Impact of Initial eGlycemic Management System Dosing Strategy on Time to Target Blood Glucose Range.

BACKGROUND: Glucommander™ (GM), an electronic glycemic management system, was implemented across a multi-hospital health system as the standard of care for glycemic control. GM provides insulin dosing recommendations based on patient-specific blood glucose (BG) trends after providers select either a custom dose or weight-based multiplier as the initial dosing strategy for the first 24 hours. This study evaluated the impact of initial subcutaneous (SC) GM insulin dosing strategies on glycemic management. METHODS: Non-intensive care unit patients treated with SC GM using either initial custom (based on provider discretion) or weight-based multiplier settings (0.3, 0.5, or 0.7 units/kg/day) were evaluated in this retrospective chart review. The primary endpoint was time to target BG range defined as time to first two consecutive in range point of care BG. Secondary endpoints included percentage of BG values in target range, percentage of orders following institutional recommendations, length of stay (LOS), average BG, and incidence of hypoglycemia and hyperglycemia. RESULTS: A review of 348 patients showed time to target BG was not significantly different between custom and multiplier groups (55 vs 64 hours, P = .07). Target BG was achieved in less than half of patients in both groups (47% vs 44%, respectively). There were no differences in hospital LOS, proportion of BG in target range, rates of hypo/hyperglycemia, and average BG. CONCLUSIONS: Custom initial SC GM insulin dosing settings showed a nonsignificant decrease in time to target BG range compared to pre-defined multiplier settings. Future studies evaluating the impact of compliance with institutional recommendations on BG control are warranted.

The development and first six years of a nurse-led chest pain clinic.

AIM: Chest pain is a common symptom that creates significant anxiety for patients until a diagnosis can be offered. However, hospital cardiology services can struggle to cope with referral demands from primary care. The aim of this paper is to describe the development and implementation of a nurse-led chest pain service, its care processes and clinical outcomes to show feasibility, safety and sustainability. METHOD: We retrospectively analysed referral, demographic, cardiovascular risk, management and clinical outcome data relating to patients assessed in the nurse-led chest pain clinic in a large metropolitan district health board. RESULTS: Between January 2010 to December 2016, 3,587 patients attended the clinic, median 2.6 weeks (IQR 2-3) from referral to attendance. 1,921 (54%) were male and 2,059 (57%) were less than 60 years old. Most patients, 3,059 (85%), had an exercise tolerance test (ETT) and of those, 294 (10%) were positive, 572 (18%) non-diagnostic and 2,193 (72%) negative. Cardiovascular disease (CVD) prevention medication was added or modified for 1,150 (32%) patients, all patients who smoked were offered cessation support and all patients were provided with tailored lifestyle advice depending on their absolute CVD risk. Of the 319 (9%) referred for a diagnostic coronary angiogram, 205 (64%) had important coronary disease. The majority of patients, 2,088 (58%) were able to be discharged without any further investigation planned. Over a median follow-up period of 3.6 years, we identified 14 (0.4%) cardiac-related deaths, median (IQR) 2 (1-4) years from review to death. CONCLUSION: The nurse-led clinic offers an enhanced prevention focus that is sustainably managing large numbers of patients with outcomes similar to international studies and within recommended local timeframes.

The Tinnitus Retraining Therapy Trial (TRTT): study protocol for a randomized controlled trial.

BACKGROUND: Subjective tinnitus is the perception of sound in the absence of a corresponding external sound for which there is no known medical etiology. For a minority of individuals with tinnitus, the condition impacts their ability to lead a normal lifestyle and is severely debilitating. There is no known cure for tinnitus, so current therapy focuses on reducing the effect of tinnitus on the patient's quality of life. Tinnitus retraining therapy (TRT) uses nonpsychiatric tinnitus-specific educational counseling and sound therapy in a habituation-based protocol to reduce the patient's tinnitus-evoked negative reaction to, and awareness of, the tinnitus, with the ultimate goal of reducing the tinnitus impact on the patient's quality of life. Some studies support the efficacy of TRT, but no trial to date has compared TRT with the current standard of care or evaluated the separate contributions of TRT counseling and sound therapy. The Tinnitus Retraining Therapy Trial (TRTT) is a randomized, double-blind, placebo-controlled, multicenter trial for individuals with intolerable tinnitus. METHODS/DESIGN: The TRTT is enrolling active-duty and retired military personnel and their dependents with functionally adequate hearing sensitivity and severe tinnitus at US Air Force, Navy, and Army medical centers. Eligible study participants are randomized to TRT, partial TRT, or standard care to determine the efficacy of TRT and its components (TRT counseling and sound therapy). The primary outcome is change in score on the Tinnitus Questionnaire assessed longitudinally between baseline and follow-up (3, 6, 12, and 18 months following treatment). Secondary outcomes include subscale score changes in the Tinnitus Questionnaire, overall and subscale score changes in the Tinnitus Functional Index and Tinnitus Handicap Inventory, and change in the visual analog scale of the TRT Interview Form. Audiological outcomes include tinnitus pitch and loudness match and measures of loudness discomfort levels. The incidence of depression as a safety measure is assessed at each visit using the Beck Depression Inventory Fast Screen. TRIAL REGISTRATION: Clinicaltrials.gov NCT01177137.

