Impact of COVID-19 on percutaneous coronary intervention utilization and mortality in New York.

BACKGROUND: COVID-19 has disrupted the care of all patients, and little is known about its impact on the utilization and short-term mortality of percutaneous coronary intervention (PCI) patients, particularly nonemergency patients. METHODS: New York State's PCI registry was used to study the utilization of PCI and the presence of COVID-19 in four patient subgroups ranging in severity from ST-elevation myocardial infarction (STEMI) to elective patients before (December 01, 2018-February 29, 2020) and during the COVID-19 era (March 01, 2020-May 31, 2021), as well as to examine the impact of different COVID severity levels on the mortality of different types of PCI patients. RESULTS: Decreases in the mean quarterly PCI volume from the prepandemic period to the first quarter of the pandemic ranged from 20% for STEMI patients to 61% for elective patients, with the other two subgroups having decreases in between these values. PCI quarterly volume rebounds from the prepandemic period to the second quarter of 2021 were in excess of 90% for all patient subgroups, and 99.7% for elective patients. Existing COVID-19 was rare among PCI patients, ranging from 1.74% for STEMI patients to 3.66% for elective patients. PCI patients with COVID-19 and acute respiratory distress syndrome (ARDS) who were not intubated, and PCI patients with COVID-19 and ARDS who were either intubated or were not intubated because of Do Not Resuscitate//Do Not Intubate status had higher risk-adjusted mortality ([adjusted ORs = 10.81 [4.39, 26.63] and 24.53 [12.06, 49.88], respectively]) than patients who never had COVID-19. CONCLUSIONS: There were large decreases in the utilization of PCI during COVID-19, with the percentage of decrease being highly sensitive to patient acuity. By the second quarter of 2021, prepandemic volumes were nearly restored for all patient subgroups. Very few PCI patients had current COVID-19 throughout the pandemic period, but the number of PCI patients with a COVID-19 history increased steadily during the pandemic. PCI patients with COVID-19 accompanied by ARDS were at much higher risk of short-term mortality than patients who never had COVID-19. COVID-19 without ARDS and history of COVID-19 were not associated with higher mortality for PCI patients as of the second quarter of 2021.

Impact of salinity origin on microbial communities in saline springs within the Illinois Basin, USA.

Saline springs within the Illinois Basin result from the discharge of deep-seated evaporated seawater (brine) and likely contain diverse and complex microbial communities that are poorly understood. In this study, seven saline/mineral springs with different geochemical characteristics and salinity origins were investigated using geochemical and molecular microbiological analyses to reveal the composition of microbial communities inhabiting springs and their key controlling factors. The 16S rRNA sequencing results demonstrated that each spring harbours a unique microbial community influenced by its geochemical properties and subsurface conditions. The microbial communities in springs that originated from Cambrian/Ordovician strata, which are deep confined units that have limited recharge from overlying formations, share a greater similarity in community composition and have a higher species richness and more overlapped taxa than those that originated from shallower Pennsylvanian strata, which are subject to extensive regional surface and groundwater recharge. The microbial distribution along the spring flow paths at the surface indicates that 59.8%-94.2% of total sequences in sedimentary samples originated from spring water, highlighting the role of springs in influencing microbiota in the immediate terrestrial environment. The results indicate that the springs introduce microbiota with a high biodiversity into surface terrestrial or aquatic ecosystems, potentially affecting microbial reservoirs in downstream ecosystems.

Sex differences in the treatment and outcomes of patients hospitalized with ST-elevation myocardial infarction.

OBJECTIVES: To compare mortality for women and men hospitalized with ST-elevation myocardial infarction (STEMI) by age and revascularization status. BACKGROUND: There is little information on the mortality of men and women not undergoing revascularization, and the impact of age on relative male-female mortality needs to be revisited. METHODS AND RESULTS: An observational database of 23,809 patients with STEMI presenting at nonfederal New York State hospitals between 2013 and 2015 was used to compare risk-adjusted inhospital/30-day mortality for women and men and to explore the impact of age on those differences. Women had significantly higher mortality than men overall (adjusted odds ratio [AOR] = 1.15, 95% CI [1.04, 1.28]), and among patients aged 65 and older. Women had lower revascularization rates in general (AOR = 0.64 [0.59, 0.69]) and for all age groups. Among revascularized STEMI patients, women overall (AOR = 1.30 [1.10, 1.53]) and over 65 had higher mortality than men. Among patients not revascularized, women between the ages of 45 and 64 had lower mortality (AOR = 0.68 [0.48, 0.97]). CONCLUSIONS: Women with STEMI, and especially older women, had higher inhospital/30-day mortality rates than their male counterparts. Women had higher mortality among revascularized patients, but not among patients who were not revascularized.

