ENTPD3 Marks Mature Stem Cell-Derived ß-Cells Formed by Self-Aggregation In Vitro.

Stem cell-derived ß-like cells (sBC) carry the promise of providing an abundant source of insulin-producing cells for use in cell replacement therapy for patients with diabetes, potentially allowing widespread implementation of a practical cure. To achieve their clinical promise, sBC need to function comparably with mature adult ß-cells, but as yet they display varying degrees of maturity. Indeed, detailed knowledge of the events resulting in human ß-cell maturation remains obscure. Here we show that sBC spontaneously self-enrich into discreet islet-like cap structures within in vitro cultures, independent of exogenous maturation conditions. Multiple complementary assays demonstrate that this process is accompanied by functional maturation of the self-enriched sBC (seBC); however, the seBC still contain distinct subpopulations displaying different maturation levels. Interestingly, the surface protein ENTPD3 (also known as nucleoside triphosphate diphosphohydrolase-3 [NDPTase3]) is a specific marker of the most mature seBC population and can be used for mature seBC identification and sorting. Our results illuminate critical aspects of in vitro sBC maturation and provide important insights toward developing functionally mature sBC for diabetes cell replacement therapy.

Treatment Practices and Outcomes in Continuous Spike and Wave during Slow Wave Sleep: A Multicenter Collaboration.

OBJECTIVES: To determine how continuous spike and wave during slow wave sleep (CSWS) is currently managed and to compare the effectiveness of current treatment strategies using a database from 11 pediatric epilepsy centers in the US. STUDY DESIGN: This retrospective study gathered information on baseline clinical characteristics, CSWS etiology, and treatment(s) in consecutive patients seen between 2014 and 2016 at 11 epilepsy referral centers. Treatments were categorized as benzodiazepines, steroids, other antiseizure medications (ASMs), or other therapies. Two measures of treatment response (clinical improvement as noted by the treating physician; and electroencephalography improvement) were compared across therapies, controlling for baseline variables. RESULTS: Eighty-one children underwent 153 treatment trials during the study period (68 trials of benzodiazepines, 25 of steroids, 45 of ASMs, 14 of other therapies). Children most frequently received benzodiazepines (62%) or ASMs (27%) as first line therapy. Treatment choice did not differ based on baseline clinical variables, nor did these variables correlate with outcome. After adjusting for baseline variables, children had a greater odds of clinical improvement with benzodiazepines (OR 3.32, 95%CI 1.57-7.04, P = .002) or steroids (OR 4.04, 95%CI 1.41-11.59, P = .01) than with ASMs and a greater odds of electroencephalography improvement after steroids (OR 3.36, 95% CI 1.09-10.33, P = .03) than after ASMs. CONCLUSIONS: Benzodiazepines and ASMs are the most frequent initial therapy prescribed for CSWS in the US. Our data suggests that ASMs are inferior to benzodiazepines and steroids and support earlier use of these therapies. Multicenter prospective studies that rigorously assess treatment protocols and outcomes are needed.

Genotypic variations in leaf and whole-plant water use efficiencies are closely related in bread wheat genotypes under well-watered and water-limited conditions during grain filling.

