"Who receives statins? Variations in physicians’ prescribing patterns for patients with coronary heart disease, dyslipidemia, and diabetes"

Our objective is to estimate the extent to which clinical and non-clinical factors are associated with physicians’ prescribing patterns for statins. The data are from the National Ambulatory Medical Care Survey for the period 1992 through 2004. The three samples examined included more than 14,000 patients who were diagnosed with coronary heart disease, high cholesterol, or diabetes, individuals who are most likely to benefit from being prescribed a statin drug. Using a multinomial logit framework, we find disparities in prescribing patterns based on non-clinical factors. Namely, whites and patients who have private insurance are more likely to be prescribed a statin than nonwhites and those with public insurance. Also, even though a large increase occurred in the uptake of statins over the period 1992 to 2004, our results for 2004 show that only about 50 percent of patients diagnosed with coronary heart disease were prescribed a statin. Because coronary heart disease is the leading cause of death in the U.S. and currently is estimated to cost over $150 billion annually in the U.S. in direct and indirect costs, observed differences in prescribing patterns along these dimensions is troubling and should be part of discussions dealing with health care reform.Pharmaceuticals; Statins; Equity in Physician Prescribing Patterns; Insurance

Connective tissue disease-associated pulmonary arterial hypertension.

Although rare in its idiopathic form, pulmonary arterial hypertension (PAH) is not uncommon in association with various associated medical conditions, most notably connective tissue disease (CTD). In particular, it develops in approximately 10% of patients with systemic sclerosis and so these patients are increasingly screened to enable early detection. The response of patients with systemic sclerosis to PAH-specific therapy appears to be worse than in other forms of PAH. Survival in systemic sclerosis-associated PAH is inferior to that observed in idiopathic PAH. Potential reasons for this include differences in age, the nature of the underlying pulmonary vasculopathy and the ability of the right ventricle to cope with increased afterload between patients with systemic sclerosis-associated PAH and idiopathic PAH, while coexisting cardiac and pulmonary disease is common in systemic sclerosis-associated PAH. Other forms of connective tissue-associated PAH have been less well studied, however PAH associated with systemic lupus erythematosus (SLE) has a better prognosis than systemic sclerosis-associated PAH and likely responds to immunosuppression

Effect of dual pulmonary vasodilator therapy in pulmonary arterial hypertension associated with congenital heart disease: a retrospective analysis

Background: Patients with pulmonary arterial hypertension (PAH) are managed according to evidence-based treatment guidelines. Methods and results: In this single-centre retrospective analysis, we examined outcomes of patients with PAH caused by congenital heart disease (PAH-CHD) with respect to exercise capacity and survival of adults treated with either bosentan or sildenafil monotherapy or bosentan-sildenafil dual therapy between January 2007 and January 2014. Of the 82 patients analysed, 29 had Down syndrome; 54 (65.8%) received bosentan monotherapy, 16 (19.5%) sildenafil monotherapy and 12 (14.6%) dual therapy. Mean treatment duration was 2.5 years for all patients and 4.1 years for 38 patients treated for ≥2 years. Pooled patient and treatment data showed initial improvement followed by stabilisation in mean 6 min walk distance (6MWD). For Down and non-Down patients, mean 6MWD increased and then stabilised on bosentan monotherapy. Mean 6MWD of patients on dual therapy at the time of analysis was 246.3 m before PAH-specific therapy initiation, 211.9 m immediately prior to addition of a second therapy and 214.4 m at last visit while on dual therapy. 1, 2 and 3- year survival rates for all patients from time of treatment initiation were 96%, 87% and 80%, respectively. Conclusions: For the majority of patients, monotherapy with a PAH-specific medication provided improved and sustained exercise benefits. For the small percentage of patients who required it, add-on therapy appeared to prevent further deterioration in exercise capacity but did not improve 6MWD

Increased DNA methylation near TREM2 is consistently seen in the superior temporal gyrus in Alzheimer's disease brain

Although mutations within the TREM2 gene have been robustly associated with Alzheimer's disease, it is not known whether alterations in the regulation of this gene are also involved in pathogenesis. Here, we present data demonstrating increased DNA methylation in the superior temporal gyrus in Alzheimer's disease brain at a CpG site located 289 bp upstream of the transcription start site of the TREM2 gene in 3 independent study cohorts using 2 different technologies (Illumina Infinium 450K methylation beadchip and pyrosequencing). A meta-analysis across all 3 cohorts reveals consistent AD-associated hypermethylation (p = 3.47E-08). This study highlights that extending genetic studies of TREM2 in AD to investigate epigenetic changes may nominate additional mechanisms by which disruption to this gene increases risk

