Reversible unfolding of single RNA molecules by mechanical force.
Here we use mechanical force to induce the unfolding and refolding of single RNA molecules: a simple RNA hairpin, a molecule containing a three-helix junction, and the P5abc domain of the Tetrahymena thermophila ribozyme. All three molecules (P5abc only in the absence of Mg2+) can be mechanically unfolded at equilibrium, and when kept at constant force within a critical force range, are bi-stable and hop between folded and unfolded states. We determine the force-dependent equilibrium constants for folding/unfolding these single RNA molecules and the positions of their transition states along the reaction coordinate.


Anticoagulant drugs in noncompaction: a mandatory therapy?
Noncompaction of left ventricular myocardium is a rare congenital cardiomyopathy resulting from an incomplete myocardial morphogenesis that leads to the persistence of the embryonic myocardium. This condition is characterized by a thin compacted epicardial and an extremely thickened endocardial layer with prominent trabeculations and deep intertrabecular recesses. It is not clear, in noncompaction of myocardium, whether intertrabecular recesses could be responsible for thrombi formation and thromboembolic complications. The prevalence of stroke and echocardiographic finding of thrombus was evaluated in a continuous series of 229 patients (men and women) affected by noncompaction of the left ventricular myocardium, who were included in the SIEC registry. We excluded patients affected by atrial fibrillation. The mean age of the patients was 49.5 years. Fifty percent of the patients were affected by a ventricular systolic dysfunction. The mean period of follow-up was 7.3 years. Only four patients had a history of ischemic stroke. A large thrombus into the left ventricular chamber was observed in a 1-year-old child affected by Behcet's disease (high risk of thrombi formation). Noncompaction of the left ventricular myocardium, by itself, does not seem to be a risk factor for stroke or embolic results, so there is no indication for oral anticoagulant therapy.


Photon-efficient imaging with a single-photon camera.
Reconstructing a scene's 3D structure and reflectivity accurately with an active imaging system operating in low-light-level conditions has wide-ranging applications, spanning biological imaging to remote sensing. Here we propose and experimentally demonstrate a depth and reflectivity imaging system with a single-photon camera that generates high-quality images from ∼1 detected signal photon per pixel. Previous achievements of similar photon efficiency have been with conventional raster-scanning data collection using single-pixel photon counters capable of ∼10-ps time tagging. In contrast, our camera's detector array requires highly parallelized time-to-digital conversions with photon time-tagging accuracy limited to ∼ns. Thus, we develop an array-specific algorithm that converts coarsely time-binned photon detections to highly accurate scene depth and reflectivity by exploiting both the transverse smoothness and longitudinal sparsity of natural scenes. By overcoming the coarse time resolution of the array, our framework uniquely achieves high photon efficiency in a relatively short acquisition time.


Association of Coffee and Tea Intake with the Oral Microbiome: Results from a Large Cross-Sectional Study.
Background: The oral microbiota play a central role in oral health, and possibly in carcinogenesis. Research suggests that coffee and tea consumption may have beneficial health effects. We examined the associations of these common beverages with the oral ecosystem in a large cross-sectional study.Methods: We assessed oral microbiota in mouthwash samples from 938 participants in two U.S. cohorts using 16S rRNA gene sequencing. Coffee and tea intake were assessed from food frequency questionnaires. We examined associations of coffee and tea intake with overall oral microbiota diversity and composition using linear regression and permutational MANOVA, respectively, and with taxon abundance using negative binomial generalized linear models; all models adjusted for age, sex, cohort, body mass index, smoking, ethanol intake, and energy intake.Results: Higher tea intake was associated with greater oral microbiota richness (P = 0.05) and diversity (P = 0.006), and shifts in overall community composition (P = 0.002); coffee was not associated with these microbiome parameters. Tea intake was associated with altered abundance of several oral taxa; these included Fusobacteriales, Clostridiales, and Shuttleworthia satelles (higher with increasing tea) and Bifidobacteriaceae, Bergeyella, Lactobacillales, and Kingella oralis (lower with increasing tea). Higher coffee intake was only associated with greater abundance of Granulicatella and Synergistetes.Conclusions: In the largest study to date of tea and coffee consumption in relation to the oral microbiota, the microbiota of tea drinkers differed in several ways from nondrinkers.Impact: Tea-driven changes to the oral microbiome may contribute to previously observed associations between tea and oral and systemic diseases, including cancers. Cancer Epidemiol Biomarkers Prev; 27(7); 814-21. ©2018 AACR.


Using matrix peaks to map topography: increased mass resolution and enhanced sensitivity in chemical imaging.
It is well known in secondary ion mass spectrometry (SIMS) that sample topography leads to decreased mass resolution. Specifically, the ion's time of flight is dependent on where it was generated. Here, using matrix-enhanced SIMS, it is demonstrated that, in addition to increasing the yield of intact pseudomolecular ions, the matrix allows the user to semiquantitatively record the topography of a sample. Through mapping the topography-related mass shifts of the matrix (which leads to decreased mass resolution), the analogous mass shifts of higher mass ions can be deconvoluted and higher resolution and greater sensitivity obtained. Furthermore, the semiquantitative topographical map obtained can be compared with any chemical images obtained, allowing the user to quickly ascertain whether local intensity maximums are due to topological features or represent genuine features of interest.


The Relationship Between Green Space and Prosocial Behaviour Among Children and Adolescents: A Systematic Review.
The plausible role of nearby green space in influencing prosocial behaviour among children and adolescents has been studied recently. However, no review has been conducted of the evidence testing the association between green space and prosocial behaviour. This systematic review addresses this gap among children and adolescents. Within this review, we propose a conceptual framework describing potential pathways linking green space to prosocial behaviour, discuss the direction, magnitude, moderators, and mediators of the association, and develop a narrative synthesis of future study directions. Out of 63 extracted associations from 15 studies, 44 were in the positive or expected direction, of which 18 were reported to be statistically significant (p < 0.05). Overall, the current evidence shows that exposure to green space may potentially increase prosocial behaviour among children and adolescents, with some contingencies (e.g., child's sex and ethnic background). However, the volume and quality of this evidence is not yet sufficient to draw conclusions on causality. Further, heterogeneity in the indicators of green space exposure could lead to mixed findings. In addition, none of the included studies investigated potential mediators. Nevertheless, this review provides preliminary evidence and a basis for further investigation with rigorous study methodology capable of drawing causal inferences and testing potential effect modifiers, linking pathways, and relevant green space measures.


Phase-independent rhythmic analysis of genome-wide expression patterns.
We introduce a model-based analysis technique for extracting and characterizing rhythmic expression profiles from genome-wide DNA microarray hybridization data. These patterns are clues to discovering rhythmic genes implicated in cell-cycle, circadian, or other biological processes. The algorithm, implemented in a program called RAGE (Rhythmic Analysis of Gene Expression), decouples the problems of estimating a pattern's wavelength and phase. Our algorithm is linear-time in frequency and phase resolution, an improvement over previous quadratic-time approaches. Unlike previous approaches, RAGE uses a true distance metric for measuring expression profile similarity, based on the Hausdorff distance. This results in better clustering of expression profiles for rhythmic analysis. The confidence of each frequency estimate is computed using Z-scores. We demonstrate that RAGE is superior to other techniques on synthetic and actual DNA microarray hybridization data. We also show how to replace the discretized phase search in our method with an exact (combinatorially precise) phase search, resulting in a faster algorithm with no complexity dependence on phase resolution.


Statistical issues in the analysis of Illumina data.
Illumina bead-based arrays are becoming increasingly popular due to their high degree of replication and reported high data quality. However, little attention has been paid to the pre-processing of Illumina data. In this paper, we present our experience of analysing the raw data from an Illumina spike-in experiment and offer guidelines for those wishing to analyse expression data or develop new methodologies for this technology. We find that the local background estimated by Illumina is consistently low, and subtracting this background is beneficial for detecting differential expression (DE). Illumina's summary method performs well at removing outliers, producing estimates which are less biased and are less variable than other robust summary methods. However, quality assessment on summarised data may miss spatial artefacts present in the raw data. Also, we find that the background normalisation method used in Illumina's proprietary software (BeadStudio) can cause problems with a standard DE analysis. We demonstrate that variances calculated from the raw data can be used as inverse weights in the DE analysis to improve power. Finally, variability in both expression levels and DE statistics can be attributed to differences in probe composition. These differences are not accounted for by current analysis methods and require further investigation. Analysing Illumina expression data using BeadStudio is reasonable because of the conservative estimates of summary values produced by the software. Improvements can however be made by not using background normalisation. Access to the raw data allows for a more detailed quality assessment and flexible analyses. In the case of a gene expression study, data can be analysed on an appropriate scale using established tools. Similar improvements can be expected for other Illumina assays.


Mesenchymal stem cell: does it work in an experimental model with acute respiratory distress syndrome?
We hypothesized that bone marrow-derived mesenchymal stem cells (BM-MSCs) would have a possible role in the treatment of acute respiratory distress syndrome (ARDS). ARDS disease model was developed in Wistar albino male rats by intratracheal instillation of physiological saline solution. Anesthezied and tracheotomized rats (n = 8) with ARDS were pressure-controlled ventilated. Isolated and characterized rat (r-) BM-MSCs were labeled with GFP gene, and introduced in the lungs of the ARDS rat-model. After applying of MSCs, the life span of each rat was recorded. When rats died, their lung tissues were removed for histopathological examination. Also the tissue sections were analyzed for GFP labeled rBM-MSCs and stained for vimentin, CK19, proinflammatory (MPO, IL-1β, IL-6 and MIP-2) and anti-inflammatory [IL-1ra and prostaglandin E2 receptor (EP3)] cytokines. The histopathological signs of rat-model ARDS were similar to the acute phase of ARDS in humans. rBM-MSCs were observed to home in lung paranchyma. Although the infiltration of neutrophils slightly decreased in the interalveolar, peribronchial and perivascular area, a notable improvement was determined in the degree of hemorrhage, edema and hyaline membrane formation in rats treated with rBM-MSCs. Also decreased proinflammatory cytokines levels and increased the intensity of anti-inflammatory cytokines were established. Therefore MSCs could promote alveolar epithelial repair by mediating of cytokines from a proinflammatory to an anti-inflammatory response. As a novel therapeutic approach, mesenchymal stem cell treatment with intratracheal injection could be helpful in the management of critically ill patients with ARDS.