Wheat plants growing under Mediterranean rain-fed conditions are exposed to water deficit, particularly during the grain filling period, and this can lead to a strong reduction in grain yield (GY). This study examines the effects of water deficit after during the grain filling period on photosynthetic and water-use efficiencies at the leaf and whole-plant level for 14 bread wheat genotypes grown in pots under glasshouse conditions. Two glasshouse experiments were conducted, one in a conventional glasshouse at the Universidad de Talca, Chile (Experiment 1), and another at the National Plant Phenomics Centre (NPPC), Aberystwyth, UK (Experiment 2), in 2015. Plants were grown under well-watered (WW) and water-limited (WL) conditions during grain filling. The reductions in leaf water potential (Ψ), net CO2 assimilation (An) and stomatal conductance (gs) due to water deficit were 79, 35 and 55%, respectively, during grain filling but no significant differences were found among genotypes. However, chlorophyll fluorescence parameters (as determined on dark-adapted and illuminated leaves) and chlorophyll content (Chl) were significantly different among genotypes, but not between water conditions. Under both water conditions, An presented a positive and linear relationship with the effective photochemical quantum yield of Photosystem II (Y(II)) and the maximum rate of electron transport (ETRmax), and negative with the quantum yield of non-photochemical energy conversion in Photosystem II (Y(NPQ)). The relationship between An and Chl was positive and linear for both water conditions, but under WL conditions An tended to be lower at any Chl value. Both, instantaneous (An/E) and intrinsic (An/gs) water-use efficiencies at the leaf level exhibited a positive and linear relationship with plant water-use efficiency (WUEp = plant dry weight/water use). Carbon discrimination (Δ13C) in kernels presented a negative relationship with WUEp, at both WW and WL conditions, and a positive relationship with GY. Our results indicate that during grain filling wheat plants face limitations to the assimilation process due to natural senesce and water stress. The reduction in An and gs after anthesis in both water conditions was mainly due a decline in the chlorophyll content (non-stomatal limitation), whereas the observed differences between water conditions were mainly due to a stomatal limitation.

Leaf-cutter ants engineer large nitrous oxide hot spots in tropical forests.

Though tropical forest ecosystems are among the largest natural sources of the potent greenhouse gas nitrous oxide (N2O), the spatial distribution of emissions across landscapes is often poorly resolved. Leaf cutter ants (LCA; Atta and Acromyrmex, Myrmicinae) are dominant herbivores throughout Central and South America, and influence multiple aspects of forest structure and function. In particular, their foraging creates spatial heterogeneity by concentrating large quantities of organic matter (including nitrogen, N) from the surrounding canopy into their colonies, and ultimately into colony refuse dumps. Here, we demonstrate that refuse piles created by LCA species Atta colombica in tropical rainforests of Costa Rica provide ideal conditions for extremely high rates of N2O production (high microbial biomass, potential denitrification enzyme activity, N content and anoxia) and may represent an unappreciated source of heterogeneity in tropical forest N2O emissions. Average instantaneous refuse pile N2O fluxes surpassed background emissions by more than three orders of magnitude (in some cases exceeding 80 000 µg N2O-N m-2 h-1) and generating fluxes comparable to or greater than those produced by engineered systems such as wastewater treatment tanks. Refuse-concentrating Atta species are ubiquitous in tropical forests, pastures and production ecosystems, and increase density strongly in response to disturbance. As such, LCA colonies may represent an unrecognized greenhouse gas point source throughout the Neotropics.

A randomized, placebo-controlled trial of patient education for acute low back pain (PREVENT Trial): statistical analysis plan.

BACKGROUND: Statistical analysis plans increase the transparency of decisions made in the analysis of clinical trial results. The purpose of this paper is to detail the planned analyses for the PREVENT trial, a randomized, placebo-controlled trial of patient education for acute low back pain. RESULTS: We report the pre-specified principles, methods, and procedures to be adhered to in the main analysis of the PREVENT trial data. The primary outcome analysis will be based on Mixed Models for Repeated Measures (MMRM), which can test treatment effects at specific time points, and the assumptions of this analysis are outlined. We also outline the treatment of secondary outcomes and planned sensitivity analyses. We provide decisions regarding the treatment of missing data, handling of descriptive and process measure data, and blinded review procedures. CONCLUSIONS: Making public the pre-specified statistical analysis plan for the PREVENT trial minimizes the potential for bias in the analysis of trial data, and in the interpretation and reporting of trial results. TRIAL REGISTRATION: ACTRN12612001180808 (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12612001180808).

Use of corticosteroids for pain control in cancer patients with bone metastases: a comprehensive literature review.

