Cell‐to‐cell and type‐to‐type heterogeneity of signaling networks: insights from the crowd

Recent technological developments allow us to measure the status of dozens of proteins in individual cells. This opens the way to understand the heterogeneity of complex multi‐signaling networks across cells and cell types, with important implications to understand and treat diseases such as cancer. These technologies are, however, limited to proteins for which antibodies are available and are fairly costly, making predictions of new markers and of existing markers under new conditions a valuable alternative. To assess our capacity to make such predictions and boost further methodological development, we organized the Single Cell Signaling in Breast Cancer DREAM challenge. We used a mass cytometry dataset, covering 36 markers in over 4,000 conditions totaling 80 million single cells across 67 breast cancer cell lines. Through four increasingly difficult subchallenges, the participants predicted missing markers, new conditions, and the time‐course response of single cells to stimuli in the presence and absence of kinase inhibitors. The challenge results show that despite the stochastic nature of signal transduction in single cells, the signaling events are tightly controlled and machine learning methods can accurately predict new experimental data.     

Number and type of guideline implementation tools varies by guideline,clinical condition,country of origin,and type of developer organization: content analysis of guidelines

Background

Guideline implementation tools (GI tools) can improve clinician behavior and patient outcomes. Analyses of guidelines published before 2010 found that many did not offer GI tools. Since 2010 standards, frameworks and instructions for GI tools have emerged. This study analyzed the number and types of GI tools offered by guidelines published in 2010 or later.

Methods

Content analysis and a published GI tool framework were used to categorize GI tools by condition, country, and type of organization. English-language guidelines on arthritis, asthma, colorectal cancer, depression, diabetes, heart failure, and stroke management were identified in the National Guideline Clearinghouse. Screening and data extraction were in triplicate. Findings were reported with summary statistics.

Results

Eighty-five (67.5%) of 126 eligible guidelines published between 2010 and 2017 offered one or more of a total of 464 GI tools. The mean number of GI tools per guideline was 5.5 (median 4.0, range 1 to 28) and increased over time. The majority of GI tools were for clinicians (239, 51.5%), few were for patients (113, 24.4%), and fewer still were to support implementation (66, 14.3%) or evaluation (46, 9.9%). Most clinician GI tools were guideline summaries (116, 48.5%), and most patient GI tools were condition-specific information (92, 81.4%). Government agencies (patient 23.5%, clinician 28.9%, implementation 24.1%, evaluation 23.5%) and developers in the UK (patient 18.5%, clinician 25.2%, implementation 27.2%, evaluation 29.1%) were more likely to generate guidelines that offered all four types of GI tools. Professional societies were more likely to generate guidelines that included clinician GI tools.

Conclusions

Many guidelines do not include any GI tools, or a variety of GI tools for different stakeholders that may be more likely to prompt guideline uptake (point-of-care forms or checklists for clinicians, decision-making or self-management tools for patients, implementation and evaluation tools for managers and policy-makers). While this may vary by country and type of organization, and suggests that developers could improve the range of GI tools they develop, further research is needed to identify determinants and potential solutions. Research is also needed to examine the cost-effectiveness of various types of GI tools so that developers know where to direct their efforts and scarce resources.

     

