Description: Background— The value of American Board of Internal Medicine certification has been questioned. We evaluated the Association of Interventional Cardiology certification with in-hospital outcomes of patients undergoing percutaneous coronary intervention (PCI) in 2010. Methods and Results— We identified physicians who performed ≥10 PCIs in 2010 in the CathPCI Registry and determined interventional cardiology (ICARD) certification status using American Board of Internal Medicine data. We compared in-hospital outcomes of patients treated by certified and noncertified physicians using hierarchical multivariable models adjusted for differences in patient characteristics and PCI volume. Primary end points were all-cause in-hospital mortality and bleeding complications. Secondary end points included emergency coronary artery bypass grafting, vascular complications, and a composite of any adverse outcome. With 510 708 PCI procedures performed by 5175 physicians, case mix and unadjusted outcomes were similar among certified and noncertified physicians. The adjusted risks of in-hospital mortality (odds ratio, 1.10; 95% confidence interval, 1.02–1.19) and emergency coronary artery bypass grafting (odds ratio, 1.32; 95% confidence interval, 1.12–1.56) were higher in the non–ICARD-certified group, but the risks of bleeding and vascular complications and the composite end point were not statistically significantly different between groups. Conclusions— We did not observe a consistent association between ICARD certification and the outcomes of PCI procedures. Although there was a significantly higher risk of mortality and emergency coronary artery bypass grafting in patients treated by non–ICARD-certified physicians, the risks of vascular complications and bleeding were similar. Our findings suggest that ICARD certification status alone is not a strong predictor of patient outcomes and indicate a need to enhance the value of subspecialty certification.

Description: Some mitochondrial long noncoding RNAs (lncRNAs) are encoded by nuclear DNA, but the mechanisms that mediate their transport to mitochondria are poorly characterized. Using affinity RNA pull-down followed by mass spectrometry analysis, we found two RNA-binding proteins (RBPs), HuR (human antigen R) and GRSF1 (G-rich RNA sequence-binding factor 1), that associated with the nuclear DNA-encoded lncRNA RMRP and mobilized it to mitochondria. In cultured human cells, HuR bound RMRP in the nucleus and mediated its CRM1 (chromosome region maintenance 1)-dependent export to the cytosol. After RMRP was imported into mitochondria, GRSF1 bound RMRP and increased its abundance in the matrix. Loss of GRSF1 lowered the mitochondrial levels of RMRP , in turn suppressing oxygen consumption rates and modestly reducing mitochondrial DNA replication priming. Our findings indicate that RBPs HuR and GRSF1 govern the cytoplasmic and mitochondrial localization of the lncRNA RMRP , which is encoded by nuclear DNA but has key functions in mitochondria.

Description: Angkor (Cambodia) was the seat of the Khmer Empire from the 9th to 15th century AD. The site is noted for its monumental architecture and complex hydro-engineering systems, comprised of canals, moats, embankments, and large reservoirs, known as barays. We infer a 1,000-y, 14C-dated paleoenvironmental record from study of an approximately 2-m sediment core taken in the largest Khmer reservoir, the West Baray. The baray was utilized and managed from the time of construction in the early 11th century, through the 13th century. During that time, the West Baray received relatively high rates of detrital input. In the 14th century, linear sedimentation rates diminished by an order of magnitude, yielding a condensed section that correlates temporally with episodes of regional monsoon failure during the late 14th and early 15th century, recorded in tree ring records from Vietnam. Our results demonstrate that changes in the water management system were associated with the decline of the Angkorian kingdom during that period. By the 17th century, the West Baray again functioned as a limnetic system. Ecologic and sedimentologic changes over the last millennium, detected in the baray deposits, are attributed to shifts in regional-scale Khmer water management, evolving land use practices in the catchment, and regional climate change.

