Gefapixant in two randomised dose-escalation studies in chronic cough.

BACKGROUND AND OBJECTIVES: Gefapixant has previously demonstrated efficacy in the treatment of refractory chronic cough at a high daily dose. The current investigations explore efficacy and tolerability of gefapixant, a P2X3 receptor antagonist, for the treatment of chronic cough using a dose-escalation approach. MATERIALS AND METHODS: Two randomised, double-blind, placebo-controlled, crossover, dose-escalation studies recruited participants with refractory chronic cough. Patients were assigned to receive ascending doses of gefapixant (study 1: 50-200 mg, study 2: 7.5-50 mg) or placebo for 16 days, then crossed-over after washout. The primary end-point was awake cough frequency assessed using a 24-h ambulatory cough monitor at baseline and on day 4 of each dose. Patient-reported outcomes included a cough severity visual analogue scale and the cough severity diary. RESULTS: In clinical studies, gefapixant doses ≥30 mg produced maximal improvements in cough frequency compared with placebo (p<0.05); reported cough severity measures improved at similar doses. Taste disturbance exhibited a different relationship with dose, apparently maximal at doses ≥150 mg. CONCLUSIONS: P2X3 antagonism with gefapixant demonstrates anti-tussive efficacy and improved tolerability at lower doses than previously investigated. Studies of longer duration are warranted.

Postsynaptic P2X3-containing receptors in gustatory nerve fibres mediate responses to all taste qualities in mice.

Taste buds release ATP to activate ionotropic purinoceptors composed of P2X2 and P2X3 subunits, present on the taste nerves. Mice with genetic deletion of P2X2 and P2X3 receptors (double knockout mice) lack responses to all taste stimuli presumably due to the absence of ATP-gated receptors on the afferent nerves. Recent experiments on the double knockout mice showed, however, that their taste buds fail to release ATP, suggesting the possibility of pleiotropic deficits in these global knockouts. To test further the role of postsynaptic P2X receptors in afferent signalling, we used AF-353, a selective antagonist of P2X3-containing receptors to inhibit the receptors acutely during taste nerve recording and behaviour. The specificity of AF-353 for P2X3-containing receptors was tested by recording Ca(2+) transients to exogenously applied ATP in fura-2 loaded isolated geniculate ganglion neurons from wild-type and P2X3 knockout mice. ATP responses were completely inhibited by 10 µm or 100 µm AF-353, but neither concentration blocked responses in P2X3 single knockout mice wherein the ganglion cells express only P2X2-containing receptors. Furthermore, AF-353 had no effect on taste-evoked ATP release from taste buds. In wild-type mice, i.p. injection of AF-353 or simple application of the drug directly to the tongue, inhibited taste nerve responses to all taste qualities in a dose-dependent fashion. A brief access behavioural assay confirmed the electrophysiological results and showed that preference for a synthetic sweetener, SC-45647, was abolished following i.p. injection of AF-353. These data indicate that activation of P2X3-containing receptors is required for transmission of all taste qualities.

Evaluating the structure of the Patient Assessment of Chronic Illness Care (PACIC) survey from the patient's perspective.

BACKGROUND: The Patient Assessment of Chronic Illness Care (PACIC) survey is a widely used instrument to assess the patient experience with healthcare delivery. PURPOSE: This study aims to evaluate the factorial structure of PACIC from the patient perspective. METHODS: A postal survey was mailed to 4,796 randomly selected adults with diabetes from 34 primary care clinics. Internal consistencies of PACIC subscales were assessed by Cronhach's α. Factorial structure was evaluated by confirmatory and exploratory factor analyses. RESULTS: Based on responses of 2,055 patients (43% response rate), exploratory factor analysis discerned a 4-factor, not 5-factor, model dominated by patient evaluation of healthcare services (explaining 74% of the variance). The other 3 factors addressed patient involvement (goal setting, participating in the healthcare team) and social support for self-management. CONCLUSIONS: The underlying factorial structure of PACIC, which reflects the patient perspective, is dynamic, patient-centered, and differs from the original 5-factor model that was more aligned with views of healthcare delivery stakeholders.

Blood glucose screening rates among Minnesota adults with hypertension, Behavioral Risk Factor Surveillance System, 2011.