Neural substrates of implicit cueing effect on prospective memory.
Functional magnetic resonance imaging was used to examine the maintenance of intentions during an ongoing task involving implicit cues. Participants were required to detect target words while engaging in the ongoing task. Cues matched to the target category and cues matched to the action for targets were presented implicitly during the ongoing task. Implicit categorical target cues were found to enhance prospective memory performance, and implicit action cues accelerated responses more than irrelevant implicit cues in the prospective memory task. We found increased caudal anterior cingulate cortex (cACC) activity during the ongoing task with both implicit target and action cues, suggesting that alertness or preparatory attentional processes were strengthened by implicit cues. Implicit target cues elicited enhanced activity in the lateral anterior prefrontal cortex (Brodmann's area 10), which may be involved in dual processing of the ongoing task and the maintained intention. These results suggest that implicit cues may boost primitive attention toward an intended action and may be accessible to off-line maintenance. The facilitation of prospective target detection and the action execution by target cues were associated with increased supplementary motor area (SMA) activity. In contrast, we found enhanced premotor cortex (PMC) activation with action cue during the prospective memory task, suggesting that the PMC may be involved in stimulus-induced and rather automatic action. These results demonstrate the effectiveness of implicit cues for examining the maintenance of intention. Overall, we found that implicit target cues can facilitate prospective memory performance, and implicit action cues can accelerate responses. The above-mentioned neural underpinnings suggest that attentional and motor control processes are involved in the enhancement of prospective memory.


Apolipoprotein E genotype and the diagnostic accuracy of cerebrospinal fluid biomarkers for Alzheimer disease.
Several studies suggest that the apolipoprotein E (APOE) ε4 allele modulates cerebrospinal fluid (CSF) levels of β-amyloid 42 (Aβ42). Whether this effect is secondary to the association of the APOE ε4 allele with cortical Aβ deposition or whether APOE ε4 directly influences CSF levels of Aβ42 independently of Aβ pathology remains unknown. To evaluate whether the APOE genotype affects the diagnostic accuracy of CSF biomarkers for Alzheimer disease (AD), in particular Aβ42 levels, and whether the association of APOE ε4 with CSF biomarkers depends on cortical Aβ status. We collected data from 4 different centers in Sweden, Finland, and Germany. Cohort A consisted of 1345 individuals aged 23 to 99 years with baseline CSF samples, including 309 with AD, 287 with prodromal AD, 399 with stable mild cognitive impairment, 99 with dementias other than AD, and 251 controls. Cohort B included 105 nondemented younger individuals (aged 20-34 years) with CSF samples available. Cohort C included 118 patients aged 60 to 80 years with mild cognitive symptoms who underwent flutemetamol F 18 ([18F]flumetamol) positron emission tomography amyloid imaging and CSF tap. Standard care. Cerebrospinal fluid levels of Aβ42 and total and phosphorylated tau in relation to the APOE ε2/ε3/ε4 polymorphism in different diagnostic groups and in cases with or without cortical uptake of [18F]flutemetamol. The CSF levels of Aβ42 but not total and phosphorylated tau were lower in APOE ε4 carriers compared with noncarriers irrespective of diagnostic group (cohort A). Despite this, CSF levels of Aβ42 differed between participants with AD when compared with controls and those with stable mild cognitive impairment, even when stratifying for APOE genotype (P < .001 to P = .006). Multiple binary logistic regression revealed that CSF levels of Aβ42 and APOE ε4 genotype were independent predictors of AD diagnosis. In cohort B, APOE ε4 carrier status did not influence CSF levels of Aβ42. Moreover, when stratifying for cortical uptake of [18F]flutemetamol in cohort C, APOE ε4 genotype did not influence CSF levels of Aβ42. This result was replicated in a cohort with individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) using carbon 11-labeled Pittsburgh Compound B scanning. Cerebrospinal fluid levels of Aβ42 are strongly associated with the diagnosis of AD and cortical Aβ accumulation independent of APOE genotype. The clinical cutoff for CSF levels of Aβ42 should be the same for all APOE genotypes.


A rare case of fetal extensive intracranial hemorrhage and whole-cerebral hypoplasia due to latent maternal vitamin K deficiency.
We present here a late preterm infant with extensive brain lesions resulting from vitamin K deficiency. A female infant was born after 35 weeks of gestation by emergent cesarean section because of non-reassuring fetal status. Her mother had severe eating disorder and recurrent vomiting since early pregnancy. She was immediately intubated and ventilated because she was extremely pale, hypotonic, and non-reactive. Cerebral magnetic resonance imaging immediately after birth showed intraparenchymal hemorrhage in the left frontal lobe and cerebellum, marked cerebral edema, and cerebellar hypoplasia. Coagulation studies of the infant showed hepaplastin test <5%, prolonged PT and APTT, and a marked elevation of protein induced by vitamin K absence or antagonist-II. This case highlighted a potential risk of intracranial bleeding due to maternal vitamin K deficiency and difficulty in its prediction before delivery. Vitamin K supplementation to high risk mothers might be indispensable for preventing severe fetal vitamin K deficiency. Even when coagulation studies in mothers is normal, it is imperative to provide vitamin K supplementation for total protection.


Primary care multidisciplinary teams in practice: a qualitative study.
Current recommendations for strengthening the US healthcare system consider restructuring primary care into multidisciplinary teams as vital to improving quality and efficiency. Yet, approaches to the selection of team designs remain unclear. This project describes current primary care team designs, primary care professionals' perceptions of ideal team designs, and perceived facilitating factors and barriers to implementing ideal team-based care. Qualitative study of 44 health care professionals at 6 primary care practices in North Carolina using focus group discussions and surveys. Data was analyzed using framework content analysis. Practices used a variety of multidisciplinary team designs with the specific design being influenced by the social and policy context in which practices were embedded. Practices overwhelmingly located barriers to adopting ideal multidisciplinary teams as being outside of their individual practices and outside of their control. Participants viewed internal organizational contexts as the major facilitators of multidisciplinary primary care teams. The majority of practices described their ideal team design as including a social worker to meet the needs of socially complex patients. Primary care multidisciplinary team designs vary across practices, shaped in part by contextual factors perceived as barriers outside of the practices' control. Facilitating factors within practices provide a culture of support to team members, but they are insufficient to overcome the perceived barriers. The common desire to add social workers to care teams reflects practices' struggles to meet the complex demands of patients and external agencies. Government or organizational policies should avoid one-size-fits-all approaches to multidisciplinary care teams, and instead allow primary care practices to adapt to their specific contextual circumstances.


Animal-assisted therapy and agitation and depression in nursing home residents with dementia: a matched case-control trial.
To investigate the efficacy of animal-assisted therapy (AAT) on symptoms of agitation/aggression and depression in nursing home residents with dementia in a randomized controlled trial. Previous studies have indicated that AAT has beneficial effects on neuropsychiatric symptoms in various psychiatric disorders but few studies have investigated the efficacy of AAT in patients suffering from dementia. Of 65 nursing home residents with dementia (mean [standard deviation] age: 81.8 [9.2] years; mean Mini-Mental State Examination score: 7.1 [0.7]), 27 matched pairs (N = 54) were randomly assigned to either treatment as usual or treatment as usual combined with AAT, administered over 10 weekly sessions. Blinded raters assessed cognitive impairment with the Mini-Mental State Examination, presence of agitation/aggression with the Cohen-Mansfield Agitation Inventory, and depression with the Dementia Mood Assessment Scale at baseline and during a period of 4 weeks after AAT intervention. In the control group, symptoms of agitation/aggression and depression significantly increased over 10 weeks; in the intervention group, patients receiving combined treatment displayed constant frequency and severity of symptoms of agitation/aggression (F1,48 = 6.43; p <0.05) and depression (F1,48 = 26.54; p <0.001). Symptom amelioration did not occur in either group. AAT is a promising option for the treatment of agitation/aggression and depression in patients with dementia. Our results suggest that AAT may delay progression of neuropsychiatric symptoms in demented nursing home residents. Further research is needed to determine its long-time effects.


Geographic origins and population genetics of bats killed at wind-energy facilities.
An unanticipated impact of wind-energy development has been large-scale mortality of insectivorous bats. In eastern North America, where mortality rates are among the highest in the world, the hoary bat (Lasiurus cinereus) and the eastern red bat (L. borealis) comprise the majority of turbine-associated bat mortality. Both species are migratory tree bats with widespread distributions; however, little is known regarding the geographic origins of bats killed at wind-energy facilities or the diversity and population structure of affected species. We addressed these unknowns by measuring stable hydrogen isotope ratios (δ2 H) and conducting population genetic analyses of bats killed at wind-energy facilities in the central Appalachian Mountains (USA) to determine the summering origins, effective size, structure, and temporal stability of populations. Our results indicate that ~1% of hoary bat mortalities and ~57% of red bat mortalities derive from non-local sources, with no relationship between the proportion of non-local bats and sex, location of mortality, or month of mortality. Additionally, our data indicate that hoary bats in our sample consist of an unstructured population with a small effective size (Ne ) and either a stable or declining history. Red bats also showed no evidence of population genetic structure, but in contrast to hoary bats, the diversity contained in our red bat samples is consistent with a much larger Ne that reflects a demographic expansion after a bottleneck. These results suggest that the impacts of mortality associated with intensive wind-energy development may affect bat species dissimilarly, with red bats potentially better able to absorb sustained mortality than hoary bats because of their larger Ne . Our results provide important baseline data and also illustrate the utility of stable isotopes and population genetics for monitoring bat populations affected by wind-energy development.


