, comparing it with other competitive statistical approaches and demonstrating its suitability as a drop-in replacement for other generalized linear regression techniques.


The effect of the number of carbohydrate moieties on the azaphthalocyanine properties.
A series of azaphthalocyanines (AzaPc) bearing one, two, four or eight isopropylidene-protected galactosyl units was prepared by azide-alkyne click reaction or by classical Pc template cyclotetramerization of the corresponding dicyanopyrazine and AzaPc properties important for photodynamic therapy were compared. All compounds absorbed at long wavelengths (above 650 nm) and belonged to strong singlet oxygen producers (Φ(Δ) = 0.58-0.64) retaining significant fluorescence emission (Φ(F) = 0.026-0.23). The only exception was the compound with four isopropyliden-protected galactosyl units where partial aggregation was observed. Removal of protecting groups increased the polar character of all AzaPc. However, only AzaPc bearing eight galactoses was found to be water-soluble (105 mg mL(-1)) but noticeably aggregated in water as well as in organic solvents (DMF, DMSO). Amphiphilic AzaPc bearing one deprotected galactose was incorporated into the lipidic bilayer of liposomes in a nonaggregated form. Liposomes may therefore be a suitable delivery system for this amphiphilic photosensitizer.


Expression of HbC and HbS, but not HbA, results in activation of K-Cl cotransport activity in transgenic mouse red cells.
Elevation of K-Cl cotransport in patients with homozygous hemoglobin (Hb) S or HbC increases red cell mean corpuscular hemoglobin concentration (MCHC) and contributes significantly to pathology. Elucidation of the origin of elevated K-Cl cotransport in red cells with mutant hemoglobins has been confounded by the concomitant presence of reticulocytes with high K-Cl cotransport. In red cells of control mice (C57BL), transgenic mice that express only human HbA, and transgenic mice that express both mouse globins and human HbS, volume stimulation is weak and insensitive to NO3- and dihydroindenyl-oxy-alkanoic acid (DIOA). DIOA and NO3- are inhibitors in all other mammalian red cells. In contrast, in knock-out mice expressing exclusively human hemoglobin HbC or HbS+ gamma, replacement of isotonic Cl- media by hypotonic Cl- resulted in strong volume stimulation and sensitivity to DIOA, okadaic acid, and NO3-. In summary, we find that HbC, under all conditions, and HbS+ gamma, in the absence of mouse globins, have significant quantitative and qualitative effects on K-Cl cotransport in mouse red cells and activate mouse K-Cl. We conclude that human globins are able to stimulate the activity and/or regulation of K-Cl cotransport in mouse red cells. These observations support the contention that HbS and HbC stimulate K-Cl cotransport in human red cells.


L-glutamine and whole protein restore first-phase insulin response and increase glucagon-like peptide-1 in type 2 diabetes patients.
L-glutamine triggers glucagon-like peptide-1 (GLP-1) release from L cells in vitro and when ingested pre-meal, decreases postprandial glycaemia and increases circulating insulin and GLP-1 in type 2 diabetes (T2D) patients. We aimed to evaluate the effect of oral L-glutamine, compared with whole protein low in glutamine, on insulin response in well-controlled T2D patients. In a randomized study with a crossover design, T2D patients (n = 10, 6 men) aged 65.1 ± 5.8, with glycosylated hemoglobin (HbA1c) 6.6% ± 0.7% (48 ± 8 mmol/mol), received oral L-glutamine (25 g), protein (25 g) or water, followed by an intravenous glucose bolus (0.3 g/kg) and hyperglycemic glucose clamp for 2 h. Blood was frequently collected for analyses of glucose, serum insulin and plasma total and active GLP-1 and area under the curve of glucose, insulin, total and active GLP-1 excursions calculated. Treatments were tested 1-2 weeks apart. Both L-glutamine and protein increased first-phase insulin response (p ≤ 0.02). Protein (p = 0.05), but not L-glutamine (p = 0.2), increased second-phase insulin response. Total GLP-1 was increased by both L-glutamine and protein (p ≤ 0.02). We conclude that oral L-glutamine and whole protein are similarly effective in restoring first-phase insulin response in T2D patients. Larger studies are required to further investigate the utility of similar approaches in improving insulin response in diabetes.


