Dissecting the Workforce and Workplace for Clinical Endocrinology, and the Work of Endocrinologists Early in Their Careers

[Excerpt] No national mechanism is in place for an informed, penetrating, and systematic assessment of the physician workforce such as that achieved by the National Science Foundation (NSF) for the periodic evaluation of the nation’s scientists and engineers. Likewise, knowledge of the workforce for clinical research is enigmatic and fragmentary despite the serial recommendations of “blue-ribbon” panels to establish a protocol for the recurrent assessment of clinical investigators early in their careers. Failure to adopt a national system for producing timely, high-quality data on the professional activities of physicians limits the application of improvement tools for advancing clinical investigation and ultimately improving clinical practice. The present study was designed as a pilot project to test the feasibility of using Web-based surveys to estimate the administrative, clinical, didactic, and research work of subspecialty physicians employed in academic, clinical, federal, and pharmaceutical workplaces. Physician members of The Endocrine Society (TES) were used as surrogate prototypes of a subspecialty workforce because of their manageable number and investigative tradition. The results establish that Web-based surveys provide a tool to assess the activities of a decentralized workforce employed in disparate workplaces and underscore the value of focusing on physician work within the context of particular workplaces within a subspecialty. Our report also provides a new and timely snapshot of the amount and types of research performed by clinically trained endocrinologists and offers an evidenced-based framework for improving the investigative workforce in this medical subspecialty

Adjusting for inflation and currency changes within health economic studies

Objectives: Within health economic studies, it is often necessary to adjust costs obtained from different time periods for inflation. Nevertheless, many studies do not report the methods used for this in sufficient detail. In this article, we outline the principal methods used to adjust for inflation, with a focus on studies relating to healthcare interventions in low- and middle-income countries. We also discuss issues relating to converting local currencies to international dollars and US$and adjusting cost data collected from other countries or previous studies. Methods: We outlined the 3 main methods used to adjust for inflation for studies in these settings: exchanging the local currency to US$ or international dollars and then inflating using US inflation rates (method 1); inflating the local currency using local inflation rates and then exchanging to US$or international dollars (method 2); splitting the costs into tradable and nontradable resources and using method 1 on the tradable resources and method 2 on the nontradable resources (method 3). Results: In a hypothetical example of adjusting a cost of US$100 incurred in Vietnam from 2006 to 2016 prices, the adjusted cost from the 3 methods were US$116.84, US$172.09, and US$161.04, respectively. Conclusions: The different methods for adjusting for inflation can yield substantially different results. We make recommendations regarding the most appropriate method for various scenarios. Moving forward, it is vital that studies report the methodology they use to adjust for inflation more transparently

Visual contrast response functions in Parkinson's disease: evidence from electroretinograms, visually evoked potentials and psychophysics

Objectives: Visual contrast detection thresholds and suprathreshold contrast discrimination thresholds were compared to luminance and flash/pattern electroretinograms (ERG) and visually evoked potentials (VEP) in patients with Parkinson's disease (n=31), patients with multiple system atrophy (n=6), patients with progressive supranuclear palsy (n=6) and control patients without central nervous disease (n=33). Methods: The stimuli were luminance modulated full-field (flash) or horizontally oriented sinewave gratings (pattern), the latter having either a low (0.5 cycles/deg) or medium (4.0 cycles/deg) spatial frequency. Stimulus contrast ranged from 10 to 80% so that contrast response functions could be derived. Results: Contrast thresholds were higher in the patients with Parkinson's disease than in the control patients. Contrast discrimination thresholds were also somewhat elevated in patients with Parkinson's disease. Pattern ERG amplitudes were significantly reduced in patients with Parkinson's disease for the medium spatial frequency stimulus, but less for the low spatial frequency and flash stimuli. Conclusions: Our results suggest that Parkinson’s disease impairs contrast processing in the retina. VEP amplitudes did not significantly differ between the groups for the conditions tested. Patients with progressive supranuclear palsy also showed impaired contrast perception and reduced ERG amplitudes, whereas patients with multiple system atrophy were less impaired

Predictive response-relevant clustering of expression data provides insights into disease processes

This article describes and illustrates a novel method of microarray data analysis that couples model-based clustering and binary classification to form clusters of ;response-relevant' genes; that is, genes that are informative when discriminating between the different values of the response. Predictions are subsequently made using an appropriate statistical summary of each gene cluster, which we call the ;meta-covariate' representation of the cluster, in a probit regression model. We first illustrate this method by analysing a leukaemia expression dataset, before focusing closely on the meta-covariate analysis of a renal gene expression dataset in a rat model of salt-sensitive hypertension. We explore the biological insights provided by our analysis of these data. In particular, we identify a highly influential cluster of 13 genes-including three transcription factors (Arntl, Bhlhe41 and Npas2)-that is implicated as being protective against hypertension in response to increased dietary sodium. Functional and canonical pathway analysis of this cluster using Ingenuity Pathway Analysis implicated transcriptional activation and circadian rhythm signalling, respectively. Although we illustrate our method using only expression data, the method is applicable to any high-dimensional datasets

Critical research gaps and recommendations to inform research prioritisation for more effective prevention and improved outcomes in colorectal cancer

