Nano-designed semiconductors for electro- and photoelectro-catalytic conversion of carbon dioxide.
Development of novel catalysts with high efficiency for CO2 conversion is of great research interest, because of the climate hazards caused by the gradual increase in CO2 concentration. Among various types of catalysts, semiconductors have been widely used as effective candidates for both electro- and photoelectro-CO2 conversion. Very recently, with the emerging nanotechnology and advanced characterization techniques, tremendous achievements have been made in highly efficient and clean CO2 conversion based on semiconductor catalysts. This review gives a systematic overview of this field, including the rational design of semiconductor catalysts for electro- and photoelectro-chemical CO2 conversion. Recent advances in the development of mechanism understandings on reaction pathways of CO2 and the feasibility for industrial production are discussed. Furthermore, the challenges and future perspectives of electro- and photoelectro-catalytic CO2 conversion are outlined.


Substitution of Fish for Red Meat or Poultry and Risk of Ischemic Stroke.
We investigated the risk of ischemic stroke and its subtypes when red meat or poultry was substituted with fish. A total of 57,053 participants aged 50⁻65 years at baseline were included in the Danish Diet, Cancer and Health study. All participants filled in a food-frequency questionnaire at recruitment. Potential ischemic stroke cases were identified by linkage to the Danish National Patient Register, and all cases were validated and subclassified. Substitutions were investigated as 150 g/week of fish for 150 g/week of red meat or of poultry using multivariable Cox proportional hazard regression models. During 13.5 years of follow-up, 1879 participants developed an ischemic stroke. Replacing red meat or poultry with fish was not associated with the rate of total ischemic stroke, but there was a statistically significant lower rate of large artery atherosclerosis when fish replaced processed (hazard ratio (HR): 0.78; 95% confidence interval (CI): 0.67; 0.90) and unprocessed (HR: 0.87; 95% CI: 0.75; 0.99) red meat. A statistically significant higher rate of cardioembolism was found when poultry was replaced by total fish (HR: 1.42; 95% CI: 1.04; 1.93). When fatty fish replaced unprocessed red meat, a statistically significant lower rate of small-vessel occlusion was found (HR: 0.88; 95% CI: 0.77; 0.99). In conclusion, replacing red meat with fish was not associated with risk of total ischemic stroke but was associated with a lower risk of subtypes of ischemic stroke.


Preferential growth of single-walled carbon nanotubes with metallic conductivity.
Single-walled carbon nanotubes can be classified as either metallic or semiconducting, depending on their conductivity, which is determined by their chirality. Existing synthesis methods cannot controllably grow nanotubes with a specific type of conductivity. By varying the noble gas ambient during thermal annealing of the catalyst, and in combination with oxidative and reductive species, we altered the fraction of tubes with metallic conductivity from one-third of the population to a maximum of 91%. In situ transmission electron microscopy studies reveal that this variation leads to differences in both morphology and coarsening behavior of the nanoparticles that we used to nucleate nanotubes. These catalyst rearrangements demonstrate that there are correlations between catalyst morphology and resulting nanotube electronic structure and indicate that chiral-selective growth may be possible.


Mechanisms of H and CO loss from the uracil nucleobase following low energy electron irradiation.
Ionising radiation in cells generates secondary low energy electrons (LEEs) which can induce biomolecular damage when incident upon a particular biomolecule. Notable biomolecules include those contained within double-stranded DNA and RNA helices, which upon exposure to LEEs, may form reactive intermediate products that show detriment to their specific structures and functions. Such damaging processes are understood to proceed via dissociative electron attachment (DEA). Using anion resonance stabilisation methods, coupled to state-of-the-art electronic structure methods, and reaction path mapping, the work presented herein highlights the detailed mechanisms associated with molecular elimination of CO and H from the uracil nucleobase following LEE irradiation - providing a rationale for earlier experiments. The results highlight a subset of resonances that show a labile route for forming CO + anionic 1,3-dihydroimidazole (1,3-DHIM-). The nascent 1,3-DHIM anion is itself unstable with respect to N-H bond fission - ultimately forming anionic 1-imidazole (1-IM-) + H products. This hitherto unknown mechanism sheds light on the possible lesion processes that may be encountered by biomolecular constituents when exposed to electron energies analogous to those present in medicinal X-ray diagnostics, aviation and interstellar space. The work also offers some insight into the reactive processes that may have occurred in prebiotic earth.


MGST2 and WNT2 are candidate genes for comitant strabismus susceptibility in Japanese patients.
Strabismus is a common condition with misalignment between two eyes that may lead to decrease of visual acuity, lack of binocularity, and diplopia. It is caused by heterogeneous environmental and genetic risk factors. Our previous research has identified new chromosomal susceptibility loci in 4q28.3 and 7q31.2 regions for comitant strabismus in Japanese families. We conducted a verification study by linkage analysis to narrow the chromosomal loci down to a single gene. From Japanese and U.S. databases, 24 rsSNPs and 233 rsSNPs were chosen from the 4q28.3 and 7q31.2 region, respectively, and were typed in 108 affected subjects and 96 unaffected subjects of 58 families with primary and non-syndromic comitant strabismus. Three major analytical methods were used: transmission disequilibrium test (TDT), TDT allowing for errors (TDTae), and linkage analysis under dominant and recessive inheritance. The SNPs with significant P values in TDT and TDTae were located solely at the gene, microsomal glutathione S-transferase 2 (MGST2), on chromosome 4q28.3 locus. In contrast, significant SNPs were dispersed in a few genes, containing wingless-type MMTV integration site family member 2 (WNT2), on chromosome 7q31.2 locus. The distribution of significant SNPs on the 7q31.2 locus showed that only the ST7 to WNT2 region in the same big haplotype block contained significant SNPs for all three methods of linkage analysis. This study suggests that MGST2 and WNT2 are potential candidates for comitant strabismus in Japanese population.


Endocardial cells are a distinct endothelial lineage derived from Flk1+ multipotent cardiovascular progenitors.
Identification of multipotent cardiac progenitors has provided important insights into the mechanisms of myocardial lineage specification, yet has done little to clarify the origin of the endocardium. Despite its essential role in heart development, characterization of the endocardial lineage has been limited by the lack of specific markers of this early vascular subpopulation. To distinguish endocardium from other vasculature, we generated an NFATc1-nuc-LacZ BAC transgenic mouse line capable of labeling this specific endothelial subpopulation at the earliest stages of cardiac development. To further characterize endocardiogenesis, embryonic stem cells (ESCs) derived from NFATc1-nuc-LacZ blastocysts were utilized to demonstrate that endocardial differentiation in vitro recapitulates the close temporal-spatial relationship observed between myocardium and endocardium seen in vivo. Endocardium is specified as a cardiac cell lineage, independent from other vascular populations, responding to BMP and Wnt signals that enhance cardiomyocyte differentiation. Furthermore, a population of Flk1+ cardiovascular progenitors, distinct from hemangioblast precursors, represents a mesodermal precursor of the endocardial endothelium, as well as other cardiovascular lineages. Taken together, these studies emphasize that the endocardium is a unique cardiac lineage and provides further evidence that endocardium and myocardium are derived from a common precursor.


Araucnephia iberaensis n. sp., a neotropical black fly with a peculiar distribution (Diptera-Simuliidae).
Araucnephia Wygodzinsky & Coscarón is a Neotropical black fly genus in which only one species from Central Chile is known. Another species has now been found in Corrientes province on the eastern side of the Iberá tropical swamps of Argentina, on the western border of the mountainous region of southern Brazil. This new species, A. iberaensis, is herein described and illustrated and information on its bionomics is recorded. It is an interesting species because previous to its discovery no black fly genus or subgenus from Central Chile region has been found in tropical areas, because these two regions are separated by the Monte and Pampas realms. Similarly, no Brazilian genus or subgenus has crossed the Andes mountains to Chile. A comparison with other Neotropical, Nearctic, Ethiopian (Afrotropical) and Australian Prosimuliini (sensu Crosskey & Howard) showed Araucnephia to be a valid taxon most closely related to Araucnephioides (sympatric in Chile). Araucnephia also shows great affinities with Lutzsimulium from Southeast Brazil and Argentina and Paracnephia from South Africa.


Monocytes but Not Lymphocytes Carrying HIV-1 on Their Surface Transmit Infection to Human Tissue Ex Vivo.
Unprotected sexual intercourse with HIV-infected men is the major cause of new infections. HIV virions are released into semen by various cells of the male genital tract, as well as by infected monocytes and lymphocytes present in semen. Some of these virions may attach to the surfaces of cells, infected or uninfected. We investigated whether cells carrying attached HIV on their surfaces can transmit infection. We addressed this question in a model system of human tissue exposed ex vivo to monocytes and lymphocytes carrying HIV on their surfaces. We gamma irradiated the cells to prevent their productive infection. In spite of comparable amounts of HIV attached to monocytes and lymphocytes, only monocytes were capable of transmitting infection and triggering productive infection in tissue. This HIV-1 transmission was mediated by cell-cell contacts. Our experiments suggest that in vivo, HIV attached to infected or uninfected monocytes, which far outnumber lymphocytes in HIV-infected semen, may contribute to sexual transmission of HIV from men to their partners. The vast majority of new HIV infections occur through sexual transmission, in which HIV is transferred from the semen of an infected male to an uninfected partner. In semen, HIV-1 particles may exist as free-floating virions; inside infected cells; or attached to the surfaces of cells, whether they are infected or not. Here, we investigated whether HIV attached to the surfaces of monocytes or lymphocytes could transmit infection to human tissue. Incubation of human tissue with monocyte-attached HIV resulted in productive tissue infection. In contrast, there was no infection of tissues when they were incubated with lymphocyte-attached HIV-1. Our results highlight the important role that seminal monocytes may play in HIV transmission in vivo, especially since monocytes far outnumber lymphocytes in the semen of HIV-infected individuals.