INTRODUCTION: Many US adults have multiple chronic conditions, and hypertension and diabetes are among the most common dyads. Diabetes and prediabetes prevalence are increasing, and both conditions negatively affect cardiovascular health. Early diagnosis and treatment of diabetes and prediabetes can benefit people with hypertension by preventing cardiovascular complications. METHODS: We analyzed 2011 Minnesota Behavioral Risk Factor Surveillance System data to describe the proportion of adults with hypertension screened for diabetes according to US Preventive Services Task Force Recommendations for blood glucose testing. Covariates associated with lower odds of recent screening among adults without diabetes were determined using weighted logistic regression. RESULTS: Of Minnesota adults with self-reported hypertension, 19.6% had a diagnosis of diabetes and 10.7% had a diagnosis of prediabetes. Nearly one-third of adults with hypertension without diabetes had not received blood glucose screening in the past 3 years. Factors associated with greater odds of not being screened in multivariable models included being aged 18 to 44 years (adjusted odds ratio [AOR], 1.77; 95% confidence interval [CI], 1.23-2.55); being nonobese, with stronger effects for normal body mass index; having no check-up in the past 2 years (AOR, 2.49; 95% CI, 1.49-4.17); having hypertension treated with medication (AOR, 2.01; 95% CI, 1.49-2.71); and completing less than a college degree (AOR, 1.45; 95% CI, 1.14-1.84). Excluding respondents with prediabetes or those not receiving a check-up did not change the results. CONCLUSIONS: Failure to screen among providers and failure to understand the importance of screening among individuals with hypertension may mean missed opportunities for early detection, clinical management, and prevention of diabetes.

Putting diabetes on the map: what does population health really look like at the local level?

Population health data are used to profile local conditions, call attention to areas of need, and evaluate health-related programs. Demand for data to inform health care decision making has spurred development of data sources and online systems, but these are often poorly integrated or limited in scope. Our objective was to identify existing data about diabetes mellitus-related conditions in Minnesota, build an online data resource, and identify what data are currently missing that, if available, would better inform assessment of health conditions in the state. A Web site was developed and populated with existing data and data not available elsewhere. It features functionality identified as most important by users, such as maps and county profiles. The site could serve as a flexible tool for stakeholder engagement, but issues were identified during development, including concerns about interpreting map data and open questions about sustainability, that need to be addressed.

A brief Patient-Reported Outcomes Quality of Life (PROQOL) instrument to improve patient care.

Jeff Sloan and colleagues describe the development of the Patient-Reported Outcomes Quality of Life (PROQOL) instrument, which captures and stores patient-recorded outcomes in the medical record for patients with diabetes. Please see later in the article for the Editors' Summary.

The ghrelin agonist RM-131 accelerates gastric emptying of solids and reduces symptoms in patients with type 1 diabetes mellitus.

BACKGROUND & AIMS: RM-131, a synthetic ghrelin agonist, greatly accelerates gastric emptying of solids in patients with type 2 diabetes and delayed gastric emptying (DGE). We investigated the safety and effects of a single dose of RM-131 on gastric emptying and upper gastrointestinal (GI) symptoms in patients with type 1 diabetes and previously documented DGE. METHODS: In a double-blind cross-over study, 10 patients with type 1 diabetes (age, 45.7 ± 4.4 y; body mass index, 24.1 ± 1.1 kg/m(2)) and previously documented DGE were assigned in random order to receive a single dose of RM-131 (100 µg, subcutaneously) or placebo. Thirty minutes later, they ate a radiolabeled solid-liquid meal containing EggBeaters (ConAgra Foods, Omaha, NE), and then underwent 4 hours of gastric emptying and 6 hours of colonic filling analyses by scintigraphy. Upper GI symptoms were assessed using a daily diary, gastroparesis cardinal symptom index (total GCSI-DD) and a combination of nausea, vomiting, fullness, and pain (NVFP) scores (each rated on a 0-5 scale). RESULTS: At screening, participants' mean level of hemoglobin A1c was 9.1% ± 0.5%; their total GCSI-DD score was 1.66 ± 0.38 (median, 1.71), and their total NVFP score was 1.73 ± 0.39 (median, 1.9). The t1/2 of solid gastric emptying was 84.9 ± 31.6 minutes when subjects were given RM-131 and 118.7 ± 26.7 when they were given a placebo. The median difference (Δ)was 33.9 minutes (interquartile range [IQR] -12, -49), or -54.7% (IQR, -21%,-110%). RM-131 decreased gastric retention of solids at 1 hour (P = .005) and 2 hours (P = .019). Numeric differences in t1/2 for gastric emptying of liquids, solid gastric emptying lag time, and colonic filling at 6 hours were not significant. Total GCSI-DD scores were 0.79 on placebo (IQR, 0.75, 2.08) and 0.17 on RM-131 (IQR, 0.00, 0.67; P = .026); NVFP scores were lower on RM-131 (P = .041). There were no significant adverse effects. CONCLUSIONS: RM-131 significantly accelerates gastric emptying of solids and reduces upper GI symptoms in patients with type 1 diabetes and documented DGE.