Assessment of repeat target lesion percutaneous coronary intervention as a quality measure for public reporting and general quality assessment for PCIs.

BACKGROUND: Target lesion percutaneous coronary intervention (TLPCI) within 1 year of PCI has been proposed by critics of public reporting of short-term mortality as an alternative measure for PCI reporting. METHODS: New York's PCI registry was used to identify 1-year repeat TLPCI and 1-year repeat TLPCI/mortality for patients discharged between December 1, 2013 and November 30, 2014. Significant independent predictors of the outcomes were identified. Hospital and cardiologist risk-adjusted outcomes were calculated, and outlier status and correlations of risk-adjusted rates were examined for the three outcomes. RESULTS: The adverse outcome rates were 1.30, 4.21, and 8.97% for in-hospital/30-day mortality, 1-year repeat TLPCI, and 1-year repeat TLPCI/mortality. There were many commonalities but also many differences in significant predictors of the outcomes. Hospital and cardiologist risk-adjusted 1-year repeat TLPCI rates and repeat TLPCI/mortality rates were poorly correlated with risk-adjusted in-hospital/30-day mortality rates (eg, Spearman R = -.16 [p = .23] and .27 [p = .04], respectively, for hospital 1-year repeat TLPCI vs. in-hospital/30-day mortality). Many more providers were found to have significantly higher and lower rates for repeat TLPCI than for short-term mortality. CONCLUSIONS: Hospital and cardiologist quality assessments are very different for TLPCI and repeat TLPCI/mortality than they are for short-term mortality. Repeat TLPCI/mortality rates are highly correlated with repeat TLPCI rates, but outlier providers differ. More study of repeat TLPCI and all the patient, cardiologist, and hospital factors associated with it may be required before using it as a supplement to, or in lieu of, short-term mortality in public reporting of PCI outcomes.

Impact of Regionalization of ST-Segment-Elevation Myocardial Infarction Care on Treatment Times and Outcomes for Emergency Medical Services-Transported Patients Presenting to Hospitals With Percutaneous Coronary Intervention: Mission: Lifeline Accelerator-2.

BACKGROUND: Regional variations in reperfusion times and mortality in patients with ST-segment-elevation myocardial infarction are influenced by differences in coordinating care between emergency medical services (EMS) and hospitals. Building on the Accelerator-1 Project, we hypothesized that time to reperfusion could be further reduced with enhanced regional efforts. METHODS: Between April 2015 and March 2017, we worked with 12 metropolitan regions across the United States with 132 percutaneous coronary intervention-capable hospitals and 946 EMS agencies. Data were collected in the ACTION (Acute Coronary Treatment and Intervention Outcomes Network)-Get With The Guidelines Registry for quarterly Mission: Lifeline reports. The primary end point was the change in the proportion of EMS-transported patients with first medical contact to device time ≤90 minutes from baseline to final quarter. We also compared treatment times and mortality with patients treated in hospitals not participating in the project during the corresponding time period. RESULTS: During the study period, 10 730 patients were transported to percutaneous coronary intervention-capable hospitals, including 974 in the baseline quarter and 972 in the final quarter who met inclusion criteria. Median age was 61 years; 27% were women, 6% had cardiac arrest, and 6% had shock on admission; 10% were black, 12% were Latino, and 10% were uninsured. By the end of the intervention, all process measures reflecting coordination between EMS and hospitals had improved, including the proportion of patients with a first medical contact to device time of ≤90 minutes (67%-74%; P<0.002), a first medical contact to device time to catheterization laboratory activation of ≤20 minutes (38%-56%; P<0.0001), and emergency department dwell time of ≤20 minutes (33%-43%; P<0.0001). Of the 12 regions, 9 regions reduced first medical contact to device time, and 8 met or exceeded the national goal of 75% of patients treated in ≤90 minutes. Improvements in treatment times corresponded with a significant reduction in mortality (in-hospital death, 4.4%-2.3%; P=0.001) that was not apparent in hospitals not participating in the project during the same time period. CONCLUSIONS: Organization of care among EMS and hospitals in 12 regions was associated with significant reductions in time to reperfusion in patients with ST-segment-elevation myocardial infarction as well as in in-hospital mortality. These findings support a more intensive regional approach to emergency care for patients with ST-segment-elevation myocardial infarction.