Changing physician behavior: what works?
There are various interventions for guideline implementation in clinical practice, but the effects of these interventions are generally unclear. We conducted a systematic review to identify effective methods of implementing clinical research findings and clinical guidelines to change physician practice patterns, in surgical and general practice. Systematic review of reviews. We searched electronic databases (MEDLINE, EMBASE, and PubMed) for systematic reviews published in English that evaluated the effectiveness of different implementation methods. Two reviewers independently assessed eligibility for inclusion and methodological quality, and extracted relevant data. Fourteen reviews covering a wide range of interventions were identified. The intervention methods used include: audit and feedback, computerized decision support systems, continuing medical education, financial incentives, local opinion leaders, marketing, passive dissemination of information, patient-mediated interventions, reminders, and multifaceted interventions. Active approaches, such as academic detailing, led to greater effects than traditional passive approaches. According to the findings of 3 reviews, 71% of studies included in these reviews showed positive change in physician behavior when exposed to active educational methods and multifaceted interventions. Active forms of continuing medical education and multifaceted interventions were found to be the most effective methods for implementing guidelines into general practice. Additionally, active approaches to changing physician performance were shown to improve practice to a greater extent than traditional passive methods. Further primary research is necessary to evaluate the effectiveness of these methods in a surgical setting.


Using the Q10 model to simulate E. coli survival in cowpats on grazing lands.
Microbiological quality of surface waters can be affected by microbial load in runoff from grazing lands. This effect, with other factors, depends on the survival of microorganisms in animal waste deposited on pastures. Since temperature is a leading environmental parameter affecting survival, it indirectly impacts water microbial quality. The Q10 model is widely used to predict the effect of temperature on rates of biological processes, including survival. Objectives of this work were to (i) evaluate the applicability of the Q10 model to Escherichia coli inactivation in bovine manure deposited on grazing land (i.e., cowpats) and (ii) identify explanatory variables for the previously reported E. coli survival dynamics in cowpats. Data utilized in this study include published results on E. coli concentrations in natural and repacked cowpats from research conducted the U.S. (Virginia and Maryland), New Zealand, and the United Kingdom. Inspection of the datasets led to conceptualizing E. coli survival (in cowpats) as a two-stage process, in which the initial stage was due to growth, inactivation or stationary state of the population and the second stage was the approximately first-order inactivation. Applying the Q10 model to these datasets showed a remarkable similarity in inactivation rates, using the thermal time. The reference inactivation rate constant of 0.042 (thermal days)(-1) at 20 °C gave a good approximation (R(2)=0.88) of all inactivation stage data with Q10=1.48. The reference inactivation rate constants in individual studies were no different from the one obtained by pooling all data (P<0.05). The rate of logarithm of the E. coli concentration change during the first stage depended on temperature. Duration of the first stage, prior to the first-order inactivation stage and the initial concentration of E. coli in cowpats, could not be predicted from available data. Diet and age are probable factors affecting these two parameters however, until their environmental and management predictors are known, microbial water quality modeling must treat them as a stochastic source of uncertainty in simulation results.


Preface for buccal drug delivery theme issue.
During the past years, buccal drug delivery has attracted the attention of researchers looking for alternative delivery routes of administration. As an alternative to oral drug delivery, the buccal mucosal route avoids the passage through the acidic gastric environment, intestinal and bacterial enzymatic activity, absorption issues associated with the intestinal epithelium (e.g. P-glycoprotein efflux), and the first pass metabolism of the liver. Therefore, the buccal route could be a good delivery route for macromolecules and other drugs not compatible with the gastrointestinal tract environment. This "Buccal Drug Delivery" special edition of Drug Development and Industrial Pharmacy aims to bring together a range of different aspects relevant to the growing field of buccal drug delivery. The special edition includes thorough reviews of the literature, as well as original research articles touching on most prominent features related to buccal drug delivery systems, such as the move toward the use of nanotechnology in different ways to facilitate buccal drug delivery with the potential to prompt future product developments.


CAROLS: a new airborne L-band radiometer for ocean surface and land observations.
The "Cooperative Airborne Radiometer for Ocean and Land Studies" (CAROLS) L-Band radiometer was designed and built as a copy of the EMIRAD II radiometer constructed by the Technical University of Denmark team. It is a fully polarimetric and direct sampling correlation radiometer. It is installed on board a dedicated French ATR42 research aircraft, in conjunction with other airborne instruments (C-Band scatterometer-STORM, the GOLD-RTR GPS system, the infrared CIMEL radiometer and a visible wavelength camera). Following initial laboratory qualifications, three airborne campaigns involving 21 flights were carried out over South West France, the Valencia site and the Bay of Biscay (Atlantic Ocean) in 2007, 2008 and 2009, in coordination with in situ field campaigns. In order to validate the CAROLS data, various aircraft flight patterns and maneuvers were implemented, including straight horizontal flights, circular flights, wing and nose wags over the ocean. Analysis of the first two campaigns in 2007 and 2008 leads us to improve the CAROLS radiometer regarding isolation between channels and filter bandwidth. After implementation of these improvements, results show that the instrument is conforming to specification and is a useful tool for Soil Moisture and Ocean Salinity (SMOS) satellite validation as well as for specific studies on surface soil moisture or ocean salinity.


Clinical features and treatment response of light chain (AL) amyloidosis diagnosed in patients with previous diagnosis of multiple myeloma.
To identify and assess the clinical features and treatment response of light chain (AL) amyloidosis diagnosed in patients with previous diagnosis of multiple myeloma (MM). From a prospectively maintained database, we identified 47 patients seen between January 1, 1990, and August 31, 2008, with a diagnosis of AL amyloidosis that was made at least 6 months after MM diagnosis; these patients form the study group. Among the 47 patients, 36 developed typical features, 3 had atypical features, and 8 had an incidental finding of amyloidosis. Amyloid deposits were demonstrated in bone marrow, subcutaneous fat aspirate, or organ biopsy in 24, 19, and 12 patients, respectively. One organ was involved in 29 patients (62%), whereas 11 patients (23%) had involvement in more than one organ. At diagnosis of AL amyloidosis, treatment was changed or started in 22 patients, whereas the same treatment was continued in 21 patients, and no treatment data were available for the rest. The best hematologic response included partial response or better in 11 patients (23%) and stable disease in 18 patients (38%). Improvement in an organ was seen in 3 of the 21 evaluable patients. The median overall survival from diagnosis of AL amyloidosis was 9.1 months (95% confidence interval, 4-14). Of the 6 patients still alive, 2 underwent peripheral blood stem cell transplant, and none had cardiac involvement or involvement in more than one organ. Delayed onset of AL amyloidosis is rarely seen in patients with MM and requires a high index of suspicion for prompt diagnosis. Outcome of these patients is poor, especially in the presence of cardiac involvement.


Circulating vitamin D, calcium and risk of cerebrovascular disease: a systematic review and meta-analysis.
Available literature suggests that both vitamin D and calcium may be associated with a wide range of non-skeletal outcomes. However, epidemiological evidence supporting their individual associations with incident cerebrovascular disease is scarce. We conducted a systematic review and meta-analysis of prospective cohort studies, published before February 2012 and sought from MEDLINE, EMBASE, BIOSIS and the Science Citation Index databases, and reported cerebrovascular disease (defined as any fatal or non-fatal ischemic stroke, hemorrhagic stroke, cerebrovascular accident or transient ischemic attack) by circulating vitamin D (25-hydroxy vitamin D [25(OH)D] as active metabolite) and calcium levels. Two independent investigators abstracted information on 25(OH)D and calcium, cerebrovascular outcomes and other characteristics from selected studies. Relative risks (RRs) were pooled by both random and fixed effects meta-analyses and were further examined under different study-level characteristics. Publication bias was assessed with funnel plots and Egger's asymmetry test. From 5,778 initial references, nine unique prospective cohort studies met our inclusion criteria. Seven studies (involving 47,809 participants and 926 cerebrovascular events) focused on circulating 25(OH)D and 3 reported on circulating calcium (22,577 participants and 727 events). For 25(OH)D, in a comparison of individuals in the top third versus those in the bottom third at baseline, the combined RR for cerebrovascular disease, adjusted for several conventional risk factors, was 0.60 (95 % CI 0.48, 0.72). The corresponding RR in the prospective studies that reported on baseline circulating calcium levels for cerebrovascular disease was 1.40 (95 % CI 1.19, 1.64). There was no apparent evidence of heterogeneity or publication bias among included studies. Available data indicate that higher circulating level of vitamin D is associated with a decreased risk of cerebrovascular disease. Conversely, higher circulating calcium concentration is associated with an increased risk of cerebrovascular disease.


Male burying beetles extend, not reduce, parental care duration when reproductive competition is high.
Male parents spend less time caring than females in many species with biparental care. The traditional explanation for this pattern is that males have lower confidence of parentage, so they desert earlier in favour of pursuing other mating opportunities. However, one recent alternative hypothesis is that prolonged male parental care might also evolve if staying to care actively improves paternity. If this is the case, an increase in reproductive competition should be associated with increased paternal care. To test this prediction, we manipulated the level of reproductive competition experienced by burying beetles, Nicrophorus vespilloides (Herbst, 1783). We found that caregiving males stayed for longer and mated more frequently with their partner when reproductive competition was greater. Reproductive productivity did not increase when males extended care. Our findings provide support for the increased paternity hypothesis. Extended duration of parental care may be a male tactic both protecting investment (in the current brood) and maximizing paternity (in subsequent brood(s) via female stored sperm) even if this fails to maximize current reproductive productivity and creates conflict of interest with their mate via costs associated with increased mating frequency.


Statistical adaptive sensing by detectors with spectrally overlapping bands.
It has recently been reported that by using a spectral-tuning algorithm, the photocurrents of multiple detectors with spectrally overlapping responsivities can be optimally combined to synthesize, within certain limits, the response of a detector with an arbitrary responsivity. However, it is known that the presence of noise in the photocurrent can degrade the performance of this algorithm significantly, depending on the choice of the responsivity spectrum to be synthesized. We generalize this algorithm to accommodate noise. The results are applied to quantum-dot mid-infrared detectors with bias-dependent spectral responses. Simulation and experiment are used to show the ability of the algorithm to reduce the adverse effect of noise on its spectral-tuning capability.


