D-dimer and factor VIIa in atrial fibrillation - prognostic values for cardiovascular events and effects of anticoagulation therapy. A RE-LY substudy.
Coagulation markers may improve monitoring the risk of stroke and bleeding in patients with atrial fibrillation (AF) during anticoagulant treatment. We examined baseline levels of D-dimer and their association with stroke, cardiovascular death and major bleeding in 6,202 AF patients randomised to dabigatran or warfarin in the RE-LY trial. The effects of treatment on serial levels of D-dimer and coagulation factor (F) VIIa in 2,567 patients were also analysed. Baseline D-dimer levels were related to the rate of stroke/systemic embolism (SEE) with 0.64 % in the lowest quartile (Q1, as reference) (D-dimer < 298 µg/l), 1.38 % Q2 (D-dimer 298-473 µg/l), 1.71 % Q3 (D-dimer 474-822 µg/l) and 2.00 % in Q4 (D-dimer > 822 µg/l) (p=0.0007). Similar associations were shown for cardiovascular death and major bleeding. Addition of baseline D-dimer to established clinical risk factors improved prediction of stroke/SEE, cardiovascular death and major bleeding (C-index increased from 0.66 to 0.68, 0.71 to 0.73 and 0.66 to 0.67, respectively). Dabigatran provided a greater reduction of D-dimer levels than warfarin regardless of baseline anticoagulant treatment. On-treatment levels of FVIIa were markedly reduced by warfarin (median 12.1-13.8 mU/ml) but significantly higher with dabigatran (median 39.4-49.0 mU/ml) at all-time points. Dabigatran is associated with greater reduction in D-dimer without the pronounced reduction of FVIIa seen with warfarin. These different effects on the coagulation system might explain the better efficacy and less intracranial bleeding observed with dabigatran compared with warfarin.


How the Brain Represents Language and Answers Questions? Using an AI System to Understand the Underlying Neurobiological Mechanisms.
To understand the computations that underlie high-level cognitive processes we propose a framework of mechanisms that could in principle implement START, an AI program that answers questions using natural language. START organizes a sentence into a series of triplets, each containing three elements (subject, verb, object). We propose that the brain similarly defines triplets and then chunks the three elements into a spatial pattern. A complete sentence can be represented using up to 7 triplets in a working memory buffer organized by theta and gamma oscillations. This buffer can transfer information into long-term memory networks where a second chunking operation converts the serial triplets into a single spatial pattern in a network, with each triplet (with corresponding elements) represented in specialized subregions. The triplets that define a sentence become synaptically linked, thereby encoding the sentence in synaptic weights. When a question is posed, there is a search for the closest stored memory (having the greatest number of shared triplets). We have devised a search process that does not require that the question and the stored memory have the same number of triplets or have triplets in the same order. Once the most similar memory is recalled and undergoes 2-level dechunking, the sought for information can be obtained by element-by-element comparison of the key triplet in the question to the corresponding triplet in the retrieved memory. This search may require a reordering to align corresponding triplets, the use of pointers that link different triplets, or the use of semantic memory. Our framework uses 12 network processes; existing models can implement many of these, but in other cases we can only suggest neural implementations. Overall, our scheme provides the first view of how language-based question answering could be implemented by the brain.


Experts' views regarding Australian school-leavers' knowledge of nutrition and food systems.
To explore Australian experts' views regarding strengths and gaps in school-leavers' knowledge of nutrition and food systems ( N&FS) and factors that influence that knowledge. Semi-structured interviews were conducted with 21 highly experienced food-related experts in Australia. Qualitative data were analysed thematically using Attride-Stirling's thematic network framework. Two global themes and several organising themes were identified. The first global theme, 'structural curriculum-based problems', emerged from three organising themes of: inconsistencies in provided food education programs at schools in Australia; insufficient coverage of food-related skills and food systems topics in school curricula; and the lack of trained school teachers. The second global theme, 'insufficient levels of school-leavers knowledge of N&FS ', was generated from four organising themes, which together described Australian school-leavers' poor knowledge of N&FS more broadly and knowledge translation problem for everyday practices. Study findings identified key problems relating to current school-based N&FS education programs in Australia and reported knowledge gaps in relation to N&FS among Australian school-leavers. These findings provide important guidance for N&FS curriculum development, to clearly articulate broadly-based N&FS knowledge acquisition in curriculum policy and education documents for Australian schools.


Effect of vitamin D3 supplementation on upper respiratory tract infections in healthy adults: the VIDARIS randomized controlled trial.
Observational studies have reported an inverse association between serum 25-hydroxyvitamin D (25-OHD) levels and incidence of upper respiratory tract infections (URTIs). However, results of clinical trials of vitamin D supplementation have been inconclusive. To determine the effect of vitamin D supplementation on incidence and severity of URTIs in healthy adults. Randomized, double-blind, placebo-controlled trial conducted among 322 healthy adults between February 2010 and November 2011 in Christchurch, New Zealand. Participants were randomly assigned to receive an initial dose of 200,000 IU oral vitamin D3, then 200,000 IU 1 month later, then 100,000 IU monthly (n = 161), or placebo administered in an identical dosing regimen (n = 161), for a total of 18 months. The primary end point was number of URTI episodes. Secondary end points were duration of URTI episodes, severity of URTI episodes, and number of days of missed work due to URTI episodes. The mean baseline 25-OHD level of participants was 29 (SD, 9) ng/mL. Vitamin D supplementation resulted in an increase in serum 25-OHD levels that was maintained at greater than 48 ng/mL throughout the study. There were 593 URTI episodes in the vitamin D group and 611 in the placebo group, with no statistically significant differences in the number of URTIs per participant (mean, 3.7 per person in the vitamin D group and 3.8 per person in the placebo group; risk ratio, 0.97; 95% CI, 0.85-1.11), number of days of missed work as a result of URTIs (mean, 0.76 days in each group; risk ratio, 1.03; 95% CI, 0.81-1.30), duration of symptoms per episode (mean, 12 days in each group; risk ratio, 0.96; 95% CI, 0.73-1.25), or severity of URTI episodes. These findings remained unchanged when the analysis was repeated by season and by baseline 25-OHD levels. In this trial, monthly administration of 100,000 IU of vitamin D did not reduce the incidence or severity of URTIs in healthy adults. anzctr.org.au Identifier: ACTRN12609000486224.


Repeat-induced point mutation (RIP) as an alternative mechanism of evolution toward virulence in Leptosphaeria maculans.
Three avirulence genes, AvrLm1, AvrLm6, and AvrLm4-7, were recently identified in Leptosphaeria maculans and found to be localized as solo genes within large noncoding, heterochromatin-like regions mainly composed of retrotransposons, truncated and degenerated by repeat-induced point mutation (RIP). The Rlm6 resistance gene has been overcome within 3 years in outdoor experiments in France and, here, we investigate the molecular basis of evolution toward virulence at the AvrLm6 locus. A region of 235 kb was sequenced in a virulent isolate and showed the deletion of AvrLm6 and three divergent mosaics of retrotransposons. AvrLm6 was found to be absent from 66% of 70 virulent isolates, with multiple events of deletion. The sequencing of virulent alleles in 24 isolates revealed a few cases of point mutations that had created stop codons in the sequence. The most frequent mutation events, however, were RIP, leading to the modification of 4 to 9% of the bases compared with the avirulent allele and generating 2 to 4 stop codons. Thus, RIP is described for the first time as an efficient mechanism leading to virulence and the multiple patterns of mutation observed suggest that multiple RIP events could occur independently in a single field population during 1 year.


Three-dimensional kinematics and wake structure of the pectoral fins during locomotion in leopard sharks Triakis semifasciata.
The classical theory of locomotion in sharks proposes that shark pectoral fins are oriented to generate lift forces that balance the moment produced by the oscillating heterocercal tail. Accordingly, previous studies of shark locomotion have used fixed-wing aircraft as a model assuming that sharks have similar stability and control mechanisms. However, unlike airplanes, sharks are propelled by undulations of the body and tail and have considerable control of pectoral fin motion. In this paper, we use a new approach to examine the function of the pectoral fins of leopard sharks, Triakis semifasciata, during steady horizontal swimming at speeds of 0.5-2.0ls(-1), where l is total body length, and during vertical maneuvering (rising and sinking) in the water column. The planar orientation of the pectoral fin was measured using three-dimensional kinematics, while fluid flow in the wake of the pectoral fin and forces exerted on the water by the fin were quantified using digital particle image velocimetry (DPIV). Steady horizontal swimming in leopard sharks is characterized by continuous undulations of the body with a positive body tilt to the flow that decreases from a mean of 11 degrees to 0.6 degrees with increasing flow speeds from 0. 5 to 2.0ls(-1). Three-dimensional analysis showed that, during steady horizontal locomotion, the pectoral fins are cambered, concave downwards, at a negative angle of attack that we predict to generate no significant lift. Leopard shark pectoral fins are also oriented at a substantial negative dihedral angle that amplifies roll moments and hence promotes rapid changes in body position. Vortices shed from the trailing edge of the pectoral fin were detected only during vertical maneuvering. Starting vortices are produced when the posterior plane of the pectoral fin is actively flipped upwards or downwards to initiate rising or sinking, respectively, in the water column. The starting vortex produced by the pectoral fin induces a pitching moment that reorients the body relative to the flow. Body and pectoral fin surface angle are altered significantly when leopard sharks change vertical position in the water column. Thus, locomotion in leopard sharks is not analogous to flight in fixed-wing aircraft. Instead, a new force balance for swimming leopard sharks is proposed for steady swimming and maneuvering. Total force balance on the body is adjusted by altering the body angle during steady swimming as well as during vertical maneuvering, while the pectoral fins appear to be critical for initiating maneuvering behaviors, but not for lift production during steady horizontal locomotion.


Method for determination of the dielectric function of a thin absorbing film on variable substrates from transmission spectra.
Transmission spectra of bilayers of a strongly absorbing dye molecule on thin semitransparent metallic films show a pronounced variation of the shape as a function of the thickness of the metal film. The shape changes with increasing thickness of the metal film from the form of an absorption spectrum as determined by the imaginary part of the dielectric function to an antisymmetric shape characteristic of the dispersion of the real part of the dielectric function in the vicinity of a resonance. These different spectra shapes were exploited to derive the complex dielectric function of a dye layer from transmission spectra of the layer on metal films of a different thickness. This method proved to be a simple alternative to determination of the dielectric function of a thin film of a dye by spectroscopic ellipsometry.