Vaccination coverage in the context of the emerging Yellow Fever threat in French Guiana.
French Guiana, a French overseas department located in South America between Brazil and Surinam, is the only European territory geographically located in the Amazonian forest complex and is considered endemic for yellow fever (YF). In the context of the emergent threat of YF in Latin America, we conducted a large household cross-sectional survey from June to October 2017 to estimate vaccination coverage in the population and to determine associations with sociodemographic and geographical characteristics. In total, 1,415 households and 2,697 individuals were included from the 22 municipalities of French Guiana. YF vaccination coverage was estimated at 95.0% (95% CI: 93.4-96.2) in the entire territory but was spatially heterogeneous, with the lowest levels estimated in the western part of the territory along the Surinamese cross-border region, particularly in children under 16 years who were not enrolled in school, immigrant adults and disadvantaged populations with low socioeconomic indexes. Despite the good vaccination coverage against YF in the general population of French Guiana resulting from the compulsory nature of YF vaccination for residents and travelers, there is an urgent need to improve vaccination coverage in vulnerable populations living in the northwestern part of the territory to limit the risk of transmission in the context of the emerging YF threat in South America. Despite the relative rarity of YF and the significant number of infectious and tropical diseases in French Guiana, clinicians should adopt a high index of suspicion for YF, particularly in vulnerable and at-risk populations.


Binding of benzodiazepines and some major metabolites at their sites in normal human frontal cortex in vitro.
Using [3H]flunitrazepam in radioligand binding assays, we determined equilibrium dissociation constants (Kd's) at 37 degrees C for 22 benzodiazepines (15 parent compounds and 7 major metabolites) at benzodiazepine binding sites in human frontal cortex. This list included several compounds never studied before at human receptors. Although dissociation was too rapid to measure reliably at this temperature, the Kd's for flunitrazepam were not significantly different when either rapid filtration or centrifugation was used to separate the bound from free radioligand. The most potent compound was triazolam (Kd = 0.54 nM); the least potent, chlordiazepoxide (Kd = 684 nM). The Kd's were significantly lower (about 3- to 7-fold) for several compounds tested at an equilibrium temperature of 0 degrees C compared to those obtained at 37 degrees C. There was a strong correlation for 15 compounds for the log Kd at rat brain receptors (data obtained from the literature) vs. the log Kd for human brain. In addition, the log Kd's of the various benzodiazepines for their receptor were significantly correlated with the log of their minimum daily dosages used to treat patients. Many of the benzodiazepines have clinically important active metabolites that have higher affinity for benzodiazepine binding sites in human brain than their parent compounds. Such data have important implications in the clinical use of these compounds.


Review of 11 national policies for rare diseases in the context of key patient needs.
Rare diseases collectively exert a global public health burden in the severity of their manifestations and the total number of people they afflict. For many patients, considerable barriers exist in terms of access to appropriate care, delayed diagnosis and limited or non-existing treatment options. Motivated by these challenges, the rare disease patient community has played a critical role, elevating the patient voice and mobilizing legislation to support the development of programs that address the needs of patients with rare diseases.The US Orphan Drug Act of 1983 served as a key milestone in this journey, providing a roadmap for other countries to introduce and implement similar orphan drug legislation; more recently, the European Union (EU) has gone further to encourage the widespread adoption and implementation of rare disease plans or strategies designed to more adequately address the comprehensive needs of patients with rare diseases. Despite these legislative efforts and the growing contributions of patient advocacy groups in moving forward implementation and adoption of rare disease programs, gaps still exist across the policy landscape for several countries. To gain deeper insights into the challenges and opportunities to address key needs of rare disease patients, it is critical to define the current status of rare disease legislation and policy across a geographically and economically diverse selection of countries. We analyzed the rare disease policy landscape across 11 countries: Germany, France, the United Kingdom, Canada, Bulgaria, Turkey, Argentina, Mexico, Brazil, China, and Taiwan. The status and implementation of policy was evaluated for each country in the context of key patient needs across 5 dimensions: improving coordination of care, diagnostic resources, access to treatments, patient awareness and support, and promoting innovative research. Our findings highlight the continuing role of the patient community in driving the establishment and adoption of legislation and programs to improve rare disease care. Further, we found that while national rare disease plans provide important guidance for improving care, implementation of plans is uneven across countries. More research is needed to demonstrate the effect of specific elements of rare disease plans on patient outcomes.