PURPOSE OF REVIEW: Despite a limited understanding of the exact mechanism, corticosteroids are commonly employed for pain control in patients with bone metastases. The aim of this review was to evaluate the efficacy of corticosteroid-mediated pain control in patients with bone metastases associated with solid cancers. RECENT FINDINGS: A literature search was conducted using OVID MEDLINE and Embase databases (from 1946 up to July 19, 2016). Studies involving patients with bone metastases receiving corticosteroids as the primary means of pain control were included. Screening and data extraction were conducted by paired reviewers, with consensus established by discussion, or a third adjudicator. A total of 12 studies were included. Rates of pain relief achieved with corticosteroid use varied from 30 to 70%, but generally reflected moderate pain control. Corticosteroid use significantly reduced the incidence of pain flare alongside radiotherapy, reportedly by almost half of baseline pain severity. Adverse events were not documented consistently across studies, though grade two to three hyperglycemia was noted in approximately 2% of patients by some studies. SUMMARY: Recent evidence suggests that short-term corticosteroid use may provide moderate pain and pain flare control with radiotherapy for patients with bone metastases. The risk of developing adverse effects should be carefully considered prior to therapy initiation on a case-by-case basis.

Crowdsourcing the General Public for Large Scale Molecular Pathology Studies in Cancer.

BACKGROUND: Citizen science, scientific research conducted by non-specialists, has the potential to facilitate biomedical research using available large-scale data, however validating the results is challenging. The Cell Slider is a citizen science project that intends to share images from tumors with the general public, enabling them to score tumor markers independently through an internet-based interface. METHODS: From October 2012 to June 2014, 98,293 Citizen Scientists accessed the Cell Slider web page and scored 180,172 sub-images derived from images of 12,326 tissue microarray cores labeled for estrogen receptor (ER). We evaluated the accuracy of Citizen Scientist's ER classification, and the association between ER status and prognosis by comparing their test performance against trained pathologists. FINDINGS: The area under ROC curve was 0.95 (95% CI 0.94 to 0.96) for cancer cell identification and 0.97 (95% CI 0.96 to 0.97) for ER status. ER positive tumors scored by Citizen Scientists were associated with survival in a similar way to that scored by trained pathologists. Survival probability at 15 years were 0.78 (95% CI 0.76 to 0.80) for ER-positive and 0.72 (95% CI 0.68 to 0.77) for ER-negative tumors based on Citizen Scientists classification. Based on pathologist classification, survival probability was 0.79 (95% CI 0.77 to 0.81) for ER-positive and 0.71 (95% CI 0.67 to 0.74) for ER-negative tumors. The hazard ratio for death was 0.26 (95% CI 0.18 to 0.37) at diagnosis and became greater than one after 6.5 years of follow-up for ER scored by Citizen Scientists, and 0.24 (95% CI 0.18 to 0.33) at diagnosis increasing thereafter to one after 6.7 (95% CI 4.1 to 10.9) years of follow-up for ER scored by pathologists. INTERPRETATION: Crowdsourcing of the general public to classify cancer pathology data for research is viable, engages the public and provides accurate ER data. Crowdsourced classification of research data may offer a valid solution to problems of throughput requiring human input.

Prostate cancer discrimination in the peripheral zone with a reduced field-of-view T(2)-mapping MRI sequence.

OBJECTIVES: To evaluate the performance of T2 mapping in discriminating prostate cancer from normal prostate tissue in the peripheral zone using a practical reduced field-of-view MRI sequence requiring less than 3 minutes of scan time. MATERIALS AND METHODS: Thirty-six patients with biopsy-proven peripheral zone prostate cancer without prior treatment underwent routine multiparametric MRI at 3.0T with an endorectal coil. An Inner-Volume Carr-Purcell-Meiboom-Gill imaging sequence that required 2.8 minutes to obtain data for quantitative T2 mapping covering the entire prostate gland was added to the routine multiparametric protocol. Suspected cancer (SC) and suspected healthy (SH) tissue in the peripheral zone were identified in consensus by three radiologists and were correlated with available biopsy results. Differences in mean T2 values in SC and SH regions-of-interest (ROIs) were tested for significance using unpaired Student's two-tailed t-test. The area under the receiver operating characteristic curve was used to assess the optimal threshold T2 value for cancer discrimination. RESULTS: ROI analyses revealed significantly (p<0.0001) shorter T2 values in SC (85.4±12.3ms) compared to SH (169.6±38.7ms). An estimated T2 threshold of 99ms yielded a sensitivity of 92% and a specificity of 97% for prostate cancer discrimination. CONCLUSIONS: Quantitative values derived from this clinically practical T2-mapping sequence allow high precision discrimination between healthy and cancerous peripheral zone in the prostate.