Production of tetravalent dengue virus envelope protein domain III based antigens in lettuce chloroplasts and immunologic analysis for future oral vaccine development.
Dengue fever is a mosquito (Aedes aegypti) -transmitted viral disease that is endemic in more than 125 countries around the world. There are four serotypes of the dengue virus (DENV 1-4) and a safe and effective dengue vaccine must provide protection against all four serotypes. To date, the first vaccine, Dengvaxia (CYD-TDV), is available after many decades' efforts, but only has moderate efficacy. More effective and affordable vaccines are hence required. Plants offer promising vaccine production platforms and food crops offer additional advantages for the production of edible human and animal vaccines, thus eliminating the need for expensive fermentation, purification, cold storage and sterile delivery. Oral vaccines can elicit humoural and cellular immunity via both the mucosal and humoral immune systems. Here, we report the production of tetravalent EDIII antigen (EDIII-1-4) in stably transformed lettuce chloroplasts. Transplastomic EDIII-1-4-expressing lettuce lines were obtained and homoplasmy was verified by Southern blot analysis. Expression of EDIII-1-4 antigens was demonstrated by immunoblotting, with the EDIII-1-4 antigen accumulating to 3.45% of the total protein content. Immunological assays in rabbits showed immunogenicity of EDIII-1-4. Our in vitro gastrointestinal digestion analysis revealed that EDIII-1-4 antigens are well protected when passing through the oral and gastric digestion phases but underwent degradation during the intestinal phase. Our results demonstrate that lettuce chloroplast engineering is a promising approach for future production of an affordable oral dengue vaccine.


Driven optical matter: Dynamics of electrodynamically coupled nanoparticles in an optical ring vortex.
To date investigations of the dynamics of driven colloidal systems have focused on hydrodynamic interactions and often employ optical (laser) tweezers for manipulation. However, the optical fields that provide confinement and drive also result in electrodynamic interactions that are generally neglected. We address this issue with a detailed study of interparticle dynamics in an optical ring vortex trap using 150-nm diameter Ag nanoparticles. We term the resultant electrodynamically interacting nanoparticles a driven optical matter system. We also show that a superior trap is created by using a Au nanoplate mirror in a retroreflection geometry, which increases the electric field intensity, the optical drive force, and spatial confinement. Using nanoparticles versus micron sized colloids significantly reduces the surface hydrodynamic friction allowing us to access small values of optical topological charge and drive force. We quantify a further 50% reduction of hydrodynamic friction when the nanoparticles are driven over the Au nanoplate mirrors versus over a mildly electrostatically repulsive glass surface. Further, we demonstrate through experiments and electrodynamics-Langevin dynamics simulations that the optical drive force and the interparticle interactions are not constant around the ring for linearly polarized light, resulting in a strong position-dependent variation in the nanoparticle velocity. The nonuniformity in the optical drive force is also manifest as an increase in fluctuations of interparticle separation, or effective temperature, as the optical driving force is increased. Finally, we resolve an open issue in the literature on periodic modulation of interparticle separation with comparative measurements of driven 300-nm-diameter polystyrene beads that also clearly reveal the significance of electrodynamic forces and interactions in optically driven colloidal systems. Therefore, the modulations in the optical forces and electrodynamic interactions that we demonstrate should not be neglected for dielectric particles and might give rise to some structural and dynamic features that have previously been attributed exclusively to hydrodynamic interactions.


Rural deprivation: reflecting reality.
In the United Kingdom (UK) there is currently an upsurge of interest in rural affairs. This brings the potential to address some of the gaps in rural health care research. The appropriate description and measurement of rural deprivation is one area consistently identified by UK rural practitioners and policymakers as urgently requiring evidence. Appropriate identification and measurement of deprivation within a rural context is important so that primary care resources can be targeted at those with greatest need. It is believed that current measures of deprivation are inappropriate for rural settings, but relationships between life circumstances and health are only beginning to be addressed by empirical research. In this paper we propose an approach to researching rural deprivation. It is important to be clear about definitions of rurality and deprivation and about the purpose of measurement. The requirement to test a range of indicators for their association with health status and health care need in rural areas and to gather more locally relevant data within primary care settings is highlighted. The relevance, for primary care, of exploring rural deprivation is suggested, along with ideas about a way forward in generating knowledge that can help to characterise and measure rural deprivation in a more sensitive manner.


[Engaging patients with serious mental illness in care services by Critical Time Intervention].
Patients with serious mental illness who are difficult to engage in services often face multiple complex problems, like homelessness, debts, and poor hygiene and social skills. Critical Time Intervention (CTI) is a time-limited, manual-guided case management approach intended to enhance continuity of care for mentally ill patients. We present two patients who received intensive outpatient CTI care. A 42-year-old woman diagnosed with depression and addiction to alcohol and medication and a 38-year-old man diagnosed with autism were offered practical and emotional support while they became linked to a long term support system. CTI offers pro-active case management where the patient lives, taking into account the patient's strengths and informal support system. CTI is especially suited for patients relatively new to psychiatric care, who would not engage in services without support.


Ecological consequences of anomalies in atmospheric moisture and snowpack.
Although increased frequency of extreme-weather events is one of the most secure predictions associated with contemporary climate change, effects of such events on distribution and abundance of climate-sensitive species remain poorly understood. Montane ecosystems may be especially sensitive to extreme weather because of complex abiotic and biotic interactions that propagate from climate-driven reductions in snowpack. Snowpack not only protects subnivean biotas from extreme cold, but also influences forage availability through timing of melt-off and water availability. We related relative abundances of an alpine mammal, the American pika (Ochotona princeps), to measures of weather and snowpack dynamics over an 8-yr period that included before and after a year of record-low snowpack in Washington, USA. We sought to (1) quantify any change in pika abundance associated with the snowpack anomaly and (2) identify aspects of weather and snowpack that influenced abundance of pikas. Pikas showed a 1-yr lag response to the snowpack anomaly and exhibited marked declines in abundance at elevations below 1,400 m simultaneous with increased abundances at higher elevations. Atmospheric moisture, indexed by vapor pressure deficit (VPD), was especially important, evidenced by strong support for the top-ranked model that included the interaction of VPD with snowpack duration. Notably, our novel application of VPD from gridded climate data for analyses of animal abundances shows strong potential for improving species distribution models because VPD represents an important aspect of weather that influences the physiology and habitat of biota. Pikas were apparently affected by cold stress without snowpack at mid elevations, whereas changes to forage associated with snowpack and VPD were influential at high and low elevations. Our results reveal context dependency in pika responses to weather and illustrate how snow drought can lead to rapid change in the abundance of subnivean animals.


Neocortical pathological high-frequency oscillations are associated with frequency-dependent alterations in functional network topology.
Synchronization of neural oscillations is thought to integrate distributed neural populations into functional cell assemblies. Epilepsy is widely regarded as a disorder of neural synchrony. Knowledge is scant, however, regarding whether ictal changes in synchrony involving epileptogenic cortex are expressed similarly across various frequency ranges. Cortical regions involved in epileptic networks also exhibit pathological high-frequency oscillations (pHFOs, >80 Hz), which are increasingly utilized as biomarkers of epileptogenic tissue. It is uncertain how pHFO amplitudes are related to epileptic network connectivity. By calculating phase-locking values among intracranial electrodes implanted in children with intractable epilepsy, we constructed ictal connectivity networks and performed graph theoretical analysis to characterize their network properties at distinct frequency bands. Ictal data from 17 children were analyzed with a hierarchical mixed-effects model adjusting for patient-level covariates. Epileptogenic cortex was defined in two ways: 1) a hypothesis-driven method using the visually defined seizure-onset zone and 2) a data-agnostic method using the high-frequency amplitude of each electrode. Epileptogenic cortex exhibited a logarithmic decrease in interregional functional connectivity at high frequencies (>30 Hz) during seizure initiation and propagation but not at termination. At slower frequencies, conversely, epileptogenic cortex expressed a relative increase in functional connectivity. Our findings suggest that pHFOs reflect epileptogenic network interactions, yielding theoretical support for their utility in the presurgical evaluation of intractable epilepsy. The view that abnormal network synchronization plays a critical role in ictogenesis and seizure dynamics is supported by the observation that functional isolation of epileptogenic cortex at high frequencies is absent at seizure termination.


Enteric-coated mycophenolate sodium as a steroid-sparing agent in pemphigus treatment: a retrospective study.
Several immunosuppressive drugs are used as steroid-sparing agents in pemphigus vulgaris (PV) treatment, with the aim of reducing the cumulative dose of steroids and minimizing the side effects of long-term steroid treatment. The objective of this study is to evaluate the efficacy and safety of enteric-coated mycophenolate sodium (EC-MPS) as a steroid-sparing agent in PV patients. We performed a retrospective study on PV patients who had attended our dermatology department between October 2004 and December 2010 and who had been treated with a combined therapy of systemic corticosteroids and EC-MPS. In the 16 enrolled patients, the introduction of EC-MPS allowed the tapering of systemic corticosteroids, and in 12 of these patients, complete remission was achieved in the time of observation, on average in 4.3 months. Corticosteroid withdrawal was possible in two patients, and EC-MPS was very well tolerated. No serious adverse events were recorded. EC-MPS is a valid therapeutic opportunity as a steroid-sparing agent in PV patients.