Effects of various fluoride solutions on enamel erosion in vitro.
The objective of this in vitro study was to investigate the effect of different fluoride solutions on enamel erosion. Human enamel specimens were pretreated with 1 of 10 different fluoride solutions (n = 20): TiF(4), NaF, AmF, ZnF(2), or SnF(2), each at native pH (pH range: 1.2-7.8) or buffered pH (pH = 4). The control group samples received no fluoride pretreatment. All samples were then eroded by citric acid (pH 2.6) for 6 x 1 min daily over 5 days. Between the erosive cycles, the samples were stored in artificial saliva. Erosion effects were investigated by surface profilometry (n = 10), scanning electron microscopy (n = 4), and energy-dispersive X-ray spectroscopy (n = 6) after fluoride pretreatment and after erosion. To test the effects of pH only, additional experiments were carried out with fluoride-free solutions at similar pH to that of fluoride solutions. In general, AmF solution was more effective in protecting enamel erosion compared to all other fluoride agents. However, the application of native TiF(4), native and buffered SnF(2), and native and buffered AmF solutions also resulted in significantly less enamel loss compared to the control group. A Ti-rich coating was formed after application of native TiF(4), but partially dissolved due to erosive attack. Samples pretreated with SnF(2) showed a significant increase in surface tin content. Surface fluoride concentration was significantly increased by native TiF(4), native and buffered AmF, buffered ZnF(2), and buffered NaF application. Under the current experimental setting, the fluoride agents at lower pH had better protective potential. Highly concentrated TiF(4), AmF, and SnF(2) solution was effective in inhibiting erosion of enamel.


Cost-effectiveness analysis of recurrence score-guided treatment using a 21-gene assay in early breast cancer.
Most guidelines for hormone receptor (HR)-positive early breast cancer recommend addition of adjuvant chemotherapy for most women, leading to overtreatment, which causes considerable morbidity and cost. There has been recent incorporation of gene expression analysis in aiding decision making. We evaluated the cost-effectiveness of recurrence score (RS)-guided treatment using 21-gene assay as compared with treatment guided by the Adjuvant! Online program (AOL). A Markov model was developed to compare the cost-effectiveness of treatment guided either by 21-gene assay or by AOL in a 50-year-old woman with lymph node-negative HR-positive breast cancer over a lifetime horizon. We assumed that women classified to be at high risk all received chemotherapy followed by tamoxifen and those classified to be at low risk received tamoxifen only. The model took a health care payer's perspective with results reported in 2008 Canadian dollars ($). Event rates, costs, and utilities were derived from the literature. Both costs and benefits were discounted at 5%. Outcome measures were life years gained, quality-adjusted life years (QALYs), lifetime costs, and incremental cost-effectiveness ratios (ICERs). For a 50-year-old woman, RS-guided treatment was associated with an incremental lifetime cost of $4,102 and a gain in 0.065 QALY, with an ICER of $63,064 per QALY compared with AOL-guided treatment. ICER increased with increasing cost of 21-gene assay and increasing age of patients. Results were most sensitive to probabilities relating to risk categorization and recurrence rate. The 21-gene assay appears cost-effective from a Canadian health care perspective.


Viruses and vestibular neuritis: review of human and animal studies.
There is increasing evidence in man and animals that several human viruses can damage the vestibular labyrinth. Clinical and serologic studies of patients with vestibular neuritis suggest that the viruses may play a role in the pathogenesis of this disease. Temporal bone studies of patients dying after vestibular neuritis have found maximal damage in the distal branches of the vestibular nerve. These changes are felt to be consistent with a viral etiology. No satisfactory animal viral model of vestibular neuritis currently exists. However, animal studies have demonstrated that several human viruses including rubeola, herpes simplex, reovirus, mouse and guinea pig cytomegalovirus, and neurotropic strains of influenza A and mumps virus, can infect the vestibular nerve and the vestibular membranous labyrinth.


Geographic variation in the community structure of lice on western scrub-jays.
Parasites are incredibly diverse. An important factor in the evolution of this diversity is the fact that many parasite species are restricted to 1, or just a few, host species. In addition, some parasites exhibit geographic specificity that is nested within their specificity to a particular species of host. The environmental factors that restrict parasites to particular regions within the host's range are poorly understood, and it is often difficult to know whether such patterns of geographic specificity are real, or merely artifacts of uneven host sampling. For over a decade, we sampled communities of ectoparasitic lice (Phthiraptera) from western scrub-jays (Aphelocoma californica) throughout their range in the United States, and found 3 common species of lice. Philopterus crassipes was found throughout the host range, whereas the other 2 species of lice had more restricted distributions. Brueelia deficiens was found only on the woodhouseii host subspecies group, and Myrsidea sp. was found largely on the californica host subspecies group. We suggest that differential tolerance to arid conditions and interspecific competition has led to the restricted geographic distributions of these 2 species of lice.


