Selective P2X7 receptor antagonists for chronic inflammation and pain

ATP, acting on P2X7 receptors, stimulates changes in intracellular calcium concentrations, maturation, and release of interleukin-1β (IL-1β), and following prolonged agonist exposure, cell death. The functional effects of P2X7 receptor activation facilitate several proinflammatory processes associated with arthritis. Within the nervous system, these proinflammatory processes may also contribute to the development and maintenance of chronic pain. Emerging data from genetic knockout studies have indicated specific roles for P2X7 receptors in inflammatory and neuropathic pain states. The discovery of multiple distinct chemical series of potent and highly selective P2X7 receptor antagonists have enhanced our understanding of P2X7 receptor pharmacology and the diverse array of P2X7 receptor signaling mechanisms. These antagonists have provided mechanistic insight into the role(s) P2X7 receptors play under pathophysiological conditions. In this review, we integrate the recent discoveries of novel P2X7 receptor-selective antagonists with a brief update on P2X7 receptor pharmacology and its therapeutic potential

Impact of clinical phenotypes on management and outcomes in European atrial fibrillation patients: a report from the ESC-EHRA EURObservational Research Programme in AF (EORP-AF) General Long-Term Registry

Background: Epidemiological studies in atrial fibrillation (AF) illustrate that clinical complexity increase the risk of major adverse outcomes. We aimed to describe European AF patients\u2019 clinical phenotypes and analyse the differential clinical course. Methods: We performed a hierarchical cluster analysis based on Ward\u2019s Method and Squared Euclidean Distance using 22 clinical binary variables, identifying the optimal number of clusters. We investigated differences in clinical management, use of healthcare resources and outcomes in a cohort of European AF patients from a Europe-wide observational registry. Results: A total of 9363 were available for this analysis. We identified three clusters: Cluster 1 (n = 3634; 38.8%) characterized by older patients and prevalent non-cardiac comorbidities; Cluster 2 (n = 2774; 29.6%) characterized by younger patients with low prevalence of comorbidities; Cluster 3 (n = 2955;31.6%) characterized by patients\u2019 prevalent cardiovascular risk factors/comorbidities. Over a mean follow-up of 22.5 months, Cluster 3 had the highest rate of cardiovascular events, all-cause death, and the composite outcome (combining the previous two) compared to Cluster 1 and Cluster 2 (all P <.001). An adjusted Cox regression showed that compared to Cluster 2, Cluster 3 (hazard ratio (HR) 2.87, 95% confidence interval (CI) 2.27\u20133.62; HR 3.42, 95%CI 2.72\u20134.31; HR 2.79, 95%CI 2.32\u20133.35), and Cluster 1 (HR 1.88, 95%CI 1.48\u20132.38; HR 2.50, 95%CI 1.98\u20133.15; HR 2.09, 95%CI 1.74\u20132.51) reported a higher risk for the three outcomes respectively. Conclusions: In European AF patients, three main clusters were identified, differentiated by differential presence of comorbidities. Both non-cardiac and cardiac comorbidities clusters were found to be associated with an increased risk of major adverse outcomes

Financial implications of skilled attendance at delivery in Nepal.

OBJECTIVE: To measure costs and willingness-to-pay for delivery care services in 8 districts of Nepal. METHOD: Household costs were used to estimate total resource requirements to finance: (1) the current pattern of service use; (2) all women to deliver in a health facility; (3) skilled attendance at home deliveries with timely referral of complicated cases to a facility offering comprehensive obstetric services. RESULTS: The average cost to a household of a home delivery ranged from 410 RS (5.43 dollars) (with a friend or relative attending) to 879 RS (11.63 dollars) (with a health worker). At a facility the average fee for a normal delivery was 678 RS (8.97 dollars). When additional charges, opportunity and transport costs were added, the total amount paid exceeded 5,300 RS (70 dollars). For a caesarean section the total household cost was more than 11,400 RS (150 dollars). Based on these figures, the cost of financing current practice is 45 RS (0.60 dollar) per capita. A policy of universal institutional delivery would cost 238 RS (3.15 dollars) per capita while a policy of skilled attendance at home with early referral of cases from remote areas would cost around 117 RS (1.55 dollars) per capita. These are significant sums in the context of a health budget of about 400 RS (5 dollars) per capita. Conclusions The financial cost of developing a skilled attendance strategy in Nepal is substantial. The mechanisms to direct funding to women in need must to be improved, pricing needs to be more transparent, and payment exemptions in public facilities must be better financed if we are to overcome both supply and demand-side barriers to care seeking

Population-Based Study of Food Insecurity and HIV Transmission Risk Behaviors and Symptoms of Sexually Transmitted Infections Among Linked Couples in Nepal

Food insecurity has recently emerged as an important risk factor for HIV acquisition among women worldwide. No previous studies have used linked data that would permit investigation of the extent to which food insecurity may have differential associations with HIV transmission risk behaviors or symptoms of sexually transmitted infections (STIs) among men and women in the same households. We used nationally representative data on linked couples from the Nepal 2011 Demographic and Health Survey. The primary explanatory variable of interest was food insecurity, measured with the Household Food Insecurity Access Scale. In multivariable logistic regression models, women in food insecure householdswere less likely to report recent condom use and more likely to report symptoms consistent with STIs. These patterns were absent among men. Interventions targeting food insecurity may have beneficial implications for both HIV prevention and gender equity in Nepal