Alcohol: A Simple Nutrient with Complex Actions on Bone in the Adult Skeleton.
Alcohol is an important nonessential component of diet, but the overall impact of drinking on bone health, especially at moderate levels, is not well understood. Bone health is important because fractures greatly reduce quality of life and are a major cause of morbidity and mortality in the elderly. Regular alcohol consumption is most common following skeletal maturity, emphasizing the importance of understanding the skeletal consequences of drinking in adults. This review focuses on describing the complex effects of alcohol on the adult skeleton. Studies assessing the effects of alcohol on bone in adult humans as well as skeletally mature animal models published since the year 2000 are emphasized. Light to moderate alcohol consumption is generally reported to be beneficial, resulting in higher bone mineral density (BMD) and reduced age-related bone loss, whereas heavy alcohol consumption is generally associated with decreased BMD, impaired bone quality, and increased fracture risk. Bone remodeling is the principal mechanism for maintaining a healthy skeleton in adults and dysfunction in bone remodeling can lead to bone loss and/or decreased bone quality. Light to moderate alcohol may exert beneficial effects in older individuals by slowing the rate of bone remodeling, but the impact of light to moderate alcohol on bone remodeling in younger individuals is less certain. The specific effects of alcohol on bone remodeling in heavy drinkers are even less certain because the effects are often obscured by unhealthy lifestyle choices, alcohol-associated disease, and altered endocrine signaling. Although there have been advances in understanding the complex actions of alcohol on bone, much remains to be determined. Limited evidence implicates age, skeletal site evaluated, duration, and pattern of drinking as important variables. Few studies systematically evaluating the impact of these factors have been conducted and should be made a priority for future research. In addition, studies performed in skeletally mature animals have potential to reveal mechanistic insights into the precise actions of alcohol and associated comorbidity factors on bone remodeling.


Association between timing and number of antenatal care visits on uptake of intermittent preventive treatment for malaria during pregnancy among Malawian women.
Malaria in pregnancy is a critical public health challenge, and intermittent preventive treatment for malaria during pregnancy (IPTp) has proven to be an effective intervention. However, access to and use of malaria interventions, including IPTp, remains a considerable problem among African women. This cross-sectional study investigated factors, including antenatal care (ANC) attendance (both numbers of visits and timing of the first visit) and socio-demographics, associated with the uptake of the recommended IPTp dose among Malawian women. A nationally representative sample of women with a live birth in the 2 years preceding the survey from the Malawi Demographic Health Survey 2015-2016 dataset was analysed. Self-reported data on socio-demographics, ANC attendance and IPTp uptake were collected using a questionnaire and analysed using logistic models. Of the 6549 included women, 1981 (30.2%) took the recommended three or more IPTp doses. Despite inadequate ANC visits, early ANC initiation increased the likelihood of these women taking the recommended IPTp dose; women who initiated ANC in the first [adjusted odds ratio (aOR) = 2.24; 95% confidence interval (CI) = 1.44-3.49] and second (aOR = 2.19; 95% CI = 1.56-3.08) trimesters were more likely to take the recommended IPTp dose compared to late initiators. The effect of the number of ANC visits on IPTp uptake was significant in married women (aOR = 1.68, 95% CI = 1.42-1.98), and the timing of first ANC visit was associated with IPTp uptake only among rural women (aOR = 2.13, 95% CI = 1.54-2.95). ANC attendance is vital in IPTp uptake. The results highlight the need for health care providers to encourage women, particularly those in high-risk groups, to make frequent ANC visits and receive early ANC initiation to ensure high coverage of the recommended IPTp dose.


Larval behaviours and their contribution to the distribution of the intertidal coral reef sponge Carteriospongia foliascens.
Sponges (Phylum Porifera) are an evolutionary and ecologically significant group; however information on processes influencing sponge population distributions is surprisingly limited. Carteriospongia foliascens is a common Indo-Pacific sponge, which has been reported from the intertidal to the mesophotic. Interestingly, the distribution of C. foliascens at inshore reefs of the Great Barrier Reef is restricted to the intertidal with no individuals evident in adjacent subtidal habitats. The abundance of C. foliascens and substrate availability was first quantified to investigate the influence of substrate limitation on adult distribution. Pre-settlement processes of larval spawning, swimming speeds, phototaxis, vertical migration, and settlement to intertidal and subtidal substrate cues were also quantified. Notably, suitable settlement substrate (coral rubble) was not limiting in subtidal habitats. C. foliascens released up to 765 brooded larvae sponge(-1) day(-1) during the day, with larvae (80%±5.77) being negatively phototactic and migrating to the bottom within 40 minutes from release. Subsequently, larvae (up to 58.67%±2.91) migrated to the surface after the loss of the daylight cue (nightfall), and after 34 h post-release >98.67% (±0.67) of larvae had adopted a benthic habit regardless of light conditions. Intertidal and subtidal biofilms initiated similar settlement responses, inducing faster (as early 6 h post-release) and more successful metamorphosis (>60%) than unconditioned surfaces. C. foliascens has a high larval supply and larval behaviours that support recruitment to the subtidal. The absence of C. foliascens in subtidal habitats at inshore reefs is therefore proposed to be a potential consequence of post-settlement mortalities.


Dietary interventions to prevent and manage diabetes in worksite settings: a meta-analysis.
The translation of lifestyle intervention to improve glucose tolerance into the workplace has been rare. The objective of this meta-analysis is to summarize the evidence for the effectiveness of dietary interventions in worksite settings on lowering blood sugar levels. We searched for studies in PubMed, Embase, Econlit, Ovid, Cochrane, Web of Science, and Cumulative Index to Nursing and Allied Health Literature. Search terms were as follows: (1) Exposure-based: nutrition/diet/dietary intervention/health promotion/primary prevention/health behavior/health education/food /program evaluation; (2) Outcome-based: diabetes/hyperglycemia/glucose/HbA1c/glycated hemoglobin; and (3) Setting-based: workplace/worksite/occupational/industry/job/employee. We manually searched review articles and reference lists of articles identified from 1969 to December 2016. We tested for between-studies heterogeneity and calculated the pooled effect sizes for changes in HbA1c (%) and fasting glucose (mg/dl) using random effect models for meta-analysis in 2016. A total of 17 articles out of 1663 initially selected articles were included in the meta-analysis. With a random-effects model, worksite dietary interventions led to a pooled -0.18% (95% CI, -0.29 to -0.06; P<0.001) difference in HbA1c. With the random-effects model, the interventions resulted in 2.60 mg/dl lower fasting glucose with borderline significance (95% CI: -5.27 to 0.08, P=0.06). In the multivariate meta-regression model, the interventions with high percent of female participants and that used the intervention directly delivered to individuals, rather the environment changes, were associated with more effective interventions. Workplace dietary interventions can improve HbA1c. The effects were larger for the interventions with greater number of female participants and with individual-level interventions.


Carbon tetrachloride-induced hepatic and renal damages in rat: inhibitory effects of cacao polyphenol.
Here, we investigated the protective effect of cacao polyphenol extract (CPE) on carbon tetrachloride (CCl4)-induced hepato-renal oxidative stress in rats. Rats were administered CPE for 7 days and then received intraperitoneal injection of CCl4. Two hours after injection, we found that CCl4 treatment significantly increased biochemical injury markers, lipid peroxides (phosphatidylcholine hydroperoxide (PCOOH) and malondialdehyde (MDA)) and decreased glutathione peroxidase activity in kidney rather than liver, suggesting that kidney is more vulnerable to oxidative stress under the present experimental conditions. CPE supplementation significantly reduced these changes, indicating that this compound has antioxidant properties against CCl4-induced oxidative stress. An inhibitory effect of CPE on CCl4-induced CYP2E1 mRNA degradation may provide an explanation for CPE antioxidant property. Together, these results provide quantitative evidence of the in vivo antioxidant properties of CPE, especially in terms of PCOOH and MDA levels in the kidneys of CCl4-treated rats.


Highly Multiplexed Phenotyping of Immunoregulatory Proteins in the Tumor Microenvironment by CODEX Tissue Imaging.
Immunotherapies are revolutionizing cancer treatment by boosting the natural ability of the immune system. In addition to antibodies against traditional checkpoint molecules or their ligands (i.e., CTLA-4, PD-1, and PD-L1), therapies targeting molecules such as ICOS, IDO-1, LAG-3, OX40, TIM-3, and VISTA are currently in clinical trials. To better inform clinical care and the design of therapeutic combination strategies, the co-expression of immunoregulatory proteins on individual immune cells within the tumor microenvironment must be robustly characterized. Highly multiplexed tissue imaging platforms, such as CO-Detection by indEXing (CODEX), are primed to meet this need by enabling >50 markers to be simultaneously analyzed in single-cells on formalin-fixed paraffin-embedded (FFPE) tissue sections. Assembly and validation of antibody panels is particularly challenging, with respect to the specificity of antigen detection and robustness of signal over background. Herein, we report the design, development, optimization, and application of a 56-marker CODEX antibody panel to eight cutaneous T cell lymphoma (CTCL) patient samples. This panel is comprised of structural, tumor, and immune cell markers, including eight immunoregulatory proteins that are approved or currently undergoing clinical trials as immunotherapy targets. Here we provide a resource to enable extensive high-dimensional, spatially resolved characterization of the tissue microenvironment across tumor types and imaging modalities. This framework provides researchers with a readily applicable blueprint to study tumor immunology, tissue architecture, and enable mechanistic insights into immunotherapeutic targets.


Personal responsibility and obesity: a constructive approach to a controversial issue.
The concept of personal responsibility has been central to social, legal, and political approaches to obesity. It evokes language of blame, weakness, and vice and is a leading basis for inadequate government efforts, given the importance of environmental conditions in explaining high rates of obesity. These environmental conditions can override individual physical and psychological regulatory systems that might otherwise stand in the way of weight gain and obesity, hence undermining personal responsibility, narrowing choices, and eroding personal freedoms. Personal responsibility can be embraced as a value by placing priority on legislative and regulatory actions such as improving school nutrition, menu labeling, altering industry marketing practices, and even such controversial measures as the use of food taxes that create healthier defaults, thus supporting responsible behavior and bridging the divide between views based on individualistic versus collective responsibility.