The burden of pediatric diarrhea: a cross-sectional study of incurred costs and perceptions of cost among Bolivian families.

BACKGROUND: Worldwide, acute gastroenteritis represents an enormous public health threat to children under five years of age, causing one billion episodes and 1.9 to 3.2 million deaths per year. In Bolivia, which has one of the lower GDPs in South America, an estimated 15% of under-five deaths are caused by diarrhea. Bolivian caregiver expenses related to diarrhea are believed to be minimal, as citizens benefit from universal health insurance for children under five. The goals of this report were to describe total incurred costs and cost burden associated with caregivers seeking treatment for pediatric gastroenteritis, and to quantify relationships among costs, cost burden, treatment setting, and perceptions of costs. METHODS: From 2007 to 2009, researchers interviewed caregivers (n=1,107) of pediatric patients (<5 years of age) seeking treatment for diarrhea in sentinel hospitals participating in Bolivia's diarrheal surveillance program across three main geographic regions. Data collected included demographics, clinical symptoms, direct costs (e.g. medication, consult fees) and indirect costs (e.g. lost wages). RESULTS: Patient populations were similar across cities in terms of gender, duration of illness, and age, but familial income varied significantly (p<0.05) when stratified on appointment type. Direct, indirect, and total costs to families were significantly higher for inpatients as compared to outpatients of urban (p<0.001) and rural (p<0.05) residence. Consult fees and indirect costs made up a large proportion of total costs. Forty-five percent of patients' families paid ≥1% of their annual household income for this single diarrheal episode. The perception that cost was affecting family finances was more frequent among those with higher actual cost burden. CONCLUSIONS: This study demonstrated that indirect costs due to acute pediatric diarrhea were a large component of total incurred familial costs. Additionally, familial costs associated with a single diarrheal episode affected the actual and perceived financial situation of a large number of caregivers. These data serve as a baseline for societal diarrheal costs before and immediately following the implementation of the rotavirus vaccine and highlight the serious economic importance of a diarrheal episode to Bolivian caregivers.

Synergistic associations between hookworm and other helminth species in a rural community in Brazil.

OBJECTIVE: To identify possible synergistic associations of hookworm and other helminths. METHOD: Cross-sectional survey of all households within 10 km2 of Americaninhas, a rural community in Minas Gerais, Brazil. We determined the prevalence and intensity of single and multiple helminth species infection in an age-stratified sample of 1332 individuals from 335 households. RESULTS: Hookworm was the most prevalent helminth infection (68.2%), followed by Ascaris lumbricoides (48.8%) and Schistosoma mansoni (45.3%). Overall, 60.6% of individuals harboured mixed helminth infections. Multivariate analysis indicated significant positive associations for co-infection with hookworm and S. mansoni and for co-infection with hookworm and A. lumbricoides. Co-infections with hookworm and A. lumbricoides resulted in higher egg counts for both, suggesting a synergistic relationship between these species, although, we found important age differences in this relationship. However, the intensity of S. mansoni or A. lumbricoides co-infection did not differ from that of mono-infection. CONCLUSION: These results have implications for the epidemiology, immunology and control of multiple helminth infections. More research is needed to examine the rates of re-infection and immune responses after chemotherapy, and to what extent the effects of polyparasitism are altered by chemotherapy.