Exploring the promises of intersectionality for advancing women's health research.
Women's health research strives to make change. It seeks to produce knowledge that promotes action on the variety of factors that affect women's lives and their health. As part of this general movement, important strides have been made to raise awareness of the health effects of sex and gender. The resultant base of knowledge has been used to inform health research, policy, and practice. Increasingly, however, the need to pay better attention to the inequities among women that are caused by racism, colonialism, ethnocentrism, heterosexism, and able-bodism, is confronting feminist health researchers and activists. Researchers are seeking new conceptual frameworks that can transform the design of research to produce knowledge that captures how systems of discrimination or subordination overlap and "articulate" with one another. An emerging paradigm for women's health research is intersectionality. Intersectionality places an explicit focus on differences among groups and seeks to illuminate various interacting social factors that affect human lives, including social locations, health status, and quality of life. This paper will draw on recently emerging intersectionality research in the Canadian women's health context in order to explore the promises and practical challenges of the processes involved in applying an intersectionality paradigm. We begin with a brief overview of why the need for an intersectionality approach has emerged within the context of women's health research and introduce current thinking about how intersectionality can inform and transform health research more broadly. We then highlight novel Canadian research that is grappling with the challenges in addressing issues of difference and diversity. In the analysis of these examples, we focus on a largely uninvestigated aspect of intersectionality research - the challenges involved in the process of initiating and developing such projects and, in particular, the meaning and significance of social locations for researchers and participants who utilize an intersectionality approach. The examples highlighted in the paper represent important shifts in the health field, demonstrating the potential of intersectionality for examining the social context of women's lives, as well as developing methods which elucidate power, create new knowledge, and have the potential to inform appropriate action to bring about positive social change.


Genome Maps, a new generation genome browser.
Genome browsers have gained importance as more genomes and related genomic information become available. However, the increase of information brought about by new generation sequencing technologies is, at the same time, causing a subtle but continuous decrease in the efficiency of conventional genome browsers. Here, we present Genome Maps, a genome browser that implements an innovative model of data transfer and management. The program uses highly efficient technologies from the new HTML5 standard, such as scalable vector graphics, that optimize workloads at both server and client sides and ensure future scalability. Thus, data management and representation are entirely carried out by the browser, without the need of any Java Applet, Flash or other plug-in technology installation. Relevant biological data on genes, transcripts, exons, regulatory features, single-nucleotide polymorphisms, karyotype and so forth, are imported from web services and are available as tracks. In addition, several DAS servers are already included in Genome Maps. As a novelty, this web-based genome browser allows the local upload of huge genomic data files (e.g. VCF or BAM) that can be dynamically visualized in real time at the client side, thus facilitating the management of medical data affected by privacy restrictions. Finally, Genome Maps can easily be integrated in any web application by including only a few lines of code. Genome Maps is an open source collaborative initiative available in the GitHub repository (https://github.com/compbio-bigdata-viz/genome-maps). Genome Maps is available at: http://www.genomemaps.org.


Dehydroepiandrosterone sulfotransferase is a target for transcriptional induction by the vitamin D receptor.
Dehydroepiandrosterone sulfotransferase (SULT2A1) is a cytosolic enzyme that mediates sulfo-conjugation of endogenous hydroxysteroids (dehydroepiandrosterone, testosterone, bile acids), and diverse xenobiotic compounds. Upon sulfonation, SULT2A1 substrates become polar and water-soluble and thus suitable for rapid excretion. SULT2A1 is abundantly expressed in the liver and intestine. Recent evidence has shown that the ligand-activated vitamin D receptor (VDR) can transcriptionally induce the xenobiotic-metabolizing cytochrome P450 enzymes. Herein, we report that VDR also targets SULT2A1 for transcriptional activation. Vitamin D stimulated endogenous SULT2A1 expression and induced transfected human, mouse, and rat SULT2A1 promoters in liver and intestinal cells upon cotransfection with VDR. An inverted repeat DNA element (IR0), located within -191 to -168 positions of mouse and rat Sult2A1, mediates VDR induction of Sult2A1. DNase1 footprinting, competition EMSA, and antibody supershift assay showed that the IR0 is a binding site for the RXR-alpha/VDR heterodimer. Point mutations within the IR0 prevented RXR/VDR binding and abolished VDR-mediated Sult2A1 induction. The IR0 element conferred VDR responsiveness on a thymidine kinase promoter. Thus, VDR-mediated nuclear signaling may be important in the phase II metabolism involving Sult2A1. The rodent Sult2A1 gene is also induced by the farnesoid X receptor (FXR) and pregnane X receptor (PXR) through the same IR0. In competition transfections, FXR or PXR inhibited VDR induction of the IR0. Competitive functional interactions among VDR, PXR, and FXR suggest that the intracellular hormonal and metabolic milieu may determine the extent to which a specific nuclear receptor pathway would influence steroid/xenobiotic metabolism using dehydroepiandrosterone sulfotransferase.


GM-CSF controls nonlymphoid tissue dendritic cell homeostasis but is dispensable for the differentiation of inflammatory dendritic cells.
GM-CSF (Csf-2) is a critical cytokine for the in vitro generation of dendritic cells (DCs) and is thought to control the development of inflammatory DCs and resident CD103(+) DCs in some tissues. Here we showed that in contrast to the current understanding, Csf-2 receptor acts in the steady state to promote the survival and homeostasis of nonlymphoid tissue-resident CD103(+) and CD11b(+) DCs. Absence of Csf-2 receptor on lung DCs abrogated the induction of CD8(+) T cell immunity after immunization with particulate antigens. In contrast, Csf-2 receptor was dispensable for the differentiation and innate function of inflammatory DCs during acute injuries. Instead, inflammatory DCs required Csf-1 receptor for their development. Thus, Csf-2 is important in vaccine-induced CD8(+) T cell immunity through the regulation of nonlymphoid tissue DC homeostasis rather than control of inflammatory DCs in vivo.


Chronic traumatic encephalopathy in an epilepsy surgery cohort: Clinical and pathologic findings.
To determine the occurrence of chronic traumatic encephalopathy (CTE) in young adult patients undergoing epilepsy surgery. Ten patients who underwent epilepsy surgery were randomly selected for this retrospective study. The patients were 18-45 years of age, had preoperative neuropsychological evaluation, and had 1 year postoperative follow-up. Microscopic sections from resections were evaluated for the presence of CTE with standard stains and antibodies to tau (clone AT8). The median age at resection was 32.5 years (range 23-43) and the median duration of seizures was 23.5 years (range 3-28). Eight had a history of head injury. Preoperative neuropsychological testing showed mild to moderate cognitive impairment in 8 patients (80%). Pathologic examination in one patient showed focal sparse tau-immunoreactive lesions along descending rami and cortical gyral depths of the resected frontal lobe. Nine patients had no evidence of CTE. All focal cortical resections showed variable subpial and subcortical gliosis commonly identified in patients with chronic seizure disorders. The present small retrospective observational study suggests that CTE may occur, but appears uncommon, in young adult patients undergoing surgical treatment for drug-resistant focal epilepsy. The significance of these findings requires further investigation to define the relative importance of tau accumulation in younger adult patients with drug-resistant focal epilepsy and cognitive decline.


Assessing the role of basic control measures, antivirals and vaccine in curtailing pandemic influenza: scenarios for the US, UK and the Netherlands.
An increasing number of avian flu cases in humans, arising primarily from direct contact with poultry, in several regions of the world have prompted the urgency to develop pandemic preparedness plans worldwide. Leading recommendations in these plans include basic public health control measures for minimizing transmission in hospitals and communities, the use of antiviral drugs and vaccination. This paper presents a mathematical model for the evaluation of the pandemic flu preparedness plans of the United States (US), the United Kingdom (UK) and the Netherlands. The model is used to assess single and combined interventions. Using data from the US, we show that hospital and community transmission control measures alone can be highly effective in reducing the impact of a potential flu pandemic. We further show that while the use of antivirals alone could lead to very significant reductions in the burden of a pandemic, the combination of transmission control measures, antivirals and vaccine gives the most 'optimal' result. However, implementing such an optimal strategy at the onset of a pandemic may not be realistic. Thus, it is important to consider other plausible alternatives. An optimal preparedness plan is largely dependent on the availability of resources; hence, it is country-specific. We show that countries with limited antiviral stockpiles should emphasize their use therapeutically (rather than prophylactically). However, countries with large antiviral stockpiles can achieve greater reductions in disease burden by implementing them both prophylactically and therapeutically. This study promotes alternative strategies that may be feasible and attainable for the US, UK and the Netherlands. It emphasizes the role of hospital and community transmission control measures in addition to the timely administration of antiviral treatment in reducing the burden of a flu pandemic. The latter is consistent with the preparedness plans of the UK and the Netherlands. Our results indicate that for low efficacy and coverage levels of antivirals and vaccine, the use of a vaccine leads to the greatest reduction in morbidity and mortality compared with the singular use of antivirals. However, as these efficacy and coverage levels are increased, the use of antivirals is more effective.


A Biomarker-based Biological Age in UK Biobank: Composition and Prediction of Mortality and Hospital Admissions.
Chronological age is the strongest risk factor for most chronic diseases. Developing a biomarker-based age and understanding its most important contributing biomarkers may shed light on the effects of age on later-life health and inform opportunities for disease prevention. A subpopulation of 141 254 individuals healthy at baseline were studied, from among 480 019 UK Biobank participants aged 40-70 recruited in 2006-2010, and followed up for 6-12 years via linked death and secondary care records. Principal components of 72 biomarkers measured at baseline were characterized and used to construct sex-specific composite biomarker ages using the Klemera Doubal method, which derived a weighted sum of biomarker principal components based on their linear associations with chronological age. Biomarker importance in the biomarker ages was assessed by the proportion of the variation in the biomarker ages that each explained. The proportions of the overall biomarker and chronological age effects on mortality and age-related hospital admissions explained by the biomarker ages were compared using likelihoods in Cox proportional hazard models. Reduced lung function, kidney function, reaction time, insulin-like growth factor 1, hand grip strength, and higher blood pressure were key contributors to the derived biomarker age in both men and women. The biomarker ages accounted for >65% and >84% of the apparent effect of age on mortality and hospital admissions for the healthy and whole populations, respectively, and significantly improved prediction of mortality (p < .001) and hospital admissions (p < 1 × 10-10) over chronological age alone. This study suggests that a broader, multisystem approach to research and prevention of diseases of aging warrants consideration.