A novel binary matrix consisting of graphene oxide and caffeic acid for the analysis of scutellarin and its metabolites in mouse kidney by MALDI imaging.
Although the in vivo metabolic pathways of scutellarin, a traditional Chinese medicine, have been investigated via different liquid chromatography techniques, studies on the distribution and location of scutellarin within organ tissue sections have not been reported. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) can generate in situ spatial distribution profiles for scutellarin and its metabolites in a kidney section. However, the direct detection of a small molecule (m/z < 600) using conventional matrices often results in ion suppression and matrix interferences. In this study, we demonstrated a novel methodology using MALDI-MSI for the in situ spatial localization of scutellarin and its metabolites in kidney tissues by applying a binary matrix of graphene oxide (GO) and caffeic acid (CA). The results indicated that the binary matrix (GO/CA) significantly improved the detection efficiency of scutellarin and its metabolites with relatively high sensitivity, selectivity and reproducibility on tissue sections. This methodology was successfully applied to map scutellarin and its metabolites with MALDI-MSI in mouse kidney tissues. Specifically, scutellarin and scutellarein were found to be located in the cortex and medulla regions of the kidney with relatively high abundance, whereas the remaining metabolites appeared in the cortex with low abundance. We believe that the novel imaging methodology may also be used for the studies of cancerous tissues and inform the development of the future therapies of kidney tumors.


Bayesian approach to feature selection and parameter tuning for support vector machine classifiers.
A Bayesian point of view of SVM classifiers allows the definition of a quantity analogous to the evidence in probabilistic models. By maximizing this one can systematically tune hyperparameters and, via automatic relevance determination (ARD), select relevant input features. Evidence gradients are expressed as averages over the associated posterior and can be approximated using Hybrid Monte Carlo (HMC) sampling. We describe how a Nyström approximation of the Gram matrix can be used to speed up sampling times significantly while maintaining almost unchanged classification accuracy. In experiments on classification problems with a significant number of irrelevant features this approach to ARD can give a significant improvement in classification performance over more traditional, non-ARD, SVM systems. The final tuned hyperparameter values provide a useful criterion for pruning irrelevant features, and we define a measure of relevance with which to determine systematically how many features should be removed. This use of ARD for hard feature selection can improve classification accuracy in non-ARD SVMs. In the majority of cases, however, we find that in data sets constructed by human domain experts the performance of non-ARD SVMs is largely insensitive to the presence of some less relevant features. Eliminating such features via ARD then does not improve classification accuracy, but leads to impressive reductions in the number of features required, by up to 75%.


Non-linear interactions between consumers and flow determine the probability of plant community dominance on Maine rocky shores.
Although consumers can strongly influence community recovery from disturbance, few studies have explored the effects of consumer identity and density and how they may vary across abiotic gradients. On rocky shores in Maine, recent experiments suggest that recovery of plant- or animal- dominated community states is governed by rates of water movement and consumer pressure. To further elucidate the mechanisms of consumer control, we examined the species-specific and density-dependent effects of rocky shore consumers (crabs and snails) on community recovery under both high (mussel dominated) and low flow (plant dominated) conditions. By partitioning the direct impacts of predators (crabs) and grazers (snails) on community recovery across a flow gradient, we found that grazers, but not predators, are likely the primary agent of consumer control and that their impact is highly non-linear. Manipulating snail densities revealed that herbivorous and bull-dozing snails (Littorina littorea) alone can control recovery of high and low flow communities. After ∼1.5 years of recovery, snail density explained a significant amount of the variation in macroalgal coverage at low flow sites and also mussel recovery at high flow sites. These density-dependent grazer effects were were both non-linear and flow-dependent, with low abundance thresholds needed to suppress plant community recovery, and much higher levels needed to control mussel bed development. Our study suggests that consumer density and identity are key in regulating both plant and animal community recovery and that physical conditions can determine the functional forms of these consumer effects.


Multidisciplinary care for stroke patients living in the community: a systematic review.
A systematic review of randomized controlled trials was performed to evaluate the effectiveness of multidisciplinary care for stroke patients living in the community. Databases PubMed, EMBASE, CINAHL and the Cochrane Library from January 1980 until July 2012. Randomized controlled trials focused on multidisciplinary interventions for stroke patients living at home after hospitalization or inpatient rehabilitation were selected. The outcome domains were activities of daily living, social participation and quality of life. A total of 14 studies were included. Two authors independently extracted the data and independently assessed the quality of reporting of the included studies using the Consolidated Standards of Reporting Trials (CONSORT) statement 2010. None of the studies showed favourable effects of the intervention on activities of daily living and none assessed social participation. Furthermore, two studies reported favourable effects of the intervention in terms of quality of life. These concerned an intervention combining assessment with follow-up care and a rehabilitation intervention. There is little evidence for the effectiveness of multidisciplinary care for stroke patients being discharged home. Additional research should provide more insight into potentially effective multidisciplinary care for community-living stroke patients.


Adherence to oral antibiotic therapy in patients with bone and joint infection: A pilot study.
The management of bone and joint infections (BJI) is complex and requires prolonged antimicrobial therapy. Few data exist on adherence to anti-infectious treatment other than HIV, and none on BJI, even though compliance is considered as a major determinant of clinical outcome. This work aimed at evaluating adherence to oral antimicrobial treatment in patients with BJI. This is a prospective observational blinded pilot study evaluating adherence by a 6-item questionnaire at 6 weeks (W6) and 3 months (M3) post-surgery. The primary endpoint was the proportion of patients with high, moderate and poor adherence at W6. Secondary endpoints included change in adherence between W6 and M3, and the exploration of potential variables influencing adherence. Analysis was performed on 65 questionnaires obtained from 43 patients including 35 with device-associated BJI. At W6, 11 out of 34 patients were highly adherent to oral antibiotic therapy, 22 moderately adherent and 1 poorly adherent. There was no significant change in adherence to antibiotic therapy between W6 and M3. The only variable significantly associated with the level of adherence at W6 and M3 was the number of daily doses of antibiotic (P=0.04 and 0.02 at W6 and M3, respectively). This study provided a snapshot of patients' adherence in BJI. Adherence to antibiotic therapy appeared to be stable up to 3 months and a higher number of daily doses of antibiotic was associated with poorer adherence. These observations need to be confirmed in future large-scale studies using electronic pill monitoring systems.


Dental lamina as source of odontogenic stem cells: evolutionary origins and developmental control of tooth generation in gnathostomes.
This study considers stem cells for odontogenic capability in biological tooth renewal in the broad context of gnathostome dentitions and the derivation of them from oral epithelium. The location of the developmental site and cell dynamics of the dental lamina are parameters of a possible source for odontogenic epithelial stem cells, but the phylogenetic history is not known. Understanding the phylogenetic basis for stem cell origins throughout continuous tooth renewal in basal jawed vertebrates is the ultimate objective of this study. The key to understanding the origin and location of stem cells in the development of the dentition is sequestration of stem cells locally for programmed tooth renewal. We suggest not only the initial pattern differences in each dentate field but local control subsequently for tooth renewal within each family. The role of the specialized odontogenic epithelium (odontogenic band) is considered as that in which the stem cells reside and become partitioned. These regulate time, position and shape in sequential tooth production. New histological data for chondrichthyan fish show first a thickening of the oral epithelium (odontogenic band). After this, all primary and successive teeth are only generated deep to the oral epithelium from a dental lamina. In contrast, in osteichthyan fish the first teeth develop directly within the odontogenic band. In addition, successors are initiated at each tooth site in the predecessor tooth germ (without a dental lamina). We suggest that stem cells specified for each tooth family are set up and located in intermediate cells between the outer and inner dental epithelia.


Longitudinal PET imaging demonstrates biphasic CAR T cell responses in survivors.
Clinical monitoring of adoptive T cell transfer (ACT) utilizes serial blood analyses to discern T cell activity. While useful, these data are 1-dimensional and lack spatiotemporal information related to treatment efficacy or toxicity. We utilized a human genetic reporter, somatostatin receptor 2 (SSTR2), and PET, to quantitatively and longitudinally visualize whole-body T cell distribution and antitumor dynamics using a clinically approved radiotracer. Initial evaluations determined that SSTR2-expressing T cells were detectable at low densities with high sensitivity and specificity. SSTR2-based PET was applied to ACT of chimeric antigen receptor (CAR) T cells targeting intercellular adhesion molecule-1, which is overexpressed in anaplastic thyroid tumors. Timely CAR T cell infusions resulted in survival of tumor-bearing mice, while later infusions led to uniform death. Real-time PET imaging revealed biphasic T cell expansion and contraction at tumor sites among survivors, with peak tumor burden preceding peak T cell burden by several days. In contrast, nonsurvivors displayed unrelenting increases in tumor and T cell burden, indicating that tumor growth was outpacing T cell killing. Thus, longitudinal PET imaging of SSTR2-positive ACT dynamics enables prognostic, spatiotemporal monitoring with unprecedented clarity and detail to facilitate comprehensive therapy evaluation with potential for clinical translation.


Cytokinin oxidase PpCKX1 plays regulatory roles in development and enhances dehydration and salt tolerance in Physcomitrella patens.
PpCKX1 localizes to vacuoles and is dominantly expressed in the stem cells. PpCKX1 regulates developmental changes with increased growth of the rhizoid and enhances dehydration and salt tolerance. Cytokinins (CKs) are plant hormones that regulate plant development as well as many physiological processes, such as cell division, leaf senescence, control of shoot/root ratio, and reproductive competence. Cytokinin oxidases/dehydrogenases (CKXs) control CK concentrations by degradation, and thereby influence plant growth and development. In the moss Physcomitrella patens, an evolutionarily early divergent plant, we identified six putative CKXs that, by phylogenetic analysis, form a monophyletic clade. We also observed that ProPpCKX1:GUS is expressed specifically in the stem cells and surrounding cells and that CKX1 localizes to vacuoles, as indicated by Pro35S:PpCKX1-smGFP. Under normal growth conditions, overexpression of PpCKX1 caused many phenotypic changes at different developmental stages, and we suspected that increased growth of the rhizoid could affect those changes. In addition, we present evidence that the PpCKX1-overexpressor plants show enhanced dehydration and salt stress tolerance. Taken together, we suggest that PpCKX1 plays regulatory roles in development and adaptation to abiotic stresses in this evolutionarily early land plant species.