An investigation of child mortality in Kingston and St. Andrew, Jamaica - abstract

This study was carried out as one of the thirteen field projects in the Inter-American Investigation of Mortality in Childhood, which was sponsored by PAHO/WHO. The objective of the study was to investigate causes of death in infancy and early childhood, taking into account nutritional, sociological and other environmental factors. This preliminary report is for the year 1969. An attempt was made to get complete data on all deaths of children under five years of age in the parishes of Kingston and St. Andrew, Jamaica - an area with total mean population of 547,500 in 1969. The investigation was carried out through interviews in homes, hospitals and clinics and with physicians so as to obtain complete records of the fatal illness, results of laboratory and other examinations and autopsy findings. The study area was sub-divided into urban and rural. The total number of deaths under five years of age for the year was 906, 835 of which were from the urban area. The demographic (provisional) of the Registrar General for 1969 reported 803 infant deaths, thus giving an infant mortality rate of 35.4, while the study had 763 infant deaths with an infant mortality rate of 33.8. There were 836 deaths (92 percent) under two years of age, with 469 (51.6 percent) in the neonatal period and 294 (32.5 percent) in the post neonatal period. In 1-4 years age group, 73 deaths occurred among the one-year olds and this represents 52.5 percent of deaths in this age group. Thus there were four times as many deaths in the post-neonatal period as there were in the second year of life and those in the second year of life were more than half of those deaths occurring in the 1-4 year old group. The geographic distribution was analysed according to postal zones for the urban area. Out of 835 urban deaths occurring in 21 postal zones, 445 (53.2 percent) occurred in zones 0, 11, 12 and 13 which accounted individually for the highest numbers of death. Hence establishing priorities in developing a maternal and child health programme to improve health services and reduce child mortality, emphasis must necessarily be given to children under two years old, and special attention to certain geographic areas (AU)

An investigation of child mortality in Kingston and St. Andrew, Jamaica: Preliminary review for 1969

It has been shown that mortality in childhood in Jamaica is declining rapidly in all parts of the island. Regional differences however are still found with higher rates in the Western parishes. This paper describes a preliminary review of deaths of children under five years of age in the corprate area of Kingston & St. Andrew, Jamaica, for the year 1969. Between the ages of six month and two years, gastro-enteritis and malnutrition still account for a high proportion of deaths. Children whose mothers lack antenatal care and whose mothers were very young, were at a greater risk of dying in the neonatal period. There was also a relative preponderance of deaths among children in a well defined geographic area of a lower socio-economic status. Prematurity and obstetrical complications were the chief causes of deaths in the neonatal period. There were also 12 deaths from gastro-enteritis and 8 from tetanus in this period, and 22 from diphtheria and whooping cough in the postneonatal and early childhood periods. Hence in establishing priorities in developing and improving a maternal and child health programme, emphasis must necessarily be given to children under two years of age and special attention to certain geographic areas. It is hoped that this report help to point out needs for preventive programmes and for other uses of the results in health planning. This preliminary analysis has been done in order to obtain some early information that would be useful to the Ministry of Health, Jamaica. (SUMMARY)

Inter-American investigation of mortality in childhood: 1968-1970 organization and some preliminary results - abstract

The Inter-American Investigation of Mortality in Childhood was inaugurated by PAHO/WHO in 1967 following a successful inter-American study of adult urban mortality. The study, an exercise in international and interdisciplinary co-operation, is being conducted in fifteen centres in the Western hemisphere, including Kingston and St. Andrew, Jamaica, and is being coordinated by the Health Statistics Department of PAHO/WHO under Dr. Ruth Puffer. A team including physicians, social workers, nurses, and a medical statistician is studying the deaths of all children under five years in the Kingston and St. Andrew area during the years 1968-1970. To enable valid conclusion to be drawn, similar data on social, economic and environmental factors are being collected for a representative sample of living children from the same area and in the same age group. The aim of the study is to elucidate the various factors contributing to death so as to make more accurate data available for those responsible planning the health services and for appropriate preventive measures. Preliminary analysis of the first year's data on approximately 1,000 deaths has shown that the principal underlying causes of death in the age group studied are perinatal causes (38 percent), gastroenteritis (18.4 percent) congenital anomalies (7.9 percent), respiratory tract infections (7.3 percent), malnutrition (7.1 percent), and accidents (3.4 percent) AU