Changing malaria intervention coverage, transmission and hospitalization in Kenya.
Reports of declining incidence of malaria disease burden across several countries in Africa suggest that the epidemiology of malaria across the continent is in transition. Whether this transition is directly related to the scaling of intervention coverage remains a moot point. Paediatric admission data from eight Kenyan hospitals and their catchments have been assembled across two three-year time periods: September 2003 to August 2006 (pre-scaled intervention) and September 2006 to August 2009 (post-scaled intervention). Interrupted time series (ITS) models were developed adjusting for variations in rainfall and hospital use by surrounding communities to show changes in malaria hospitalization over the two periods. The temporal changes in factors that might explain changes in disease incidence were examined sequentially for each hospital setting, compared between hospital settings and ranked according to plausible explanatory factors. In six out of eight sites there was a decline in Malaria admission rates with declines between 18% and 69%. At two sites malaria admissions rates increased by 55% and 35%. Results from the ITS models indicate that before scaled intervention in September 2006, there was a significant month-to-month decline in the mean malaria admission rates at four hospitals (trend P < 0.05). At the point of scaled intervention, the estimated mean admission rates for malaria was significantly less at four sites compared to the pre-scaled period baseline. Following scaled intervention there was a significant change in the month-to-month trend in the mean malaria admission rates in some but not all of the sites. Plausibility assessment of possible drivers of change pre- versus post-scaled intervention showed inconsistent patterns however, allowing for the increase in rainfall in the second period, there is a suggestion that starting transmission intensity and the scale of change in ITN coverage might explain some but not all of the variation in effect size. At most sites where declines between observation periods were documented admission rates were changing before free mass ITN distribution and prior to the implementation of ACT across Kenya. This study provides evidence of significant within and between location heterogeneity in temporal trends of malaria disease burden. Plausible drivers for changing disease incidence suggest a complex combination of mechanisms, not easily measured retrospectively.


Heterozygosity-fitness correlations in a bottlenecked island species: a case study on the Seychelles warbler.
We used capture-mark-recapture models to investigate the effects of both individual and parental heterozygosity, measured at microsatellite loci on the survival of Seychelles warblers (Acrocephalus sechellensis), an endemic island species which went through a severe population bottleneck in the middle of the last century. We found that an individual's survival was not correlated with multilocus heterozygosity, or with heterozygosity at any specific locus. However, maternal, but not paternal, multilocus heterozygosity was positively associated with offspring survival, but only in years with low survival probabilities. A nestling cross-fostering experiment showed that this was a direct maternal effect as there was an effect of the genetic mother's, but not of the social mother's, heterozygosity. Heterozygosity-fitness correlations at microsatellite markers were generally assumed to reflect genome-wide effects. Although this might be true in partially inbred populations, such correlations may also arise as a result of local effects with specific markers being closely linked to genes which determine fitness. However, heterozygosity at the individual microsatellite loci was not correlated and therefore does not seem to reflect genome-wide heterozygosity. This suggests that even in a small bottlenecked population, heterozygosity-fitness correlations may not be caused by genome-wide effects. Support for the local effects hypothesis was also equivocal; although three specific loci were associated with offspring survival, including all single-locus heterozygosities as independent predictors for the variation in survival was not supported by the data. Furthermore, in contrast to the local effects hypothesis, the loci which contributed most to the heterozygosity-survival relationship were not more polymorphic than the other loci. This study highlights the difficulties in distinguishing between the two hypotheses.


Bullying perspectives among rural youth: a mixed methods approach.
Few studies have examined violence among rural youth even though it is recognized as a societal concern. A mixed method, descriptive study was conducted to examine violence among rural youth including their perceptions and experiences of it. This article focuses specifically on the perceptions and experiences of bullying among rural youth that were generated from the Qualitative Phase One interviews and Quantitative Phase Two responses. A mixed method study was conducted in two separate phases. The information generated from the Qualitative Phase One (n = 52) was used to develop a survey instrument employed in the subsequent Quantitative Phase Two (n = 180). The youth who were involved in each phase lived in different geographic areas of a Western Canadian province. The qualitative phase generated a number of comments about the experience of being bullied or how it felt to be a bully. In the survey instrument, specific questions related to bullying were embedded within it. Demographic information was collected in both phases of the study. Research assistants were used to collect the data in each phase. The transcripts from the qualitative phase were analyzed for categories and themes. The survey instrument included demographic questions and seventy questions that included a four-point Likert scale. The data were analyzed using SPSS v14 (SPSS Inc; Chicago, IL, USA). For this article, the survey questions that focused on bullying were considered alongside the qualitative comments in order to more fully understand the perceptions and viewpoints of rural youth regarding this particular aspect of violence. Conducting a mixed method study provides a more in-depth understanding of bullying among youth in the rural context. The pain and humiliation of being bullied provided a personalized understanding of the survey responses that indicated which youth are targets of bullying. For example, comments were made about being picked on because of personal characteristics such as being overweight or dressing in an unacceptable manner. In addition, bullies openly talked about the power they gained from their role. The frequency responses to the questions in the survey confirmed that bullies obtain power from their behavior and that youth who are different are bullied. The participants also noted that something needed to be done to address bullying but remarked that they would not seek professionals' help. The findings negate the myth that rural places are ideal places to raise children. Although the youth did not identify that they would access professionals, it is important for members of rural communities to acknowledge bullying, its impacts and how they can prevent it. Working from the social structure of rural communities is a first step in this process. Rural communities will benefit as a whole if bullying, an important societal concern, is addressed. Building on the social structure of rural communities is important, However, listening to rural youth themselves is the key if true change is to be implemented.


The nucleus accumbens in monkeys (Macaca fascicularis): I. The organization of behaviour.
A behavioural comparison was made between six unoperated control monkeys and six monkeys which received bilateral ibotenic acid lesions of the nucleus accumbens. Two of the control monkeys were subsequently given bilateral lesions of the anterior cingulate and medial frontal cortex (areas 24, 25 and 32) and were retested on the behavioural tasks. The NA lesioned monkeys, but not the anterior cingulate lesioned monkeys, were significantly impaired on a hoarding task in which they were required to remove 18 peanuts from their shells and store them in their cheek pouches. These same monkeys were not impaired when the nuts were presented without shells. Evidence is provided which suggests that this deficit is not motivational or due to gross motor impairments. A second task in which the animals were required to search through four boxes to retrieve food revealed a decrease in the tendency for the NA and cingulate lesioned animals to use an organized pattern of searching. Both groups were found to return to a previously opened box more often than controls. However, neither group showed signs of perseverative behaviour. Data from a ten-box version of this task suggest that these return errors were not due to a decrease in working memory. Together these studies suggest that both the NA and the anterior cingulate cortex contribute to the ability to organize behaviour temporally and spatially.


Genetic Variation, Magnesium Sulfate Exposure, and Adverse Neurodevelopmental Outcomes Following Preterm Birth.
To evaluate the association of magnesium sulfate (MgSO4) exposure and candidate gene polymorphisms with adverse neurodevelopmental outcomes following preterm birth. We performed a nested case-control analysis of a randomized trial of maternal MgSO4 before anticipated preterm birth for the prevention of cerebral palsy (CP). Cases were children who died within 1 year of life or were survivors with abnormal neurodevelopment at age 2 years. Controls were race- and sex-matched survivors with normal neurodevelopment. We analyzed 45 candidate gene polymorphisms in inflammation, coagulation, and vascular regulation pathways and their association with (1) psychomotor delay, (2) mental delay, (3) CP, and (4) combined outcome of death/CP. Logistic regression analyses, conditional on maternal race and child sex, and adjusted for treatment group, gestational age at birth and maternal education, were performed. Four hundred and six subjects, 211 cases and 195 controls, were analyzed. The strongest association was for IL6R (rs 4601580) in which each additional copy of the minor allele was associated with an increased risk of psychomotor delay (adjusted odds ratio 3.3; 95% confidence interval, 1.7-6.5; p < 0.001). Candidate gene polymorphisms are associated with death and adverse neurodevelopmental outcomes following preterm birth. MgSO4 may abrogate this genotype association for some loci.


Global trends in exclusive breastfeeding.
Infant and young child feeding is critical for child health and survival. Proportion of infants 0-5 months who are fed exclusively with breast milk is a common indicator used for monitoring and evaluating infant and young child feeding in a given country and region. Despite progress made since 1990, a previous review in 2006 of global and regional trends found improvement to be modest. The current study provides an update in global and regional trends in exclusive breastfeeding from 1995 to 2010, taking advantage of the wealth of data from recent household surveys. Using the global database of infant and young child feeding maintained by the United Nations Children's Fund, the authors examined estimates from 440 household surveys in 140 countries over the period between 1995 and 2010 and calculated global and regional averages of the rate of exclusive breastfeeding among infants 0-5 months for the two time points to assess the trends. Trend data suggest the prevalence of exclusive breastfeeding among infants younger than six months in developing countries increased from 33% in 1995 to 39% in 2010. The prevalence increased in almost all regions in the developing world, with the biggest improvement seen in West and Central Africa. In spite of the well-recognized importance of exclusive breastfeeding, the practice is not widespread in the developing world and increase on the global level is still very modest with much room for improvement. Child nutrition programmes worldwide continue to require investments and commitments to improve infant feeding practices in order to have maximum impact on children's lives.


Modeling, clustering, and segmenting video with mixtures of dynamic textures.
A dynamic texture is a spatio-temporal generative model for video, which represents video sequences as observations from a linear dynamical system. This work studies the mixture of dynamic textures, a statistical model for an ensemble of video sequences that is sampled from a finite collection of visual processes, each of which is a dynamic texture. An expectationmaximization (EM) algorithm is derived for learning the parameters of the model, and the model is related to previous works in linear systems, machine learning, time-series clustering, control theory, and computer vision. Through experimentation, it is shown that the mixture of dynamic textures is a suitable representation for both the appearance and dynamics of a variety of visual processes that have traditionally been challenging for computer vision (e.g. fire, steam, water, vehicle and pedestrian traffic, etc.). When compared with state-of-the-art methods in motion segmentation, including both temporal texture methods and traditional representations (e.g. optical flow or other localized motion representations), the mixture of dynamic textures achieves superior performance in the problems of clustering and segmenting video of such processes.


