Increased force levels after shortening and restretching skinned cardiac muscle

Summary At steady calcium activation, changes in loading conditions were imposed on single skinned cardiac myocytes and on multicellular skinned cardiac muscle. Despite the initial steady level of activation, an increase in isometric force (i.e. force gain) was observed after stretching following a period of shortening. Force gain was most pronounced at low levels of free activating calcium, but it was present at any level of free calcium, including maximal activation. The extent of shortening did not influence the amount of force gain. An increased level of shortening (i.e. shortening gain) was observed after clamping a single myocyte under afterloaded conditions. Since no membranous systems were present, the mechanism causing force and shortening gain were shown to be located at the level of the contractile proteins. The hypothesis is suggested that different steady states of the crossbridges could exist despite a constant steady level of calcium activation.     

Hidden costs: The ethics of cost-effectiveness analyses for health interventions in resource-limited settings

Cost-effectiveness analysis (CEA) is an increasingly appealing tool for evaluating and comparing health-related interventions in resource-limited settings. The goal is to inform decision-makers regarding the health benefits and associated costs of alternative interventions, helping guide allocation of limited resources by prioritising interventions that offer the most health for the least money. Although only one component of a more complex decision-making process, CEAs influence the distribution of health-care resources, directly influencing morbidity and mortality for the world’s most vulnerable populations. However, CEA-associated measures are frequently setting-specific valuations, and CEA outcomes may violate ethical principles of equity and distributive justice. We examine the assumptions and analytical tools used in CEAs that may conflict with societal values. We then evaluate contextual features unique to resource-limited settings, including the source of health-state utilities and disability weights, implications of CEA thresholds in light of economic uncertainty, and the role of external donors. Finally, we explore opportunities to help align interpretation of CEA outcomes with values and budgetary constraints in resource-limited settings. The ethical implications of CEAs in resource-limited settings are vast. It is imperative that CEA outcome summary measures and implementation thresholds adequately reflect societal values and ethical priorities in resource-limited settings.     

Randomized Phase 1 Trial of Pembrolizumab with Sequential Versus Concomitant Stereotactic Body Radiotherapy in Metastatic Urothelial Carcinoma

Preclinical data indicate that radiotherapy works synergistically with pembrolizumab, but the effect and toxicity of this combination may depend on radiotherapy timing. We conducted a randomized phase 1 trial combining pembrolizumab with either sequential (A) or concomitant (B) stereotactic body radiotherapy (SBRT) in metastatic urothelial carcinoma (mUC). No dose-limiting toxicity occurred. Treatment-related adverse events (trAEs; Common Terminology Criteria for Adverse Events v4.0) of grade 1–2 occurred in six of nine and all nine patients in arms A and B, respectively. One grade 3 trAE occurred in arm B. No grade 4–5 trAEs occurred. Overall response rates of 0% and 44.4% were noted in arms A and B, respectively, as per Response Evaluation Criteria in Solid Tumors v1.1. The trial was not powered to compare efficacy between arms. Targeted sequencing of tissue DNA and circulating tumor DNA (ctDNA) revealed high genomic concordance. Treatment response was associated with ctDNA fraction decline. We conclude that sequential and concomitant SBRT can be safely combined with pembrolizumab in mUC and that the effect of SBRT timing on efficacy is worth exploring further.

Diapocynin neuroprotective effects in 3-nitropropionic acid Huntington’s disease model in rats: emphasis on Sirt1/Nrf2 signaling pathway

Inflammopharmacology - Huntington's disease (HD) is a rare inherited disease portrayed with marked cognitive and motor decline owing to extensive neurodegeneration. NADPH oxidase is considered...