The European carbon balance. Part 3: forests

We present a new synthesis, based on a suite of complementary approaches, of the primary production and carbon sink in forests of the 25 member states of the European Union (EU‐25) during 1990–2005. Upscaled terrestrial observations and model‐based approaches agree within 25% on the mean net primary production (NPP) of forests, i.e. 520±75 g C m^?2 yr^?1 over a forest area of 1.32 × 10⁶ km² to 1.55 × 10⁶ km² (EU‐25). New estimates of the mean long‐term carbon forest sink (net biome production, NBP) of EU‐25 forests amounts 75±20 g C m^?2 yr^?1. The ratio of NBP to NPP is 0.15±0.05. Estimates of the fate of the carbon inputs via NPP in wood harvests, forest fires, losses to lakes and rivers and heterotrophic respiration remain uncertain, which explains the considerable uncertainty of NBP. Inventory‐based assessments and assumptions suggest that 29±15% of the NBP (i.e., 22 g C m^?2 yr^?1) is sequestered in the forest soil, but large uncertainty remains concerning the drivers and future of the soil organic carbon. The remaining 71±15% of the NBP (i.e., 53 g C m^?2 yr^?1) is realized as woody biomass increments. In the EU‐25, the relatively large forest NBP is thought to be the result of a sustained difference between NPP, which increased during the past decades, and carbon losses primarily by harvest and heterotrophic respiration, which increased less over the same period.     

Sentinel Hospital-Based Surveillance for Assessment of Burden of Rotavirus Gastroenteritis in Children in Pakistan

Objectives

To determine the burden and molecular epidemiology of rotavirus gastroenteritis in children hospitalized with severe acute watery diarrhea in Pakistan prior to introduction of rotavirus vaccine.

Methods

A cross-sectional study was carried out over a period of two years from 2006 – 2008 at five sentinel hospitals in the cities of Karachi, Lahore, Rawalpindi, and Peshawar. Stool samples collected from children under five years of age hospitalized with severe acute watery diarrhea were tested for rotavirus antigen via enzyme immunoassay (EIA) (IDEA REF K6020 Oxoid Ltd (Ely), Cambridge, United Kingdom). A subset of EIA positive stool samples were further processed for genotyping.

Results

6679 children were enrolled and stool specimens of 2039 (30.5%) were positive for rotavirus. Rotavirus positivity ranged from 16.3% to 39.4% in the 5 hospitals with highest positivity in Lahore. 1241 (61%) of all rotavirus cases were in infants under one year of age. Among the strains examined for G-serotypes, the occurrence of G1, G2, G9 and G4 strains was found to be 28%, 24%, 14% and 13%, respectively. Among P-types, the most commonly occurring strains were P6 (31.5%) followed by P8 (20%) and P4 (12%). Prevalent rotavirus genotype in hospitalized children of severe diarrhea were G1P[8] 11.6% (69/593), followed by G2P[4] 10.4% (62/593), and G4P[6] 10.1% (60/593).

Conclusions

Approximately one third of children hospitalized with severe gastroenteritis in urban centers in Pakistan have rotavirus. Introduction of rotavirus vaccine in Pakistan''s national immunization program could prevent many severe episodes and diarrheal deaths.     

The European carbon balance. Part 1: fossil fuel emissions

We analyzed the magnitude, the trends and the uncertainties of fossil‐fuel CO₂ emissions in the European Union 25 member states (hereafter EU‐25), based on emission inventories from energy‐use statistics. The stability of emissions during the past decade at EU‐25 scale masks decreasing trends in some regions, offset by increasing trends elsewhere. In the recent 4 years, the new Eastern EU‐25 member states have experienced an increase in emissions, reversing after a decade‐long decreasing trend. Mediterranean and Nordic countries have also experienced a strong acceleration in emissions. In Germany, France and United Kingdom, the stability of emissions is due to the decrease in the industry sector, offset by an increase in the transportation sector. When four different inventories models are compared, we show that the between‐models uncertainty is as large as 19% of the mean for EU‐25, and even bigger for individual countries. Accurate accounting for fossil CO₂ emissions depends on a clear understanding of system boundaries, i.e. emitting activities included in the accounting. We found that the largest source of errors between inventories is the use of distinct systems boundaries (e.g. counting or not bunker fuels, cement manufacturing, nonenergy products). Once these inconsistencies are corrected, the between‐models uncertainty can be reduced down to 7% at EU‐25 scale. The uncertainty of emissions at smaller spatial scales than the country scale was analyzed by comparing two emission maps based upon distinct economic and demographic activities. A number of spatial and temporal biases have been found among the two maps, indicating a significant increase in uncertainties when increasing the resolution at scales finer than ≈200 km. At 100 km resolution, for example, the uncertainty of regional emissions is estimated to be 60 g C m^?2 yr^?1, up to 50% of the mean. The uncertainty on regional fossil‐fuel CO₂ fluxes to the atmosphere could be reduced by making accurate ¹⁴C measurements in atmospheric CO₂, and by combining them with transport models.     