An evolutionary model and classification scheme for nephrite jade based on veining, fabric development, and the role of dissolution-precipitation.

Although nephrite jade has been collected and treasured since the Stone Age, we lack a clear understanding of how it forms during deformation and metasomatism in shear zones. Using microstructural analysis of samples from Taiwan, California, and New Zealand, we propose a conceptual model for the evolution of nephrite jade that distinguishes four nephrite types based on mode of formation and textural characteristics: (1) primary (type 1a) or folded (type 1b) vein nephrite, (2) crenulated nephrite (type 2), (3) foliated semi-nephrite (type 3), and (4) nodular or domainal nephrite (type 4). We interpret the texture of our analysed samples to represent snapshots of a progressive textural evolution similar to that experienced by other deformed and fine-grained metamorphic rocks that develop under fluid-present, greenschist-facies conditions. Our observations suggest that types 2 and 3 nephrite can evolve from vein nephrite (type 1) by the development of crenulated and foliated metamorphic fabrics, during which the most important deformation process is dissolution-precipitation. However, development of metamorphic fabrics can be interrupted by transient brittle deformation, leading to the formation of type 4 nephrite that is characterised by nodular or angular clasts of nephrite in a nephritic matrix.

Making sense of diabetes medication decisions: a mixed methods cluster randomized trial using a conversation aid intervention.

PURPOSE: To determine the effectiveness of a shared decision-making (SDM) tool versus guideline-informed usual care in translating evidence into primary care, and to explore how use of the tool changed patient perspectives about diabetes medication decision making. METHODS: In this mixed methods multicenter cluster randomized trial, we included patients with type 2 diabetes mellitus and their primary care clinicians. We compared usual care with or without a within-encounter SDM conversation aid. We assessed participant-reported decisions made and quality of SDM (knowledge, satisfaction, and decisional conflict), clinical outcomes, adherence, and observer-based patient involvement in decision-making (OPTION12-scale). We used semi-structured interviews with patients to understand their perspectives. RESULTS: We enrolled 350 patients and 99 clinicians from 20 practices and interviewed 26 patients. Use of the conversation aid increased post-encounter patient knowledge (correct answers, 52% vs. 45%, p = 0.02) and clinician involvement of patients (Mean between-arm difference in OPTION12, 7.3 (95% CI 3, 12); p = 0.003). There were no between-arm differences in treatment choice, patient or clinician satisfaction, encounter length, medication adherence, or glycemic control. Qualitative analyses highlighted differences in how clinicians involved patients in decision making, with intervention patients noting how clinicians guided them through conversations using factors important to them. CONCLUSIONS: Using an SDM conversation aid improved patient knowledge and involvement in SDM without impacting treatment choice, encounter length, medication adherence or improved diabetes control in patients with type 2 diabetes. Future interventions may need to focus specifically on patients with signs of poor treatment fit. CLINICAL TRIAL REGISTRATION: ClinicalTrial.gov: NCT01502891.

Quality Adjustment for Health Care Spending on Chronic Disease: Evidence from Diabetes Treatment, 1999­2009.

US health care expenditures reached $2.5 trillion in 2009, representing 17.6 percent of gross domestic product (GDP) and $8,086 per person (US Department of Health and Human Services Centers for Medicare and Medicaid Services 2011). Since health care represents a large and growing share of the economy, and factors such as population aging imply that chronic disease treatment will continue to expand as a share of health expenditures, developing methods for assessing the value of quality improvement for chronic disease spending is of increasing importance for accurately measuring real economic activity. This paper develops a method for assessing the value of quality changes associated with health care for patients living with one important chronic disease, diabetes mellitus, using 11 years of detailed data on spending and quality of care for over 800 patients. We first provide an overview of measurement issues for health care quality, and then present our data, methods, results, and a brief discussion.

Lightning-induced high temperature and pressure microstructures in surface and subsurface fulgurites.