There is no such thing like a single ACL injury: Profiles of ACL-injured patients.
Current ACL registries rarely include non-operatively treated patients thus delivering an incomplete picture of the ACL-injured population. The aim of this study was to get an image of the population and treatment decision of an intrahospital registry. Our hypotheses were that patient-specific subtypes can be identified and that the percentage of operated patients differs between them. Three hundred and forty-six operated and non-operated patients were included from March 2011 to December 2013. Standardized questionnaires allowed for data collection on gender, age, sports practice and previous ACL injuries. Chi-square tests allowed to compare these parameters between genders and age groups. A cluster analysis was computed to determine profiles of patients with similar characteristics. Three age groups were considered (I: ≤20; II: 21-35; III: ≥36 years). For males, the highest frequency of injuries was noted in group II with a greater proportion of injuries compared to females. In group III, more females were injured than males. Before injury, 54% patients were involved in competitive sports. Males were more likely to be injured in pivoting/contact sports before 35 and females during recreational skiing after 35. Twenty-one percent of the patients had had a previous ACL injury. The percentage of surgical treatment was superior to 80% in patients under 35 years involved in competitive sports, of 60-80% for those not involved in competitive sports and inferior to 60% for patients above 35 years. Systematic data collection allowed to identify specific subtypes of ACL-injured patient according to gender, age, previous ACL injury and preinjury level of practice. The decision-making process for or against ACL reconstructions at time of presentation depended on these characteristics. Consideration of these parameters will serve as a basis for an individualized treatment approach and a better understanding of patients at risk for ACL injuries. III.


Reliable selection of the number of fascicles in diffusion images by estimation of the generalization error.
A number of diffusion models have been proposed to overcome the limitations of diffusion tensor imaging (DTI) which cannot represent multiple fascicles with heterogeneous orientations at each voxel. Among them, generative models such as multi-tensor models, CHARMED or NODDI represent each fascicle with a parametric model and are of great interest to characterize and compare white matter properties. However, the identification of the appropriate model, and particularly the estimation of the number of fascicles, has proven challenging. In this context, different model selection approaches have been proposed to identify the number of fascicles at each voxel. Most approaches attempt to maximize the quality of fit while penalizing complex models to avoid overfitting. However, the choice of a penalization strategy and the trade-off between penalization and quality of fit are rather arbitrary and produce highly variable results. In this paper, we propose for the first time to determine the number of fascicles at each voxel by assessing the generalization error. This criterion naturally prevents overfitting by comparing how the models predict new data not included in the model estimation. Since the generalization error cannot be directly computed, we propose to estimate it by the 632 bootstrap technique which has low bias and low variance. Results on synthetic phantoms and in vivo data show that our approach performs better than existing techniques, and is robust to the choice of decision threshold. Together with generative models of the diffusion signal, this technique will enable accurate identification of the model complexity at each voxel and accurate assessment of the white matter characteristics.


The prevalence and clinical associations of mood instability in adults living in England: results from the Adult Psychiatric Morbidity Survey 2007.
Mood instability is underinvestigated but potentially clinically important. This study aimed to describe the prevalence of mood instability in adults living in England and test whether it is important in explaining the extent of symptoms of common mental disorders, suicidality and healthcare use. An analysis of data from the adult psychiatric morbidity survey 2007, a household survey of private households in England (N=7403), was completed. The prevalence of mood instability was 13.9%. In univariate analysis it was strongly associated with socio-demographic and clinical variables. In regression modelling mood instability was independently associated with non-psychotic psychopathology, increasing the odds by 9.89. It was also linked with suicidal ideas (odds ratios (OR): 2.04) but not suicidal acts, and associated with being in receipt of medication, counselling or therapy for mental health problems (OR: 1.88), independent of a diagnosis of borderline personality disorder. Mood instability is relatively common in the adult population, occurs frequently in common mental disorders and appears to be an important symptom in its own right. It is associated with two important measures in psychiatry, namely suicidal thinking and healthcare service use. It warrants more widespread recognition and further research is required to understand if, when and how to intervene.