The importance of demographic niches to tree diversity.
Most ecological hypotheses about species coexistence hinge on species differences, but quantifying trait differences across species in diverse communities is often unfeasible. We examined the variation of demographic traits using a global tropical forest data set covering 4500 species in 10 large-scale tree inventories. With a hierarchical Bayesian approach, we quantified the distribution of mortality and growth rates of all tree species at each site. This allowed us to test the prediction that demographic differences facilitate species richness, as suggested by the theory that a tradeoff between high growth and high survival allows species to coexist. Contrary to the prediction, the most diverse forests had the least demographic variation. Although demographic differences may foster coexistence, they do not explain any of the 16-fold variation in tree species richness observed across the tropics.


GOLPH2 expression in renal cell cancer.
Renal cell carcinomas (RCC) are among the most common and most lethal genitourinary malignancies. GOLPH2 (golgi phosphoprotein 2, GOLM1) has recently been proposed as a biomarker for hepatocellular and prostate cancer. In this study we analysed the expression patterns and the prognostic and diagnostic value of GOLPH2 in RCC. GOLPH2 protein expression was analysed by immunohistochemistry in 104 clinically well characterized RCC cases in comparison with matched normal kidney tissue and in association with clinico-pathological parameters. Statistical analyses including Kaplan Meier analyses were performed with SPSS version 15.0. GOLPH2 was highly expressed in normal renal tubules and in almost half of RCC with a statistically significant predominance in the papillary and chromophobe histological subtypes. No other associations with clinico-pathological parameters were detectable. The Kaplan-Meier curves showed a weak trend for unfavourable prognosis of tumours with high GOLPH2 expression, but failed significance. GOLPH2 protein is expressed in normal renal tissue (especially in distal tubular epithelia) and is down-regulated in the majority of clear cell RCC. In papillary and chromophobe RCC GOLPH2 expression is consistently present. In contrast to its diagnostic value in hepatocellular and prostatic carcinomas, a prognostic or diagnostic value of GOLPH2 in RCC appears to be unlikely.


Phylogenetic and mutational analyses of human LEUTX, a homeobox gene implicated in embryogenesis.
Recently, human PAIRED-LIKE homeobox transcription factor (TF) genes were discovered whose expression is limited to the period of embryo genome activation up to the 8-cell stage. One of these TFs is LEUTX, but its importance for human embryogenesis is still subject to debate. We confirmed that human LEUTX acts as a TAATCC-targeting transcriptional activator, like other K50-type PAIRED-LIKE TFs. Phylogenetic comparisons revealed that Leutx proteins are conserved across Placentalia and comprise two conserved domains, the homeodomain, and a Leutx-specific domain containing putative transcriptional activation motifs (9aaTAD). Examination of human genotype resources revealed 116 allelic variants in LEUTX. Twenty-four variants potentially affect function, but they occur only heterozygously at low frequency. One variant affects a DNA-specificity determining residue, mutationally reachable by a one-base transition. In vitro and in silico experiments showed that this LEUTX mutation (alanine to valine at position 54 in the homeodomain) results in a transactivational loss-of-function to a minimal TAATCC-containing promoter and a 36 bp motif enriched in genes involved in embryo genome activation. A compensatory change in residue 47 restores function. The results support the notion that human LEUTX functions as a transcriptional activator important for human embryogenesis.


Regulation of HIF1α under Hypoxia by APE1/Ref-1 Impacts CA9 Expression: Dual Targeting in Patient-Derived 3D Pancreatic Cancer Models.
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related mortality in the United States. Aggressive treatment regimens have not changed the disease course, and the median survival has just recently reached a year. Several mechanisms are proposed to play a role in PDAC therapeutic resistance, including hypoxia, which creates a more aggressive phenotype with increased metastatic potential and impaired therapeutic efficacy. AP Endonuclease-1/Redox Effector Factor 1 (APE1/Ref-1) is a multifunctional protein possessing a DNA repair function in base excision repair and the ability to reduce oxidized transcription factors, enabling them to bind to their DNA target sequences. APE1/Ref-1 regulates several transcription factors involved in survival mechanisms, tumor growth, and hypoxia signaling. Here, we explore the mechanisms underlying PDAC cell responses to hypoxia and modulation of APE1/Ref-1 redox signaling activity, which regulates the transcriptional activation of hypoxia-inducible factor 1 alpha (HIF1α). Carbonic anhydrase IX (CA9) is regulated by HIF1α and functions as a part of the cellular response to hypoxia to regulate intracellular pH, thereby promoting cell survival. We hypothesized that modulating APE1/Ref-1 function will block activation of downstream transcription factors, STAT3 and HIF1α, interfering with the hypoxia-induced gene expression. We demonstrate APE1/Ref-1 inhibition in patient-derived and established PDAC cells results in decreased HIF1α-mediated induction of CA9. Furthermore, an ex vivo three-dimensional tumor coculture model demonstrates dramatic enhancement of APE1/Ref-1-induced cell killing upon dual targeting of APE1/Ref-1 and CA9. Both APE1/Ref-1 and CA9 are under clinical development; therefore, these studies have the potential to direct novel PDAC therapeutic treatment. Mol Cancer Ther; 15(11); 2722-32. ©2016 AACR.


Arabidopsis Mutants Lacking Blue Light-Dependent Inhibition of Hypocotyl Elongation.
We have isolated a new class of photomorphogenic mutants in Arabidopsis. Hypocotyl elongation is not inhibited in the mutant seedlings by continuous blue light but is inhibited by far red light, indicating that these mutations are phenotypically different from the previously isolated long hypocotyl (hy) mutants. Complementation analysis indicated that recessive nuclear mutations at three genetic loci, designated blu1, blu2, and blu3, can result in the blu mutant phenotype and that these mutants are genetically distinct from other long hypocotyl mutants. The BLU genes appear to be important only during seedling development because the blu mutations have little effect on mature plants, whereas hypocotyl elongation and cotyledon expansion are altered in seedlings. The genetic separation of the blue and far red sensitivities of light-induced hypocotyl inhibition in the blu and hy mutants demonstrates that two photosensory systems function in this response.


Whether depositing fat or losing weight, fish maintain a balance.
In fish, the relative amount of tissues of different densities changes significantly over short periods throughout the year, depending on the availability of food, nutrition and their developmental status, such as sexual maturation. If a land-living animal accumulates fat it influences not only its general state of health, but also markedly increases its energy expenditure for locomotion owing to the force of gravity. On a body submerged in water, this force, which acts on the centre of gravity (COG), is counterbalanced by a lifting force that is negligible in air and which acts on the centre of buoyancy (COB). Any difference in the longitudinal positions of the two centres will therefore result in pitching moments that must be counteracted by body or fin movements. The displacement of the COG away from the COB is a result of tissues of different density (e.g. bones and fat) not being distributed homogeneously along the body axis. Moreover, the proportions of tissues of different densities change significantly with feeding status. It is still unknown whether these changes produce a displacement of the COG and thus affect the hydrostatic stability of fish. Analysis of computed tomography and magnetic resonance imaging images of Atlantic herring, Atlantic salmon and Atlantic mackerel reveals that the COG is fairly constant in each species, although we recorded major interspecies differences in the relative amount of fat, muscle and bone. We conclude that the distribution of different tissues along the body axis is very closely adjusted to the swimming mode of the fish by keeping the COG constant, independent of the body fat status, and that fish can cope with large variations in energy intake without jeopardizing their COG and thus their swimming performance.


The relationship between the components of pulmonary artery pressure remains constant under all conditions in both health and disease.
The relationships among systolic pulmonary artery pressure (SPAP), diastolic pulmonary artery pressure (DPAP), and mean pulmonary artery pressure (MPAP) have been found to be constant in humans breathing air, at rest, while supine. It would be important for those studying the pulmonary circulation if this relationship were maintained under other circumstances, such as change in posture, during exercise, or after pharmacologic manipulation. In particular, it would be useful if the relationship were maintained when treating pulmonary hypertension because this would allow different methods of measurement to be compared, such as SPAP from echocardiography and MPAP from right heart catheterization. Data were reviewed from both healthy subjects and those with pulmonary hypertension (n = 65) who had a micromanometer-tipped, high-fidelity pulmonary artery catheter inserted for between 6 and 36 h in the Scottish Pulmonary Vascular Unit between 1997 and 2003. The 5-min averages, while the patient was supine at rest, were analyzed by linear regression to compare the response of SPAP and DPAP with MPAP. There were linear relationships (measured in millimeters of mercury) of SPAP with MPAP (SPAP = 1.50 MPAP + 0.46), and DPAP with MPAP (DPAP = 0.71 MPAP - 0.66). These were maintained with a high degree of accuracy following changes in posture and activity. SPAP, MPAP, and DPAP were strongly related, and these relationships were maintained under varying conditions. This finding will allow comparison between invasive and noninvasive descriptions of pulmonary hemodynamics found in the literature.


Animal personality in a foundation species drives community divergence and collapse in the wild.
Despite thousands of papers on the topic, precious few of the studies on animal personality have considered the role of personality in shaping community-level processes. Here, we test the effect of individual variation on the long-term trajectories of biological communities, from initiation to their demise. The spider Anelosimus studiosus builds webs that serve as habitat for >50 species of spider, which together construct a species-rich silken reef. This species also exhibits a temporally consistent behavioural polymorphism where females exhibit either an aggressive or docile phenotype (personality). In this study, we established incipient colonies of either two docile or two aggressive females and then tracked community succession and persistence over 7 years in the field. In particular, we noted the community compositions associated with colony extinction/collapse events, which are common in this species. The community composition of webs founded by different phenotypes diverged rapidly in their early successional stages. However, this period of divergence was ephemeral and all communities eventually converged on a similar composition; communities founded by aggressive females merely took longer to reach it. This secondary stage of community convergence was itself short-lived and independent of founders' personality; all communities collapsed within a year of achieving it. Experimentally imposing this fatal climax composition on colonies caused 80% of communities to collapse within a year, suggesting that this climax composition actually causes the collapse of the community. Community collapse was characterized by a complete die-off of the foundation species and the dispersal of all other spiders. Thus, the behavioural traits of the founding, foundational individuals of these communities dictate their path of succession and longevity in the wild.