Imaging of podocyte foot processes by fluorescence microscopy.
Visualizing podocyte foot processes requires electron microscopy, a technique that depends on special equipment, requires immunogold for colabeling, and does not take advantage of the growing number of in vivo fluorophores available. To address these limitations, we developed a genetic strategy to allow detailed visualization of single podocytes and their foot processes by conventional fluorescence microscopy. We generated a transgenic mouse line expressing a GFP-Cre-ERT2 fusion protein under the control of the collagen α1(I) promoter with strong podocyte expression. Administration of submaximal tamoxifen allowed genetic labeling of single podocytes when crossed with a Cre-reporter line. Of three different reporter systems that we evaluated for the ability to reveal fine structural details of podocytes, bigenic Coll1α1GCE;Gt(ROSA)26Sor(tm9(CAG-tdTomato)) mice allowed podocyte labeling with a strong and homogeneous reporter signal that was easily observed by epifluorescence. We could easily detect anatomic features of podocytes down to tertiary foot processes, and we were able to visualize and quantitate ultrastructural changes to foot processes after podocyte injury. In summary, using this method of genetic labeling and conventional fluorescence microscopy to visualize podocyte foot processes will complement electron microscopy and facilitate the analysis of podocytes and their precursors in vivo.


Associations between specific autoimmune diseases and subsequent dementia: retrospective record-linkage cohort study, UK.
To determine whether hospital admission for autoimmune disease is associated with an elevated risk of future admission for dementia. Retrospective, record-linkage cohort study using national hospital care and mortality administrative data, 1999-2012. Cohorts of people admitted to hospital with a range of autoimmune diseases were constructed, along with a control cohort, and followed forward in time to see if they developed dementia. 1 833 827 people were admitted to hospital with an autoimmune disease; the number of people in cohorts for each autoimmune disease ranged from 1019 people in the Goodpasture's syndrome cohort, to 316 043 people in the rheumatoid arthritis cohort. The rate ratio for dementia after admission for an autoimmune disease, compared with the control cohort, was 1.20 (95% CI 1.19 to 1.21). Where dementia type was specified, the rate ratio was 1.06 (1.04 to 1.08) for Alzheimer's disease and 1.28 (1.26 to 1.31) for vascular dementia. Of 25 autoimmune diseases studied, 18 showed significant positive associations with dementia at p<0.05 (with 14 significant at p<0.001) including Addison's disease (1.48, 1.34 to 1.64), multiple sclerosis (1.97, 1.88 to 2.07), psoriasis (1.29, 1.25 to 1.34) and systemic lupus erythematosus (1.46, 1.32 to 1.61). The associations with vascular dementia may be one component of a broader association between autoimmune diseases and vascular damage. Though findings were significant, effect sizes were small. Clinicians should be aware of the possible coexistence of autoimmune disease and dementia in individuals. Further studies are needed to confirm or refute our findings and to explore possible mechanisms mediating any elevation of risk.


The degree of acute descending control of spinal nociception in an area of primary hyperalgesia is dependent on the peripheral domain of afferent input.
Descending controls of spinal nociceptive processing play a critical role in the development of inflammatory hyperalgesia. Acute peripheral nociceptor sensitization drives spinal sensitization and activates spino-supraspinal-spinal loops leading to descending inhibitory and facilitatory controls of spinal neuronal activity that further modify the extent and degree of the pain state. The afferent inputs from hairy and glabrous skin are distinct with respect to both the profile of primary afferent classes and the degree of their peripheral sensitization. It is not known whether these differences in afferent input differentially engage descending control systems to different extents or in different ways. Injection of complete Freund's adjuvant resulted in inflammation and swelling of hairy hind foot skin in rats, a transient thermal hyperalgesia lasting <2 h, and longlasting primary mechanical hyperalgesia (≥7 days). Much longer lasting thermal hyperalgesia was apparent in glabrous skin (1 h to >72 h). In hairy skin, transient hyperalgesia was associated with sensitization of withdrawal reflexes to thermal activation of either A- or C-nociceptors. The transience of the hyperalgesia was attributable to a rapidly engaged descending inhibitory noradrenergic mechanism, which affected withdrawal responses to both A- and C-nociceptor activation and this could be reversed by intrathecal administration of yohimbine (α-2-adrenoceptor antagonist). In glabrous skin, yohimbine had no effect on an equivalent thermal inflammatory hyperalgesia. We conclude that acute inflammation and peripheral nociceptor sensitization in hind foot hairy skin, but not glabrous skin, rapidly activates a descending inhibitory noradrenergic system. This may result from differences in the engagement of descending control systems following sensitization of different primary afferent classes that innervate glabrous and hairy skin.


Effects of temporal clumping and payoff accumulation on impulsiveness and cooperation.
Animals show impulsiveness when they prefer a smaller more immediate option, even though a larger more delayed option produces a higher intake rate. This impulsive behavior has implications for several behavioral problems including social cooperation. This paper presents two experiments using captive blue jays (Cyanocitta cristata) that consider the effects of payoff accumulation and temporal clumping on impulsiveness and cooperation. Payoff accumulation refers to a situation where the benefits gained from each choice trial accumulate from one trial to the next, and only become available to the animal after it has completed a fixed number of trials. We hypothesized that this would reduce impulsiveness because it removes the advantage of quickly realizing food gains. Clumping refers to situation in which the animal experiences several choice trials in quick succession followed by a long pause before the next clump. We hypothesized that if payoffs accumulated over a clump of trials this would enhance the effect of accumulation. We tested the effects of accumulation and clumping on impulsiveness in a self-control situation. We found a significant interaction between clumping and accumulation. Payoff accumulation reduced impulsiveness, but only when trials were clumped. Post hoc analyses suggest that clumping alone increases impulsiveness. A second experiment applied these results to cooperation. This experiment reveals an interaction between payoff accumulation and trial's position within the clump. Jays were more likely to cooperate on the first trial of a clump, but the likelihood of cooperation dropped after the first trial. However, this drop was larger when payoffs did not accumulate. This observation suggests that the difference between accumulated and un-accumulated treatments that we reported previously may be largely due to differences in how animals behave in the first trial of a clump.


Prediction of Coronary Artery Disease and Major Adverse Cardiovascular Events Using Clinical and Genetic Risk Scores for Cardiovascular Risk Factors.
Coronary artery disease (CAD) and major adverse cardiovascular events (MACE) are the leading causes of death in the general population, but risk stratification remains suboptimal. CAD genetic risk scores (GRSs) predict risk independently from clinical tools, like QRISK3. We assessed the added value of GRSs for a variety of cardiovascular traits (CV GRSs) for predicting CAD and MACE and tested their early-life screening potential by comparing against the CAD GRS only. We used data from 379 581 participants in the UK Biobank without known cardiovascular conditions (follow-up, 11.3 years; 3.3% CAD cases and 5.2% MACE cases). In a training subset (50%) we built 3 scores: QRISK3; QRISK3 and an established CAD GRS; and QRISK3, the CAD GRS and the CV GRSs. In an independent subset (50%), we evaluated each score's performance using the concordance index, odds ratio and net reclassification index. We then repeated the analyses without considering QRISK3. For CAD, the combination of QRISK3 and the CAD GRS had a better performance than QRISK3 alone (concordance index, 0.766 versus 0.753; odds ratio, 5.47 versus 4.82; net reclassification index, 7.7%). Adding the CV GRSs did not significantly improve risk stratification. When only looking at genetic information, the combination of CV GRSs and the CAD GRS had a better performance than the CAD GRS alone (concordance index, 0.637 versus 0.625; odds ratio, 2.17 versus 2.07; net reclassification index, 3.3%). Similar results were obtained for MACE. In individuals without known cardiovascular disease, the inclusion of CV GRSs to a clinical tool and an established CAD GRS does not improve CAD or MACE risk stratification. However, their combination only with the CAD GRS increases prediction performance indicating potential use in early-life screening before the advanced development of conventional cardiovascular risk factors.


Discussion of Stokes' hypothesis through the smoothed particle hydrodynamics model.
Stokes' hypothesis, the zeroing of the bulk viscosity in a Newtonian fluid, is discussed in this paper. To this aim, a continuum macroscopic fluid domain is initially modeled as a Hamiltonian system of discrete particles, for which the interparticle dissipative forces are required to be radial in order to conserve the angular momentum. The resulting system of particles is then reconverted to the continuum domain via the framework of the smoothed particle hydrodynamics (SPH) model. Since an SPH-consistent approximation of the Newtonian viscous term in the momentum equation incorporates interparticle radial as well as nonradial terms, it is postulated that the latter must be null. In the present work it is shown that this constraint implies that first and second viscosities are equal, resulting in a positive value for the bulk viscosity, in contradiction to the cited Stokes' hypothesis. Moreover, it is found that this postulate leads to bulk viscosity coefficients close to values found in the experimental literature for monoatomic gases and common liquids such as water.


Social networks strongly predict the gut microbiota of wild mice.
The mammalian gut teems with microbes, yet how hosts acquire these symbionts remains poorly understood. Research in primates suggests that microbes can be picked up via social contact, but the role of social interactions in non-group-living species remains underexplored. Here, we use a passive tracking system to collect high resolution spatiotemporal activity data from wild mice (Apodemus sylvaticus). Social network analysis revealed social association strength to be the strongest predictor of microbiota similarity among individuals, controlling for factors including spatial proximity and kinship, which had far smaller or nonsignificant effects. This social effect was limited to interactions involving males (male-male and male-female), implicating sex-dependent behaviours as driving processes. Social network position also predicted microbiota richness, with well-connected individuals having the most diverse microbiotas. Overall, these findings suggest social contact provides a key transmission pathway for gut symbionts even in relatively asocial mammals, that strongly shapes the adult gut microbiota. This work underlines the potential for individuals to pick up beneficial symbionts as well as pathogens from social interactions.


Symptomatic Dengue in Children in 10 Asian and Latin American Countries.
The control groups in two phase 3 trials of dengue vaccine efficacy included two large regional cohorts that were followed up for dengue infection. These cohorts provided a sample for epidemiologic analyses of symptomatic dengue in children across 10 countries in Southeast Asia and Latin America in which dengue is endemic. We monitored acute febrile illness and virologically confirmed dengue (VCD) in 3424 healthy children, 2 to 16 years of age, in Asia (Indonesia, Malaysia, the Philippines, Thailand, and Vietnam) from June 2011 through December 2013 and in 6939 children, 9 to 18 years of age, in Latin America (Brazil, Colombia, Honduras, Mexico, and Puerto Rico) from June 2011 through April 2014. Acute febrile episodes were determined to be VCD by means of a nonstructural protein 1 antigen immunoassay and reverse-transcriptase-polymerase-chain-reaction assays. Dengue hemorrhagic fever was defined according to 1997 World Health Organization criteria. Approximately 10% of the febrile episodes in each cohort were confirmed to be VCD, with 319 VCD episodes (4.6 episodes per 100 person-years) occurring in the Asian cohort and 389 VCD episodes (2.9 episodes per 100 person-years) occurring in the Latin American cohort; no trend according to age group was observed. The incidence of dengue hemorrhagic fever was less than 0.3 episodes per 100 person-years in each cohort. The percentage of VCD episodes requiring hospitalization was 19.1% in the Asian cohort and 11.1% in the Latin American cohort. In comparable age groups (9 to 12 years and 13 to 16 years), the burden of dengue was higher in Asia than in Latin America. The burdens of dengue were substantial in the two regions and in all age groups. Burdens varied widely according to country, but the rates were generally higher and the disease more frequently severe in Asian countries than in Latin American countries. (Funded by Sanofi Pasteur; CYD14 and CYD15 ClinicalTrials.gov numbers, NCT01373281 and NCT01374516.).