Non-invasive methods for the estimation of mPAP in COPD using Cardiovascular Magnetic Resonance Imaging

Purpose Pulmonary hypertension (PH) is associated with a poor outcome in chronic obstructive pulmonary disease (COPD) and is diagnosed invasively. We aimed to assess the diagnostic accuracy and prognostic value of non-invasive cardiovascular magnetic resonance (CMR) models. Methods Patients with COPD and suspected PH, who underwent CMR and right heart catheter (RHC) were identified. Three candidate models were assessed: 1, CMR-RV model, based on right ventricular (RV) mass and interventricular septal angle; 2, CMR PA/RV includes RV mass, septal angle and pulmonary artery (PA) measurements; 3, the Alpha index, based on RV ejection fraction and PA size. Results Of 102 COPD patients, 87 had PH. The CMR-PA/RV model had the strongest diagnostic accuracy (sensitivity 92%, specificity 80%, positive predictive value 96% and negative predictive value 63%, AUC 0.93, p<0.0001). Splitting RHCmPAP, CMR-RV and CMR-PA/RV models by 35mmHg gave a significant difference in survival, with log-rank chi-squared 5.03, 5.47 and 7.10. RV mass and PA relative area change were the independent predictors of mortality at multivariate Cox regression (p=0.002 and 0.030). Conclusion CMR provides diagnostic and prognostic information in PH-COPD. The CMR-PA/RV model is useful for diagnosis, the RV mass index and PA relative area change are useful to assess prognosis. Key Points • Pulmonary hypertension is a marker of poor outcome in COPD. • MRI can predict invasively measured mean pulmonary artery pressure. • Cardiac MRI allows for estimation of survival in COPD. • Cardiac MRI may be useful for follow up or future trials. • MRI is potentially useful to assess pulmonary hypertension in patients with COPD

Combining creative writing and narrative analysis to deliver new insights into the impact of pulmonary hypertension

Introduction Pulmonary hypertension is life-limiting. Delays in diagnosis are common, and even after treatment has been initiated, pulmonary hypertension has marked effects on many aspects of social and physical function. We believed that a new approach to examining disease impact could be achieved through a combination of narrative research and creative writing. Methods Detailed unstructured narrative interviews with people with pulmonary hypertension were analysed thematically. Individual moments were also summarised and studied using creative writing, in which the interviewer created microstories from narrative and interview data. Stories were shared with their subjects, and with other patients, clinicians, researchers and the wider public. The study was carried out in hospital and in patients’ homes. Results Narrative analysis generated a rich data set which highlighted profound effects of pulmonary hypertension on identity, and demonstrated how the disease results in very marked personal change with ongoing and unpredictable requirement for adaptation. The novel methodology of microstory development proved to be an effective tool to summarise, communicate, and explore the consequences of pulmonary hypertension and the clinical challenges of caring for patients with this illness. Conclusions A holistic approach to treatment of chronic respiratory diseases such as pulmonary hypertension requires and benefits from explicit exploration of the full impacts of the illness. Narrative analysis and the novel approach of targeted microstory development can form a valuable component of the repertoire of approaches to effectively comprehend chronic disease and can also facilitate patient-focused discussion and interventions

Immersion mode heterogeneous ice nucleation by an illite rich powder representative of atmospheric mineral dust