Description: Background: Despite recent improvements in survival after acute myocardial infarction (AMI), U.S. hospitals vary 2-fold in their 30-day risk-standardized mortality rates (RSMRs). Nevertheless, information is limited on hospital-level factors that may be associated with RSMRs. Objective: To identify hospital strategies that were associated with lower RSMRs. Design: Cross-sectional survey of 537 hospitals (91% response rate) and weighted multivariate regression by using data from the Centers for Medicare & Medicaid Services to determine the associations between hospital strategies and hospital RSMRs. Setting: Acute care hospitals with an annualized AMI volume of at least 25 patients. Participants: Patients hospitalized with AMI between 1 January 2008 and 31 December 2009. Measurements: Hospital performance improvement strategies, characteristics, and 30-day RSMRs. Results: In multivariate analysis, several hospital strategies were significantly associated with lower RSMRs and in aggregate were associated with clinically important differences in RSMRs. These strategies included holding monthly meetings to review AMI cases between hospital clinicians and staff who transported patients to the hospital (RSMR lower by 0.70 percentage points), having cardiologists always on site (lower by 0.54 percentage points), fostering an organizational environment in which clinicians are encouraged to solve problems creatively (lower by 0.84 percentage points), not cross-training nurses from intensive care units for the cardiac catheterization laboratory (lower by 0.44 percentage points), and having physician and nurse champions rather than nurse champions alone (lower by 0.88 percentage points). Fewer than 10% of hospitals reported using at least 4 of these 5 strategies. Limitation: The cross-sectional design demonstrates statistical associations but cannot establish causal relationships. Conclusion: Several strategies, which are currently implemented by relatively few hospitals, are associated with significantly lower 30-day RSMRs for patients with AMI. Primary Funding Source: The Agency for Healthcare Research and Quality, the United Health Foundation, and the Commonwealth Fund.

Description: Background: Despite recent improvements in survival after acute myocardial infarction (AMI), U.S. hospitals vary 2-fold in their 30-day risk-standardized mortality rates (RSMRs). Nevertheless, information is limited on hospital-level factors that may be associated with RSMRs. Objective: To identify hospital strategies that were associated with lower RSMRs. Design: Cross-sectional survey of 537 hospitals (91% response rate) and weighted multivariate regression by using data from the Centers for Medicare & Medicaid Services to determine the associations between hospital strategies and hospital RSMRs. Setting: Acute care hospitals with an annualized AMI volume of at least 25 patients. Participants: Patients hospitalized with AMI between 1 January 2008 and 31 December 2009. Measurements: Hospital performance improvement strategies, characteristics, and 30-day RSMRs. Results: In multivariate analysis, several hospital strategies were significantly associated with lower RSMRs and in aggregate were associated with clinically important differences in RSMRs. These strategies included holding monthly meetings to review AMI cases between hospital clinicians and staff who transported patients to the hospital (RSMR lower by 0.70 percentage points), having cardiologists always on site (lower by 0.54 percentage points), fostering an organizational environment in which clinicians are encouraged to solve problems creatively (lower by 0.84 percentage points), not cross-training nurses from intensive care units for the cardiac catheterization laboratory (lower by 0.44 percentage points), and having physician and nurse champions rather than nurse champions alone (lower by 0.88 percentage points). Fewer than 10% of hospitals reported using at least 4 of these 5 strategies. Limitation: The cross-sectional design demonstrates statistical associations but cannot establish causal relationships. Conclusion: Several strategies, which are currently implemented by relatively few hospitals, are associated with significantly lower 30-day RSMRs for patients with AMI. Primary Funding Source: The Agency for Healthcare Research and Quality, the United Health Foundation, and the Commonwealth Fund.