Child Mortality Estimation 2013: An Overview of Updates in Estimation Methods by the United Nations Inter-Agency Group for Child Mortality Estimation

Background

In September 2013, the United Nations Inter-agency Group for Child Mortality Estimation (UN IGME) published an update of the estimates of the under-five mortality rate (U5MR) and under-five deaths for all countries. Compared to the UN IGME estimates published in 2012, updated data inputs and a new method for estimating the U5MR were used.

Methods

We summarize the new U5MR estimation method, which is a Bayesian B-spline Bias-reduction model, and highlight differences with the previously used method. Differences in UN IGME U5MR estimates as published in 2012 and those published in 2013 are presented and decomposed into differences due to the updated database and differences due to the new estimation method to explain and motivate changes in estimates.

Findings

Compared to the previously used method, the new UN IGME estimation method is based on a different trend fitting method that can track (recent) changes in U5MR more closely. The new method provides U5MR estimates that account for data quality issues. Resulting differences in U5MR point estimates between the UN IGME 2012 and 2013 publications are small for the majority of countries but greater than 10 deaths per 1,000 live births for 33 countries in 2011 and 19 countries in 1990. These differences can be explained by the updated database used, the curve fitting method as well as accounting for data quality issues. Changes in the number of deaths were less than 10% on the global level and for the majority of MDG regions.

Conclusions

The 2013 UN IGME estimates provide the most recent assessment of levels and trends in U5MR based on all available data and an improved estimation method that allows for closer-to-real-time monitoring of changes in the U5MR and takes account of data quality issues.     

No genetic association between attention-deficit/hyperactivity disorder (ADHD) and Parkinson’s disease in nine ADHD candidate SNPs

Attention-deficit/hyperactivity disorder (ADHD) and Parkinson’s disease (PD) involve pathological changes in brain structures such as the basal ganglia, which are essential for the control of motor and cognitive behavior and impulsivity. The cause of ADHD and PD remains unknown, but there is increasing evidence that both seem to result from a complicated interplay of genetic and environmental factors affecting numerous cellular processes and brain regions. To explore the possibility of common genetic pathways within the respective pathophysiologies, nine ADHD candidate single nucleotide polymorphisms (SNPs) in seven genes were tested for association with PD in 5333 cases and 12,019 healthy controls: one variant, respectively, in the genes coding for synaptosomal-associated protein 25 k (SNAP25), the dopamine (DA) transporter (SLC6A3; DAT1), DA receptor D4 (DRD4), serotonin receptor 1B (HTR1B), tryptophan hydroxylase 2 (TPH2), the norepinephrine transporter SLC6A2 and three SNPs in cadherin 13 (CDH13). Information was extracted from a recent meta-analysis of five genome-wide association studies, in which 7,689,524 SNPs in European samples were successfully imputed. No significant association was observed after correction for multiple testing. Therefore, it is reasonable to conclude that candidate variants implicated in the pathogenesis of ADHD do not play a substantial role in PD.     