Troponin measurements during drug development--considerations for monitoring and management of potential cardiotoxicity: an educational collaboration among the Cardiac Safety Research Consortium, the Duke Clinical Research Institute, and the US Food and Drug Administration.

Drug-induced cardiac toxicity is a recognized challenge in development and implementation of pharmacotherapy. Appropriate biomarkers are needed to detect these abnormalities early in development and to manage the risk of potentially cardiotoxic drugs or biologic agents. Circulating cardiac troponin (cTn) is the most widely used biomarker for detection of myocardial injury. Although most commonly used to detect myonecrosis in the setting of ischemia, cTns are also elevated with other acute and chronic disease processes, including heart failure, renal failure, sepsis, pulmonary embolic disease, and many others. High-sensitivity assays for both cTnI and cTnT are now available that achieve acceptable imprecision (coefficient of variation <10%) at the 99th percentile of a normal reference population. Even more sensitive assays are being developed that detect cTn in ranges that are near the level of normal cellular turnover (apoptosis). These properties of cTn and the continuing evolution of highly sensitive assays position cTn as a potentially uniquely informative marker for early detection of cardiac toxicity. This article summarizes collaborative discussions among key stakeholders in the Cardiac Safety Research Consortium about the use of cTn monitoring in drug development.

Development and regulatory strategies for drug and diagnostic co-development.

At the 5th FDA-Drug Industry Association (DIA) Workshop on 'Pharmacogenomics in Drug Development and Regulatory Decision Making', track four focused on the current thinking and issues in the co-development of therapeutic drugs or biologics, and their companion diagnostic products. Identification and validation of genomic and other biomarkers are becoming important components of drug-development strategies, and recent successes show the power of personalized approaches to change the benefit-risk paradigm for new drugs.

Personalized medicine in diabetes: regulatory considerations.

Personalized medicine has become a topic of great interest because of its potential to improve patient care and optimize therapeutic strategy. The U.S. Food and Drug Administration (FDA) is interested in promoting personalized medicine, whenever appropriate, to protect and promote the public health. The ability to better diagnose, screen, and manage patients with diabetes in order to individualize care should lead to better health outcomes and a large benefit to public health. This article describes FDA regulatory considerations for devices intended for use as personalized medicine tools for the diagnosis and treatment of patients with diabetes.

Comparison of methods for genomic localization of gene trap sequences.

BACKGROUND: Gene knockouts in a model organism such as mouse provide a valuable resource for the study of basic biology and human disease. Determining which gene has been inactivated by an untargeted gene trapping event poses a challenging annotation problem because gene trap sequence tags, which represent sequence near the vector insertion site of a trapped gene, are typically short and often contain unresolved residues. To understand better the localization of these sequences on the mouse genome, we compared stand-alone versions of the alignment programs BLAT, SSAHA, and MegaBLAST. A set of 3,369 sequence tags was aligned to build 34 of the mouse genome using default parameters for each algorithm. Known genome coordinates for the cognate set of full-length genes (1,659 sequences) were used to evaluate localization results. RESULTS: In general, all three programs performed well in terms of localizing sequences to a general region of the genome, with only relatively subtle errors identified for a small proportion of the sequence tags. However, large differences in performance were noted with regard to correctly identifying exon boundaries. BLAT correctly identified the vast majority of exon boundaries, while SSAHA and MegaBLAST missed the majority of exon boundaries. SSAHA consistently reported the fewest false positives and is the fastest algorithm. MegaBLAST was comparable to BLAT in speed, but was the most susceptible to localizing sequence tags incorrectly to pseudogenes. CONCLUSION: The differences in performance for sequence tags and full-length reference sequences were surprisingly small. Characteristic variations in localization results for each program were noted that affect the localization of sequence at exon boundaries, in particular.

The International Gene Trap Consortium Website: a portal to all publicly available gene trap cell lines in mouse.

