Phospholamban antisense oligonucleotides improve cardiac function in murine cardiomyopathy

Heart failure (HF) is a major cause of morbidity and mortality worldwide, highlighting an urgent need for novel treatment options, despite recent improvements. Aberrant Ca(2+) handling is a key feature of HF pathophysiology. Restoring the Ca(2+) regulating machinery is an attractive therapeutic strategy supported by genetic and pharmacological proof of concept studies. Here, we study antisense oligonucleotides (ASOs) as a therapeutic modality, interfering with the PLN/SERCA2a interaction by targeting Pln mRNA for downregulation in the heart of murine HF models. Mice harboring the PLN R14del pathogenic variant recapitulate the human dilated cardiomyopathy (DCM) phenotype; subcutaneous administration of PLN-ASO prevents PLN protein aggregation, cardiac dysfunction, and leads to a 3-fold increase in survival rate. In another genetic DCM mouse model, unrelated to PLN (Cspr3/Mlp(−/−)), PLN-ASO also reverses the HF phenotype. Finally, in rats with myocardial infarction, PLN-ASO treatment prevents progression of left ventricular dilatation and improves left ventricular contractility. Thus, our data establish that antisense inhibition of PLN is an effective strategy in preclinical models of genetic cardiomyopathy as well as ischemia driven HF

Patient satisfaction with antiretroviral services at primary health-care facilities in the Free State, South Africa – a two-year study using four waves of cross-sectional data

<p>Abstract</p> <p>Background</p> <p>The study's first objective was to determine the levels of patient satisfaction with services at antiretroviral treatment (ART) assessment sites. Differences in patient satisfaction with several aspects of service over time and among health districts were measured. The second objective was to examine the association between human resource shortages and levels of patient satisfaction with services.</p> <p>Methods</p> <p>Four cross-sectional waves of data were collected from a random sample of 975 patients enrolled in the Free State's public-sector ART programme. One-way analysis of variance (ANOVA) with the Bonferroni adjustment for multiple comparisons was used to assess the differences in patient satisfaction among the Province's five districts and among the four waves of data. Correlation coefficient analysis using Pearson's <it>r </it>was used to assess the association between ART nurse vacancy rates and patient satisfaction with the services provided by nurses over time.</p> <p>Results</p> <p>With respect to both general services and the services provided by nurses, our results indicate high overall satisfaction among Free State patients receiving public-sector ART. However, our data present a less positive picture of patient satisfaction with waiting times. Patients in Fezile Dabi District were generally slightly dissatisfied with the waiting times at their assessment sites. In fact, waiting times at assessment sites were the most important predictor of discontent among ART patients. Significant geographical (<it>P </it>< 0.001) and temporal differences (<it>P </it>< 0.005) were observed in these three aspects of patient satisfaction. Patients were most satisfied in Thabo Mofutsanyana District and least satisfied in Motheo District. Patients in Fezile Dabi District were generally slightly dissatisfied with the waiting times at their assessment sites. Finally, our analysis revealed a strong negative association (<it>r </it>= -0.438, <it>P </it>< 0.001) between nurse vacancy rates and mean satisfaction levels with services performed by nurses at baseline. Patients attending facilities with high professional nurse vacancy rates reported significantly less satisfaction with nurses' services than did those attending facilities with fewer vacant nursing posts.</p> <p>Conclusion</p> <p>Collectively, our findings show high levels of patient satisfaction with ART-related services, but also confirm claims by other studies, which have identified human resource shortages as the most important obstacle to a successful South African AIDS strategy.</p

The threat of piracy on maritime transportation

Matt Elbeck and Ercan Tirtirogl

Qualifying Purchase Intentions Using Queueing Theory

We propose that a consumer’s purchase behaviour emulates a cognitive framework such that an appropriately selected queueing model can be used to assess the credibility of a consumer’s expression of purchase intention to proceed into purchase action. The modelling idea is to envision that the customer has a mental queue of needs, and the surfacing of a need represents a new arrival to this queue while a purchase satisfying a need represents a departure from the queue. Using queueing formulae (and/or readily available tables on queueing), several statistics known as "operating characteristics" can be computed to capture and describe the individual’s current need status. Hence, a description of the customer’s state of readiness or prospect of actually executing the expressed purchase intention for a product (good or service) whose future sales are of interest in a market survey may be obtained. In this paper, such a description is termed Individual Buyer Profile (IBP), and IBP is offered as a purchase intention qualifier.Ercan Tirtiroglu, Matt Elbec