Review of Film Directing: Shot by Shot—25th Anniversary Edition: Visualizing from Concept to Screen

Review of Film Directing: Shot by Shot—25th Anniversary Edition: Visualizing from Concept to Screen

Revisiting diagenesis on the Ontong Java Plateau: Evidence for authigenic crust precipitation in Globorotalia tumida

The calcite tests of foraminifera lie in marine sediments for thousands to millions of years, before being analysed to generate trace element and isotope palaeoproxy records. These sediments constitute a distinct physio-chemical environment from the conditions in which the tests formed. Storage in sediments can modify the trace element and isotopic content of foraminiferal calcite through diagenetic alteration, which has the potential to confound their palaeoceanographic interpretation. A previous study of G. tumida from the Ontong Java Plateau, western equatorial Pacific, found that preferential dissolution of higher-Mg chamber calcite, and the preservation of a low-Mg crust on the tests significantly reduced whole-test Mg/Ca and Sr/Ca [Brown and Elderfield, 1996]. Here, we revisit these specimens with a combination of synchrotron X-ray computed tomography (sXCT) and electron probe micro-analyses (EPMA) to re-evaluate the nature of their diagenetic alteration. The dissolution of higher-Mg calcite with depth was directly observed in the sXCT data, confirming the inference of the previous study. The sXCT data further reveal a thickening of the chemically and structurally distinct calcite crust with depth. We propose that these crusts have a diagenetic origin, driven by the simultaneous dissolution of high-Mg chamber calcite and precipitation of low-Mg crust from the resulting modified pore-water solution. While the breadth of the study is limited by the nature of the techniques, the observation of both dissolution and re-precipitation of foraminiferal calcite serves to demonstrate the action of two simultaneous diagenetic alteration processes, with significant impacts on the resulting palaeoproxy signals.The authors would like to acknowledge Aleksey Sadekov, Gerald Langer, India Weidle, Alberto de Fanis, Andrew Bodey, Joan Vila-Comamala and Ulrich Wagner for their help with the project. The work was funded by the Diamond Light Source and by the ERC (2010-NEWLOG ADG-267931 grant to HE).This is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1002/2014PA00275

Evidence-based decision support for pediatric rheumatology reduces diagnostic errors.

BACKGROUND: The number of trained specialists world-wide is insufficient to serve all children with pediatric rheumatologic disorders, even in the countries with robust medical resources. We evaluated the potential of diagnostic decision support software (DDSS) to alleviate this shortage by assessing the ability of such software to improve the diagnostic accuracy of non-specialists. METHODS: Using vignettes of actual clinical cases, clinician testers generated a differential diagnosis before and after using diagnostic decision support software. The evaluation used the SimulConsult® DDSS tool, based on Bayesian pattern matching with temporal onset of each finding in each disease. The tool covered 5405 diseases (averaging 22 findings per disease). Rheumatology content in the database was developed using both primary references and textbooks. The frequency, timing, age of onset and age of disappearance of findings, as well as their incidence, treatability, and heritability were taken into account in order to guide diagnostic decision making. These capabilities allowed key information such as pertinent negatives and evolution over time to be used in the computations. Efficacy was measured by comparing whether the correct condition was included in the differential diagnosis generated by clinicians before using the software ( unaided ), versus after use of the DDSS ( aided ). RESULTS: The 26 clinicians demonstrated a significant reduction in diagnostic errors following introduction of the software, from 28% errors while unaided to 15% using decision support (p \u3c 0.0001). Improvement was greatest for emergency medicine physicians (p = 0.013) and clinicians in practice for less than 10 years (p = 0.012). This error reduction occurred despite the fact that testers employed an open book approach to generate their initial lists of potential diagnoses, spending an average of 8.6 min using printed and electronic sources of medical information before using the diagnostic software. CONCLUSIONS: These findings suggest that decision support can reduce diagnostic errors and improve use of relevant information by generalists. Such assistance could potentially help relieve the shortage of experts in pediatric rheumatology and similarly underserved specialties by improving generalists\u27 ability to evaluate and diagnose patients presenting with musculoskeletal complaints. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02205086

