Recommendations for the clinical management of patients receiving macitentan for pulmonary arterial hypertension (PAH): A Delphi consensus document

In patients treated with macitentan (Opsumit®, Actelion Pharmaceuticals Ltd., Basel, Switzerland) for pulmonary arterial hypertension (PAH), prevention and/or effective management of treatment-related adverse events may improve adherence. However, management of these adverse events can be challenging and the base of evidence and clinical experience for macitentan is limited. In the absence of evidence, consensus recommendations from physicians experienced in using macitentan to treat PAH may benefit patients and physicians who are using macitentan. Consensus recommendations were developed by a panel of physicians experienced with macitentan and PAH using a modified Delphi process. Over three iterations, panelists developed and refined a series of statements on the use of macitentan in PAH and rated their agreement with each statement on a Likert scale. The panel of 18 physicians participated and developed a total of 118 statements on special populations, add-on therapy, drug-drug interactions, warnings and precautions, hospitalization and functional class, and adverse event management. The resulting consensus recommendations are intended to provide practical guidance on real-world issues in using macitentan to treat patients with PAH

Determining crystal structures through crowdsourcing and coursework

We show here that computer game players can build high-quality crystal structures. Introduction of a new feature into the computer game Foldit allows players to build and real-space refine structures into electron density maps. To assess the usefulness of this feature, we held a crystallographic model-building competition between trained crystallographers, undergraduate students, Foldit players and automatic model-building algorithms. After removal of disordered residues, a team of Foldit players achieved the most accurate structure. Analysing the target protein of the competition, YPL067C, uncovered a new family of histidine triad proteins apparently involved in the prevention of amyloid toxicity. From this study, we conclude that crystallographers can utilize crowdsourcing to interpret electron density information and to produce structure solutions of the highest quality

Filgrastim in Patients With Pneumonia and Severe Sepsis or Septic Shock

Evaluate the safety of filgrastim(recombinant methionyl human granulocyte colony-stimulating factor)administration, combined with standard therapy, in patients withpneumonia and either septic shock or severe sepsis who were receivingmechanical ventilation. Multicenter, double-blind, randomized, placebo-controlled study. ICU, multicenter. Eighteen patients with pneumonia and hypotension, or in the absence ofshock, two or more end-organ dysfunctions, were enrolled and treated. Baseline acute physiology and chronic health evaluation II scores andmedian age for the filgrastim (n = 12) and placebo (n = 6) groupswere 25.0 and 49.5 years and 31.5 and 56.5 years, respectively. Filgrastim (300 μg) or placebo wasadministered IV daily for up to 5 days. Study end points included safety; biologicalresponse, including endogenous cytokine levels, endotoxin levels, andneutrophil counts; and mortality. Cytokine and endotoxin levels werehighly variable in both groups. By day 29, 3 of 12 filgrastim-treatedpatients and 4 of 6 placebo-treated patients had died. There were nodifferences in types and occurrences of adverse events, including ARDS, or in outcome between the two groups. Three of four placebo-treatedpatients had persistent bacterial growth on bronchoscopy repeated after48 h compared with 2 of 10 filgrastim-treated patients. Filgrastim appeared to be well tolerated inthis population of patients with pneumonia and severe sepsis or septicshock. Larger studies to determine the benefit of filgrastim inpatients with pneumonia and sepsis or organ dysfunction arewarranted

Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension

AbstractObjectivesThe aim of this study was to evaluate the relationships between echocardiographic findings and clinical outcomes in patients with severe primary pulmonary hypertension (PPH).BackgroundPrimary pulmonary hypertension is associated with abnormalities of right heart structure and function that contribute to the poor prognosis of the disease. Echocardiographic abnormalities associated with PPH have been described, but the prognostic significance of these findings remains poorly characterized.MethodsEchocardiographic studies, invasive hemodynamic measurements and 6-min walk tests were performed and outcomes prospectively followed in 81 patients with severe PPH. Subjects were participants in a 12-week randomized trial examining the effects of prostacyclin plus conventional therapy compared with conventional therapy alone.ResultsDuring the mean follow-up period of 36.9 ± 15.4 months, 20 patients died and 21 patients underwent transplantation. Pericardial effusion (p = 0.003) and indexed right atrial area (p = 0.005) were predictors of mortality. Pericardial effusion (p = 0.017), indexed right atrial area (p = 0.012) and the degree of septal shift in diastole (p = 0.004) were predictors of a composite end point of death or transplantation. In multivariable analyses incorporating clinical, hemodynamic and echocardiographic variables, pericardial effusion and an enlarged right atrium remained predictors of adverse outcomes. Six-minute walk results, mixed venous oxygen saturation and initial treatment randomization were also independently associated with a poor prognosis.ConclusionsPericardial effusion, right atrial enlargement and septal displacement are echocardiographic abnormalities that reflect the severity of right heart failure and predict adverse outcomes in patients with severe PPH. These characteristics may help identify patients appropriate for more intensive medical therapy or earlier transplantation