Excess nicotinamide increases plasma serotonin and histamine levels.
Methylation, a methyl group-consuming reaction, plays a key role in the degradation (i.e., inactivation) of monoamine neurotransmitters, including catecholamines, serotonin and histamine. Without labile methyl groups, the methylation-mediated degradation cannot take place. Although high niacin (nicotinic acid and nicotinamide) intake, which is very common nowadays, is known to deplete the body's methyl-group pool, its effect on monoamine-neurotransmitter degradation is not well understood. The aim of this article was to investigate the effect of excess nicotinamide on the levels of plasma serotonin and histamine in healthy subjects. Urine and venous blood samples were collected from nine healthy male volunteers before and after oral loading with 100 mg nicotinamide. Plasma N(1)-methylnicotinamide, urinary N(1)-methyl-2-pyridone-5-carboxamide (2-Py), and plasma betaine levels were measured by using high-performance liquid chromatography (HPLC). Plasma concentrations of choline, serotonin and histamine were measured using commercial kits. The results showed that the plasma N(1)-methylnicotinamide level and the urinary excretion of 2-Py significantly increased after oral loading with 100 mg nicotinamide, which was accompanied with a decrease in the methyl-group donor betaine. Compared with those before nicotinamide load, five-hour postload plasma serotonin and histamine levels significantly increased. These results suggest that excess nicotinamide can disturb monoamine-neurotransmitter metabolism. These findings may be of significance in understanding the etiology of monoamine-related mental diseases, such as schizophrenia and autism (a neurodevelopmental disorder).


Confronting the Challenging Asymmetric Carbonyl 1,2-Addition Using Vinyl Heteroarene Pronucleophiles: Ligand-Controlled Regiodivergent Processes through a Dearomatized Allyl-Cu Species.
The selective reductive coupling of vinyl heteroarenes with aldehydes and ketones represents a versatile approach for the rapid construction of enantiomerically enriched secondary and tertiary alcohols, respectively. Herein, we demonstrate a CuH-catalyzed regiodivergent coupling of vinyl heteroarenes with carbonyl-containing electrophiles, in which the selectivity is controlled by the ancillary ligand. This approach leverages an in situ generated benzyl- or dearomatized allyl-Cu intermediate, yielding either the dearomatized or exocyclic addition products, respectively. The method exhibits excellent regio-, diastereo-, and enantioselectivity and tolerates a range of common functional groups and heterocycles. The dearomative pathway allows direct access to a variety of functionalized saturated heterocyclic structures. The reaction mechanism was probed using a combination of experimental and computational approach. Density functional theory studies suggest that the ligand-controlled regioselectivity results from the C-H/π interaction and steric repulsion in transition states, leading to the major and minor regioisomers, respectively. Hydrocupration of vinyl heteroarene pronucleophile is the enantiodetermining step, whereas the diastereoselectivity is enforced by steric interactions between the benzylic or allyl-Cu intermediate and carbonyl-containing substrates in a six-membered cyclic transition state.


Topography of cytochrome oxidase activity in owl monkey cortex.
In primate cortical tissue which has been stained for the mitochondrial enzyme cytochrome oxidase, a topographical pattern of regularly spaced blobs has been demonstrated in primary visual cortex (Hendrickson, A. E., S. P. Hunt, and J. -Y. Wu (1981) Nature 292: 605-607; Horton, J. C., and D. H. Hubel (1981) Nature 292: 762-764), and a pattern of stripes has been shown in secondary visual cortex (V2) as well (Livingstone, M. S., and D. H. Hubel (1982) Proc. Natl. Acad. Sci. U. S. A. 79: 6098-6101; Tootell, R. B. H., M. S. Silverman, E. Switkes, and R. L. De Valois (1982) Soc. Neurosci. Abstr. 8: 707). These regular cytoarchitectonic landmarks have proven extremely useful in parsing the functional and anatomical architecture of these two cortical areas. In order to look for similar landmarks in other cortical areas of a primate, we completely unfolded the cortical gray matter in the owl monkey (Aotus trivirgatus), sectioned it parallel with the flattened cortical surface, and stained the tissue for cytochrome oxidase. Distinctive cytochrome oxidase topographies were found in about seven different cortical areas. As in other primates, area V1 is characterized by blobs and area V2 is characterized by strips. In the owl monkey, area MT is characterized by an elaborate topography of dark staining in layers 1 to 4, interspersed with light blob-shaped regions, and partially surrounded by a dark ring. Many of these topographic inhomogeneities are also reflected in the lower layer myelination topography in MT. Visual area(s) VP/VA is characterized by an irregular or strip-like topography. In some animals, a distinctive topography can be seen in area DX, which is presumably equivalent to either area DM or DI. Primary auditory cortex stains very darkly, but the overall shape of area A is quite variable and the borders are indistinct. Somatosensory area 3B stains quite darkly with sharp borders, but again the overall shape of area 3B is different from that previously described.


The Influence of Aerobic Fitness on Heart Rate Responses of Custody Assistant Recruits during Circuit Training Sessions.
This study captured heart rate (HR) responses of custody assistant (CA) recruits undertaking circuit training sessions. Data from 10 male and 12 female CA recruits were analyzed. Based on YMCA step test recovery HR, recruits were divided into higher fitness (HF; top 25%), lower fitness (LF; bottom 25%), and moderate fitness (MF; remaining recruits) groups. HR was measured during two circuit training sessions featuring calisthenics and running. HR zones were defined as: very light (<57% of age-predicted maximum heart-rate [HRmax]); light (57-63% HRmax); moderate (64-76% HRmax); vigorous (77-95% HRmax); and very vigorous (>95% HRmax). A one-way ANOVA, with Bonferroni post hoc, calculated between-group differences in time spent, and percentage of total time, in the HR zones. In session one, the LF group spent less time in the light training zone compared to the MF group, and more time in the very vigorous zone compared to the HF group (p = 0.027-0.047). In session two, the LF group spent more time in the moderate zone compared to both groups, and a greater percentage of time in the very vigorous zone compared to the MF group (p = 0.002-0.004). LF recruits generally worked harder during circuit training than their fitter counterparts, which supported recommendations for ability-based modifications.


Two-photon spectroscopy and analysis with a white-light continuum probe.
We present a powerful experimental tool and analysis for characterization of two-photon absorption (2PA) spectra. We demonstrate this method with ZnS and then apply it to organic dyes in solution. We also compare the results with those from other methods such as two-photon fluorescence spectroscopy. This femtosecond pump-probe method uses a white-light continuum (WLC) as the probe to produce a nondegenerate 2PA spectrum. The extreme chirp of the WLC requires that transmittance data be collected over a range of temporal delays between pump and probe pulses. These data then need to be corrected for the effects of this chirp as well as for the temporal walk-off of the pulses in the sample that result from the frequency nondegenerate nature of the experiment. We present a simple analytic solution for the transmitted fluence through the sample, which is applicable for most practical cases.


Comparison of antioxidant and free radical scavenging activities of the essential oils from flowers and fruits of Otostegia persica Boiss.
The aerial parts of the endemic plant of Otostegia persica Boiss. in two different stages of flowering and fruiting were hydro-distilled to extract oils in the yields of 0.3 and 0.15% (v/w), respectively. The oils were analyzed by GC and GC/MS. Twenty-eight and thirty-one components were identified, representing 97.59 and 94.61% of the oils, respectively. The main compounds of the essential oil flowers (EOFL) were alpha-pinene (17.21%), 1-octen,3-ol (13.44%) and cubenol (7.27%), whereas diisooctyl phthalate (45%) and hexadecanoic acid (11.07%) were the major constituents of the essential oil of the fruits (EOFR). The oils were screened for their possible antioxidant activities by two complementary test systems, namely DPPH free radical-scavenging and ammonium thiocyanate. In both tested systems, EOFL exerted greater antioxidant and radical scavenging activity. In the first case, EOFL exerted antioxidant activity with an IC50 19.8 +/- 1.8 microg mL(-1) almost similar to BHA and ascorbic acid (15.2 +/- 1.1 and 17.4 +/- 1.3), respectively. In the ammonium thiocyanate system, the inhibition rate of oxidation of linoleic acid for EOFL was estimated 93.5 +/- 2.8. The higher activity of this oil in comparison to EOFR may be attributed to its high content of monoterpenes, especially oxygenated ones in the oil of the flowers.


Translational considerations in injectable cell-based therapeutics for neurological applications: concepts, progress and challenges.
Significant progress has been made during the past decade towards the clinical adoption of cell-based therapeutics. However, existing cell-delivery approaches have shown limited success, with numerous studies showing fewer than 5% of injected cells persisting at the site of injection within days of transplantation. Although consideration is being increasingly given to clinical trial design, little emphasis has been given to tools and protocols used to administer cells. The different behaviours of various cell types, dosing accuracy, precise delivery, and cell retention and viability post-injection are some of the obstacles facing clinical translation. For efficient injectable cell transplantation, accurate characterisation of cellular health post-injection and the development of standardised administration protocols are required. This review provides an overview of the challenges facing effective delivery of cell therapies, examines key studies that have been carried out to investigate injectable cell delivery, and outlines opportunities for translating these findings into more effective cell-therapy interventions.


Mastery learning for health professionals using technology-enhanced simulation: a systematic review and meta-analysis.
Competency-based education requires individualization of instruction. Mastery learning, an instructional approach requiring learners to achieve a defined proficiency before proceeding to the next instructional objective, offers one approach to individualization. The authors sought to summarize the quantitative outcomes of mastery learning simulation-based medical education (SBME) in comparison with no intervention and nonmastery instruction, and to determine what features of mastery SBME make it effective. The authors searched MEDLINE, EMBASE, CINAHL, ERIC, PsycINFO, Scopus, key journals, and previous review bibliographies through May 2011. They included original research in any language evaluating mastery SBME, in comparison with any intervention or no intervention, for practicing and student physicians, nurses, and other health professionals. Working in duplicate, they abstracted information on trainees, instructional design (interactivity, feedback, repetitions, and learning time), study design, and outcomes. They identified 82 studies evaluating mastery SBME. In comparison with no intervention, mastery SBME was associated with large effects on skills (41 studies; effect size [ES] 1.29 [95% confidence interval, 1.08-1.50]) and moderate effects on patient outcomes (11 studies; ES 0.73 [95% CI, 0.36-1.10]). In comparison with nonmastery SBME instruction, mastery learning was associated with large benefit in skills (3 studies; effect size 1.17 [95% CI, 0.29-2.05]) but required more time. Pretraining and additional practice improved outcomes but, again, took longer. Studies exploring enhanced feedback and self-regulated learning in the mastery model showed mixed results. Limited evidence suggests that mastery learning SBME is superior to nonmastery instruction but takes more time.


