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.

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.

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.

Dynamic earthquake rupture preserved in a creeping serpentinite shear zone.

Laboratory experiments on serpentinite suggest that extreme dynamic weakening at earthquake slip rates is accompanied by amorphisation, dehydration and possible melting. However, hypotheses arising from experiments remain untested in nature, because earthquake ruptures have not previously been recognised in serpentinite shear zones. Here we document the progressive formation of high-temperature reaction products that formed by coseismic amorphisation and dehydration in a plate boundary-scale serpentinite shear zone. The highest-temperature products are aggregates of nanocrystalline olivine and enstatite, indicating minimum peak coseismic temperatures of ca. 925 ± 60 °C. Modelling suggests that frictional heating during earthquakes of magnitude 2.7-4 can satisfy the petrological constraints on the coseismic temperature profile, assuming that coseismic fluid storage capacity and permeability are increased by the development of reaction-enhanced porosity. Our results indicate that earthquake ruptures can propagate through serpentinite shear zones, and that the signatures of transient frictional heating can be preserved in the fault rock record.

Novel prodrug PRX-P4-003, selectively activated by gut enzymes, may reduce the risk of iatrogenic addiction and abuse.

OBJECTIVES: Prescription stimulants are vulnerable to oral and parenteral abuse. Intravenous forms of abuse may be most detrimental due to an enhanced risk of dependence, overdose, and infectious diseases. Our objective was to discover an orally active prodrug of a stimulant that would not be easily converted to its parent when injected, thus hindering intravenous abuse. METHODS: Following an initial analysis of stimulant structures, the fencamfamine isomer [(-)-FCF; (N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine)] was chosen as a parent drug due to its favorable biochemical properties. Subsequently, PRX-P4-003 {(-)-N-(Octadecanoyloxymethoxycarbonyl)-N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine} qualified for further development. Experimental testing of PRX-P4-003 included radioligand binding assays, stability studies, and rodent pharmacokinetic and locomotor assays. RESULTS: Prodrug PRX-P4-003 is a pharmacologically inactive, hydrophobic compound, whereas its parent (-)-FCF is a dopamine reuptake inhibitor with weaker effects on norepinephrine reuptake (Ki = 0.07 and 0.80 µM, respectively). PRX-P4-003 is metabolized to (-)-FCF in simulated intestinal fluid (with pancreatin) but not in simulated gastric fluid (with pepsin). Finally, PRX-P4-003 shows a significant oral but no intravenous increase in locomotion, correlating with its pharmacokinetics by these different routes of administration. CONCLUSIONS: PRX-P4-003 is a novel prodrug stimulant enzymatically activated in the gut. Our data suggest a pancreatic, lipase-based mechanism of activation and as only 1% of this enzyme is found in the systemic circulation, PRX-P4-003 is unlikely to be bioactive if injected intravenously. Enzymatic release of (-)-FCF is needed prior to its systemic absorption, which may discourage oral abuse (e.g., by chewing). PRX-P4-003 is being developed for apathy in Alzheimer's disease and binge eating disorder.

Development and Validation of HealthImpact: An Incident Diabetes Prediction Model Based on Administrative Data.

OBJECTIVE: To develop and validate a model of incident type 2 diabetes based solely on administrative data. DATA SOURCES/STUDY SETTING: Optum Labs Data Warehouse (OLDW), a national commercial administrative dataset. STUDY DESIGN: HealthImpact model was developed and internally validated using nested case-control study design; n = 473,049 in training cohort and n = 303,025 in internal validation cohort. HealthImpact was externally validated in 2,000,000 adults followed prospectively for 3 years. Only adults ≥18 years were included. DATA COLLECTION/EXTRACTION METHODS: Patients with incident diabetes were identified using HEDIS rules. Control subjects were sampled from patients without diabetes. Medical and pharmacy claims data collected over 3 years prior to index date were used to build the model variables. PRINCIPAL FINDINGS: HealthImpact, scored 0-100, has 48 variables with c-statistic 0.80815. We identified HealthImpact threshold of 90 as identifying patients at high risk of incident diabetes. HealthImpact had excellent discrimination in external validation cohort (c-statistic 0.8171). The sensitivity, specificity, positive predictive value, and negative predictive value of HealthImpact >90 for new diagnosis of diabetes within 3 years were 32.35, 94.92, 22.25, and 96.90 percent, respectively. CONCLUSIONS: HealthImpact is an efficient and effective method of risk stratification for incident diabetes that is not predicated on patient-provided information or laboratory tests.

Mealtime Insulin Dosing by Carbohydrate Counting in Hospitalized Cardiology Patients: A Retrospective Cohort Study.