Cloud-to-ground lightning causes both high-temperature and high-pressure metamorphism of rocks, forming rock fulgurite. We demonstrate that a range of microstructural features indicative of high temperatures and pressures can form in fulgurites at the surface and in fractures up to several meters below the surface. In comparison to a granite reference sample collected from a borehole at a depth of 138 m, microstructures in both the surface and fracture fulgurite are characterized by: (i) the presence of glass, (ii) a phase transformation in K-feldspar with the presence of exsolution lamellae of plagioclase, and (iii) high residual stresses up to 1.5 GPa. Since this is the first time that fracture-related fulgurite has been described, we also carried out a 1-D numerical model to investigate the processes by which these can form. The model shows that the electric current density in fractures up to 40 m from the landing point can be as high as that on the surface, providing an explanation for the occurrence of fracture-related fulgurites. Our work broadens the near-surface environments in which rock fulgurite has been reported, and provides a detailed description of microstructures that can be compared to those formed during other types of extreme metamorphic events.

Novel sulfamoyl benzamides as selective CB(2) agonists with improved in vitro metabolic stability.

A lead optimization campaign in our previously reported sulfamoyl benzamide class of CB(2) agonists was conducted to improve the in vitro metabolic stability profile in this series while retaining high potency and selectivity for the CB(2) receptor. From this study, compound 14, N-(3,4-dimethyl-5-(morpholinosulfonyl)phenyl)-2,2-dimethylbutanamide, was identified as a potent and selective CB(2) agonist exhibiting moderate in vitro metabolic stability and oral bioavailability. Compound 14 demonstrated in vivo efficacy in a rat model of post-surgical pain.

The net value of health care for patients with type 2 diabetes, 1997 to 2005.

BACKGROUND: The net economic value of increased health care spending remains unclear, especially for chronic diseases. OBJECTIVE: To assess the net value of health care for patients with type 2 diabetes. DESIGN: Economic analysis of observational cohort data. SETTING: Mayo Clinic, Rochester, Minnesota, a not-for-profit integrated health care delivery system. PATIENTS: 613 patients with type 2 diabetes. MEASUREMENTS: Changes in inflation-adjusted annual health care spending and in health status between 1997 and 2005 (with health status defined as 10-year cardiovascular risk), holding age and diabetes duration constant across the observation period ("modifiable risk"), and simulated outcomes for all diabetes complications based on the UKPDS (United Kingdom Perspective Diabetes Study) Outcomes Model. Net value was estimated as the present discounted monetary value of improved survival and avoided treatment spending for coronary heart disease minus the increase in annual spending per patient. RESULTS: Assuming that 1 life-year is worth $200,000 and accounting for changes in modifiable cardiovascular risk, the net value of changes in health care for patients with type 2 diabetes was $10,911 per patient (95% CI, -$8480 to $33,402) between 1997 and 2005, a positive dollar value that suggests the value of health care has improved despite increased spending. A second approach based on diabetes complications yielded a net value of $6931 per patient (CI, -$186,901 to $211,980). LIMITATION: The patient population was homogeneous and small, and the wide CIs of the estimates are compatible with a decrease as well as an increase in value. CONCLUSION: The economic value of improvements in health status for patients with type 2 diabetes seems to exceed or equal increases in health care spending, suggesting that those increases were worth the extra cost. However, the possibility that society is getting less value for its money could not be statistically excluded, and there is opportunity to improve the value of diabetes-related health care. PRIMARY FUNDING SOURCE: None.

Automated processing of electronic medical records is a reliable method of determining aspirin use in populations at risk for cardiovascular events.

BACKGROUND: Low-dose aspirin reduces cardiovascular risk; however, monitoring over-the-counter medication use relies on the time-consuming and costly manual review of medical records. Our objective is to validate natural language processing (NLP) of the electronic medical record (EMR) for extracting medication exposure and contraindication information. METHODS: The text of EMRs for 499 patients with type 2 diabetes was searched using NLP for evidence of aspirin use and its contraindications. The results were compared to a standardised manual records review. RESULTS: Of the 499 patients, 351 (70%) were using aspirin and 148 (30%) were not, according to manual review. NLP correctly identified 346 of the 351 aspirin-positive and 134 of the 148 aspirin-negative patients, indicating a sensitivity of 99% (95% CI 97-100) and specificity of 91% (95% CI 88-97). Of the 148 aspirin-negative patients, 66 (45%) had contraindications and 82 (55%) did not, according to manual review. NLP search for contraindications correctly identified 61 of the 66 patients with contraindications and 58 of the 82 patients without, yielding a sensitivity of 92% (95% CI 84-97) and a specificity of 71% (95% CI 60-80). CONCLUSIONS: NLP of the EMR is accurate in ascertaining documented aspirin use and could potentially be used for epidemiological research as a source of cardiovascular risk factor information.