OBJECTIVE: Colorectal cancer (CRC) leads to significant morbidity/mortality worldwide. Defining critical research gaps (RG), their prioritisation and resolution, could improve patient outcomes.DESIGN: RG analysis was conducted by a multidisciplinary panel of patients, clinicians and researchers (n=71). Eight working groups (WG) were constituted: discovery science; risk; prevention; early diagnosis and screening; pathology; curative treatment; stage IV disease; and living with and beyond CRC. A series of discussions led to development of draft papers by each WG, which were evaluated by a 20-strong patient panel. A final list of RGs and research recommendations (RR) was endorsed by all participants.RESULTS: Fifteen critical RGs are summarised below: RG1: Lack of realistic models that recapitulate tumour/tumour micro/macroenvironment; RG2: Insufficient evidence on precise contributions of genetic/environmental/lifestyle factors to CRC risk; RG3: Pressing need for prevention trials; RG4: Lack of integration of different prevention approaches; RG5: Lack of optimal strategies for CRC screening; RG6: Lack of effective triage systems for invasive investigations; RG7: Imprecise pathological assessment of CRC; RG8: Lack of qualified personnel in genomics, data sciences and digital pathology; RG9: Inadequate assessment/communication of risk, benefit and uncertainty of treatment choices; RG10: Need for novel technologies/interventions to improve curative outcomes; RG11: Lack of approaches that recognise molecular interplay between metastasising tumours and their microenvironment; RG12: Lack of reliable biomarkers to guide stage IV treatment; RG13: Need to increase understanding of health related quality of life (HRQOL) and promote residual symptom resolution; RG14: Lack of coordination of CRC research/funding; RG15: Lack of effective communication between relevant stakeholders.CONCLUSION: Prioritising research activity and funding could have a significant impact on reducing CRC disease burden over the next 5 years.</p

Highly variable iron content modulates iceberg-ocean fertilisation and potential carbon export

Marine phytoplankton growth at high latitudes is extensively limited by iron availability. Icebergs are a vector transporting the bioessential micronutrient iron into polar oceans. Therefore, increasing iceberg fluxes due to global warming have the potential to increase marine productivity and carbon export, creating a negative climate feedback. However, the magnitude of the iceberg iron flux, the subsequent fertilization effect and the resultant carbon export have not been quantified. Using a global analysis of iceberg samples, we reveal that iceberg iron concentrations vary over 6 orders of magnitude. Our results demonstrate that, whilst icebergs are the largest source of iron to the polar oceans, the heterogeneous iron distribution within ice moderates iron delivery to offshore waters and likely also affects the subsequent ocean iron enrichment. Future marine productivity may therefore be not only sensitive to increasing total iceberg fluxes, but also to changing iceberg properties, internal sediment distribution and melt dynamics

Patterns of Spiny Lobster (Panulirus argus) Postlarval Recruitment in the Carribbean: A CRTR Project

As part of the Coral Reef Targeted Research (CRTR) Program, a partnership between the Global Environment Facility and the World Bank, our research team examined the recruitment patterns of Caribbean spiny lobster (Panulirus argus) postlarvae among regions in the Caribbean, with a particular focus on Mesoamerica. Our goal was to collect comparable information on postlarval supply among regions and to provide data to test predictions of connectivity generated from a coupled biophysical oceanographic model of lobster larval dispersal. Here we present the results of the postlarval recruitment monitoring program. We monitored the catch of postlarvae on Witham-style collectors at sites in the Caribbean from March 2006 to May 2009, although the duration and frequency of sampling varied among locations. Recruitment varied considerably among months and locations. It peaked in the Western Caribbean in the fall (Oct - Dec), whereas in Florida, Puerto Rico, and Venezuela peaks were in spring (Feb - April) with a smaller peak in the fall. Sites generally fell into two groups with respect to monthly variability in recruitment: low variability sites (e.g., Honduras, southern Mexico, Venezuela) and high variability sites (e.g., Florida, San Andres Islands, Puerto Rico, northern Mexico). Recruitment magnitude varied locally, but generally increased (lowest to highest) from Puerto Rico, San Andres Islands, Honduras, Mexico, Venezuela, to Florida. Recruitment trends mirrored fishery catch in some locations, implying a recruit-to-stock linkage. Recruitment was significantly correlated among several sites, suggesting similarity in their larval sources and oceanographic regimes

Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk.

Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10(-14), odds ratio = 0.86, 95% confidence interval = 0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression

Delayed Treatment with Systemic (S)-Roscovitine Provides Neuroprotection and Inhibits In Vivo CDK5 Activity Increase in Animal Stroke Models

Although quite challenging, neuroprotective therapies in ischemic stroke remain an interesting strategy to counter mechanisms of ischemic injury and reduce brain tissue damage. Among potential neuroprotective drug, cyclin-dependent kinases (CDK) inhibitors represent interesting therapeutic candidates. Increasing evidence indisputably links cell cycle CDKs and CDK5 to the pathogenesis of stroke. Although recent studies have demonstrated promising neuroprotective efficacies of pharmacological CDK inhibitors in related animal models, none of them were however clinically relevant to human treatment.In the present study, we report that systemic delivery of (S)-roscovitine, a well known inhibitor of mitotic CDKs and CDK5, was neuroprotective in a dose-dependent manner in two models of focal ischemia, as recommended by STAIR guidelines. We show that (S)-roscovitine was able to cross the blood brain barrier. (S)-roscovitine significant in vivo positive effect remained when the compound was systemically administered 2 hrs after the insult. Moreover, we validate one of (S)-roscovitine in vivo target after ischemia. Cerebral increase of CDK5/p25 activity was observed 3 hrs after the insult and prevented by systemic (S)-roscovitine administration. Our results show therefore that roscovitine protects in vivo neurons possibly through CDK5 dependent mechanisms.Altogether, our data bring new evidences for the further development of pharmacological CDK inhibitors in stroke therapy