Reliability in patient-centered observations of family physicians.
Patient-centered communication is an important component of primary care and related to improved patient health outcomes and satisfaction. The Patient-Centered Observation Form (PCOF) was developed as an educational assessment tool to improve resident physician-patient communication. However, reliability of the tool has not been tested. Residents and patients were observed in routine medical encounters in a Midwestern family medicine residency center as part of a prospective, quasi-experimental study. Four independent observers (two faculty clinicians and two social scientists) used the PCOF to rate videorecorded patient encounters in the areas of establishing rapport, maintaining relationships, agenda setting, efficiency, information gathering, assessing patient perspectives, effective and open use of the electronic medical record (EMR), sharing information, discussion of behavior changes, co-creating a plan, and shared decision making. A total of 13 physician-patient encounters were observed. Mean overall reliability for the PCOF was 0.67 using four raters, 0.45 for clinicians only, and 0.62 for social scientists. Adequate reliability (>0.7) was found for behavior change discussion (0.89) in clinician ratings but not with social scientists (0.62). Social scientists had adequate reliability in assessing patients' perspectives on health (0.86) and shared decision making (0.78), but these were not considered reliable among clinicians (0.46 and 0.00, respectively). Reliability of the PCOF for assessing patient-centered competence is dependent on the content of communication being scored and the training history of the evaluator. These results challenge researchers and physicians to develop more reliable scoring instructions and tools for assessing patient-centered competence.


Relationship between heterosexual anal sex, injection drug use and HIV infection among black men and women.
US blacks carry a disproportionate risk of heterosexually transmitted HIV. This study aimed to evaluate the association between self-reported heterosexual anal intercourse and HIV. Using respondent-driven sampling (RDS), we recruited and interviewed 909 blacks from areas of high poverty and HIV prevalence in Houston, Texas, and who reported heterosexual sex in the last year. All individuals were tested for HIV. Weighted prevalence values were calculated to account for non-random recruitment associated with RDS. The weighted population prevalence of HIV infection was 2.4% and 2.5% among men and women, respectively. Education, employment status, income and crack cocaine use were not associated with HIV infection. Lifetime injection drug use (odds ratio [OR] 3.31, 95% confidence interval [CI] 1.31-8.33%) and heterosexual anal intercourse (OR 2.41, 95% CI 1.02-5.73%) were associated with HIV infection. Individuals who reported both injection drug use and heterosexual anal intercourse had 6.21 increased odds of HIV (95% CI 2.47-15.61%). Our results suggest that heterosexual anal sex may be a vector for HIV transmission, especially in the context of injection drug use. Prevention strategies directed at curbing the HIV epidemic among black heterosexuals require that we correctly identify the risks so that appropriate interventions can be developed.


Immunogenic Subtypes of Breast Cancer Delineated by Gene Classifiers of Immune Responsiveness.
The abundance and functional orientation of tumor-infiltrating lymphocytes in breast cancer is associated with distant metastasis-free survival, yet how this association is influenced by tumor phenotypic heterogeneity is poorly understood. Here, a bioinformatics approach defined tumor biologic attributes that influence this association and delineated tumor subtypes that may differ in their ability to sustain durable antitumor immune responses. A large database of breast tumor expression profiles and associated clinical data was compiled, from which the ability of phenotypic markers to significantly influence the prognostic performance of a classification model that incorporates immune cell-specific gene signatures was ascertained. Markers of cell proliferation and intrinsic molecular subtype reproducibly distinguished two breast cancer subtypes that we refer to as immune benefit-enabled (IBE) and immune benefit-disabled (IBD). The IBE tumors, comprised mostly of highly proliferative tumors of the basal-like, HER2-enriched, and luminal B subtypes, could be stratified by the immune classifier into significantly different prognostic groups, while IBD tumors could not, indicating the potential for productive engagement of metastasis-protective immunity in IBE tumors, but not in IBD tumors. The prognostic stratification in IBE was independent of conventional variables. Gene network analysis predicted the activation of TNFα/IFNγ signaling pathways in IBE tumors and the activation of the transforming growth factor-β pathway in IBD tumors. This prediction supports a model in which breast tumors can be distinguished on the basis of their potential for metastasis-protective immune responsiveness. Whether IBE and IBD represent clinically relevant contexts for evaluating sensitivity to immunotherapeutic agents warrants further investigation. Cancer Immunol Res; 4(7); 600-10. ©2016 AACR.


Cognitive Training in Young Patients With Traumatic Brain Injury: A Fixel-Based Analysis.
Background. Traumatic brain injury (TBI) is associated with altered white matter organization and impaired cognitive functioning. Objective. We aimed to investigate changes in white matter and cognitive functioning following computerized cognitive training. Methods. Sixteen adolescents with moderate-to-severe TBI (age 15.6 ± 1.8 years, 1.2-4.6 years postinjury) completed the 8-week BrainGames program and diffusion weighted imaging (DWI) and cognitive assessment at time point 1 (before training) and time point 2 (after training). Sixteen healthy controls (HC) (age 15.6 ± 1.8 years) completed DWI assessment at time point 1 and cognitive assessment at time point 1 and 2. Fixel-based analyses were used to examine fractional anisotropy (FA), mean diffusivity (MD), and fiber cross-section (FC) on a whole brain level and in tracts of interest. Results. Patients with TBI showed cognitive impairments and extensive areas with decreased FA and increased MD together with an increase in FC in the body of the corpus callosum and left superior longitudinal fasciculus (SLF) at time point 1. Patients improved significantly on the inhibition measure at time point 2, whereas the HC group remained unchanged. No training-induced changes were observed on the group level in diffusion metrics. Exploratory correlations were found between improvements on verbal working memory and reduced MD of the left SLF and between increased performance on an information processing speed task and increased FA of the right precentral gyrus. Conclusions. Results are indicative of positive effects of BrainGames on cognitive functioning and provide preliminary evidence for neuroplasticity associated with cognitive improvements following cognitive intervention in TBI.


Dynamic Modelling Reveals 'Hotspots' on the Pathway to Enzyme-Substrate Complex Formation.
Dihydrodipicolinate synthase (DHDPS) catalyzes the first committed step in the diaminopimelate pathway of bacteria, yielding amino acids required for cell wall and protein biosyntheses. The essentiality of the enzyme to bacteria, coupled with its absence in humans, validates DHDPS as an antibacterial drug target. Conventional drug design efforts have thus far been unsuccessful in identifying potent DHDPS inhibitors. Here, we make use of contemporary molecular dynamics simulation and Markov state models to explore the interactions between DHDPS from the human pathogen Staphylococcus aureus and its cognate substrate, pyruvate. Our simulations recover the crystallographic DHDPS-pyruvate complex without a priori knowledge of the final bound structure. The highly conserved residue Arg140 was found to have a pivotal role in coordinating the entry of pyruvate into the active site from bulk solvent, consistent with previous kinetic reports, indicating an indirect role for the residue in DHDPS catalysis. A metastable binding intermediate characterized by multiple points of intermolecular interaction between pyruvate and key DHDPS residue Arg140 was found to be a highly conserved feature of the binding trajectory when comparing alternative binding pathways. By means of umbrella sampling we show that these binding intermediates are thermodynamically metastable, consistent with both the available experimental data and the substrate binding model presented in this study. Our results provide insight into an important enzyme-substrate interaction in atomistic detail that offers the potential to be exploited for the discovery of more effective DHDPS inhibitors and, in a broader sense, dynamic protein-drug interactions.


Functionalized polymer-iron oxide hybrid nanofibers: Electrospun filtration devices for metal oxyanion removal.
Via a single-pot electrospinning synthesis, we developed a functionalized polymer-metal oxide nanofiber filter for point of use (POU) water treatment of metal oxyanions (e.g., arsenate and chromate). Polyacrylonitrile (PAN) functionalization was accomplished by inclusion of surface-active, quaternary ammonium salts (QAS) [cetyltrimethylammonium bromide (CTAB) or tetrabutylammonium bromide (TBAB)] that provide strong base ion exchange sites. Embedded iron oxide [ferrihydrite (Fh)] nanoparticles were used for their established role as metal sorbents. We examined the influence of QAS and Fh loading on composite properties, including nanofiber morphology, surface area, surface chemical composition, and the accessibility of embedded nanoparticles to solution. Composite performance was then evaluated using kinetic, isotherm, and pH-edge sorption experiments with arsenate and chromate, and benchmarked to unmodified PAN nanofibers and freely dispersed Fh nanoparticles. We also assessed the long-term stability of QAS in the composite matrix. For composites containing QAS or Fh nanoparticles, increasing QAS/Fh nanoparticle loading generally yielded increasing metal oxyanion uptake. The optimized composite (PAN 7 wt%, Fh 3 wt%, TBAB 1 wt%) exhibited two distinct sites for simultaneous, non-competitive metal binding (i.e., iron oxide sites for arsenate removal via sorption and well-retained QAS sites for chromate removal via ion exchange). Moreover, surface-segregating QAS enriched Fh abundance at the nanofiber surface, allowing immobilized nanoparticles to exhibit reactivity comparable to that of unsupported (i.e., suspended or freely dispersed) nanoparticles. To simulate POU application, the optimized composite was tested in a dead-end, flow-through filtration system for arsenate and chromate removal at environmentally relevant concentrations (e.g., μg/L) in both idealized and simulated tap water matrices. Performance trends indicate that dual mechanisms for uptake are maintained in kinetically limited regimes. Although chromate removal via ion exchange is more susceptible to interfering counter-ions, arsenate removal in simulated tap water indicates that ∼130 g of the composite could produce an individual's annual supply of drinking water (assuming an influent contaminated with 100 μg As/L, which is 10 times the current MCL).