The Circumpolar Arctic vegetation map

Abstract. Question: What are the major vegetation units in the Arctic, what is their composition, and how are they distributed among major bioclimate subzones and countries? Location: The Arctic tundra region, north of the tree line. Methods: A photo‐interpretive approach was used to delineate the vegetation onto an Advanced Very High Resolution Radiometer (AVHRR) base image. Mapping experts within nine Arctic regions prepared draft maps using geographic information technology (ArcInfo) of their portion of the Arctic, and these were later synthesized to make the final map. Area analysis of the map was done according to bioclimate subzones, and country. The integrated mapping procedures resulted in other maps of vegetation, topography, soils, landscapes, lake cover, substrate pH, and above‐ground biomass. Results: The final map was published at 1:7 500 000 scale map. Within the Arctic (total area = 7.11 × 106 km²), about 5.05 × 10⁶ km² is vegetated. The remainder is ice covered. The map legend generally portrays the zonal vegetation within each map polygon. About 26% of the vegetated area is erect shrublands, 18% peaty graminoid tundras, 13% mountain complexes, 12% barrens, 11% mineral graminoid tundras, 11% prostrate‐shrub tundras, and 7% wetlands. Canada has by far the most terrain in the High Arctic mostly associated with abundant barren types and prostrate dwarf‐shrub tundra, whereas Russia has the largest area in the Low Arctic, predominantly low‐shrub tundra. Conclusions: The CAVM is the first vegetation map of an entire global biome at a comparable resolution. The consistent treatment of the vegetation across the circumpolar Arctic, abundant ancillary material, and digital database should promote the application to numerous land‐use, and climate‐change applications and will make updating the map relatively easy.     

Growing Season Temperatures in Europe and Climate Forcings Over the Past 1400 Years

Background

The lack of instrumental data before the mid-19th-century limits our understanding of present warming trends. In the absence of direct measurements, we used proxies that are natural or historical archives recording past climatic changes. A gridded reconstruction of spring-summer temperature was produced for Europe based on tree-rings, documentaries, pollen assemblages and ice cores. The majority of proxy series have an annual resolution. For a better inference of long-term climate variation, they were completed by low-resolution data (decadal or more), mostly on pollen and ice-core data.

Methodology/Principal Findings

An original spectral analog method was devised to deal with this heterogeneous dataset, and to preserve long-term variations and the variability of temperature series. So we can replace the recent climate changes in a broader context of the past 1400 years. This preservation is possible because the method is not based on a calibration (regression) but on similarities between assemblages of proxies. The reconstruction of the April-September temperatures was validated with a Jack-knife technique. It was also compared to other spatially gridded temperature reconstructions, literature data, and glacier advance and retreat curves. We also attempted to relate the spatial distribution of European temperature anomalies to known solar and volcanic forcings.

Conclusions

We found that our results were accurate back to 750. Cold periods prior to the 20^th century can be explained partly by low solar activity and/or high volcanic activity. The Medieval Warm Period (MWP) could be correlated to higher solar activity. During the 20^th century, however only anthropogenic forcing can explain the exceptionally high temperature rise. Warm periods of the Middle Age were spatially more heterogeneous than last decades, and then locally it could have been warmer. However, at the continental scale, the last decades were clearly warmer than any period of the last 1400 years. The heterogeneity of MWP versus the homogeneity of the last decades is likely an argument that different forcings could have operated. These results support the fact that we are living a climate change in Europe never seen in the past 1400 years.     

An international project to confirm Soviet-era results on immunological and teratological effects of RF field exposure in Wistar rats and comments on Grigoriev et al. [2010

Results of key Soviet-era studies dealing with effects on the immune system and teratological consequences in rats exposed to radiofrequency (RF) fields serve, in part, as a basis for setting exposure limits in the USSR and the current RF standards in Russia. The World Health Organization's (WHO) International EMF Project considered these Soviet results important enough that they should be confirmed using more modern methods. Since the Soviet papers did not contain comprehensive details on how the results were obtained, Professor Yuri Grigoriev worked with Dr. Bernard Veyret to agree on the final study protocol and to conduct separate studies in Moscow and Bordeaux under the same protocol. The International Oversight Committee (IOC) provided oversight on the conduct of the studies and was the firewall committee that dealt with the sponsors and researchers. This paper gives the IOC comments and conclusions on the differing results between the two studies.