Recent Developments in the Analysis of the Black Mat Layer and Cosmic Impact at 12.8ka

Recent analyses of sediment samples from "black mat" sites in South America and Europe support previous interpretations of an ET impact event that reversed the Late Glacial demise of LGM ice during the Bølling Allerød warming, resulting in a resurgence of ice termed the Younger Dryas (YD) cooling episode. The breakup or impact of a cosmic vehicle at the YD boundary coincides with the onset of a 1-kyr long interval of glacial resurgence, one of the most studied events of the Late Pleistocene. New analytical databases reveal a corpus of data indicating that the cosmic impact was a real event, most possibly a cosmic airburst from Earth's encounter with the Taurid Complex comet or unknown asteroid, an event that led to cosmic fragments exploding interhemispherically over widely dispersed areas, including the northern Andes of Venezuela and the Alps on the Italian/French frontier. While the databases in the two areas differ somewhat, the overall interpretation is that microtextural evidence in weathering rinds and in sands of associated paleosols and glaciofluvial deposits carry undeniable attributes of melted glassy carbon and Fe spherules, planar deformation features, shock-melted and contorted quartz, occasional transition and platinum metals, and brecciated and impacted minerals of diverse lithologies. In concert with other black mat localities in the Western USA, the Netherlands, coastal France, Syria, Central Asia, Peru, Argentina and Mexico, it appears that a widespread cosmic impact by an asteroid or comet is responsible for deposition of the black mat at the onset of the YD glacial event. Whether or not the impact caused a 1-kyr interval of glacial climate depends upon whether or not the Earth had multiple centuries-long episodic encounters with the Taurid Complex or asteroid remnants; impact-related changes in microclimates sustained climatic forcing sufficient to maintain positive mass balances in the reformed ice; and/or inertia in the Atlantic thermohaline circulation system persisted for 1kyr. 

Clathrin adaptor epsinR is required for retrograde sorting on early endosomal membranes

Retrograde transport links early/recycling endosomes to the trans-Golgi network (TGN), thereby connecting the endocytic and the biosynthetic/secretory pathways. To determine how internalized molecules are targeted to the retrograde route, we have interfered with the function of clathrin and that of two proteins that interact with it, AP1 and epsinR. We found that the glycosphingolipid binding bacterial Shiga toxin entered cells efficiently when clathrin expression was inhibited. However, retrograde transport of Shiga toxin to the TGN was strongly inhibited. This allowed us to show that for Shiga toxin, retrograde sorting on early/recycling endosomes depends on clathrin and epsinR, but not AP1. EpsinR was also involved in retrograde transport of two endogenous proteins, TGN38/46 and mannose 6-phosphate receptor. In conclusion, our work reveals the existence of clathrin-independent and -dependent transport steps in the retrograde route, and establishes a function for clathrin and epsinR at the endosome-TGN interface.

Metformin use and survival after colorectal cancer: A population-based cohort study.

Preclinical evidence suggests that metformin could delay cancer progression. Previous epidemiological studies however have been limited by small sample sizes and certain time-related biases. This study aimed to investigate whether colorectal cancer patients with type 2 diabetes who were exposed to metformin had reduced cancer-specific mortality. We conducted a retrospective cohort study of 1,197 colorectal cancer patients newly diagnosed from 1998 to 2009 (identified from English cancer registries) with type 2 diabetes (based upon Clinical Practice Research Datalink, CPRD, prescription and diagnosis records). In this cohort 382 colorectal cancer-specific deaths occurred up to 2012 from the Office of National Statistics (ONS) mortality data. Metformin use was identified from CPRD prescription records. Using time-dependent Cox regression models, unadjusted and adjusted hazard ratios (HR) and 95% CIs were calculated for the association between post-diagnostic exposure to metformin and colorectal cancer-specific mortality. Overall, there was no evidence of an association between metformin use and cancer-specific death before or after adjustment for potential confounders (adjusted HR 1.06, 95% CI 0.80, 1.40). In addition, after adjustment for confounders, there was also no evidence of associations between other diabetic medications and cancer-specific mortality including sulfonylureas (HR 1.14, 95% CI 0.86, 1.51), insulin use (HR 1.35, 95% CI 0.95, 1.93) or other anti-diabetic medications including thiazolidinediones (HR 0.73, 95% CI 0.46, 1.14). Similar associations were observed by duration of use and for all-cause mortality. This population-based study, the largest to date, does not support a protective association between metformin and survival in colorectal cancer patients.