Case report: type 1 diabetes in monozygotic quadruplets.
Type 1 diabetes (T1D) is an autoimmune disease characterized by the lack of insulin due to an autoimmune destruction of pancreatic beta cells. Here, we report a unique case of a family with naturally conceived quadruplets in which T1D was diagnosed in two quadruplets simultaneously. At the same time, the third quadruplet was diagnosed with the pre-diabetic stage. Remarkably, all four quadruplets were positive for anti-islet cell antibodies, GAD65 and IA-A2. Monozygotic status of the quadruplets was confirmed by testing 14 different short tandem repeat polymorphisms. Serological examination confirmed that all quadruplets and their father suffered from a recent enteroviral infection of EV68-71 serotype. To assess the nature of the molecular pathological processes contributing to the development of diabetes, immunocompetent cells isolated from all family members were characterized by gene expression arrays, immune-cell enumerations and cytokine-production assays. The microarray data provided evidence that viral infection, and IL-27 and IL-9 cytokine signalling contributed to the onset of T1D in two of the quadruplets. The propensity of stimulated immunocompetent cells from non-diabetic members of the family to secrete high level of IFN-α further corroborates this conclusion. The number of T regulatory cells as well as plasmacytoid and/or myeloid dendritic cells was found diminished in all family members. Thus, this unique family is a prime example for the support of the so-called 'fertile-field' hypothesis proposing that genetic predisposition to anti-islet autoimmunity is 'fertilized' and precipitated by a viral infection leading to a fully blown T1D.


Language boosting by transcranial stimulation in progressive supranuclear palsy.
To explore whether transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (DLPFC) can improve language capacities in patients with progressive supranuclear palsy (PSP). We used a sham-controlled double-blind crossover design to assess the efficiency of tDCS over the DLPFC in a cohort of 12 patients with PSP. In 3 separate sessions, we evaluated the ability to boost the left DLPFC via left-anodal (excitatory) and right-cathodal (inhibitory) tDCS, while comparing them to sham tDCS. Tasks assessing lexical access (letter fluency task) and semantic access (category judgment task) were applied immediately before and after the tDCS sessions to provide a marker of potential language modulation. The comparison with healthy controls showed that patients with PSP were impaired on both tasks at baseline. Contrasting poststimulation vs prestimulation performance across tDCS conditions revealed language improvement in the category judgment task following right-cathodal tDCS, and in the letter fluency task following left-anodal tDCS. A computational finite element model of current distribution corroborated the intended effect of left-anodal and right-cathodal tDCS on the targeted DLPFC. Our results demonstrate tDCS-driven language improvement in PSP. They provide proof-of-concept for the use of tDCS in PSP and set the stage for future multiday stimulation regimens, which might lead to longer-lasting therapeutic effects promoted by neuroplasticity. This study provides Class III evidence that for patients with PSP, tDCS over the DLPFC improves performance in some language tasks.


Restriction site-associated DNA sequencing for SNP discovery and high-density genetic map construction in southern catfish (Silurus meridionalis).
Single-nucleotide polymorphism (SNP) markers and high-density genetic maps are important resources for marker-assisted selection, mapping of quantitative trait loci (QTLs) and genome structure analysis. Although linkage maps in certain catfish species have been obtained, high-density maps remain unavailable in the economically important southern catfish (Silurus meridionalis). Recently developed restriction site-associated DNA (RAD) markers have proved to be a promising tool for SNP detection and genetic map construction. The objective of the present study was to construct a high-density linkage map using SNPs generated by next-generation RAD sequencing in S. meridionalis for future genetic and genomic studies. An F1 population of 100 individuals was obtained by intraspecific crossing of two wild heterozygous individuals. In total, 77 634 putative high-quality bi-allelic SNPs between the parents were discovered by mapping the parents' paired-end RAD reads onto the reference contigs from both parents, of which 54.7% were transitions and 45.3% were transversions (transition/transversion ratio of 1.2). Finally, 26 714 high-quality RAD markers were grouped into 29 linkage groups by using de novo clustering methods (Stacks). Among these markers, 4514 were linked to the female genetic map, 23 718 to the male map and 6715 effective loci were linked to the integrated map spanning 5918.31 centimorgans (cM), with an average marker interval of 0.89 cM. High-resolution genetic maps are a useful tool for both marker-assisted breeding and various genome investigations in catfish, such as sequence assembly, gene localization, QTL detection and genome structure comparison. Hence, such a high-density linkage map will serve as a valuable resource for comparative genomics and fine-scale QTL mapping in catfish species.


A systematic review of population health interventions and Scheduled Tribes in India.
Despite India's recent economic growth, health and human development indicators of Scheduled Tribes (ST) or Adivasi (India's indigenous populations) lag behind national averages. The aim of this review was to identify the public health interventions or components of these interventions that are effective in reducing morbidity or mortality rates and reducing risks of ill health among ST populations in India, in order to inform policy and to identify important research gaps. We systematically searched and assessed peer-reviewed literature on evaluations or intervention studies of a population health intervention undertaken with an ST population or in a tribal area, with a population health outcome(s), and involving primary data collection. The evidence compiled in this review revealed three issues that promote effective public health interventions with STs: (1) to develop and implement interventions that are low-cost, give rapid results and can be easily administered, (2): a multi-pronged approach, and (3): involve ST populations in the intervention. While there is a growing body of knowledge on the health needs of STs, there is a paucity of data on how we can address these needs. We provide suggestions on how to undertake future population health intervention research with ST populations and offer priority research avenues that will help to address our knowledge gap in this area.


A Novel Nuclear Function for the Interleukin-17 Signaling Adaptor Protein Act1.
In the context of the human airway, interleukin-17A (IL-17A) signaling is associated with severe inflammation, as well as protection against pathogenic infection, particularly at mucosal surfaces such as the airway. The intracellular molecule Act1 has been demonstrated to be an essential mediator of IL-17A signaling. In the cytoplasm, it serves as an adaptor protein, binding to both the intracellular domain of the IL-17 receptor as well as members of the canonical nuclear factor kappa B (NF-κB) pathway. It also has enzymatic activity, and serves as an E3 ubiquitin ligase. In the context of airway epithelial cells, we demonstrate for the first time that Act1 is also present in the nucleus, especially after IL-17A stimulation. Ectopic Act1 expression can also increase the nuclear localization of Act1. Act1 can up-regulate the expression and promoter activity of a subset of IL-17A target genes in the absence of IL-17A signaling in a manner that is dependent on its N- and C-terminal domains, but is NF-κB independent. Finally, we show that nuclear Act1 can bind to both distal and proximal promoter regions of DEFB4, one of the IL-17A responsive genes. This transcriptional regulatory activity represents a novel function for Act1. Taken together, this is the first report to describe a non-adaptor function of Act1 by directly binding to the promoter region of IL-17A responsive genes and directly regulate their transcription.


Variation in Foot Strike Patterns among Habitually Barefoot and Shod Runners in Kenya.
Runners are often categorized as forefoot, midfoot or rearfoot strikers, but how much and why do individuals vary in foot strike patterns when running on level terrain? This study used general linear mixed-effects models to explore both intra- and inter-individual variations in foot strike pattern among 48 Kalenjin-speaking participants from Kenya who varied in age, sex, body mass, height, running history, and habitual use of footwear. High speed video was used to measure lower extremity kinematics at ground contact in the sagittal plane while participants ran down 13 meter-long tracks with three variables independently controlled: speed, track stiffness, and step frequency. 72% of the habitually barefoot and 32% of the habitually shod participants used multiple strike types, with significantly higher levels of foot strike variation among individuals who ran less frequently and who used lower step frequencies. There was no effect of sex, age, height or weight on foot strike angle, but individuals were more likely to midfoot or forefoot strike when they ran on a stiff surface, had a high preferred stride frequency, were habitually barefoot, and had more experience running. It is hypothesized that strike type variation during running, including a more frequent use of forefoot and midfoot strikes, used to be greater before the introduction of cushioned shoes and paved surfaces.


Spectrum of DNA variants for non-syndromic deafness in a large cohort from multiple continents.
Hearing loss is the most common sensory deficit in humans with causative variants in over 140 genes. With few exceptions, however, the population-specific distribution for many of the identified variants/genes is unclear. Until recently, the extensive genetic and clinical heterogeneity of deafness precluded comprehensive genetic analysis. Here, using a custom capture panel (MiamiOtoGenes), we undertook a targeted sequencing of 180 genes in a multi-ethnic cohort of 342 GJB2 mutation-negative deaf probands from South Africa, Nigeria, Tunisia, Turkey, Iran, India, Guatemala, and the United States (South Florida). We detected causative DNA variants in 25 % of multiplex and 7 % of simplex families. The detection rate varied between 0 and 57 % based on ethnicity, with Guatemala and Iran at the lower and higher end of the spectrum, respectively. We detected causative variants within 27 genes without predominant recurring pathogenic variants. The most commonly implicated genes include MYO15A, SLC26A4, USH2A, MYO7A, MYO6, and TRIOBP. Overall, our study highlights the importance of family history and generation of databases for multiple ethnically discrete populations to improve our ability to detect and accurately interpret genetic variants for pathogenicity.


Recurrent Pain in a Patient with Bilateral Scaphotrapezial Coalition and Radiocarpal Arthritis.
Carpal coalition is an uncommon and rarely reported anomaly, characterized by the union of two or more carpal bones. It is usually found incidentally during radiographic evaluation for trauma or other unassociated pathology. While lunotriquetral and capitohamate coalitions are the most common forms of carpal coalition, there are very few reports of scaphotrapezial coalitions described in the literature. This a novel case report, in which we present a case of bilateral scaphotrapezial coalition in a patient with radiocarpal arthritis and persistent wrist pain. Furthermore, this case report discusses the classification systems and treatment options of this anomaly. (Journal of Surgical Orthopaedic Advances 29(1):4849, 2020).


The interaction of C60 and its derivatives with a lipid bilayer via molecular dynamics simulations.
Coarse-grained molecular dynamics simulations have been used to explore the interactions of C(60) and its derivatives with lipid bilayers. Pristine C(60) partitions into the bilayer core, whilst C(60)(OH)(20) experiences a central energetic barrier to permeation across the bilayer. For intermediate levels of derivatization, e.g. C(60)(OH)(10), this central barrier is smaller and there is an energetic well at the bilayer/water interface, thus promoting entry into cells via bilayer permeation whilst maintaining solubility in water.