College student sleep quality and mental and physical health are associated with food insecurity in a multi-campus study

Objective: To assess the relationship between food insecurity, sleep quality, and days with mental and physical health issues among college students. Design: An online survey was administered. Food insecurity was assessed using the ten-item Adult Food Security Survey Module. Sleep was measured using the nineteen-item Pittsburgh Sleep Quality Index (PSQI). Mental health and physical health were measured using three items from the Healthy Days Core Module. Multivariate logistic regression was conducted to assess the relationship between food insecurity, sleep quality, and days with poor mental and physical health. Setting: Twenty-two higher education institutions. Participants: College students (n 17 686) enrolled at one of twenty-two participating universities. Results: Compared with food-secure students, those classified as food insecure (43·4 %) had higher PSQI scores indicating poorer sleep quality (P \u3c 0·0001) and reported more days with poor mental (P \u3c 0·0001) and physical (P \u3c 0·0001) health as well as days when mental and physical health prevented them from completing daily activities (P \u3c 0·0001). Food-insecure students had higher adjusted odds of having poor sleep quality (adjusted OR (AOR): 1·13; 95 % CI 1·12, 1·14), days with poor physical health (AOR: 1·01; 95 % CI 1·01, 1·02), days with poor mental health (AOR: 1·03; 95 % CI 1·02, 1·03) and days when poor mental or physical health prevented them from completing daily activities (AOR: 1·03; 95 % CI 1·02, 1·04). Conclusions: College students report high food insecurity which is associated with poor mental and physical health, and sleep quality. Multi-level policy changes and campus wellness programmes are needed to prevent food insecurity and improve student health-related outcomes

Tolerance of allogromiid Foraminifera to severely elevated carbon dioxide concentrations : implications to future ecosystem functioning and paleoceanographic interpretations

Author Posting. © Elsevier B.V., 2009. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Global and Planetary Change 65 (2009): 107-114, doi:10.1016/j.gloplacha.2008.10.013.Increases in the partial pressure of carbon dioxide (pCO2) in the atmosphere will significantly affect a wide variety of terrestrial fauna and flora. Because of tight atmospheric-oceanic coupling, shallow-water marine species are also expected to be affected by increases in atmospheric carbon dioxide concentrations. One proposed way to slow increases in atmospheric pCO2 is to sequester CO2 in the deep sea. Thus, over the next few centuries marine species will be exposed to changing seawater chemistry caused by ocean-atmospheric exchange and/or deep-ocean sequestration. This initial case study on one allogromiid foraminiferal species (Allogromia laticollaris) was conducted to begin to ascertain the effect of elevated pCO2 on benthic Foraminifera, which are a major meiofaunal constituent of shallow- and deep-water marine communities. Cultures of this thecate foraminiferan protist were used for 10-14-day experiments. Experimental treatments were executed in an incubator that controlled CO2 (15 000; 30 000; 60 000; 90 000; 200 000 ppm), temperature and humidity; atmospheric controls (i.e., ~375 ppm CO2) were executed simultaneously. Although the experimental elevated pCO2 values are far above foreseeable surface water pCO2, they were selected to represent the spectrum of conditions expected for the benthos if deep-sea CO2 sequestration becomes a reality. Survival was assessed in two independent ways: pseudopodial presence/absence and measurement of adenosine triphosphate (ATP), which is an indicator of cellular energy. Substantial proportions of A. laticollaris populations survived 200 000 ppm CO2 although the mean of the median [ATP] of survivors was statistically lower for this treatment than for that of atmospheric control specimens. After individuals that had been incubated in 200 000 ppm CO2 for 12 days were transferred to atmospheric conditions for ~24 hours, the [ATP] of live specimens (survivors) approximated those of the comparable atmospheric control treatment. Incubation in 200 000 ppm CO2 also resulted in reproduction by some individuals. Results suggest that certain Foraminifera are able to tolerate deep-sea CO2 sequestration and perhaps thrive as a result of elevated pCO2 that is predicted for the next few centuries, in a high-pCO2 world. Thus, allogromiid foraminiferal “blooms” may result from climate change. Furthermore, because allogromiids consume a variety of prey, it is likely that they will be major players in ecosystem dynamics of future coastal sedimentary environments.This work was funded by US Department of Energy grant # DE-FG02-03ER63696 (to J. Kennett and J. Bernhard), NSF OCE-0725966, and the WHOI Summer Student Fellow Program, which is funded by NSF Research Experience for Undergraduates Program grant #OCE-0139423

Mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification

Familial idiopathic basal ganglia calcification (IBGC) or Fahr's disease is a rare neurodegenerative disorder characterized by calcium deposits in the basal ganglia and other brain regions, which is associated with neuropsychiatric and motor symptoms. Familial IBGC is genetically heterogeneous and typically transmitted in an autosomal dominant fashion. We performed a mutational analysis of SLC20A2, the first gene found to cause IBGC, to assess its genetic contribution to familial IBGC. We recruited 218 subjects from 29 IBGC-affected families of varied ancestry and collected medical history, neurological exam, and head CT scans to characterize each patient's disease status. We screened our patient cohort for mutations in SLC20A2. Twelve novel (nonsense, deletions, missense, and splice site) potentially pathogenic variants, one synonymous variant, and one previously reported mutation were identified in 13 families. Variants predicted to be deleterious cosegregated with disease in five families. Three families showed nonsegregation with clinical disease of such variants, but retrospective review of clinical and neuroimaging data strongly suggested previous misclassification. Overall, mutations in SLC20A2 account for as many as 41 % of our familial IBGC cases. Our screen in a large series expands the catalog of SLC20A2 mutations identified to date and demonstrates that mutations in SLC20A2 are a major cause of familial IBGC. Non-perfect segregation patterns of predicted deleterious variants highlight the challenges of phenotypic assessment in this condition with highly variable clinical presentation

Human Genetics in Rheumatoid Arthritis Guides a High-Throughput Drug Screen of the CD40 Signaling Pathway

Although genetic and non-genetic studies in mouse and human implicate the CD40 pathway in rheumatoid arthritis (RA), there are no approved drugs that inhibit CD40 signaling for clinical care in RA or any other disease. Here, we sought to understand the biological consequences of a CD40 risk variant in RA discovered by a previous genome-wide association study (GWAS) and to perform a high-throughput drug screen for modulators of CD40 signaling based on human genetic findings. First, we fine-map the CD40 risk locus in 7,222 seropositive RA patients and 15,870 controls, together with deep sequencing of CD40 coding exons in 500 RA cases and 650 controls, to identify a single SNP that explains the entire signal of association (rs4810485, P = 1.4×10(−9)). Second, we demonstrate that subjects homozygous for the RA risk allele have ∼33% more CD40 on the surface of primary human CD19+ B lymphocytes than subjects homozygous for the non-risk allele (P = 10(−9)), a finding corroborated by expression quantitative trait loci (eQTL) analysis in peripheral blood mononuclear cells from 1,469 healthy control individuals. Third, we use retroviral shRNA infection to perturb the amount of CD40 on the surface of a human B lymphocyte cell line (BL2) and observe a direct correlation between amount of CD40 protein and phosphorylation of RelA (p65), a subunit of the NF-κB transcription factor. Finally, we develop a high-throughput NF-κB luciferase reporter assay in BL2 cells activated with trimerized CD40 ligand (tCD40L) and conduct an HTS of 1,982 chemical compounds and FDA–approved drugs. After a series of counter-screens and testing in primary human CD19+ B cells, we identify 2 novel chemical inhibitors not previously implicated in inflammation or CD40-mediated NF-κB signaling. Our study demonstrates proof-of-concept that human genetics can be used to guide the development of phenotype-based, high-throughput small-molecule screens to identify potential novel therapies in complex traits such as RA