Gene trapping is a method of generating murine embryonic stem (ES) cell lines containing insertional mutations in known and novel genes. A number of international groups have used this approach to create sizeable public cell line repositories available to the scientific community for the generation of mutant mouse strains. The major gene trapping groups worldwide have recently joined together to centralize access to all publicly available gene trap lines by developing a user-oriented Website for the International Gene Trap Consortium (IGTC). This collaboration provides an impressive public informatics resource comprising approximately 45 000 well-characterized ES cell lines which currently represent approximately 40% of known mouse genes, all freely available for the creation of knockout mice on a non-collaborative basis. To standardize annotation and provide high confidence data for gene trap lines, a rigorous identification and annotation pipeline has been developed combining genomic localization and transcript alignment of gene trap sequence tags to identify trapped loci. This information is stored in a new bioinformatics database accessible through the IGTC Website interface. The IGTC Website (www.genetrap.org) allows users to browse and search the database for trapped genes, BLAST sequences against gene trap sequence tags, and view trapped genes within biological pathways. In addition, IGTC data have been integrated into major genome browsers and bioinformatics sites to provide users with outside portals for viewing this data. The development of the IGTC Website marks a major advance by providing the research community with the data and tools necessary to effectively use public gene trap resources for the large-scale characterization of mammalian gene function.

FDA perspectives on pharmacogenetic testing.

The field of pharmacogenetic testing is emerging as a topic of interest for many, due to its potential to improve patient care and optimize therapeutic development. The US Food and Drug Administration is interested in incorporating pharmacogenetics into development activities whenever appropriate to protect and promote public health. This article is intended to reflect the opinions of the Office of In vitro Diagnostic Device Evaluation and Safety in the Center for Devices and Radiological Health on some issues associated with developing in vitro diagnostic devices for use in pharmacogenetics. General points and potential issues related to the analytical and clinical validation of these types of devices will be discussed.

BayGenomics: a resource of insertional mutations in mouse embryonic stem cells.

The BayGenomics gene-trap resource (http://baygenomics.ucsf.edu) provides researchers with access to thousands of mouse embryonic stem (ES) cell lines harboring characterized insertional mutations in both known and novel genes. Each cell line contains an insertional mutation in a specific gene. The identity of the gene that has been interrupted can be determined from a DNA sequence tag. Approximately 75% of our cell lines contain insertional mutations in known mouse genes or genes that share strong sequence similarities with genes that have been identified in other organisms. These cell lines readily transmit the mutation to the germline of mice and many mutant lines of mice have already been generated from this resource. BayGenomics provides facile access to our entire database, including sequence tags for each mutant ES cell line, through the World Wide Web. Investigators can browse our resource, search for specific entries, download any portion of our database and BLAST sequences of interest against our entire set of cell line sequence tags. They can then obtain the mutant ES cell line for the purpose of generating knockout mice.

PEX5 binds the PTS1 independently of Hsp70 and the peroxin PEX12.

Most peroxisomal enzymes are targeted to peroxisomes by virtue of a type-1 peroxisomal targeting signal (PTS1) at their extreme C terminus. PEX5 binds the PTS1 through its C-terminal 40-kDa tetratricopeptide repeat domain and is essential for import of PTS1-contining proteins into peroxisomes. Here we examined the PTS1-binding activity of purified, recombinant, full-length PEX5 using a fluorescence anisotropy-based assay. Like its C-terminal fragment, full-length tetrameric PEX5 exhibits high intrinsic affinity for the PTS1, with a K(d) of 35 nm for the peptide lissamine-Tyr-Gln-Ser-Lys-Leu-COO(-). The specificity of this interaction was demonstrated by the fact that PEX5 had no detectable affinity for a peptide in which the Lys was replaced with Glu, a substitution that inactivates PTS1 signals in vivo. Hsp70 has been found to regulate the affinity of PEX5 for a PTS1-containing protein, but we found that the kinetics of PEX5-PTS1 binding was unaffected by Hsp70, Hsp70 plus ATP, or Hsp70 plus ADP. In addition, we found that another protein known to interact with the PTS1-binding domain of PEX5, the PEX12 zinc RING domain, also had no discernable effect on PEX5-PTS1 binding kinetics. Taken together, these results suggest that the initial step in peroxisomal protein import, the recognition of enzymes by PEX5, is a relatively simple process and that Hsp70 most probably stimulates this process by catalyzing the folding of newly synthesized peroxisomal enzymes and/or enhancing the accessibility of their PTS1.

Peroxisomal membrane protein import does not require Pex17p.

Of the approximately 20 proteins required for peroxisome biogenesis, only four have been implicated in the process of peroxisomal membrane protein (PMP) import: Pex3p, Pex16p, Pex17p, and Pex19p. To improve our understanding of the role that Pex17p plays in PMP import, we examined the behavior of PMPs in a Pichia pastoris pex17 mutant. Relative to wild-type cells, pex17 cells appeared to have a mild reduction in PMP stability and slightly aberrant PMP behavior in subcellular fractionation experiments. However, we also found that the behavior of PMPs in the pex17 mutant was indistinguishable from PMP behavior in a pex5 mutant, which has no defect in PMP import, and was far different from PMP behavior in a pex3 mutant, which has a bona fide defect in PMP import. Furthermore, we found that a pex14 mutant, which has no defect in PMP import, lacks detectable levels of Pex17p. Based on these and other results, we propose that Pex17p acts primarily in the matrix protein import pathway and does not play an important role in PMP import.