Differences in muscle activity during hand-dexterity tasks between women with arthritis and a healthy reference group.
Impaired hand function is common in patients with arthritis and it affects performance of daily activities; thus, hand exercises are recommended. There is little information on the extent to which the disease affects activation of the flexor and extensor muscles during these hand-dexterity tasks. The purpose of this study was to compare muscle activation during such tasks in subjects with arthritis and in a healthy reference group. Muscle activation was measured in m. extensor digitorium communis (EDC) and in m. flexor carpi radialis (FCR) with surface electromyography (EMG) in women with rheumatoid arthritis (RA, n = 20), hand osteoarthritis (HOA, n = 16) and in a healthy reference group (n = 20) during the performance of four daily activity tasks and four hand exercises. Maximal voluntary isometric contraction (MVIC) was measured to enable intermuscular comparisons, and muscle activation is presented as %MVIC. The arthritis group used a higher %MVIC than the reference group in both FCR and EDC when cutting with a pair of scissors, pulling up a zipper and-for the EDC-also when writing with a pen and using a key (p < 0.02). The exercise "rolling dough with flat hands" required the lowest %MVIC and may be less effective in improving muscle strength. Women with arthritis tend to use higher levels of muscle activation in daily tasks than healthy women, and wrist extensors and flexors appear to be equally affected. It is important that hand training programs reflect real-life situations and focus also on extensor strength.


Correlation of admission criteria with dental school performance and attrition.
This study was conducted to provide current information on the relationship between admission criteria and dental school performance, including the association of admission criteria and dental school outcomes such as remediation and attrition. Standard tests of bivariate association and multivariate regression models appropriate for continuous and discrete dependent variables were used to examine the relationship between multiple indicators of admission criteria and dental school performance for six recent classes at the University of Florida College of Dentistry (UFCD). The admission criteria included the undergraduate science grade point average (GPA), undergraduate non-science GPA, Dental Admissions Test (DAT) academic score, Perceptual Motor Aptitude Test (PMAT) score, and admission interview score. Measures of dental school performance were the National Dental Board Examination Part I and Part II (NB-I, NB-II) scores, yearly and final dental school GPA, and academic progress through the UFCD program. In general, most admission criteria were good bivariate indicators of dental school performance. Multivariate analyses indicated that students with higher undergraduate science GPAs and DAT academic scores were more likely to achieve higher NB-I and NB-II scores. The undergraduate science GPA and admission interview score were the most consistent determinants of dental school GPA. Students with lower undergraduate science GPAs, DAT academic scores, and PMAT scores were more likely to remediate, to repeat an academic year, or to be dismissed. Although bivariate differences were observed in several admission criteria of students who remediated one or more courses, repeated an academic year, or were dismissed only the undergraduate science GPA and the PMAT score were indicators of programmatic progress in the multivariate analysis.


Gamma oscillations and photosensitive epilepsy.
Certain visual images, even in the absence of motion or flicker, can trigger seizures in patients with photosensitive epilepsy. As of yet, there is no systematic explanation as to why some static images are likely to provoke seizures, while others pose little or no risk. Here, we examined the neurophysiology literature to assess whether the pattern of neural responses in healthy visual cortex is predictive of the pathological responses in photosensitive epilepsy. Previous studies have suggested that gamma oscillations (30-80 Hz) measured in human visual cortex may play a role in seizure generation [1,2]. Recently, we and others have shown that increases in gamma band power can come from two very different cortical signals, one that is oscillatory (with a narrow peak between 30 Hz and 80 Hz), and another that is broadband[3]. The oscillatory signal arises from neuronal synchrony in the local population, while the broadband signal reflects the level of asynchronous neuronal activity, and is correlated with multiunit spiking [4]. These two responses have different biological origins and different selectivity for image properties. Here, we followed up on the previous proposals [1,2] to ask whether the image features that increase seizure likelihood in photosensitive epilepsy are linked to narrowband gamma oscillations specifically, or are associated with any kind of increase in visual activity. Based on published work, we compared pairs of image classes on a number of dimensions, and show that the type of image that elicits larger narrowband gamma oscillations in healthy visual cortex is also more likely to provoke seizures or pre-seizure activity in patients with photosensitive epilepsy. In contrast, images that elicit larger broadband, multiunit, or fMRI responses are much less predictive of seizure activity. We propose that a risk factor for seizures in patients with photosensitive epilepsy is engagement of the circuitry that produces gamma oscillations.


Absorption engineering of NbN nanowires deposited on silicon nitride nanophotonic circuits.
We investigate the absorption properties of U-shaped niobium nitride (NbN) nanowires atop nanophotonic circuits. Nanowires as narrow as 20nm are realized in direct contact with Si3N4 waveguides and their absorption properties are extracted through balanced measurements. We perform a full characterization of the absorption coefficient in dependence of length, width and separation of the fabricated nanowires, as well as for waveguides with different cross-section and etch depth. Our results show excellent agreement with finite-element analysis simulations for all considered parameters. The experimental data thus allows for optimizing absorption properties of emerging single-photon detectors co-integrated with telecom wavelength optical circuits.


Arabidopsis thaliana as a model for the study of plant-virus co-evolution.
Understanding plant-virus coevolution requires wild systems in which there is no human manipulation of either host or virus. To develop such a system, we analysed virus infection in six wild populations of Arabidopsis thaliana in Central Spain. The incidence of five virus species with different life-styles was monitored during four years, and this was analysed in relation to the demography of the host populations. Total virus incidence reached 70 per cent, which suggests a role of virus infection in the population structure and dynamics of the host, under the assumption of a host fitness cost caused by the infection. Maximum incidence occurred at early growth stages, and co-infection with different viruses was frequent, two factors often resulting in increased virulence. Experimental infections under controlled conditions with two isolates of the most prevalent viruses, cauliflower mosaic virus and cucumber mosaic virus, showed that there is genetic variation for virus accumulation, although this depended on the interaction between host and virus genotypes. Comparison of Q(ST)-based genetic differentiations between both host populations with F(ST) genetic differentiation based on putatively neutral markers suggests different selection dynamics for resistance against different virus species or genotypes. Together, these results are compatible with a hypothesis of plant-virus coevolution.


An Aromatic Cluster in the Active Site of epi-Isozizaene Synthase Is an Electrostatic Toggle for Divergent Terpene Cyclization Pathways.
The sesquiterpene cyclase epi-isozizaene synthase (EIZS) catalyzes the cyclization of farnesyl diphosphate to form the tricyclic precursor of the antibiotic albaflavenone. The hydrophobic active site is largely defined by aromatic residues that direct a multistep reaction sequence through multiple carbocation intermediates. The previous substitution of polar residues for a key aromatic residue, F96, converts EIZS into a high-fidelity sesquisabinene synthase: the F96S, F96M, and F96Q variants generate 78%, 91%, and 97% sesquisabinene A, respectively. Here, we report high-resolution X-ray crystal structures of two of these reprogrammed cyclases. The structures of the F96M EIZS-Mg2+3-risedronate and F96M EIZS-Mg2+3-inorganic pyrophosphate-benzyltriethylammonium cation complexes reveal structural changes in the F96 aromatic cluster that redirect the cyclization pathway leading from the bisabolyl carbocation intermediate in catalysis. The structure of the F96S EIZS-Mg2+3-neridronate complex reveals a partially occupied inhibitor and an enzyme active site caught in transition between open and closed states. Finally, three structures of wild-type EIZS complexed with the bisphosphonate inhibitors neridronate, pamidronate, and risedronate provide a foundation for understanding binding differences between wild-type and variant enzymes. These structures provide new insight regarding active site flexibility, particularly with regard to the potential for subtle expansion and contraction to accommodate ligands of varying sizes as well as bound water molecules. Additionally, these structures highlight the importance of conformational changes in the F96 aromatic cluster that could influence cation-π interactions with carbocation intermediates in catalysis.


Connexin 43 deficiency desensitizes bone to the effects of mechanical unloading through modulation of both arms of bone remodeling.
Connexin 43 (Cx43) is a gap junction protein that plays an integral role in the skeletal response to mechanical loading and unloading. In a previous study, we demonstrated preservation of trabecular bone mass and cortical bone formation rate in mice with an osteoblast/osteocyte-selective deficiency of Cx43 (cKO) following mechanical unloading via hindlimb suspension (HLS). In the present study, we sought to define the potential mechanisms underlying this response. Following three weeks of HLS, mRNA levels of Sost were significantly greater in wild-type (WT)-Suspended mice vs. WT-Control, while there was no difference between cKO control and cKO-Suspended. Unloading-induced decreases in P1NP, a serum marker of bone formation, were also attenuated in cKO-Suspended. The proportion of sclerostin-positive osteocytes was significantly lower in cKO-Control vs. WT-Control (-72%, p<0.05), a difference accounted for by the presence of numerous empty lacunae in the cortical bone of cKO vs. WT. Abundant TUNEL staining was present throughout the cortical bone of the tibia and femur, suggesting an apoptotic process. There was no difference in empty lacunae in the trabecular bone of the tibia or femur. Trabecular and cortical osteoclast indices were lower in cKO-Suspended vs. WT-Suspended; however, mRNA levels of the gene encoding RANKL increased similarly in both genotypes. Connexin 43 deficient mice experience attenuated sclerostin-mediated suppression of cortical bone formation and lower cortical osteoclast activity during unloading. Preservation of trabecular bone mass and attenuated osteoclast activity during unloading, despite an apparent lack of effect on osteocyte viability at this site, suggests that an additional mechanism independent of osteocyte apoptosis may also be important. These findings indicate that Cx43 is able to modulate both arms of bone remodeling during unloading.


Neuromyelitis optica spectrum disorders and pregnancy: therapeutic considerations.
Neuromyelitis optica spectrum disorders (NMOSD) are a type of neurological autoimmune disease characterized by attacks of CNS inflammation that are often severe and predominantly affect the spinal cord and optic nerve. The majority of individuals with NMOSD are women, many of whom are of childbearing age. Although NMOSD are rare, several small retrospective studies and case reports have indicated that pregnancy can worsen disease activity and might contribute to disease onset. NMOSD disease activity seems to negatively affect pregnancy outcomes. Moreover, some of the current NMOSD treatments are known to pose risks to the developing fetus and only limited safety data are available for others. Here, we review published studies regarding the relationship between pregnancy outcomes and NMOSD disease activity. We also assess the risks associated with using disease-modifying therapies for NMOSD during the course of pregnancy and breastfeeding. On the basis of the available evidence, we offer recommendations regarding the use of these therapies in the course of pregnancy planning in individuals with NMOSD.