Plasma Ceramides.

Objective- Ceramides are sphingolipids involved with cellular signaling. Synthesis of ceramides occurs in all tissues. Ceramides accumulate within tissues and the blood plasma during metabolic dysfunction, dyslipidemia, and inflammation. Elevations of ceramides are predictive of cardiovascular mortality. We sought to verify the utility of plasma concentrations of 4 ceramides: N-palmitoyl-sphingosine [Cer(16:0)], N-stearoyl-sphingosine [Cer(18:0)], N-nervonoyl-sphingosine [Cer(24:1)], and N-lignoceroyl-sphingosine [Cer(24:0)] in predicting major adverse cardiovascular events in a diverse patient population referred for coronary angiography. Approach and Results- Plasma ceramides were measured in 495 participants before nonurgent coronary angiography. Coronary artery disease, defined as >50% stenosis in ≥1 coronary artery, was identified 265 (54%) cases. Ceramides were not significantly associated with coronary artery disease. Patients were followed for a combined primary end point of myocardial infarction, percutaneous intervention, coronary artery bypass, stroke, or death within 4 years. Ceramides were significantly predictive of outcomes after adjusting for age, sex, body mass index, hypertension, smoking, LDL (low-density lipoprotein) cholesterol, HDL (high-density lipoprotein) cholesterol, triglycerides, serum glucose, and family history of coronary artery disease. The fully adjusted per SD hazard ratios (95% confidence interval) were 1.50 (1.16-1.93) for Cer(16:0), 1.42 (1.11-1.83) for Cer(18:0), 1.43 (1.08-1.89) for Cer(24:1), and 1.58 (1.22-2.04) for the ceramide risk score. Conclusions- Elevated plasma concentrations of ceramides are independently associated with major adverse cardiovascular events in patients with and without coronary artery disease.

Sensitivity thresholds of groundwater parameters for detecting CO2 leakage at a geologic carbon sequestration site.

Geologic carbon sequestration (GCS) projects in the USA are required to monitor groundwater quality for geochemical changes above the injection area that may be a result of CO2 or brine leakage from the storage reservoir. Should CO2 migrate into the groundwater around the compliance wells monitoring the shallower hydrologic units, each compliance parameter could react differently depending on its sensitivity to CO2. Statistically determined limits (SDLs) for detection of CO2 leakage into groundwater were calculated using background water quality data from the Illinois Basin Decatur Project (IBDP) sequestration site and prediction and tolerance intervals for specific compliance parameters. If the parameter concentrations varied outside of these ranges during the injection and post injection periods of a GCS project, then additional actions would be required to determine the reason for the changes in groundwater concentrations. Geochemical modeling can simulate the amount of CO2 needed to alter water quality parameters a statistically significant amount. This information can then inform GCS operators and regulators as to which compliance parameters are relevant (sensitive) to CO2 leakage for a given setting. For the system studied in here, Fe, Ca, K, Mg, CO2, and pH were sensitive to CO2 addition while Al, Cl, Na, and Si were not.

Inherent differences in keratinocyte function in hidradenitis suppurativa: Evidence for the role of IL-22 in disease pathogenesis.