Atmospheric dust rich in illite is transported globally from arid regions and impacts cloud properties through the nucleation of ice. We present measurements of ice nucleation in water droplets containing known quantities of an illite rich powder under atmospherically relevant conditions. The illite rich powder used here, NX illite, has a similar mineralogical composition to atmospheric mineral dust sampled in remote locations, i.e. dust which has been subject to long range transport, cloud processing and sedimentation. Arizona Test Dust, which is used in other ice nucleation studies as a model atmospheric dust, has a significantly different mineralogical composition and we suggest that NX illite is a better surrogate of natural atmospheric dust. Using optical microscopy, heterogeneous nucleation in the immersion mode by NX illite was observed to occur dominantly between 246 K and the homogeneous freezing limit. In general, higher freezing temperatures were observed when larger surface areas of NX illite were present within the drops. Homogenous nucleation was observed to occur in droplets containing low surface areas of NX illite. We show that NX illite exhibits strong particle to particle variability in terms of ice nucleating ability, with ~1 in 105 particles dominating ice nucleation when high surface areas were present. In fact, this work suggests that the bulk of atmospheric mineral dust particles may be less efficient at nucleating ice than assumed in current model parameterisations. For droplets containing ≤2 × 10−6 cm2 of NX illite, freezing temperatures did not noticeably change when the cooling rate was varied by an order of magnitude. The data obtained during cooling experiments (surface area ≤2 × 10−6 cm2) is shown to be inconsistent with the single component stochastic model, but is well described by the singular model (ns(236.2 K ≤ T ≤ 247.5 K) = exp(6.53043 × 104− 8.2153088 × 102T + 3.446885376T2 − 4.822268 × 10−3T3). However, droplets continued to freeze when the temperature was held constant, which is inconsistent with the time independent singular model. We show that this apparent discrepancy can be resolved using a multiple component stochastic model in which it is assumed that there are many types of nucleation sites, each with a unique temperature dependent nucleation coefficient. Cooling rate independence can be achieved with this time dependent model if the nucleation rate coefficients increase very rapidly with decreasing temperature, thus reconciling our measurement of nucleation at constant temperature with the cooling rate independence

Functional Redundancy of Class I Phosphoinositide 3-Kinase (PI3K) Isoforms in Signaling Growth Factor-Mediated Human Neutrophil Survival

We have investigated the contribution of individual phosphoinositide 3-kinase (PI3K) Class I isoforms to the regulation of neutrophil survival using (i) a panel of commercially available small molecule isoform-selective PI3K Class I inhibitors, (ii) novel inhibitors, which target single or multiple Class I isoforms (PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ), and (iii) transgenic mice lacking functional PI3K isoforms (p110δKOγKO or p110γKO). Our data suggest that there is considerable functional redundancy amongst Class I PI3Ks (both Class IA and Class IB) with regard to GM-CSF-mediated suppression of neutrophil apoptosis. Hence pharmacological inhibition of any 3 or more PI3K isoforms was required to block the GM-CSF survival response in human neutrophils, with inhibition of individual or any two isoforms having little or no effect. Likewise, isolated blood neutrophils derived from double knockout PI3K p110δKOγKO mice underwent normal time-dependent constitutive apoptosis and displayed identical GM-CSF mediated survival to wild type cells, but were sensitized to pharmacological inhibition of the remaining PI3K isoforms. Surprisingly, the pro-survival neutrophil phenotype observed in patients with an acute exacerbation of chronic obstructive pulmonary disease (COPD) was resilient to inactivation of the PI3K pathway

Dynamic contrast-enhanced magnetic resonance imaging in patients with pulmonary arterial hypertension.

Dynamic contrast-enhanced (DCE) time-resolved magnetic resonance (MR) imaging is a technique whereby the passage of an intravenous contrast bolus can be tracked through the pulmonary vascular system. The aim of this study was to investigate the prognostic significance of DCE-MR pulmonary blood transit times in patients with pulmonary arterial hypertension (PAH). Seventy-nine patients diagnosed with PAH underwent pulmonary DCE imaging at 1.5 T using a time-resolved three-dimensional spoiled gradient echo sequence. The prognostic significance of two DCE parameters, full width at half maximum (FWHM) of the first-pass clearance curve and pulmonary transit time (PTT), along with demographic and invasive catheter measurements, was evaluated by univariate and bivariate Cox proportional hazards regression and Kaplan-Meier analysis. DCE-MR transit times were most closely correlated with cardiac index (CI) and pulmonary vascular resistance index (PVRI) and were both found to be accurate for detecting reduced CI (FWHM area under the curve [AUC] at receiver operating characteristic analysis = 0.91 and PTT AUC = 0.92, respectively) and for detecting elevated PVRI (FWHM AUC = 0.88 and PTT AUC = 0.84, respectively). During the follow-up period, 25 patients died. Patients with longer measurements of FWHM (P = 0.0014) and PTT (P = 0.004) were associated with poor outcome at Kaplan-Meier analysis, and both parameters were strong predictors of adverse outcome from Cox proportional hazards analysis (P = 0.013 and 0.010, respectively). At bivariate analysis, DCE measurements predicted mortality independent of age, gender, and World Health Organization functional class; however, invasive hemodynamic indexes CI, PVRI, and DCE measurements were not independent of one another. In conclusion, DCE-MR transit times predict mortality in patients with PAH and are closely associated with clinical gold standards CI and PVRI