The risks of not breastfeeding for mothers and infants.
Health outcomes in developed countries differ substantially for mothers and infants who formula feed compared with those who breastfeed. For infants, not being breastfed is associated with an increased incidence of infectious morbidity, as well as elevated risks of childhood obesity, type 1 and type 2 diabetes, leukemia, and sudden infant death syndrome. For mothers, failure to breastfeed is associated with an increased incidence of premenopausal breast cancer, ovarian cancer, retained gestational weight gain, type 2 diabetes, myocardial infarction, and the metabolic syndrome. Obstetricians are uniquely positioned to counsel mothers about the health impact of breastfeeding and to ensure that mothers and infants receive appropriate, evidence-based care, starting at birth.


Generation-dependent non-educational characteristics of medical students.
Educational centers accommodate people of varying generations. Indeed, each generation has its specific priorities and values that affect its performance and decisions in various aspects, including educational aspects. Understanding the traits of members of a given generation facilitates understanding how their performance can be improved inside and outside the classroom. So, this study was designed to identify the non-educational characteristics of MD students in the universities of medical sciences in Iran. The present study adopted a qualitative exploratory approach. Data were collected through face-to-face, semi-structured interviews. Participants included general medicine students who had completed at least one semester. Sampling was purposive with maximum variation. Sampling was continued until data saturation, and a total of 32 interviews were conducted. Graneheim and Lundman's content analysis approach was adopted to analyze the data. Lincoln and Guba's reliability criteria were used to achieve the accuracy and reliability of the data. A total of 32 students were interviewed (n = 18 women and n = 14 men; age range: 19-27 years). The participants had completed 2-13 semesters and had between one and six siblings. A total of 10 major categories emerged as the generational traits of students. The main categories included devoted parents, money as the key reference of value, non-sexism, religious perplexity, experiencing oneself with others, my life's address, tunnel vision, evasion from responsibility, winning fame, and I and nothing else. For them, gender and religion have lost their former meaning and they believe in more freedom. They are also one-dimensional people, lethargic and night people, who evade responsibility and have a strong desire to be seen, approved, and respected. They also prioritize themselves and their peace of mind. Since these characteristics can have many direct and indirect effects on various aspects of their lives, including the educational aspect, it can be very beneficial for people interacting with them to identify and consider these characteristics.


The self-report Barthel Index: preliminary validation in people with Parkinson's disease.
To make a preliminary assessment of the reliability and validity of the self-report Barthel Index (SRBI) in people with Parkinson's (PWP) disease. Thirty-nine PWP completed the SRBI, the self-report Schwab & England (S & E) scale and the PDQ-39. Standard statistical procedures were incorporated to assess the reliability and validity of the SRBI. A Cronbach's alpha coefficient of 0.69 was calculated, indicating adequate internal consistency. Reliability was further demonstrated through a Guttman split-half reliability coefficient of 0.74. Validity was demonstrated through highly significant correlations between the SRBI and the S & E scale (r = 0.64, P < 0.00), the activities of daily living dimension of the PDQ-39 (r = -0.60, P < 0.00) and mobility dimension of the PDQ-39 (r = -0.49, P < 0.01). Results suggest that the SRBI has the potential to be a reliable and valid indicator of ADL in PWP and utilized in studies that make comparisons across conditions. Further validation is required in a larger sample and through assessment of additional psychometric properties.


Symptomatic Rathke cleft cysts: extent of resection and surgical complications.
Rathke cleft cysts (RCCs) are benign masses arising from the embryological Rathke pouch, and are commonly treated by transsphenoidal surgery. The authors retrospectively compared RCC extent of resection-either gross-total resection (GTR) or decompression-to the primary outcome measure, which was recurrences resulting in repeat surgery, and the secondary outcome measure, which was complications. Seventy-four patients presenting to the neurosurgical department with RCC were analyzed retrospectively. Sixty-eight patients had a total of 78 surgical procedures, with the diagnosis of RCC confirmed by histological investigation; of these, 61 patients had adequate operative notes for the authors to evaluate extent of resection. Groups were separated into GTR (32 patients) or decompression (subtotal resection or fenestration into the sphenoid sinus; 29 patients) based on operative notes and postoperative imaging. The mean follow-up duration was 60.5 ± 72.1 months (the mean is expressed ± SD throughout). The average age at the time of the initial surgery was 42.8 ± 17.4 years, and 70% of patients were female. The mean cyst diameter preoperatively was 16.9 ± 17.8 mm. Eight patients had repeat surgery, our primary outcome measure; 3 repeat operations occurred in the GTR group, and 5 in the decompression group. There was no significant difference in recurrence when comparing groups (GTR 9%, decompression 17%; p = 0.36). There were no major complications; however, analysis of postoperative minor complications revealed that 11 (34%) GTRs resulted in surgical complications, whereas the decompression cohort accounted for only 3 complications (10%) (p = 0.03), with diabetes insipidus (6) and CSF leaks (5) being the most common. Gross-total resection also resulted in an increase in postoperative hyperprolactinemia compared with decompression (p = 0.03). It appears that RCCs require repeat surgery in 13% of cases, and attempted GTR does not appear to reduce the overall rate of recurrence. However, more aggressive resections are associated with more complications in this series.


Electrospun nanostructured scaffolds for tissue engineering applications.
Despite being known for decades (since 1934), electrospinning has emerged recently as a very widespread technology to produce synthetic nanofibrous structures. These structures have morphologies and fiber diameters in a range comparable with those found in the extracellular matrix of human tissues. Therefore, nanofibrous scaffolds are intended to provide improved environments for cell attachment, migration, proliferation and differentiation when compared with traditional scaffolds. In addition, the process versatility and the highly specific surface area of nanofiber meshes may facilitate their use as local drug-release systems. Common electrospun nanofiber meshes are characterized by a random orientation. However, in some special cases, aligned distributions of the fibers can be obtained, with an interconnected microporous structure. The characteristic pore sizes and the inherent planar structure of the meshes can be detrimental for the desired cell infiltration into the inner regions, and eventually compromise tissue regeneration. Several strategies can be followed to overcome these limitations, and are discussed in detail here.


Genetic Counselling for Maternally Inherited Mitochondrial Disorders.
The aim of this review was to provide an evidence-based approach to frequently asked questions relating to the risk of transmitting a maternally inherited mitochondrial disorder (MID). We do not address disorders linked with disturbed mitochondrial DNA (mtDNA) maintenance, causing mtDNA depletion or multiple mtDNA deletions, as these are autosomally inherited. The review addresses questions regarding prognosis, recurrence risks and the strategies available to prevent disease transmission. The clinical and genetic complexity of maternally inherited MIDs represent a major challenge for patients, their relatives and health professionals. Since many of the genetic and pathophysiological aspects of MIDs remain unknown, counselling of affected patients and at-risk family members remains difficult. MtDNA mutations are maternally transmitted or, more rarely, they are sporadic, occurring de novo (~25%). Females carrying homoplasmic mtDNA mutations will transmit the mutant species to all of their offspring, who may or may not exhibit a similar phenotype depending on modifying, secondary factors. Females carrying heteroplasmic mtDNA mutations will transmit a variable amount of mutant mtDNA to their offspring, which can result in considerable phenotypic heterogeneity among siblings. The majority of mtDNA rearrangements, such as single large-scale deletions, are sporadic, but there is a small risk of recurrence (~4%) among the offspring of affected women. The range and suitability of reproductive choices for prospective mothers is a complex area of mitochondrial medicine that needs to be managed by experienced healthcare professionals as part of a multidisciplinary team. Genetic counselling is facilitated by the identification of the underlying causative genetic defect. To provide more precise genetic counselling, further research is needed to clarify the secondary factors that account for the variable penetrance and the often marked differential expressivity of pathogenic mtDNA mutations both within and between families.


Middle mesial canals in mandibular first molars: A micro-CT study in different populations.
To describe the morphological aspects of middle mesial canals (MMC) in mandibular first molars using micro-CT. Mandibular first molars collected from the Brazilian (n=136) and Turkish (n=122) populations were scanned (voxel size: 9.9μm) and mesial roots with MMC (n=48) evaluated regarding several morphological aspects. The incidence of MMC in each population was statistically compared using Chi-square test (α=0.05). Overall, the incidence of MMC was 18.6% (48 out of 258 molars) and was significantly higher in the Brazilian (n=30; 22.1%) than in the Turkish (n=18; 14.8%) population (p<0.05). In both populations, confluent configuration of the MMC was the most frequent anatomy. Most of the specimens with MMC had 3 independent orifices (n=26; 54.2%) and 3 apical foramina (n=21; 43.8%). The mean minor diameter of the MMC orifice (0.16mm) was 3 times less than the other orifices (∼0.50mm). In mesial roots with independent configuration (n=3; 6.3%), the mean volumes (mm(3)) of the MMC, mesiobuccal (MBC) and mesiolingual (MLC) canals were 0.20±0.10, 0.75±0.28, and 0.88±0.19, respectively. In the specimens with canal confluence (n=26; 54.2%), MMC merged to the MBC (n=8; 16.7%), MLC (n=4; 8.3%), or to both MBC and MLC (n=14; 29.2%). Double mesial canal was observed in only 1 specimen. MMC with an independent foramen was observed mostly in Brazilian specimens. Incidence of MMC was higher in the Brazilian molars. Confluent configuration was the most prevalent anatomic variation, while independent and fin configurations, as well as, double MMC, were found only in a few specimens.