Genetically Determined Height and Coronary Artery Disease

Background: The nature and underlying mechanisms of an inverse association between adult height and the risk of coronary artery disease (CAD) are unclear. 
Methods: We used a genetic approach to investigate the association between height and CAD, using 180 height-associated genetic variants. We tested the association between a change in genetically determined height of 1 SD (6.5 cm) with the risk of CAD in 65,066 cases and 128,383 controls. Using individual-level genotype data from 18,249 persons, we also examined the risk of CAD associated with the presence of various numbers of height-associated alleles. To identify putative mechanisms, we analyzed whether genetically determined height was associated with known cardiovascular risk factors and performed a pathway analysis of the height-associated genes. 
Results: We observed a relative increase of 13.5% (95% confidence interval [CI], 5.4 to 22.1; P<0.001) in the risk of CAD per 1-SD decrease in genetically determined height. There was a graded relationship between the presence of an increased number of height-raising variants and a reduced risk of CAD (odds ratio for height quartile 4 versus quartile 1, 0.74; 95% CI, 0.68 to 0.84; P<0.001). Of the 12 risk factors that we studied, we observed significant associations only with levels of low-density lipoprotein cholesterol and triglycerides (accounting for approximately 30% of the association). We identified several overlapping pathways involving genes associated with both development and atherosclerosis. 
Conclusions: There is a primary association between a genetically determined shorter height and an increased risk of CAD, a link that is partly explained by the association between shorter height and an adverse lipid profile. Shared biologic processes that determine achieved height and the development of atherosclerosis may explain some of the association. (Funded by the British Heart Foundation and others.)

Adiposity as a cause of cardiovascular disease: a Mendelian randomization study

Background: Adiposity, as indicated by body mass index (BMI), has been associated with risk of cardiovascular diseases in epidemiological studies. We aimed to investigate if these associations are causal, using Mendelian randomization (MR) methods.

Methods: The associations of BMI with cardiovascular outcomes [coronary heart disease (CHD), heart failure and ischaemic stroke], and associations of a genetic score (32 BMI single nucleotide polymorphisms) with BMI and cardiovascular outcomes were examined in up to 22 193 individuals with 3062 incident cardiovascular events from nine prospective follow-up studies within the ENGAGE consortium. We used random-effects meta-analysis in an MR framework to provide causal estimates of the effect of adiposity on cardiovascular outcomes.

Results: There was a strong association between BMI and incident CHD (HR = 1.20 per SD-increase of BMI, 95% CI, 1.12–1.28, P = 1.9·10−7), heart failure (HR = 1.47, 95% CI, 1.35–1.60, P = 9·10−19) and ischaemic stroke (HR = 1.15, 95% CI, 1.06–1.24, P = 0.0008) in observational analyses. The genetic score was robustly associated with BMI (β = 0.030 SD-increase of BMI per additional allele, 95% CI, 0.028–0.033, P = 3·10−107). Analyses indicated a causal effect of adiposity on development of heart failure (HR = 1.93 per SD-increase of BMI, 95% CI, 1.12–3.30, P = 0.017) and ischaemic stroke (HR = 1.83, 95% CI, 1.05–3.20, P = 0.034). Additional cross-sectional analyses using both ENGAGE and CARDIoGRAMplusC4D data showed a causal effect of adiposity on CHD.

Conclusions: Using MR methods, we provide support for the hypothesis that adiposity causes CHD, heart failure and, previously not demonstrated, ischaemic stroke.

Defining consensus norms for palliative care of people with intellectual disabilities in Europe using Delphi methods: A White Paper from the European Association of Palliative care

Background: People with intellectual disabilities often present with unique challenges that make it more difficult to meet their
palliative care needs.
Aim: To define consensus norms for palliative care of people with intellectual disabilities in Europe.
Design: Delphi study in four rounds: (1) a taskforce of 12 experts from seven European countries drafted the norms, based on available empirical knowledge and regional/national guidelines; (2) using an online survey, 34 experts from 18 European countries evaluated the draft norms, provided feedback and distributed the survey within their professional networks. Criteria for consensus
were clearly defined; (3) modifications and recommendations were made by the taskforce; and (4) the European Association for
Palliative Care reviewed and approved the final version.
Setting and participants: Taskforce members: identified through international networking strategies. Expert panel: a purposive sample identified through taskforce members’ networks.
Results: A total of 80 experts from 15 European countries evaluated 52 items within the following 13 norms: equity of access, communication, recognising the need for palliative care, assessment of total needs, symptom management, end-of-life decision making, involving those who matter, collaboration, support for family/carers, preparing for death, bereavement support, education/training
and developing/managing services. None of the items scored less than 86% agreement, making a further round unnecessary. In light of respondents’ comments, several items were modified and one item was deleted.
Conclusion: This White Paper presents the first guidance for clinical practice, policy and research related to palliative care for people with intellectual disabilities based on evidence and European consensus, setting a benchmark for changes in policy and practice.