Description: Scavenger receptors represent an important class of pattern recognition receptors shown to mediate both beneficial and detrimental roles in host defense against microbial pathogens. The role of the major macrophage scavenger receptor, scavenger receptor A (SRA), in the immune response against the pathogenic fungus, Cryptococcus neoformans , is unknown. To evaluate the role of SRA in anticryptococcal host defenses, SRA +/+ mice and SRA –/– mice were infected intratracheally with C. neoformans . Results show that infection of SRA –/– mice resulted in a reduction in the pulmonary fungal burden at the efferent phase (3 wk) compared with SRA +/+ mice. Improved fungal clearance in SRA –/– mice was associated with decreased accumulation of eosinophils and greater accumulation of CD4 + T cells and CD11b + dendritic cells. Additional parameters were consistent with enhanced anticryptococcal immunity in the infected SRA –/– mice: 1) increased expression of the costimulatory molecules CD80 and CD86 by lung APCs, 2) decreased expression of Th2 cytokines (IL-4 and IL-13) and IL-10 in lung leukocytes and in cryptococcal Ag-pulsed splenocytes, 3) diminished IgE production in sera, and 4) increased hallmarks of classical pulmonary macrophage activation. These effects were preceded by increased expression of early pro-Th1 genes in pulmonary lymph nodes at the afferent phase (1 wk). Collectively, our data show that SRA can be exploited by C. neoformans to interfere with the early events of the afferent responses that support Th1 immune polarization. This results in amplification of Th2 arm of the immune response and subsequently impaired adaptive control of C. neoformans in the infected lungs.

Description: Upon ingestion by macrophages, Cryptococcus neoformans can survive and replicate intracellularly unless the macrophages become classically activated. The mechanism enabling intracellular replication is not fully understood; neither are the mechanisms that allow classical activation to counteract replication. C. neoformans– induced lysosome damage was observed in infected murine bone marrow–derived macrophages, increased with time, and required yeast viability. To demonstrate lysosome damage in the infected host, we developed a novel flow cytometric method for measuring lysosome damage. Increased lysosome damage was found in C. neoformans– containing lung cells compared with C. neoformans –free cells. Among C. neoformans– containing myeloid cells, recently recruited cells displayed lower damage than resident cells, consistent with the protective role of recruited macrophages. The magnitude of lysosome damage correlated with increased C. neoformans replication. Experimental induction of lysosome damage increased C. neoformans replication. Activation of macrophages with IFN- abolished macrophage lysosome damage and enabled increased killing of C. neoformans. We conclude that induction of lysosome damage is an important C. neoformans survival strategy and that classical activation of host macrophages counters replication by preventing damage. Thus, therapeutic strategies that decrease lysosomal damage, or increase resistance to such damage, could be valuable in treating cryptococcal infections.

Description: High-grade serous ovarian carcinoma (HGSOC) is the most common and aggressive form of epithelial ovarian cancer, for which few targeted therapies exist. To search for new therapeutic target proteins, we performed an in vivo shRNA screen using an established human HGSOC cell line growing either subcutaneously or intraperitoneally in immunocompromised...

Description: Background— Little is known about the contemporary use of intra-aortic balloon pump (IABP) and other mechanical circulatory support (O-MCS) devices in patients undergoing percutaneous coronary intervention (PCI) in the setting of cardiogenic shock. Methods and Results— We identified 76 474 patients who underwent PCI in the setting of cardiogenic shock at one of 1429 National Cardiovascular Data Registry CathPCI participating hospitals from 2009 to 2013. Temporal trends and hospital-level variation in the use of IABP and O-MCS were evaluated. No mechanical circulatory support was used in 41 286 (54%) patients, 29 730 (39%) received IABP only, 2711 (3.5%) received O-MCS only, and 2747 (3.6%) received both IABP and O-MCS. At the start of the study period, 45% of patients undergoing PCI in the setting of cardiogenic shock received an IABP and 6.7% received O-MCS. The proportion of patients receiving IABP declined at an average rate of 0.3% per quarter, whereas the rate of O-MCS use was unchanged over the study period. The predicted probability of IABP use varied significantly by site (hospital median 42%, interquartile range 33% to 51%, range 8% to 85%). The probability of O-MCS use was 〈5% for half of hospitals and 〉20% in less than one-tenth of hospitals. Conclusions— In this large national registry, the use of IABP in the setting of PCI for cardiogenic shock decreased over time without a concurrent increase in O-MCS use. The probability of IABP and O-MCS use varied across hospitals, and the use of O-MCS was clustered at a small number of hospitals.