Population genomics of a symbiont in the early stages of a pest invasion.
Invasive species often depend on microbial symbionts, but few studies have examined the evolutionary dynamics of symbionts during the early stages of an invasion. The insect Megacopta cribraria and its bacterial nutritional symbiont Candidatus Ishikawaella capsulata invaded the southeastern US in 2009. While M. cribraria was initially discovered on wild kudzu plants, it was found as a pest on soybeans within 1 year of infestation. Because prior research suggests Ishikawaella confers the pest status--that is, the ability to thrive on soybeans--in some Megacopta species, we performed a genomic study on Ishikawaella from US. Megacopta cribraria populations to understand the role of the symbiont in driving host plant preferences. We included Ishikawaella samples collected in the first days of the invasion in 2009 and from 23 locations across the insect's 2011 US range. The 0.75 Mb symbiont genome revealed only 47 fixed differences from the pest-conferring Ishikawaella in Japan, with only one amino acid change in a nutrition-provisioning gene. This similarity, along with a lack of fixed substitutions in the US symbiont population, indicates that Ishikawella likely arrived in the US capable of being a soybean pest. Analyses of allele frequency changes between 2009 and 2011 uncover signatures of both positive and negative selection and suggest that symbionts on soybeans and kudzu experience differential selection for genes related to nutrient provisioning. Our data reveal the evolutionary trajectory of an important insect-bacteria symbiosis in the early stages of an invasion, highlighting the role microbial symbionts may play in the spread of invasive species.


A biocatalytic route towards rose oxide using chloroperoxidase.
The chiral monoterpene alcohol citronellol was converted to the corresponding bromohydrin by the haem-thiolate enzyme chloroperoxidase (CPO) from Caldariomyces fumago in the presence of hydrogen peroxide and bromide ions. A conversion rate of 51% could be achieved under adapted reaction conditions, which easily yield product in the gramme per litre range while only needing catalytic amounts of enzyme. The bromohydroxylation was shown to be highly regioselective yielding 6-bromo-3,7-dimethyloctane-1,7-diol as the sole product. Product identity was confirmed by GC-MS, (1)H- and (13)C-NMR spectroscopy and the synthesis of reference compounds. However, the reaction was shown to be non-stereospecific because enantiopure (R)- and (S)-citronellol, respectively, gave 1:1-diasteromeric mixtures of the corresponding bromohydrins. A racemic mixture of (R/S)-citronellol was bromohydroxylated without any detectable enantiodiscrimination. The total lack of stereospecificity and enantiodiscrimination points to a reaction mechanism where the oxidised bromide intermediate is not a ligand to the Fe(III)-haem at the distal site but is released from the enzyme active site. The final bromide transfer occurs probably outside the active site via a diffusible oxidised bromide species and the demonstrated regioselectivity is purely chemically controlled. The generated bromohydrins can be straightforward converted via two reactions steps into rose oxide which is a highly valuable flavour and fragrance substance.


Hardwiring microbes via direct interspecies electron transfer: mechanisms and applications.
Multicellular microbial communities are important catalysts in engineered systems designed to treat wastewater, remediate contaminated sediments, and produce energy from biomass. Understanding the interspecies interactions within them is therefore essential to design effective processes. The flow of electrons within these communities is especially important in the determination of reaction possibilities (thermodynamics) and rates (kinetics). Conventional models of electron transfer incorporate the diffusion of metabolites generated by one organism and consumed by a second, frequently referred to as mediated interspecies electron transfer (MIET). Evidence has emerged in the last decade that another method, called direct interspecies electron transfer (DIET), may occur between organisms or in conjunction with electrically conductive materials. Recent research has suggested that DIET can be stimulated in engineered systems to improve desired treatment goals and energy recovery in systems such as anaerobic digesters and microbial electrochemical technologies. In this review, we summarize the latest understanding of DIET mechanisms, the associated microorganisms, and the underlying thermodynamics. We also critically examine approaches to stimulate DIET in engineered systems and assess their effectiveness. We find that in most cases attempts to promote DIET in mixed culture systems do not yield the improvements expected based on defined culture studies. Uncertainties of other processes that may be co-occurring in real systems, such as contaminant sorption and biofilm promotion, need to be further investigated. We conclude by identifying areas of future research related to DIET and its application in biological treatment processes.


[The reduction in maternal mortality in Chile, 1990-2000].
To determine if Chile achieved the objective of reducing maternal mortality by 50% between 1990 and 2000, in line with the provisions of the Regional Plan of Action for the Reduction of Maternal Mortality in the Americas, which the governments of the Americas approved in 1990 at the 23rd Pan American Sanitary Conference. A descriptive, observational study was designed, making it possible to analyze the trend in maternal mortality in Chile from 1990 through 2000. The variables that were evaluated were the maternal mortality ratio, the causes of death, and the age of the mothers who died. The causes of death were classified according to the ninth revision of the International Classification of Diseases (ICD-9), and the raw data were obtained from the yearbooks of the National Institute of Statistics of Chile. The changes in the variables were estimated according to the percentage of cumulative change, and trends were analyzed with the Pearson correlation coefficient. The study found a 60.3% reduction in maternal mortality from 1990 to 2000. The lowest maternal mortality ratio, 18.7 per 100 000 live births, occurred in the year 2000. The five leading causes of maternal mortality were hypertension, miscarriage, other current conditions in the mother, puerperal sepsis, and postpartum hemorrhage. There was a significant downward trend in maternal mortality due to hypertension (r = -0.712; P = 0.014), abortion (r = -0.810; P = 0.003), and puerperal sepsis (r = -0.718; P = 0.013), but there were no statistically significant changes in mortality from other current conditions in the mother or from postpartum hemorrhage. The highest level of maternal mortality was found in women who were 40 years of age or older (100.2/100 000 live births), and the lowest level was in adolescents 15 to 19 years old (18.7/100 000 live births). Chile achieved the objective of the Regional Plan of Action for the Reduction of Maternal Mortality in the Americas, with a decrease of more than 50% in maternal mortality in the 1990-2000 period. That reduction is due mainly to the decline in maternal mortality from hypertension, abortion, and puerperal sepsis.


The influence of carbohydrate gelling agents on rat intestinal transport of monosaccharides and neutral amino acids in vitro.
1. In the present investigation with rings of everted rat small intestine, carbohydrate gelling agents (plant polysaccharides) such as guaran, pectin, tragacanth, carubin and carrageenan were employed to study their direct effect on intestinal absorption of alpha-methyl-D-glucoside, D-galactose, L-leucine and L-phenylalanine. 2. Inhibition was found to correlate with the viscosity of the incubation medium, a function only of the polysaccharide concentration, and was independent of other properties of the carbohydrate gelling agents. 3. Reversal of this inhibition was achieved either by washing the tissue free of polysaccharide or by raising tissue agitation. 4. Uptake kinetics in polysaccharide-containing solutions revealed a marked increase of the apparent Michaelis constant although the maximal transport capacity remained essentially unaltered. 5. Since there was no binding of the substrate by the polysaccharides under experimental conditions as judged by a membrane filtration technique, it is concluded that carbohydrate gelling agents may impair intestinal absorption by means of an increased unstirred layer resistance.


IL-17RC is required for IL-17A- and IL-17F-dependent signaling and the pathogenesis of experimental autoimmune encephalomyelitis.
It has been suggested that IL-17RC forms a complex with IL-17RA to mediate the functions of IL-17A and IL-17F homodimers as well as IL-17A/F heterodimers. It is still unclear whether IL-17RC is absolutely required for the signaling of IL-17 cytokines in vivo. By using Il-17rc-deficient mice, we show that IL-17RC is essential for the signaling of IL-17A, IL-17F, and IL-17A/F both in vitro and in vivo. IL-17RC does not preassociate with IL-17RA on the cell surface; rather IL-17A can induce the formation of an IL-17RC and IL-17RA complex. This process is not dependent on the intracellular similar expression to fibroblast growth factor genes and IL-17Rs (SEFIR) domain of IL-17RC, but the SEFIR is essential in IL-17A signal transduction. Finally, Il-17rc(-/-) mice develop much milder disease in an experimental autoimmune encephalomyelitis model, supporting an essential role for IL-17RC in mediating immune-mediated CNS inflammation.


TFAP2B -dietary protein and glycemic index interactions and weight maintenance after weight loss in the DiOGenes trial.
TFAP2B rs987237 is associated with obesity and has shown interaction with the dietary fat-to-carbohydrate ratio, which has an effect on weight loss. We investigated interactions between rs987237 and protein-to-carbohydrate ratio or glycemic index (GI) in relation to weight maintenance after weight loss. This study included 742 obese individuals from 8 European countries who participated in the Diet, Obesity, and Genes (DiOGenes) trial, lost ≥ 8% of their initial body weight during an 8-week low-calorie diet and were randomized to one of 5 ad libitum diets with a fixed energy percentage from fat: either low-protein/low-GI, low-protein/high-GI, high-protein/low-GI, or high-protein/high-GI diets, or a control diet for a 6-month weight maintenance period. Using linear regression analyses and additive genetic models, we investigated main and dietary interaction effects of TFAP2B rs987237 in relation to weight maintenance. In total, 468 completers of the trial were genotyped for rs987237. High-protein diets were beneficial for weight maintenance in the AA genotype group (67% of participants), but in the AG and GG groups no differences were observed for low- or high-protein diets. On the high-protein diet, carriers of the obesity risk allele (G allele) regained 1.84 kg (95% CI: 0.02; 3.67, p = 0.047) more body weight per risk allele than individuals on a low-protein diet. There was no interaction effect between rs987237 and GI on weight maintenance. TFAP2B rs987237 and dietary protein/carbohydrate interacted to modify weight maintenance. Considering the carbohydrate proportion of the diet, the interaction was different from the previously reported rs987237-fat-to-carbohydrate ratio interaction for weight loss. Thus, TFAP2B-macronutrient interactions might diverge depending on the nutritional state.


Submillimeter-wave atmospheric and astrophysical spectroscopy.
The paper describes the results and methods of work which has been in progress during the past five years at the U.K. National Physical Laboratory and Queen Mary College, London on the submillimeter spectrum and its application to atmospheric and astrophysical problems. The paper begins with descriptions of the spectroscopic techniques evolved and used, which provide spectral resolution more than half an order of magnitude finer than previously available, particularly at the lower frequency end of the range, from 15 cm(-1) to 25 cm(-1). Excellent signal-to-noise ratios and reproducibility have been obtained and applied as shown in the second part of the paper to both atmospheric studies (chiefly at NPL) and astrophysical problems (chiefly at QMC). The former are illustrated with aircraft-borne measurements of minor species, such as H(2)O, O(3), HNO(3), and other gases, the latter with a consideration of the cosmic background at submillimeter wavelengths. A common thread is provided by developments in observational and interpretational spectroscopic techniques needed to overcome problems peculiar to this region of the spectrum. Our current progress in understanding the region and also prospects for future submillimeter spectroscopy are each brought into review in this work.