Hidradenitis suppurativa (HS) is a chronic, recurrent, inflammatory disease of apocrine gland-bearing skin which affects approximately 1-4% of the population. Defective keratinocyte function has been postulated to play a role in HS pathogenesis. Using an in vitro scratch assay, differences between normal, HS, and chronic wound (CW) keratinocytes were evaluated. Normal keratinocytes exhibited faster scratch closure than HS or CW, with normal samples showing 93.8% closure at 96 hours compared to 80.8% in HS (p = 0.016) and 71.5% in CW (p = 0.0012). The keratinocyte viability was similar in normal and HS (91.12 ± 6.03% and 86.55 ± 3.28%, respectively, p = 0.1583), but reduced in CW (72.34 ± 13.12%, p = 0.0138). Furthermore, apoptosis measured by annexin V/propidium iodide, was higher in CW keratinocytes (32.10 ± 7.29% double negative cells compared to 68.67 ± 10.37% in normal and 55.10 ± 9.46% in HS, p = 0.0075). Normal keratinocytes exhibited a significantly higher level of IL-1α (352.83 ± 42.79 pg/ml) compared to HS (169.96 ± 61.62 pg/ml) and CW (128.23 ± 96.61 pg/ml, p = 0.004). HS keratinocytes exhibited significantly lower amounts of IL-22 (8.01 pg/ml) compared to normal (30.24 ± 10.09 pg/ml) and CW (22.20 ± 4.33 pg/ml, p = 0.0008), suggesting that defects in IL-22 signaling may play a role in HS pathogenesis. These findings support intrinsic differences in keratinocyte function in HS which cannot be attributed to reduced keratinocyte viability or increased apoptosis.

Regional Systems of Care Demonstration Project: American Heart Association Mission: Lifeline STEMI Systems Accelerator.

BACKGROUND: Up to 50% of patients fail to meet ST-segment-elevation myocardial infarction (STEMI) guideline goals recommending a first medical contact-to-device time of <90 minutes for patients directly presenting to percutaneous coronary intervention-capable hospitals and <120 minutes for transferred patients. We sought to increase the proportion of patients treated within guideline goals by organizing coordinated regional reperfusion plans. METHODS: We established leadership teams, coordinated protocols, and provided regular feedback for 484 hospitals and 1253 emergency medical services (EMS) agencies in 16 regions across the United States. RESULTS: Between July 2012 and December 2013, 23 809 patients presented with acute STEMI (direct to percutaneous coronary intervention hospital: 11 765 EMS transported and 6502 self-transported; 5542 transferred). EMS-transported patients differed from self-transported patients in symptom onset to first medical contact time (median, 47 versus 114 minutes), incidence of cardiac arrest (10% versus 3%), shock on admission (11% versus 3%), and in-hospital mortality (8% versus 3%; P<0.001 for all comparisons). There was a significant increase in the proportion of patients meeting guideline goals of first medical contact-to-device time, including those directly presenting via EMS (50% to 55%; P<0.001) and transferred patients (44%-48%; P=0.002). Despite regional variability, the greatest gains occurred among patients in the 5 most improved regions, increasing from 45% to 57% (direct EMS; P<0.001) and 38% to 50% (transfers; P<0.001). CONCLUSIONS: This Mission: Lifeline STEMI Systems Accelerator demonstration project represents the largest national effort to organize regional STEMI care. By focusing on first medical contact-to-device time, coordinated treatment protocols, and regional data collection and reporting, we were able to increase significantly the proportion of patients treated within guideline goals.

Incomplete revascularization for percutaneous coronary interventions: Variation among operators, and association with operator and hospital characteristics.

BACKGROUND: Many studies have compared outcomes for incomplete revascularization (IR) among patients undergoing percutaneous coronary interventions (PCIs), but little is known about the correlates of IR, the extent to which complete revascularization (CR) was attempted unsuccessfully, and the variation across operators in the use of IR. METHODS: New York's PCI registry was used to examine medium-term mortality for IR, the variables associated with the use of IR, and the variation across operators in the utilization of IR after controlling for patient factors. RESULTS: Incomplete revascularization occurred for 63% of all patients and was significantly associated with higher 3-year mortality (adjusted hazard ratio1.35, 95% CI 1.23-1.48) than for CR. A total of 96% of all attempted CRs were successful. Operators with 15 or fewer years in practice (the lowest half) used IR significantly more (65% vs 61%, adjusted odds ratio [AOR] 1.17, 95% CI 1.00-1.37) than other operators, and operators with annual volumes of 171 or lower (the lowest 3 quartiles) used IR more than other operators (68% vs 60%, AOR 1.35, 95% CI 1.14-1.59). Also, hospitals with annual volumes of 645 and lower (the lowest 50% of hospitals) used IR more (67% vs 62%, AOR 1.46, 95% CI 1.07-1.99) than other hospitals. CONCLUSIONS: Percutaneous coronary intervention patients without myocardial infarction who undergo IR continue to have higher medium-term (3-year) risk-adjusted mortality rates. There is a large amount of variability among operators in the frequency with which IR occurs. Operators who have been in practice longer, and higher-volume operators and hospitals have lower rates of IR. Failed attempts at CR occur very infrequently.