Does Level of Response to SI Joint Block Predict Response to SI Joint Fusion?
The degree of pain relief required to diagnose sacroiliac joint (SIJ) dysfunction following a diagnostic SIJ block (SIJB) is not known. No gold standard exists. Response to definitive (i.e., accepted as effective) treatment might be a reference standard. Subgroup analysis of 320 subjects enrolled in two prospective multicenter trials evaluating SIJ fusion (SIJF) in patients with SIJ dysfunction diagnosed by history, physical exam and standardized diagnostic SIJB. A 50% reduction in pain at 30 or 60 minutes following SIJB was considered confirmatory. The absolute and percentage improvements in Visual Analog Scale (VAS) SIJ pain and Oswestry Disability Index (ODI) scores at 6 and 12 months after SIJF were correlated with the average acute improvement in SIJ pain with SIJB. The average pain reduction during the first hour after SIJB was 79.3%. Six months after SIJF, the overall mean VAS SIJ pain reduction was 50.9 points (0-100 scale) and the mean ODI reduction was 24.6 points. Reductions at 12 months after SIJF were similar. Examined in multiple ways, improvements in SIJ pain and ODI at 6 and 12 months did not correlate with SIJB findings. The degree of pain improvement during SIJB did not predict improvements in pain or ODI scores after SIJF. A 50% SIJB threshold resulted in excellent post-SIJF responses. Using overly stringent selection criteria (i.e. 75%) to qualify patients for SIJF has no basis in evidence and would withhold a beneficial procedure from a substantial number of patients with SIJ dysfunction. Level 1. The degree of pain improvement during an SIJ block does not predict the degree of pain improvement after SIJ fusion.


Integrin α5β1 regulates PP2A complex assembly through PDE4D in atherosclerosis.
Fibronectin in the vascular wall promotes inflammatory activation of the endothelium during vascular remodeling and atherosclerosis. These effects are mediated in part by fibronectin binding to integrin α5, which recruits and activates phosphodiesterase 4D5 (PDE4D5) by inducing its dephosphorylation on an inhibitory site Ser651. Active PDE then hydrolyzes anti-inflammatory cAMP to facilitate inflammatory signaling. To test this model in vivo, we mutated the integrin binding site in PDE4D5 in mice. This mutation reduced endothelial inflammatory activation in athero-prone regions of arteries, and, in a hyperlipidemia model, reduced atherosclerotic plaque size while increasing markers of plaque stability. We then investigated the mechanism of PDE4D5 activation. Proteomics identified the PP2A regulatory subunit B55α as the factor recruiting PP2A to PDE4D5. The B55α-PP2A complex localized to adhesions and directly dephosphorylated PDE4D5. This interaction also unexpectedly stabilized the PP2A-B55α complex. The integrin-regulated, pro-atherosclerotic transcription factor Yap is also dephosphorylated and activated through this pathway. PDE4D5 therefore mediates matrix-specific regulation of EC phenotype via an unconventional adapter role, assembling and anchoring a multifunctional PP2A complex with other targets. These results are likely to have widespread consequences for control of cell function by integrins.


In utero pesticide exposure, maternal paraoxonase activity, and head circumference.
Although the use of pesticides in inner-city homes of the United States is of considerable magnitude, little is known about the potentially adverse health effects of such exposure. Recent animal data suggest that exposure to pesticides during pregnancy and early life may impair growth and neurodevelopment in the offspring. To investigate the relationship among prenatal pesticide exposure, paraoxonase (PON1) polymorphisms and enzyme activity, and infant growth and neurodevelopment, we are conducting a prospective, multiethnic cohort study of mothers and infants delivered at Mount Sinai Hospital in New York City. In this report we evaluate the effects of pesticide exposure on birth weight, length, head circumference, and gestational age among 404 births between May 1998 and May 2002. Pesticide exposure was assessed by a prenatal questionnaire administered to the mothers during the early third trimester as well as by analysis of maternal urinary pentachlorophenol levels and maternal metabolites of chlorpyrifos and pyrethroids. Neither the questionnaire data nor the pesticide metabolite levels were associated with any of the fetal growth indices or gestational age. However, when the level of maternal PON1 activity was taken into account, maternal levels of chlorpyrifos above the limit of detection coupled with low maternal PON1 activity were associated with a significant but small reduction in head circumference. In addition, maternal PON1 levels alone, but not PON1 genetic polymorphisms, were associated with reduced head size. Because small head size has been found to be predictive of subsequent cognitive ability, these data suggest that chlorpyrifos may have a detrimental effect on fetal neurodevelopment among mothers who exhibit low PON1 activity.


A new open-path eddy covariance method for nitrous oxide and other trace gases that minimizes temperature corrections.
Low-power, open-path gas sensors enable eddy covariance (EC) flux measurements in remote areas without line power. However, open-path flux measurements are sensitive to fluctuations in air temperature, pressure, and humidity. Laser-based, open-path sensors with the needed sensitivity for trace gases like methane (CH4 ) and nitrous oxide (N2 O) are impacted by additional spectroscopic effects. Corrections for these effects, especially those related to temperature fluctuations, often exceed the flux of gases, leading to large uncertainties in the associated fluxes. For example, the density and spectroscopic corrections arising from temperature fluctuations can be one or two orders of magnitude greater than background N2 O fluxes. Consequently, measuring background fluxes with laser-based, open-path sensors is extremely challenging, particularly for N2 O and gases with similar high-precision requirements. We demonstrate a new laser-based, open-path N2 O sensor and a general approach applicable to other gases that minimizes temperature-related corrections for EC flux measurements. The method identifies absorption lines with spectroscopic effects in the opposite direction of density effects from temperature and, thus, density and spectroscopic effects nearly cancel one another. The new open-path N2 O sensor was tested at a corn (Zea mays L.) field in Southwestern Michigan, United States. The sensor had an optimal precision of 0.1 ppbv at 10 Hz and power consumption of 50 W. Field trials showed that temperature-related corrections were 6% of density corrections, reducing EC random errors by 20-fold compared to previously examined lines. Measured open-path N2 O EC fluxes showed excellent agreement with those made with static chambers (m = 1.0 ± 0.3; r2 = .96). More generally, we identified absorption lines for CO2 and CH4 flux measurements that can reduce the temperature-related corrections by 10-100 times compared to existing open-path sensors. The proposed method provides a new direction for future open-path sensors, facilitating the expansion of accurate EC flux measurements.


Out of Africa: modern human origins special feature: isotopic evidence for the diets of European Neanderthals and early modern humans.
We report here on the direct isotopic evidence for Neanderthal and early modern human diets in Europe. Isotopic methods indicate the sources of dietary protein over many years of life, and show that Neanderthals had a similar diet through time (approximately 120,000 to approximately 37,000 cal BP) and in different regions of Europe. The isotopic evidence indicates that in all cases Neanderthals were top-level carnivores and obtained all, or most, of their dietary protein from large herbivores. In contrast, early modern humans (approximately 40,000 to approximately 27,000 cal BP) exhibited a wider range of isotopic values, and a number of individuals had evidence for the consumption of aquatic (marine and freshwater) resources. This pattern includes Oase 1, the oldest directly dated modern human in Europe (approximately 40,000 cal BP) with the highest nitrogen isotope value of all of the humans studied, likely because of freshwater fish consumption. As Oase 1 was close in time to the last Neanderthals, these data may indicate a significant dietary shift associated with the changing population dynamics of modern human emergence in Europe.


A tale of aborigines, conquerors and slaves: Alu insertion polymorphisms and the peopling of Canary Islands.
Classical, mitochondrial DNA (mtDNA) and Y chromosome markers have been used to examine the genetic admixture in present day inhabitants of the Canary Islands. In this study, we report the analysis of ten autosomal Alu insertion polymorphisms in 364 samples from the seven main islands of the Archipelago, and their comparison to continental samples. The detection of population-specific alleles from the Iberian Peninsula and Northwest Africa, as well as their affinities on the basis of genetic distances and principal component analysis, support a clear link between these populations. Coincident with previous results, the Canarian gene pool can be distinguished as being halfway between those of its putative parents, although with a major Iberian contribution (62-78%). Both the substantial Northwest African contribution (23-38%), and the minor sub-Saharan African input (3%), suggest that the genetic legacy from the aborigines and slaves still persists in the Canary Islanders.


Pesticide use and LINE-1 methylation among male private pesticide applicators in the Agricultural Health Study.
Cancer risk may be associated with DNA methylation (DNAm) levels in Long Interspersed Nucleotide Element 1 (LINE-1), a surrogate for global DNAm. Exposure to certain pesticides may increase risk of particular cancers, perhaps mediated in part through global DNAm alterations. To date, human data on pesticide exposure and global DNAm alterations are limited. The goal of this study was to evaluate alterations of LINE-1 DNAm by pesticides in a variety of classes. Data from 596 cancer-free male participants enrolled in the Agricultural Health Study (AHS) were used to examine associations between use of 57 pesticides and LINE-1 DNAm measured via Pyrosequencing in peripheral blood leucocytes. Participants provided information on pesticide use at three contacts between 1993 and 2010. Associations of ever/never pesticide use and lifetime days of application (years of use × days per year) and LINE-1 DNAm level were assessed using linear regression, adjusting for potential confounders (race, age at blood draw, and frequency of drinking alcohol) and other moderately correlated pesticides. After adjustment, ever application of 10 pesticides was positively associated and ever application of eight pesticides was negatively associated with LINE-1 DNAm. In dose-response analyses, increases in five pesticides (imazethapyr, fenthion, EPTC, butylate, and heptachlor) were associated with increasing LINE-1 DNAm (ptrend < 0.05) and increases in three pesticides (carbaryl, chlordane, and paraquat) were associated with decreasing LINE-1 DNAm (ptrend < 0.05). This study provides some mechanistic insight into the pesticide-cancer relationship, which may be mediated in part by epigenetics.


