13C NMR isotopomer analysis reveals a connection between pyruvate cycling and glucose-stimulated insulin secretion (GSIS)

Cellular metabolism of glucose is required for stimulation of insulin secretion from pancreatic beta cells, but the precise metabolic coupling factors involved in this process are not known. In an effort to better understand mechanisms of fuel-mediated insulin secretion, we have adapted 13C NMR and isotopomer methods to measure influx of metabolic fuels into the tricarboxylic acid (TCA) cycle in insulinoma cells. Mitochondrial metabolism of [U-13C3]pyruvate, derived from [U-13C6]glucose, was compared in four clonal rat insulinoma cell 1-derived cell lines with varying degrees of glucose responsiveness. A 13C isotopomer analysis of glutamate isolated from these cells showed that the fraction of acetyl-CoA derived from [U-13C6]glucose was the same in all four cell lines (44 +/- 5%, 70 +/- 3%, and 84 +/- 4% with 3, 6, or 12 mM glucose, respectively). The 13C NMR spectra also demonstrated the existence of two compartmental pools of pyruvate, one that exchanges with TCA cycle intermediates and a second pool derived from [U-13C6]glucose that feeds acetyl-CoA into the TCA cycle. The 13C NMR spectra were consistent with a metabolic model where the two pyruvate pools do not randomly mix. Flux between the mitochondrial intermediates and the first pool of pyruvate (pyruvate cycling) varied in proportion to glucose responsiveness in the four cell lines. Furthermore, stimulation of pyruvate cycling with dimethylmalate or its inhibition with phenylacetic acid led to proportional changes in insulin secretion. These findings indicate that exchange of pyruvate with TCA cycle intermediates, rather than oxidation of pyruvate via acetyl-CoA, correlates with glucose-stimulated insulin secretion.     

Clinically significant differences between point-of-care analysers and a standard analyser for monitoring the International Normalized Ratio in oral anticoagulant therapy: a multi-instrument evaluation in a hospital outpatient setting.

The increasing number of patients requiring oral anticoagulant therapy has lead to an expansion in the use of point-of-care test (POCT) analysers for measuring the International Normalized Ratio (INR) for monitoring purposes. Availability of new technology inevitably leads to comparisons with standard methodologies, and studies to date have reached varying conclusions about the comparability of POCT INRs with conventional testing. We compared the performance of five POCT instruments (Hemochron Junior Signature, ProTime, CoaguChek S, INRatio and TAS) against Innovin thromboplastin on a Sysmex CA1500 automated analyser. The Hemochron Junior Signature, ProTime and CoaguChek S demonstrated strong correlation with the laboratory method (R2 > 0.94). These three analysers demonstrated higher percentages of paired results within 0.5 INR units (81.5, 92.0 and 74.0%, respectively); the INRatio and TAS demonstrated 54.2 and 62.2%, respectively. Within INR ranges of up to 2.0, 2.1-3.0, 3.1-4.0 and above 4.0, none of the POCT analysers demonstrated significant agreement with the standard method in every range. All POCT instruments showed a degree of bias and greater variation from the standard method at INR values above 3.0. These data indicate the potential for POCT analysers to generate INR values sufficiently different from conventional methods that they may impact on clinical decision-making.     

Resident recognition of open-angle glaucoma

To test an educational intervention’s effect on improving detection of glaucoma by direct ophthalmoscopy, 14 medicine residents examined five patients, two with ophthalmoscopic changes of glaucoma and three with normal fundi. The residents observed a standardized slide/narrative educational intervention reviewing glaucomatous ophthalmoscopic changes and then re-examined the same patients eight to 12 weeks later. The intervention’s odds of improving residents’ diagnostic impression were significant (OR=2.2; 95% CI=1.3–36), with significant improvement in sensitivity (p=0.02) and a trend toward improved specificity. These findings confirm that the diagnosis of glaucomatous ocular changes on eye examinations by medicine residents can be improved with a brief educational intervention. Presented in abstract form at the annual meeting of the Society of General Internal Medicine, Medical Education Section, April 29–May 1, 1992, Washington, DC, and at the Southern regional meeting of the Society of General Internal Medicine, Medical Education Section, January 29–31, 1992, New Orleans, Louisiana.     