Aiding reduction of smoking with nicotine replacement medications: hope for the recalcitrant smoker?
To assess the effect of the various nicotine replacement therapies (NRT) on smoking reduction. During an initial sampling week, the subjects familiarised themselves with nicotine gum, patch, nasal spray, vaporiser (vapour inhaler) and sublingual tablet. A crossover design was used during the next four study weeks; during two of these weeks the subjects could select one nicotine replacement product of their choice to use, whereas during the other two they were randomly assigned a product to use. 143 men and women smoking an average of 22.6 (SD 7.0) cigarettes per day and exhibiting a Fagerström Tolerance Questionnaire (FTQ) score of 7.0 (SD 1.9). Subjects were asked to use as much NRT as they wished, yet to smoke enough to feel comfortable. Self-reported cigarette consumption, exhaled carbon monoxide (CO), withdrawal symptom score, cotinine plasma levels and motivation to quit were monitored over a period of five weeks. Self-reported smoking declined steadily over the five weeks, from 22.6 (SD 7.0) to 10.4 (SD 1.0) (P<0.001) cigarettes daily (54% decrease), with the biggest drop (37%) during the first product-sampling week. Smoking reduction was greater on average during the weeks when the subjects could choose their nicotine product than when products were assigned. CO readings decreased from 22.7 (SD 8.5) to 14.8 (SD 8.4) ppm (P<0.001) confirming a reduction in smoking (35% decrease), although cotinine levels remained steady, suggesting that subjects were titrating nicotine to their original levels. Withdrawal scores decreased over time (32% decrease, P<0.001), showing that there was no discomfort associated with the smoking reduction, and motivation to quit was enhanced by the treatment in most subjects (93%). NRT for aiding smoking reduction appeared to be safe, was associated with a clinically significant reduction in smoke exposure over a five-week follow up, and increased motivation to stop smoking. A smoking reduction procedure may help the very recalcitrant smoker gain confidence and increase the control over his/her smoking behaviour. More controlled research is needed to follow up these promising results.


Novel field sampling procedure for the determination of methiocarb residues in surface waters from rice fields.
Methiocarb was extracted from surface water samples collected at experimental rice field sites in Louisiana and Texas. The sampling system consisted of a single-stage 90-mm Empore extraction disk unit equipped with a battery-powered vacuum pump. After extraction, the C-18 extraction disks were stored in an inert atmosphere at -10 degrees C and shipped overnight to the laboratory. The disks were extracted with methanol and the extracts analyzed by reversed-phase high-performance liquid chromatography with a methanol/water mobile phase. Methiocarb was detected by ultraviolet absorption at 223 nm and quantified with the use of calibration standards. Recoveries from control surface water samples fortified at 5.0, 10, 50, and 100 ng/mL methiocarb averaged 92 +/- 7%. A method limit of detection for methiocarb in rice field surface water was estimated to be 0.23 ng/mL at 223 nm.


Indoor Surface Chemistry: Developing a Molecular Picture of Reactions on Indoor Interfaces.
Chemical reactions on indoor surfaces play an important role in air quality in indoor environments, where humans spend 90% of their time. We focus on the challenges of understanding the complex chemistry that takes place on indoor surfaces and identify crucial steps necessary to gain a molecular-level understanding of environmental indoor surface chemistry: (1) elucidate key surface reaction mechanisms and kinetics important to indoor air chemistry, (2) define a range of relevant and representative surfaces to probe, and (3) define the drivers of surface reactivity, particularly with respect to the surface composition, light, and temperature. Within the drivers of surface composition are the roles of adsorbed/absorbed water associated with indoor surfaces and the prevalence, inhomogeneity, and properties of secondary organic films that can impact surface reactivity. By combining laboratory studies, field measurements, and modeling we can gain insights into the molecular processes necessary to further our understanding of the indoor environment.


Disease surveillance of Atlantic herring: molecular characterization of hepatic coccidiosis and a morphological report of a novel intestinal coccidian.
Surveillance for pathogens of Atlantic herring, including viral hemorrhagic septicemia virus (VHSV), Ichthyophonus hoferi, and hepatic and intestinal coccidians, was conducted from 2012 to 2016 in the NW Atlantic Ocean, New Jersey, USA. Neither VHSV nor I. hoferi was detected in any sample. Goussia clupearum was found in the livers of 40 to 78% of adult herring in varying parasite loads; however, associated pathological changes were negligible. Phylogenetic analysis based on small subunit 18S rRNA gene sequences placed G. clupearum most closely with other extraintestinal liver coccidia from the genus Calyptospora, though the G. clupearum isolates had a unique nucleotide insertion between 604 and 729 bp that did not occur in any other coccidian species. G. clupearum oocysts from Atlantic and Pacific herring were morphologically similar, though differences occurred in oocyst dimensions. Comparison of G. clupearum genetic sequences from Atlantic and Pacific herring revealed 4 nucleotide substitutions and 2 gaps in a 1749 bp region, indicating some divergence in the geographically separate populations. Pacific G. clupearum oocysts were not directly infective, suggesting that a heteroxenous life cycle is likely. Intestinal coccidiosis was described for the first time from juvenile and adult Atlantic herring. A novel intestinal coccidian species was detected based on morphological characteristics of exogenously sporulated oocysts. A unique feature in these oocysts was the presence of 3 long (15.1 ± 5.1 µm, mean ±SD) spiny projections on both ends of the oocyst. The novel morphology of this coccidian led us to tentatively name this parasite G. echinata n. sp.


Systematic review of pre-operative exercise in colorectal cancer patients.
The aim of this systematic review was to evaluate the evidence for exercise interventions prior to surgery for colorectal cancer resection. The evidence for use of exercise to improve physical fitness and surgical outcomes is as yet unknown. A systematic search was performed of MEDLINE, EMBASE, CINAHL, AMED and BNI databases for studies involving pre-operative exercise in colorectal cancer patients. Eight studies were included in the review. There is evidence that pre-operative exercise improves functional fitness, and to a lesser extent objectively measurable cardio-respiratory fitness prior to colorectal cancer resection. There is no clear evidence at present that this improvement in fitness translates into reduced peri-operative risk or improved post-operative outcomes. Current studies are limited by risk of bias. This review highlights the common difficulty in transferring promising results in a research setting, into significant improvements in the clinical arena. Future research should focus on which type of exercise is most likely to maximise patient adherence and improvements in cardio-respiratory fitness. Ultimately, adequately powered, randomised controlled trials are needed to investigate whether pre-operative exercise improves post-operative morbidity and mortality.


The global burden of fatal self-poisoning with pesticides 2006-15: Systematic review.
Agricultural pesticide poisoning is a major contributor to the global burden of suicide. Over the last decade there has been a marked decrease in the incidence of suicide worldwide. It is unclear whether pesticide poisoning still plays a significant role in the global incidence of suicide. WHO method-specific suicide data were supplemented by a systematic review of the literature between 2006 and 2015, including searches of thirteen electronic databases and Google, citation searching and a review of reference lists and personal collections. Our primary outcome was the proportion of total suicides due to pesticide poisoning. Weighted estimates were calculated for seven WHO regional and income strata. We identified data from 108 countries (102 from WHO data, 6 from the literature). A conservative estimate based on these data indicates that there were approximately 110,000 pesticide self-poisoning deaths each year from 2010 to 2014, comprising 13.7% of all global suicides. A sensitivity analysis accounting for under-reporting of suicides in India resulted in an increased estimate of 168,000 pesticide self-poisoning deaths annually, that is, 19.7% of global suicides. The proportion of suicides due to pesticide self-poisoning varies considerably between regions, from 0.9% in low- and middle-income countries in the European region to 48.3% in low- and middle-income countries in the Western Pacific region. High quality method-specific suicide data were unavailable for a number of the most populous countries, particularly in the African and Eastern Mediterranean regions. It is likely we have underestimated incidence in these regions. There appears to have been a substantial decline in fatal pesticide self-poisoning in recent years, largely driven by a reduction in overall suicide rates in China. Nonetheless, pesticide self-poisoning remains a major public health challenge, accounting for at least one-in-seven suicides globally.


"Stop eating lollies and do lots of sports": a prospective qualitative study of the development of children's awareness of dietary restraint and exercise to lose weight.
Beliefs surrounding the usefulness of dietary restriction and physical activity as means of body shape and size modification is already present in children as young as 5-years-old, and these beliefs may increase the risk of unhealthy weight control behaviours later in life. To date, however, little is known regarding the development of these beliefs in younger children. The aim of the present study was, therefore, to explore young (aged 3- to 5-years old) children's conceptualisations of dietary restriction and physical activity as means to change body size using a prospective approach. A sample of 259 children (116 boys, 143 girls) participated in interviews at 3-, 4- and 5-years-old. Participants were shown silhouette figures of a child of their gender and age. Their responses to questions regarding how the figure could return to a previous thinner shape were qualitatively coded using thematic analysis. Children's responses revealed that while, for a subsample, modifications of food, eating, and exercise patterns were the most salient ideas, a number of other mechanisms of body change were also suggested. Responses also evidenced adoption or awareness of stigmatising attitudes towards overweight individuals (over 15% by age 5). The proportion of children demonstrating an awareness of dietary restriction and physical exercise as methods for body size change increased significantly at each time point. While only 4.2% demonstrated dieting awareness at 3-years-old, this proportion had risen to almost 28% by 5-years-old (p < .001). Similarly, the proportion of children aware of exercise as a body change strategy rose from 2.3 to 16.3% (p < .001), with 22% of 5-year-olds mentioning general physical activity as a strategy. No gender differences were found. Awareness of dietary restriction and physical exercise as strategies for weight loss and body change emerges as young as 3-years-old, and significantly increases from 3- to 5-years-old. Interventions aiming to promote healthy means of weight control and obesity prevention should consider that certain attitudes may already be present in very young children.