Effectiveness of home monitoring according to the Model of Living in hip replacement surgery patients.
To evaluate the effectiveness of home monitoring according to the Model of Living in hip replacement surgery patients. Hip replacement surgery is important for increasing the quality of life of patients. After these operations, patients may encounter many problems having an impact on their activities of daily living. Quasi-experimental. Sixty patients were included in the study: 30 in the experimental group and 30 in the control group. Patients in the control group received the existing care provided in the hospital. In addition to existing care, patients in the experimental group received training and counselling according to the Model of Living from the time of admission to the clinic. After discharge, home monitoring was performed in the 1st and 6th weeks for control group patients and in the 1st, 3rd and 6th weeks for experimental group patients. Statistical analysis was carried out using percentage calculations, mean, median, chi-square test, Fisher's exact test, likelihood ratio test, Mann-Whitney U-test, Kruskal-Wallis test, anova for repeated measures, independent-sample t-test, Friedman test, McNemar test and McNemar-Bowker tests. It was found that the experimental group patients' knowledge scores increased, they were more independent in performing activities of daily living, and they encountered less problems in the 1st and 6th week after discharge. As a result, it can be claimed that by means of providing training, counselling and home monitoring hip replacement surgery patients according to the Model of Living, the level of knowledge of patients on activities of daily living increased, they were more independent in daily living activities, and they experienced less problems. The use of the Model of Living in the home monitoring of patients who have undergone hip replacement surgery could assist in focusing on the problems most frequently experienced by patients in postoperative care and achieving effective solutions.


Get Checked… Where? The Development of a Comprehensive, Integrated Internet-Based Testing Program for Sexually Transmitted and Blood-Borne Infections in British Columbia, Canada.
Testing for sexually transmitted and blood-borne infections (STBBI) is an effective public health strategy that can promote personal control of one's health and prevent the spread of these infections. Multiple barriers deter access to testing including fear of stigmatization, inaccurate health care provider perceptions of risk, and reduced availability of clinic services and infrastructure. Concurrent increases in sexually transmitted infection (STI) rates and demands on existing clinical services make this an even more pressing concern. Web-based testing offers several advantages that may alleviate existing clinical pressures and facilitate appropriate testing access. This paper describes the planning, development, and usability testing of a novel Web-based testing service, GetCheckedOnline (GCO), as a complementary testing option integrated within existing sexual health services within British Columbia (BC). From 2009 to 2014, we engaged a multidisciplinary team in the design and development of GCO. We conducted 3 initial research studies to ascertain the opinions of youth, men who have sex with men (MSM), and STI clinic clients regarding Web-based testing and elicited perspectives of sexual health care providers through focus groups. We developed an informed consent process, risk assessment questions, and test recommendations based on provincial and national guidelines and evaluated these through consultations with clinical and community stakeholders. We also conducted a preliminary health equity impact assessment whose findings also informed the GCO program mode. Finally, from April 2011 to December 2012 we gathered qualitative data from 25 participants on the functionality and usability of a GCO prototype and incorporated their recommendations into a final model. GCO launched in the fall of 2014 across 6 pilot sites in Vancouver, BC. The service involves 3 main steps: (1) create an account, complete an assessment, and print a laboratory requisition, (2) provide blood and urine specimens at participating laboratory locations, and (3) receive test results on the Internet or by phone. During this pilot phase, we promoted GCO to existing STI clinic clients and MSM in the Greater Vancouver region. A rigorous mixed-method evaluation of GCO's uptake, acceptability, and health system impacts is currently underway. GCO is the first comprehensive Web-based STBBI testing program in Canada that is integrated with existing sexual health services, with the potential to reduce pressures on existing clinical services and reach populations facing the greatest barriers to testing. Our experience highlights the facilitators and challenges of developing and implementing novel complex eHealth interventions within the health care system, and underscores the importance of considering broader implementation contexts.


[Forensic (F)ACT: a study exploring indication, risk assessment and recidivism].
Cutbacks in clinical beds in regular and forensic psychiatry increase the burden on outpatient forensic care in The Netherlands.
 AIM: Since 2007, Dutch forensic (flexible) assertive community treatment (For(F)ACT) teams offer outpatient, intensive treatment to forensic clients with complex mental health issues. As the need for this form of intensive treatment increases, so does the need for unambiguous indication criteria to facilitate adequate care and accompanied reduction in criminal behavior.
 METHOD: The present study investigated the correlation between the clinical indication criteria and risk factors for criminal behavior in 76 For(F)ACT-clients, reviewing which criteria best predicted recidivism.
 RESULTS: A weak correlation was found between the indication criteria and risk factors. Further receiver operating characteristic (ROC) analysis showed that a combination of clinical indication criteria best predicted recidivism.
 CONCLUSION: The influential risk factors for For(F)ACT-clients are different compared to those for other groups of delinquents. Important treatment factors are breaking patterns, increasing safety and offering social and financial support. The clinical indication criteria should not be replaced by the START risk factors.


Neutrophil-activating protein 1/interleukin 8 stimulates the binding activity of the leukocyte adhesion receptor CD11b/CD18 on human neutrophils.
The cytokine NAP-1/IL-8 is produced by a variety of different cells in response to inflammatory stimuli and elicits several biological responses from PMN. Experiments presented here demonstrate that PMN exposed to NAP-1/IL-8 expressed increased amounts of CD11b/CD18, as well as CD11c/CD18 and CR1, on their cell surface, while expression of Fc gamma RIII and HLA-A,B,C remained essentially unchanged. Increased CD11b/CD18 and CD11c/CD18 appears to correspond with the release of specific granules by NAP-1/IL-8. NAP-1/IL-8 was also a potent stimulator of several of the binding activities of CD11b/CD18. Ligation of EC3bi by CD11b/CD18 was rapidly enhanced by NAP-1/IL-8, but phagocytosis of the ligated particles was not induced by the agonist. In addition, enhanced binding of EC3bi was observed in the absence of an increase in receptor expression as shown with PMN cytoplasts. NAP-1/IL-8 promoted additional adhesive interactions between CD11b/CD18 and the biosynthetic precursor of LPS, lipid IVa, fibrinogen, and endothelial cells, suggesting that NAP-1/IL-8 may promote leukocyte adhesion in vivo that could lead to recruitment of PMN to sites of tissue inflammation.


Patient-completed or symptom-based screening tools for endometriosis: a scoping review.
The objective of this review was to evaluate existing patient-completed screening questionnaires and/or symptom-based predictive models with respect to their potential for use as screening tools for endometriosis in adult women. Validated instruments were of particular interest. We conducted structured searches of PubMed and targeted searches of the gray literature to identify studies reporting on screening instruments used in endometriosis. Studies were screened according to inclusion and exclusion criteria that followed the PICOS (population, intervention, comparison, outcomes, study design) framework. A total of 16 studies were identified, of which 10 described measures for endometriosis in general, 2 described measures for endometriosis at specific sites, and 4 described measures for deep-infiltrating endometriosis. Only 1 study evaluated a questionnaire that was solely patient-completed. Most measures required physician, imaging, or laboratory assessments in addition to patient-completed questionnaires, and several measures relied on complex scoring. Validation for use as a screening tool in adult women with potential endometriosis was lacking in all studies, as most studies focused on diagnosis versus screening. This literature review did not identify any fully validated, symptom-based, patient-reported questionnaires for endometriosis screening in adult women.


Long-range nematic order and anomalous fluctuations in suspensions of swimming filamentous bacteria.
We study the collective dynamics of elongated swimmers in a very thin fluid layer by devising long filamentous nontumbling bacteria. The strong confinement induces weak nematic alignment upon collision, which, for large enough density of cells, gives rise to global nematic order. This homogeneous but fluctuating phase, observed on the largest experimentally accessible scale of millimeters, exhibits the properties predicted by standard models for flocking, such as the Vicsek-style model of polar particles with nematic alignment: true long-range nematic order and nontrivial giant number fluctuations.


Validation of a numerical indicator of microbial contamination for karst springs.
Rapid changes in spring water quality in karst areas due to rapid recharge of bacterially contaminated water are a major concern for drinking water suppliers and users. The main objective of this study was to use field experiments with fecal indicators to verify the vulnerability of a karst spring to pathogens, as determined by using a numerical modeling approach. The groundwater modeling was based on linear storage models that can be used to simulate karst water flow. The vulnerability of the karst groundwater is estimated using such models to calculate criteria that influence the likelihood of spring water being affected by microbial contamination. Specifically, the temporal variation in the vulnerability, depending on rainfall events and overall recharge conditions, can be assessed and quantified using the dynamic vulnerability index (DVI). DVI corresponds to the ratio of conduit to diffuse flow contributions to spring discharge. To evaluate model performance with respect to predicted vulnerability, samples from a spring were analyzed for Escherichia coli, enterococci, Clostridium perfringens, and heterotrophic plate count bacteria during and after several rainfall events. DVI was shown to be an indication of the risk of fecal contamination of spring water with sufficient accuracy to be used in drinking water management. We conclude that numerical models are a useful tool for evaluating the vulnerability of karst systems to pathogens under varying recharge conditions.


Sperm express a Ca2+-regulated NAADP synthase.
NAADP (nicotinic acid-adenine dinucleotide phosphate), the most potent Ca2+-mobilizing second messenger, is active in a wide range of organisms and cell types. Until now, all NAADP-producing enzymes have been thought to be members of the ADP-ribosyl cyclase family. ADP-ribosyl cyclases exhibit promiscuous substrate selectivity, synthesize a variety of products and are regulated in a limited manner, which may be non-physiological. In the present paper, we report the presence of an enzyme on the surface of sea urchin sperm that exhibits bell-shaped regulation by Ca2+ over a range (EC(50) of 10 nM and IC(50) of 50 microM) that is physiologically relevant. Uniquely, this surface enzyme possesses complete selectivity for nucleotides with a 2'-phosphate group and exhibits only base-exchange activity without any detectable cyclase activity. Taken together, these findings indicate that this novel enzyme should be considered as the first true NAADP synthase.