The poly(A)-poly(A)-binding protein complex is a major determinant of mRNA stability in vitro.
Using an in vitro mRNA decay system, we investigated how poly(A) and its associated poly(A)-binding protein (PABP) affect mRNA stability. Cell extracts used in the decay reactions were depleted of functional PABP either by adding excess poly(A) competitor or by passing the extracts over a poly(A)-Sepharose column. Polyadenylated mRNAs for beta-globin, chloramphenicol acetyltransferase, and simian virus 40 virion proteins were degraded 3 to 10 times faster in reactions lacking PABP than in those containing excess PABP. The addition of purified Saccharomyces cerevisiae or human cytoplasmic PABP to PABP-depleted reactions stabilized the polyadenylated mRNAs. In contrast, the decay rates of nonpolyadenylated mRNAs were unaffected by PABP, indicating that both the poly(A) and its binding protein were required for maintaining mRNA stability. A nonspecific single-stranded binding protein from Escherichia coli did not restore stability to polyadenylated mRNA, and the stabilizing effect of PABP was inhibited by anti-PABP antibody. The poly(A) tract was the first mRNA segment to be degraded in PABP-depleted reactions, confirming that the poly(A)-PABP complex was protecting the 3' region from nucleolytic attack. These results indicate that an important function of poly(A), in conjunction with its binding protein, is to protect polyadenylated mRNAs from indiscriminate destruction by cellular nucleases. A model is proposed to explain how the stability of an mRNA could be affected by the stability of its poly(A)-PABP complex.


Undifferentiated Endometrial Carcinomas: Clinicopathologic Characteristics and Treatment Outcomes.
Undifferentiated endometrial carcinoma (UEC) represents a recently recognized and rare diagnosis that is commonly misclassified on histopathologic evaluation. These cancers account for less than 10% of carefully reviewed series of endometrial cancers from academic medical centers. We reviewed a single-institutional experience with the management of UEC focusing on clinicopathologic characteristics and treatment outcomes. The medical records of all patients treated for histologically proven endometrial carcinoma between 2007 through 2016 were reviewed. Analysis was limited to 24 consecutive patients with histologically proven endometrial carcinomas that had at least a component of undifferentiated carcinoma on central pathology review. All patients were initially treated by definitive surgical resection. Grade 3 endometrioid carcinomas treated over the same period were used as a control group. The Kaplan-Meier method was used to estimate survival outcomes. The median age at diagnosis was 66 years (range, 37-74 years). Ten patients presented with locally advanced or metastatic disease (42%). Fifteen patients (63%) received adjuvant chemotherapy with carboplatin and paclitaxel, 12 patients (50%) received adjuvant pelvic external beam radiation, and 10 patients (42%) received adjuvant vaginal cuff brachytherapy. With a median follow-up of 14 months (range, 0.5-115 months), 4 patients (21%) had developed disease recurrence and/or progression, 2 patients (11%) had died of disease, and 1 patient died of treatment complications. Twelve patients (63%) were alive with no evidence of disease at last contact. Outcomes were comparable to those with grade 3 endometrioid carcinoma. Our data are consistent with prior studies demonstrating that UEC represents a rare clinical entity characterized by high rates of locally advanced disease at presentation. However, survival outcomes appear to be comparable to other high-grade endometrial cancers. Further studies investigating optimal adjuvant therapy in these patients are warranted.


Kawasaki disease and 13-valent pneumococcal conjugate vaccination among young children: A self-controlled risk interval and cohort study with null results.
Kawasaki disease is an acute vasculitis that primarily affects children younger than 5 years of age. Its etiology is unknown. The United States Vaccine Safety Datalink conducted postlicensure safety surveillance for 13-valent pneumococcal conjugate vaccine (PCV13), comparing the risk of Kawasaki disease within 28 days of PCV13 vaccination with the historical risk after 7-valent PCV (PCV7) vaccination and using chart-validation. A relative risk (RR) of 2.38 (95% CI 0.92-6.38) was found. Concurrently, the Food and Drug Administration (FDA) conducted a postlicensure safety review that identified cases of Kawasaki disease through adverse event reporting. The FDA decided to initiate a larger study of Kawasaki disease risk following PCV13 vaccination in the claims-based Sentinel/Postlicensure Rapid Immunization Safety Monitoring (PRISM) surveillance system. The objective of this study was to determine the existence and magnitude of any increased risk of Kawasaki disease in the 28 days following PCV13 vaccination. The study population included mostly commercially insured children from birth to <24 months of age in 2010 to 2015 from across the US. Using claims data of participating Sentinel/PRISM data-providing organizations, PCV13 vaccinations were identified by means of current procedural terminology (CPT), Healthcare Common Procedure Coding System (HCPCS), and National Drug Code (NDC) codes. Potential cases of Kawasaki disease were identified by first-in-365-days International Classification of Diseases 9th revision (ICD-9) code 446.1 or International Classification of Diseases 10th revision (ICD-10) code M30.3 in the inpatient setting. Medical records were sought for potential cases and adjudicated by board-certified pediatricians. The primary analysis used chart-confirmed cases with adjudicated symptom onset in a self-controlled risk interval (SCRI) design, which controls for time-invariant potential confounders. The prespecified risk interval was Days 1-28 after vaccination; a 28-day-long control interval followed this risk interval. A secondary analytic approach used a cohort design, with alternative potential risk intervals of Days 1-28 and Days 1-42. The varying background risk of Kawasaki disease by age was adjusted for in both designs. In the primary analysis, there were 43 confirmed cases of Kawasaki disease in the risk interval and 44 in the control interval. The age-adjusted risk estimate was 1.07 (95% CI 0.70-1.63; p = 0.76). In the secondary, cohort analyses, which included roughly 700 potential cases and more than 3 million person-years, the risk estimates of potential Kawasaki disease in the risk interval versus in unexposed person-time were 0.84 (95% CI 0.65-1.08; p = 0.18) for the Days 1-28 risk interval and 0.97 (95% CI 0.79-1.19; p = 0.80) for the Days 1-42 risk interval. The main limitation of the study was that we lacked the resources to conduct medical record review for all the potential cases of Kawasaki disease. As a result, potential cases rather than chart-confirmed cases were used in the cohort analyses. With more than 6 million doses of PCV13 administered, no evidence was found of an association between PCV13 vaccination and Kawasaki disease onset in the 4 weeks after vaccination nor of an elevated risk extending or concentrated somewhat beyond 4 weeks. These null results were consistent across alternative designs, age-adjustment methods, control intervals, and categories of Kawasaki disease case included.


Quantifying the funding gap for management of traumatic brain injury at a major trauma centre in South Africa.
Trauma is an eminently preventable disease. However, prevention programs divert resources away from other priorities. Costing trauma related diseases helps policy makers to make decisions on re-source allocation. We used data from a prospective digital trauma registry to cost Traumatic Brain Injury (TBI) at our institution over a two-year period and to estimate the funding gap that exists in the care of TBI. All patients who were admitted to the Pietermaritzburg Metropolitan Trauma Service (PMTS) with TBI were identified from the Hybrid Electronic Medical Registry (HMER). A micro-costing model was utilised to generate costs for TBI. Costs were generated for two scenarios in which all moderate and severe TBI were admitted to ICU. The actual cost was then sub-tracted from the scenario costs to establish the funding gap. During the period January 2012 to December 2014, a total of 3 301 patients were treated for TBI in PMB. The mean age was 30 years (SD 50). There were 2 632 (80%) males and 564 (20%) females. The racial breakdown was overwhelmingly African (96%), followed by Asian (2%), Caucasian (1%) and mixed race (1%). There were 2 540 mild (GCS 13-15), 326 moderate (9-12), and 329 severe (GCS ≤8) TBI admissions during the period under review. A total of 139 patients died (4.2%). A total of 242 (7.3%) patients were admitted to ICU. Of these 137 (57%) had a GCS of 9 or less. A total of 2 383 CT scans were performed. The total cost of TBI over the two-year period was ZAR 62 million. If all 326 patients with moderate TBI had been admitted to ICU there would have been a further 281 ICU admissions. This was labelled Scenario 1. If all patients with severe as well as moderate TBI had been admitted there would have been a further 500 ICU admissions. This was labelled Scenario 2. Based on Scenario 1 and Scenario 2 the total cost would have been ZAR 73 272 250 and ZAR 82 032 250 respectively. The funding gaps for Scenario 1 and Scenario 2 were ZAR 11 240 000 and ZAR 20 000 000 respectively. There is a significant burden of TBI managed by the PMTS. The cost of managing TBI each year is in the order of sixty million ZAR. A significant funding gap exists in our environment. This data does not include any data on the broader social costs of TBI. Investing in programs to reduce and prevent TBI is justified by the potential for significant savings.


Direct ex-vivo evaluation of pneumococcal specific T-cells in healthy adults.
Streptococcus pneumoniae is an encapsulated bacterium that causes significant global morbidity and mortality. The nasopharynxes of children are believed to be the natural reservoir of pneumococcus and by adulthood nasopharyngeal carriage is infrequent; such infrequency may be due to demonstrable pneumococcal specific T and B-cell responses. HLA Class 2 tetrameric complexes have been used to characterise antigen specific T-cell responses in a variety of models of infection. We therefore sought to determine the frequency and phenotype of pneumococcal specific T-cells, using a novel HLA-DRB1*1501 tetramer complex incorporating a recently defined T-cell epitope derived from the conserved pneumococcal serine/threonine kinase (StkP). We were able to detect direct ex-vivo StkP(446-60)-tetramer binding in HLA-DRB1*1501 adults. These StkP(446-60)-tetramer binding T-cells had increased CD38 expression and were enriched in CCR7- CD45RA+ expression indicating recent and on-going activation and differentiation. Furthermore, these StkP(446-60)-tetramer binding T-cells demonstrated rapid effector function by secreting interferon-gamma on stimulation with recombinant StkP. This is the first study to directly enumerate and characterise pneumococcal specific T-cells using HLA class 2 tetrameric complexes. We found that ex-vivo pneumococcal-specific T cells were detectable in healthy adults and that they were enriched with cell surface markers associated with recent antigen exposure and later stages of antigen-driven differentiation. It is likely that these activated pneumococcal specific T-cells reflect recent immunostimulatory pneumococcal exposure in the nasopharynx and it is possible that they may be preventing subsequent colonisation and disease.