BACKGROUND: Carbohydrate counting may improve glycemic control in hospitalized cardiology patients by providing individualized insulin doses tailored to meal consumption. The purpose of this study was to compare glycemic outcomes with mealtime insulin dosed by carbohydrate counting versus fixed dosing in the inpatient setting. MATERIALS AND METHODS: This single-center retrospective cohort study included 225 adult medical cardiology patients who received mealtime, basal, and correction-scale insulin concurrently for at least 72 h and up to 7 days in the interval March 1, 2010-November 7, 2013. Mealtime insulin was dosed by carbohydrate counting or with fixed doses determined prior to meal intake. An inpatient diabetes consult service was responsible for insulin management. Exclusion criteria included receipt of an insulin infusion. The primary end point compared mean daily postprandial glucose values, whereas secondary end points included comparison of preprandial glucose values and mean daily rates of hypoglycemia. RESULTS: Mean postprandial glucose level on Day 7 was 204 and 183 mg/dL in the carbohydrate counting and fixed mealtime dose groups, respectively (unadjusted P=0.04, adjusted P=0.12). There were no statistical differences between groups on Days 2-6. Greater rates of preprandial hypoglycemia were observed in the carbohydrate counting cohort on Day 5 (8.6% vs. 1.5%, P=0.02), Day 6 (1.7% vs. 0%, P=0.01), and Day 7 (7.1% vs. 0%, P=0.008). No differences in postprandial hypoglycemia were seen. CONCLUSIONS: Mealtime insulin dosing by carbohydrate counting was associated with similar glycemic outcomes as fixed mealtime insulin dosing, except for a greater incidence of preprandial hypoglycemia. Additional comparative studies that include hospital outcomes are needed.

Changing trends in type 2 diabetes mellitus treatment intensification, 2002-2010.

OBJECTIVES: Glycemic control can lower the risk of diabetes-related complications, and delayed treatment intensification can impede optimal diabetes care. This study examines trends in hyperglycemia treatment intensification between 2002 and 2010. STUDY DESIGN: Retrospective secondary data analysis of a large national administrative data set of privately insured individuals across the United States. METHODS: Adults 18 years or older with diabetes, initiated on metformin monotherapy between 2002 and 2007, were studied, stratified by date of first metformin prescription (2002-2003, 2004-2005, 2006-2007). Time to treatment intensification between 2002 and 2010, defined by the addition of ≥1 agents to metformin, was estimated using Kaplan-Meier and Cox proportional hazards regression analysis. RESULTS: There were 75,069 treatment-naïve adults with diabetes first initiated on metformin between 2002 and 2007; mean age was 60 years (SD = 11.5), 49.7% were women, and 63.1% were non-Hispanic white. Diabetes therapy was intensified in 26,169 individuals (34.6%).Treatment intensification became increasingly more likely with time for the 2004-2005 cohort (hazard ratio [HR], 1.07; 95% CI, 1.04-1.10) and for the 2006-2007 cohort (HR, 1.11; 95% CI, 1.07-1.14) compared with the 2002-2003 cohort (P < .001), after adjustment for significant confounders including sex, income level, education level, and comorbidity burden. Sulfonylureas were the most commonly used agents, though their use declined over time; thiazolidinedione use decreased; and incretin use increased (all P < .001). CONCLUSIONS: There was a significant increase in diabetes treatment intensification between 2002 and 2010. Choice of secondline agents changed as well, with decreasing prevalence of thiazolidinedione and sulfonylurea use and rising prevalence of incretin use.

BE SMART: strategies for foot care and prevention of foot complications in patients with diabetes.

BACKGROUND: Diabetic foot ulcers and lower extremity amputations are common complications of diabetes mellitus that are associated with substantial morbidity, loss of quality of life, disability, and a high social and economic burden. The implementation of strategies to prevent these complications is a key aspect of diabetes care. OBJECTIVES: The objective of this article is to provide an overview of the available evidence on preventive diabetic foot care. STUDY DESIGN: Literature review. METHODS: Narrative review based on a thorough search of previous relevant studies, systematic reviews, and clinical guidelines on diabetic foot care published in English. RESULTS: We describe diabetic foot care strategies that can be categorized within defined domains for the purpose of helping clinicians to remember them. We use the mnemonic "BE SMART" (Be aware of the risk factors, Educate patients and health providers, Structured clinical assessment, Metabolic evaluation and management, Assessment of Risk, and Team care) to organize these domains. CONCLUSION: Diabetic foot ulcers and lower extremity amputations are potentially preventable complications. Clinicians taking care of patients with diabetes should know, understand, and remember the multiple aspects of diabetic foot care. CLINICAL RELEVANCE: This review can be used as a reference source for those interested in the care of diabetic foot. It highlights the importance of risk factor recognition, education, a structured clinical and metabolic evaluation, and also the importance of assigning patients a risk category that can help guiding multidisciplinary management efforts.

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.

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.

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.