Incidence of Overuse Musculoskeletal Injuries in Military Service Members With Traumatic Lower Limb Amputation

Objective

To describe the incidence of overuse musculoskeletal injuries in service members with combat-related lower limb amputation.

Editor's Choice: Toward high-throughput phenotyping: unbiased automated feature extraction and selection from knowledge sources

Objective Analysis of narrative (text) data from electronic health records (EHRs) can improve population-scale phenotyping for clinical and genetic research. Currently, selection of text features for phenotyping algorithms is slow and laborious, requiring extensive and iterative involvement by domain experts. This paper introduces a method to develop phenotyping algorithms in an unbiased manner by automatically extracting and selecting informative features, which can be comparable to expert-curated ones in classification accuracy.Materials and methods Comprehensive medical concepts were collected from publicly available knowledge sources in an automated, unbiased fashion. Natural language processing (NLP) revealed the occurrence patterns of these concepts in EHR narrative notes, which enabled selection of informative features for phenotype classification. When combined with additional codified features, a penalized logistic regression model was trained to classify the target phenotype.Results The authors applied our method to develop algorithms to identify patients with rheumatoid arthritis and coronary artery disease cases among those with rheumatoid arthritis from a large multi-institutional EHR. The area under the receiver operating characteristic curves (AUC) for classifying RA and CAD using models trained with automated features were 0.951 and 0.929, respectively, compared to the AUCs of 0.938 and 0.929 by models trained with expert-curated features.Discussion Models trained with NLP text features selected through an unbiased, automated procedure achieved comparable or slightly higher accuracy than those trained with expert-curated features. The majority of the selected model features were interpretable.Conclusion The proposed automated feature extraction method, generating highly accurate phenotyping algorithms with improved efficiency, is a significant step toward high-throughput phenotyping.     

Post-acute care referral and inpatient rehabilitation admission criteria for persons with brain injury across two Canadian provinces

Purpose: Investigate health care providers’ perceptions of referral and admission criteria to brain injury inpatient rehabilitation in two Canadian provinces.

Methods: Health care providers (n?=?345) from brain injury programs (13 acute care and 16 rehabilitation facilities) participated in a cross-sectional web-based survey. The participants rated the likelihood of patients (traumatic brain injury and cerebral hypoxia) to be referred/admitted to rehabilitation and the influence of 19 additional factors (e.g., tracheostomy). The participants reported the perceived usefulness of referral/admission policies and assessment tools used.

Results: Ninety-one percent acute care and 98% rehabilitation participants reported the person with traumatic brain injury would likely or very likely be referred/admitted to rehabilitation compared to respectively 43% and 53% for the patient with hypoxia. Two additional factors significantly decreased the likelihood of referral/admission: older age and the combined presence of minimal learning ability, memory impairment and physical aggression. Some significant inter-provincial variations in the perceived referral/admission procedure were observed. Most participants reported policies were helpful. Similar assessment tools were used in acute care and rehabilitation.

Conclusions: Health care providers appear to consider various factors when making decisions regarding referral and admission to rehabilitation. Variations in the perceived likelihood of referral/admission suggest a need for standardized referral/admission practices.

• Implications for Rehabilitation

• Various patient characteristics influence clinicians’ decisions when selecting appropriate candidates for inpatient rehabilitation.

• In this study, acute care clinicians were less likely to refer patients that their rehabilitation counter parts would likely have admitted and a patient with hypoxic brain injury was less likely to be referred or admitted in rehabilitation than a patient with a traumatic brain injury.

• Such discrepancies suggest that policy-makers, managers and clinicians should work together to develop and implement more standardized referral practices and more specific admission criteria in order to ensure equitable access to brain injury rehabilitation services.