Discovery of N-(3-(morpholinomethyl)-phenyl)-amides as potent and selective CB2 agonists.

Recently sulfamoyl benzamides were identified as a novel series of cannabinoid receptor ligands. Replacing the sulfonamide functionality and reversing the original carboxamide bond led to the discovery of N-(3-(morpholinomethyl)-phenyl)-amides as potent and selective CB(2) agonists. Selective CB(2) agonist 31 (K(i)=2.7; CB(1)/CB(2)=190) displayed robust activity in a rodent model of postoperative pain.

CB2 selective sulfamoyl benzamides: optimization of the amide functionality.

Previous research within our laboratories identified sulfamoyl benzamides as novel cannabinoid receptor ligands. Optimization of the amide linkage led to the reverse amide 40. The compound exhibited robust antiallodynic activity in a rodent pain model when administered intraperitoneally. Efficacy after oral administration was observed only when ABT, a cytochrome P450 suicide inhibitor, was coadministered.

Optimizing the start time of statin therapy for patients with diabetes.

BACKGROUND: Clinicians often use validated risk models to guide treatment decisions for cardiovascular risk reduction. The most common risk models for predicting cardiovascular risk are the UKPDS, Framingham, and Archimedes models. In this article, the authors propose a model to optimize the selection of patients for statin therapy of hypercholesterolemia, for patients with type 2 diabetes, using each of the risk models. For each model,they evaluate the role of age, gender, and metabolic state on the optimal start time for statins. METHOD: Using clinical data from the Mayo Clinic electronic medical record, the authors construct a Markov decision process model with health states composed of cardiovascular events and metabolic factors such as total cholesterol and high-density lipoproteins. They use it to evaluate the optimal start time of statin treatment for different combinations of cardiovascular risk models and patient attributes. RESULTS: The authors find that treatment decisions depend on the cardiovascular risk model used and the age, gender, and metabolic state of the patient. Using the UKPDS risk model to estimate the probability of coronary heart disease and stroke events, they find that all white male patients should eventually start statin therapy; however, using Framingham and Archimedes models in place of UKPDS, they find that for male patients at lower risk, it is never optimal to initiate statins. For white female patients, the authors also find some patients for whom it is never optimal to initiate statins. Assuming that age 40 is the earliest possible start time, the authors find that the earliest optimal start times for UKPDS, Framingham, and Archimedes are 50, 46, and 40, respectively, for women. For men, the earliest optimal start times are 40, 40, and 40, respectively. CONCLUSIONS: In addition to age, gender, and metabolic state, the choice of cardiovascular risk model influences the apparent optimal time for starting statins in patients with diabetes.

Should clinicians deliver decision aids? Further exploration of the statin choice randomized trial results.

BACKGROUND: Statin Choice is a decision aid about taking statins. The optimal mode of delivering Statin Choice (or any other decision aid) in clinical practice is unknown. METHODS: To investigate the effect of mode of delivery on decision aid efficacy, the authors further explored the results of a concealed 2 x 2 factorial clustered randomized trial enrolling 21 endocrinologists and 98 diabetes patients and randomizing them to 1) receive either the decision aid or pamphlet about cholesterol, and 2) have these delivered either during the office visit (by the clinician) or before the visit (by a researcher). We estimated between-group differences and their 95% confidence intervals (CI) for acceptability of information delivery (1-7), knowledge about statins and coronary risk (0-9), and decisional conflict about statin use (0-100) assessed immediately after the visit. Follow-up was 99%. RESULTS: The relative efficacy of the decision aid v. pamphlet interacted with the mode of delivery. Compared with the pamphlet, patients whose clinicians delivered the decision aid during the office visit showed significant improvements in knowledge (difference of 1.6 of 9 questions, CI 0.3, 2.8) and nonsignificant trends toward finding the decision aid more acceptable (odds ratio 3.1, CI 0.9, 11.2) and having less decisional conflict (difference of 7 of 100 points, CI -4, 18) than when a researcher delivered the decision aid just before the office visit. CONCLUSIONS: Delivery of decision aids by clinicians during the visit improves knowledge and shows a trend toward better acceptability and less decisional conflict.