Moral asymmetries in judgments of agency withstand ludicrous causal deviance

Americans have been shown to attribute greater intentionality to immoral than to amoral actions in cases of causal deviance, that is, cases where a goal is satisfied in a way that deviates from initially planned means (e.g., a gunman wants to hit a target and his hand slips, but the bullet ricochets off a rock into the target). However, past research has yet to assess whether this asymmetry persists in cases of extreme causal deviance. Here, we manipulated the level of mild to extreme causal deviance of an immoral versus amoral act. The asymmetry in attributions of intentionality was observed at all but the
most extreme level of causal deviance, and, as we hypothesized, was mediated by attributions of Blame/credit and judgments of action performance. These findings are discussed as they support a multiple-concepts interpretation of the asymmetry, wherein blame renders a naïve concept of intentional action (the outcome matches the intention) more salient than a composite concept (the outcome matches the intention and was brought about by planned means), and in terms of their implications for cross-cultural research on judgments of agency.

Pleiotropic analysis of cancer risk loci on esophageal adenocarcinoma risk

Background: Several cancer-associated loci identified from genome-wide association studies (GWAS) have been associated with risks of multiple cancer sites, suggesting pleiotropic effects. We investigated whether GWAS-identified risk variants for other common cancers are associated with risk of esophageal adenocarcinoma (EA) or its precursor, Barrett's esophagus. 

Methods: We examined the associations between risks of EA and Barrett's esophagus and 387 SNPs that have been associated with risks of other cancers, by using genotype imputation data on 2,163 control participants and 3,885 (1,501 EA and 2,384 Barrett's esophagus) case patients from the Barrett's and Esophageal Adenocarcinoma Genetic Susceptibility Study, and investigated effect modification by smoking history, body mass index (BMI), and reflux/heartburn. 

Results: After correcting for multiple testing, none of the tested 387 SNPs were statistically significantly associated with risk of EA or Barrett's esophagus. No evidence of effect modification by smoking, BMI, or reflux/heartburn was observed. 

Conclusions: Genetic risk variants for common cancers identified from GWAS appear not to be associated with risks of EA or Barrett's esophagus. 

Impact: To our knowledge, this is the first investigation of pleiotropic genetic associations with risks of EA and Barrett's esophagus.

CSI 2264: Simultaneous Optical and Infrared Light Curves of Young Disk-bearing Stars in NGC 2264 with CoRoT and Spitzer—Evidence for Multiple Origins of Variability

We present the Coordinated Synoptic Investigation of NGC 2264, a continuous 30 day multi-wavelength photometric monitoring campaign on more than 1000 young cluster members using 16 telescopes. The unprecedented combination of multi-wavelength, high-precision, high-cadence, and long-duration data opens a new window into the time domain behavior of young stellar objects. Here we provide an overview of the observations, focusing on results from Spitzer and CoRoT. The highlight of this work is detailed analysis of 162 classical T Tauri stars for which we can probe optical and mid-infrared flux variations to 1% amplitudes and sub-hour timescales. We present a morphological variability census and then use metrics of periodicity, stochasticity, and symmetry to statistically separate the light curves into seven distinct classes, which we suggest represent different physical processes and geometric effects. We provide distributions of the characteristic timescales and amplitudes and assess the fractional representation within each class. The largest category (>20%) are optical "dippers" with discrete fading events lasting ~1-5 days. The degree of correlation between the optical and infrared light curves is positive but weak; notably, the independently assigned optical and infrared morphology classes tend to be different for the same object. Assessment of flux variation behavior with respect to (circum)stellar properties reveals correlations of variability parameters with Hα emission and with effective temperature. Overall, our results point to multiple origins of young star variability, including circumstellar obscuration events, hot spots on the star and/or disk, accretion bursts, and rapid structural changes in the inner disk. Based on data from the Spitzer and CoRoT missions. The CoRoT space mission was developed and is operated by the French space agency CNES, with participation of ESA's RSSD and Science Programmes, Austria, Belgium, Brazil, Germany, and Spain.

An evaluation of the effectiveness of an algorithm intervention in reducing inappropriate faecal samples sent for Clostridium difficile testing.

Background: Clostridium difficile (C. difficile) is a leading cause of infectious diarrhoea in hospitals. Sending faecal samples for testing expedites diagnosis and appropriate treatment. Clinical suspicion of C. difficile based on patient history, signs and symptoms is the basis for sampling. Sending faecal samples from patients with diarrhoea ‘just in case’ the patient has C. difficile may be an indication of poor clinical management.

Aim: To evaluate the effectiveness of an intervention by an Infection Prevention and Control Team (IPCT) in reducing inappropriate faecal samples sent for C. difficile testing.

Method: An audit of numbers of faecal samples sent before and after a decision-making algorithm was introduced. The number of samples received in the laboratory was retrospectively counted for 12-week periods before and after an algorithm was introduced.
Findings: There was a statistically significant reduction in the mean number of faecal samples sent post the algorithm. Results were compared to a similar intervention carried out in 2009 in which the same message was delivered by a memorandum. In 2009 the memorandum had no effect on the overall number of weekly samples being sent.

Conclusion: An algorithm intervention had an effect on the number of faecal samples being sent for C. difficile testing and thus contributed to the effective use of the laboratory service.