Immunotherapy for bladder cancer.
It is nearly 40 years since Bacillus Calmette-Guérin (BCG) was first used as an immunotherapy to treat superficial bladder cancer. Despite its limitations, to date it has not been surpassed by any other treatment. As a better understanding of its mechanism of action and the clinical response to it have evolved, some of the questions around optimal dosing and treatment protocols have been answered. However, its potential for toxicity and failure to produce the desired clinical effect in a significant cohort of patients presents an ongoing challenge to clinicians and researchers alike. This review summarizes the evidence behind the established mechanism of action of BCG in bladder cancer, highlighting the extensive array of immune molecules that have been implicated in its action. The clinical aspects of BCG are discussed, including its role in reducing recurrence and progression, the optimal treatment regime, toxicity and, in light of new evidence, whether or not there is a superior BCG strain. The problems of toxicity and non-responders to BCG have led to development of new techniques aimed at addressing these pitfalls. The progress made in the laboratory has led to the identification of novel targets for the development of new immunotherapies. This includes the potential augmentation of BCG with various immune factors through to techniques avoiding the use of BCG altogether; for example, using interferon-activated mononuclear cells, BCG cell wall, or BCG cell wall skeleton. The potential role of gene, virus, or photodynamic therapy as an alternative to BCG is also reviewed. Recent interest in the immune check point system has led to the development of monoclonal antibodies against proteins involved in this pathway. Early findings suggest benefit in metastatic disease, although the role in superficial bladder cancer remains unclear.


Effect of Psychosocial and Vocational Interventions on Return-to-Work Rates Post-Acute Myocardial Infarction: A SYSTEMATIC REVIEW.
To examine whether the effects of psychosocial and vocational interventions delivered in the first 3 mo post-acute myocardial infarction (AMI) are effective for improving work outcomes compared with other interventions. A search was completed for English language publications up to March 2016 across 4 electronic databases and gray literature. Inclusion criteria were (1) psychosocial and/or vocational interventions; (2) adults 18 years or older with an AMI who were within the first 3 mo post-AMI; (3) randomized or clinically controlled trials; and (4) reporting of at least 1 return-to-work (RTW) outcome: including return to paid/unpaid employment, either full-time or part-time, to the previous job role or on modified duties. Studies were independently screened by 2 reviewers and graded using the Cochrane Collaboration tool for assessing risk of bias. A narrative synthesis and meta-analysis of the included studies was undertaken. Eighteen studies of varying quality were analyzed. Individually delivered psychosocial and vocational interventions may improve work rates at 3 mo (relative risk = 1.17; P = .05) when compared with usual care but there was no difference at 6 or 12 mo. People receiving group or individual psychological/vocational counselling returned to work 6.11 d sooner than those who received usual care (95% CI, -6.95 to -5.26; P < .001). Although psychosocial and vocational interventions show promise in people within 3 mo of AMI, compelling evidence is still limited. There is a need for more detailed, high-quality studies with valid comparison groups and adequate follow-up.


An alternative N-terminal fold of the intestine-specific annexin A13a induces dimerization and regulates membrane-binding.
Annexin proteins function as Ca2+-dependent regulators of membrane trafficking and repair that may also modulate membrane curvature. Here, using high-resolution confocal imaging, we report that the intestine-specific annexin A13 (ANX A13) localizes to the tips of intestinal microvilli and determined the crystal structure of the ANX A13a isoform to 2.6 Å resolution. The structure revealed that the N terminus exhibits an alternative fold that converts the first two helices and the associated helix-loop-helix motif into a continuous α-helix, as stabilized by a domain-swapped dimer. We also found that the dimer is present in solution and partially occludes the membrane-binding surfaces of annexin, suggesting that dimerization may function as a means for regulating membrane binding. Accordingly, as revealed by in vitro binding and cellular localization assays, ANX A13a variants that favor a monomeric state exhibited increased membrane association relative to variants that favor the dimeric form. Together, our findings support a mechanism for how the association of the ANX A13a isoform with the membrane is regulated.


Moving Home: Examining the Independent Effects of Individual- and Neighborhood-Level Residential Mobility on Recidivism in High-Risk Parolees.
A number of studies have shown that the residential mobility of an offender postrelease can significantly influence recidivism. Research has also shown how the mobility of neighborhoods into which offenders are released is an important contextual factor that predicts recidivism. Within the social disorganization framework, this study combines these lines of research by examining the effect of both individual- and neighborhood-level residential mobility on recidivism for a cohort of high-risk prisoners released on parole in New Zealand. Using multilevel analysis techniques, we found that neither immediate individual-level residential mobility nor neighborhood-level mobility was associated with recidivism after controlling for various multilevel predictors. A number of individual- and neighborhood-level variables were predictive of recidivism, including the number of parole conditions placed on the released offender, and the percent foreign born in their neighborhood. These results are discussed within the context of an increasingly eclectic and diverse country.


National survey of pain clinics in Croatia: Organization and services.
To analyze organization and therapeutic procedures administered in tertiary outpatient pain clinics in Croatia. Data about organization of pain clinics, its personnel, equipment, continuing medical education, therapeutic procedures, research activities and relations with pharmaceutical industry were collected using questionnaires. Twenty-two Croatian pain clinics were included in the study. Most of the pain clinics employ exclusively anesthesiologists and nurses. The most frequently prescribed therapeutic procedures in pain clinics were pharmacotherapy, transcutaneous electrical nerve stimulation, acupuncture and trigger point injections. Almost all pain clinics provide educational material for patients. Most of the pain clinics have regular interactions with pharmaceutical companies. Prescribing decisions were based mostly on information from scientific meetings, research articles and consultations with colleagues. Information sources which are considered to be the gold standard--the systematic reviews of The Cochrane Collaboration--were used less frequently (n=12; 57%) than advertising materials from pharmaceutical companies (n=16; 76%). Few physicians and other pain clinics staff had scientific degrees or academic titles or were involved in a research project. The national study about pain clinics in Croatia pointed out that there is room for improvement of their organization and services. Pain clinics should employ health-care professionals with diverse backgrounds. They should offer treatments backed by the highest-level of scientific evidence. Since pain is a major public health issue, pain clinic staff should engage more in research to contribute to the growing field of pain research, to enhance capacities for pain research in Croatia, to incorporate scientific evidence into their daily decision-making and to enable evidence-based practice.


Evidence for improving palliative care at the end of life: a systematic review.
Many persons and their families are burdened by serious chronic illness in late life. How to best support quality of life is an important consideration for care. To assess evidence about interventions to improve palliative and end-of-life care. English-language citations (January 1990 to November 2005) from MEDLINE, the Database of Abstracts of Reviews of Effects, the National Consensus Project for Quality Palliative Care bibliography, and November 2005 to January 2007 updates from expert reviews and literature surveillance. Systematic reviews that addressed "end of life," including terminal illness (for example, advanced cancer) and chronic, eventually fatal illness with ambiguous prognosis (for example, advanced dementia), and intervention studies (randomized and nonrandomized designs) that addressed pain, dyspnea, depression, advance care planning, continuity, and caregiving. Single reviewers screened 24,423 titles to find 6381 relevant abstracts and reviewed 1274 articles in detail to identify 33 high-quality systematic reviews and 89 relevant intervention studies. They synthesized the evidence by using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) classification. Strong evidence supports treating cancer pain with opioids, nonsteroidals, radionuclides, and radiotherapy; dyspnea from chronic lung disease with short-term opioids; and cancer-associated depression with psychotherapy, tricyclics, and selective serotonin reuptake inhibitors. Strong evidence supports multi component interventions to improve continuity in heart failure. Moderate evidence supports advance care planning led by skilled facilitators who engage key decision makers and interventions to alleviate caregiver burden. Weak evidence addresses cancer-related dyspnea management, and no evidence addresses noncancer pain, symptomatic dyspnea management in advanced heart failure, or short-acting antidepressants in terminal illness. No direct evidence addresses improving continuity for patients with dementia. Evidence was weak for improving caregiver burdens in cancer and was absent for heart failure. Variable literature indexing for advanced chronic illness and end of life limited the comprehensiveness of searches, and heterogeneity was too great to do meta-analysis. Strong to moderate evidence supports interventions to improve important aspects of end-of-life care. Future research should quantify these effects and address the generalizability of insights across the conditions and settings of the last part of life. Many critical issues lack high-quality evidence.


Insights into regioselective metabolism of mefenamic acid by cytochrome P450 BM3 mutants through crystallography, docking, molecular dynamics, and free energy calculations.
Cytochrome P450 BM3 (CYP102A1) mutant M11 is able to metabolize a wide range of drugs and drug-like compounds. Among these, M11 was recently found to be able to catalyze formation of human metabolites of mefenamic acid and other nonsteroidal anti-inflammatory drugs (NSAIDs). Interestingly, single active-site mutations such as V87I were reported to invert regioselectivity in NSAID hydroxylation. In this work, we combine crystallography and molecular simulation to study the effect of single mutations on binding and regioselective metabolism of mefenamic acid by M11 mutants. The heme domain of the protein mutant M11 was expressed, purified, and crystallized, and its X-ray structure was used as template for modeling. A multistep approach was used that combines molecular docking, molecular dynamics (MD) simulation, and binding free-energy calculations to address protein flexibility. In this way, preferred binding modes that are consistent with oxidation at the experimentally observed sites of metabolism (SOMs) were identified. Whereas docking could not be used to retrospectively predict experimental trends in regioselectivity, we were able to rank binding modes in line with the preferred SOMs of mefenamic acid by M11 and its mutants by including protein flexibility and dynamics in free-energy computation. In addition, we could obtain structural insights into the change in regioselectivity of mefenamic acid hydroxylation due to single active-site mutations. Our findings confirm that use of MD and binding free-energy calculation is useful for studying biocatalysis in those cases in which enzyme binding is a critical event in determining the selective metabolism of a substrate.


Protective mAbs and Cross-Reactive mAbs Raised by Immunization with Engineered Marburg Virus GPs.
The filoviruses, which include the marburg- and ebolaviruses, have caused multiple outbreaks among humans this decade. Antibodies against the filovirus surface glycoprotein (GP) have been shown to provide life-saving therapy in nonhuman primates, but such antibodies are generally virus-specific. Many monoclonal antibodies (mAbs) have been described against Ebola virus. In contrast, relatively few have been described against Marburg virus. Here we present ten mAbs elicited by immunization of mice using recombinant mucin-deleted GPs from different Marburg virus (MARV) strains. Surprisingly, two of the mAbs raised against MARV GP also cross-react with the mucin-deleted GP cores of all tested ebolaviruses (Ebola, Sudan, Bundibugyo, Reston), but these epitopes are masked differently by the mucin-like domains themselves. The most efficacious mAbs in this panel were found to recognize a novel "wing" feature on the GP2 subunit that is unique to Marburg and does not exist in Ebola. Two of these anti-wing antibodies confer 90 and 100% protection, respectively, one hour post-exposure in mice challenged with MARV.


Methods for Presenting Braille Characters on a Mobile Device with a Touchscreen and Tactile Feedback.
Three novel interaction methods were designed for reading six-dot Braille characters from the touchscreen of a mobile device. A prototype device with a piezoelectric actuator embedded under the touchscreen was used to create tactile feedback. The three interaction methods, scan, sweep, and rhythm, enabled users to read Braille characters one at a time either by exploring the characters dot by dot or by sensing a rhythmic pattern presented on the screen. The methods were tested with five blind Braille readers as a proof of concept. The results of the first experiment showed that all three methods can be used to convey information as the participants could accurately (91-97 percent) recognize individual characters. In the second experiment the presentation rate of the most efficient and preferred method, the rhythm, was varied. A mean recognition accuracy of 70 percent was found when the speed of presenting a single character was nearly doubled from the first experiment. The results showed that temporal tactile feedback and Braille coding can be used to transmit single-character information while further studies are still needed to evaluate the presentation of serial information, i.e., multiple Braille characters.


The thymic epithelial microRNA network elevates the threshold for infection-associated thymic involution via miR-29a mediated suppression of the IFN-α receptor.
Thymic output is a dynamic process, with high activity at birth punctuated by transient periods of involution during infection. Interferon-α (IFN-α) is a critical molecular mediator of pathogen-induced thymic involution, yet despite the importance of thymic involution, relatively little is known about the molecular integrators that establish sensitivity. Here we found that the microRNA network dependent on the endoribonuclease Dicer, and specifically microRNA miR-29a, was critical for diminishing the sensitivity of the thymic epithelium to simulated infection signals, protecting the thymus against inappropriate involution. In the absence of Dicer or the miR-29a cluster in the thymic epithelium, expression of the IFN-α receptor by the thymic epithelium was higher, which allowed suboptimal signals to trigger rapid loss of thymic cellularity.


The value to patients of reducing lesion severity in plaque psoriasis.
Plaque psoriasis is associated with significant psychosocial, quality-of-life, and economic burden. The objective of this study was to quantify the value to patients of reducing the severity and size of plaque psoriasis lesions. Subjects included individuals with a self-reported diagnosis of plaque psoriasis from a nationally representative US household panel. Subjects completed a web-based conjoint analysis survey and chose between hypothetical treatments in a series of questions. Each alternative was defined by lesion severity, percentage of body surface area (BSA) covered by lesions, type of treatment, injection discomfort or pain (if treatment included injections), risk of serious lung infection, and monthly out-of-pocket cost. 28,200 panelists were invited to participate. 18,330 responded, 503 qualified, and 419 completed the survey. Mean age was 54.5 years and 52% were female. 64% (35%) of patients reported psoriasis severity as mild or mild to moderate (moderate to very severe). Patients were willing to pay $486.73 out-of-pocket per month to eliminate severe lesions covering 25% BSA on the arms and legs and $444.80 out-of-pocket per month to eliminate moderate lesions covering 4% BSA on the face. Individuals with plaque psoriasis are willing to pay substantial amounts to reduce lesion severity and percentage of BSA covered by lesions.


The effects of peer-play level on initiations and responses of preschool children with delayed play skills.
The potential impact of peer-play opportunities on the overall development of young children has been well-documented in the social development, occupational therapy, and special education literature. However, the effect of peer characteristics on the manifestation and facilitation of specific types of play roles and behaviors has received little attention. This topic is of key importance to occupational therapists who are striving to develop interventions that enhance the development of social participation and play in preschool children. The purpose of this study was to examine the differences in initiation and response exhibited by preschool-aged children with social-play delays when participating in free-play dyads with peers of differing developmental levels. A single-subject alternating treatments design was replicated across five preschool-aged children with developmental play delays. Each child was paired with one peer who had lower developmental play skills and one peer who had higher developmental play skills. The arranged dyads were given the opportunity to play together in a specially designed playroom at their school. Their interactions were videotaped and later coded. All five children generally showed more initiation and response to initiation during play with higher-level peers, although one participant showed less differentiation for initiation than the other four children. An occupational therapist working with a preschool child with play delays and wanting to facilitate the child's initiation and response in play situations should consider pairing the child with play delays with a child who has higher play skills.


Caesarean section and risk of autism across gestational age: a multi-national cohort study of 5 million births.
The positive association between caesarean section (CS) and autism spectrum disorder (ASD) may be attributed to preterm delivery. However, due to lack of statistical power, no previous study thoroughly examined this association across gestational age. Moreover, most studies did not differentiate between emergency and planned CS. Using population-based registries of four Nordic countries and Western Australia, our study population included 4 987 390 singletons surviving their first year of life, which included 671 646 CS deliveries and 31 073 ASD children. We used logistic regression to estimate odds ratios (OR) and their 95% confidence intervals (CI) for CS, adjusted for gestational age, site, maternal age and birth year. Stratified analyses were conducted by both gestational age subgroups and by week of gestation. We compared emergency versus planned CS to investigate their potential difference in the risk of ASD. Compared with vaginal delivery, the overall adjusted OR for ASD in CS delivery was 1.26 (95% CI 1.22-1.30). Stratified ORs were 1.25 (1.15-1.37), 1.16 (1.09-1.23), 1.34 (1.28-1.40) and 1.17 (1.04-1.30) for subgroups of gestational weeks 26-36, 37-38, 39-41 and 42-44, respectively. CS was significantly associated with risk of ASD for each week of gestation, from week 36 to 42, consistently across study sites (OR ranged 1.16-1.38). There was no statistically significant difference between emergency and planned CS in the risk of ASD. Across the five countries, emergency or planned CS is consistently associated with a modest increased risk of ASD from gestational weeks 36 to 42 when compared with vaginal delivery.


Cattle genomics and its implications for future nutritional strategies for dairy cattle.
The recently sequenced cattle (Bos taurus) genome unraveled the unique genomic features of the species and provided the molecular basis for applying a systemic approach to systematically link genomic information to metabolic traits. Comparative analysis has identified a variety of evolutionary adaptive features in the cattle genome, such as an expansion of the gene families related to the rumen function, large number of chromosomal rearrangements affecting regulation of genes for lactation, and chromosomal rearrangements that are associated with segmental duplications and copy number variations. Metabolic reconstruction of the cattle genome has revealed that core metabolic pathways are highly conserved among mammals although five metabolic genes are deleted or highly diverged and seven metabolic genes are present in duplicate in the cattle genome compared to their human counter parts. The evolutionary loss and gain of metabolic genes in the cattle genome may reflect metabolic adaptations of cattle. Metabolic reconstruction also provides a platform for better understanding of metabolic regulation in cattle and ruminants. A substantial body of transcriptomics data from dairy and beef cattle under different nutritional management and across different stages of growth and lactation are already available and will aid in linking the genome with metabolism and nutritional physiology of cattle. Application of cattle genomics has great potential for future development of nutritional strategies to improve efficiency and sustainability of beef and milk production. One of the biggest challenges is to integrate genomic and phenotypic data and interpret them in a biological and practical platform. Systems biology, a holistic and systemic approach, will be very useful in overcoming this challenge.


Dysregulated Provision of Oxidisable Substrates to the Mitochondria in ME/CFS Lymphoblasts.
Although understanding of the biomedical basis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is growing, the underlying pathological mechanisms remain uncertain. We recently reported a reduction in the proportion of basal oxygen consumption due to ATP synthesis by Complex V in ME/CFS patient-derived lymphoblast cell lines, suggesting mitochondrial respiratory inefficiency. This was accompanied by elevated respiratory capacity, elevated mammalian target of rapamycin complex 1 (mTORC1) signaling activity and elevated expression of enzymes involved in the TCA cycle, fatty acid β-oxidation and mitochondrial transport. These and other observations led us to hypothesise the dysregulation of pathways providing the mitochondria with oxidisable substrates. In our current study, we aimed to revisit this hypothesis by applying a combination of whole-cell transcriptomics, proteomics and energy stress signaling activity measures using subsets of up to 34 ME/CFS and 31 healthy control lymphoblast cell lines from our growing library. While levels of glycolytic enzymes were unchanged in accordance with our previous observations of unaltered glycolytic rates, the whole-cell proteomes of ME/CFS lymphoblasts contained elevated levels of enzymes involved in the TCA cycle (p = 1.03 × 10-4), the pentose phosphate pathway (p = 0.034, G6PD p = 5.5 × 10-4), mitochondrial fatty acid β-oxidation (p = 9.2 × 10-3), and degradation of amino acids including glutamine/glutamate (GLS p = 0.034, GLUD1 p = 0.048, GOT2 p = 0.026), branched-chain amino acids (BCKDHA p = 0.028, BCKDHB p = 0.031) and essential amino acids (FAH p = 0.036, GCDH p = 0.006). The activity of the major cellular energy stress sensor, AMPK, was elevated but the increase did not reach statistical significance. The results suggest that ME/CFS metabolism is dysregulated such that alternatives to glycolysis are more heavily utilised than in controls to provide the mitochondria with oxidisable substrates.