Influence of smoking on the antiplatelet effect of clopidogrel differs according to clopidogrel dose: Insights from the GRAVITAS trial.

OBJECTIVE: To examine the influence of smoking on the antiplatelet effect of clopidogrel following percutaneous coronary intervention (PCI). BACKGROUND: Certain studies suggest smokers may have enhanced clopidogrel-induced platelet inhibition compared to non-smokers after PCI. Whether this is affected by clopidogrel dose is unknown. METHODS: In this study, we conducted an analysis of 5,429 patients in the Gauging Responsiveness With A VerifyNow P2Y12 Assay: Impact on Thrombosis and Safety (GRAVITAS) trial. Platelet reactivity was assessed 12-24 hr after PCI (baseline). Patients with high on-treatment platelet reactivity (OTR) (P2Y12 reaction units [PRU] ≥ 230) were randomized to clopidogrel 75 mg or 150 mg daily. Reactivity was subsequently assessed at 30-days, and 6-months. Patients were stratified by smoking status. RESULTS: Smoking was independently associated with lower PRU (P = 0.001), and smokers were less likely to have high OTR (odds ratio 0.80, 95% confidence interval 0.68-0.94; P = 0.006) at baseline. Among patients assigned to clopidogrel 75 mg, smokers had lower PRU and were less likely to still have high OTR at 30-days (P < 0.001) and 6-months (P < 0.001). However, in patients assigned clopidogrel 150 mg, PRU and high OTR did not differ by smoking status at any time. Tests demonstrated an interaction between smoking and dose at 30 days (P = 0.007), and a trend at 6-months (P = 0.098). CONCLUSIONS: Smokers treated with clopidogrel exhibit reduced platelet reactivity and are less likely to have persistent high OTR than non-smokers. This difference is mitigated by clopidogrel 150 mg, indicating non-smokers may require double-dose therapy to achieve a similar antiplatelet effect after PCI. © 2016 Wiley Periodicals, Inc.

Impact of pre-hospital electrocardiograms on time to treatment and one year outcome in a rural regional ST-segment elevation myocardial infarction network.

BACKGROUND: Pre-hospital electrocardiograms (ECGs) are believed to reduce time to reperfusion in ST Segment Elevation Myocardial Infarction (STEMI) patients. Little is known of their impact on clinical outcomes in a rural setting. Geisinger regional STEMI network provides percutaneous coronary intervention (PCI) care to over a 100-mile radius in rural central Pennsylvania. METHODS: A retrospective analysis identified 280 consecutive STEMI patients treated with PCI between 1/1/09 and 8/31/11. Comparison between two STEMI groups was performed: 205 patients who were taken by the emergency medical system (EMS) to the nearest hospital (a non-PCI center), underwent an ECG revealing a STEMI, and were transported immediately to Geisinger Medical Center (GMC) for PCI (transfer group) versus 75 patients in whom a pre-hospital ECG was obtained and who were transported by EMS directly to Geisinger for PCI, bypassing the nearest hospital that did not perform PCI (the pre-hospital ECG group). RESULTS: Analysis of baseline characteristics revealed that the pre-hospital ECG cohort was older (65 vs. 60 years); had a higher percentage of previous myocardial infarctions (MI) (28% vs. 15%), heart failure (11% vs. 4%), and prior PCI (23% vs. 13%; p < 0.05 all comparisons). Median time from EMS contact to pre-hospital ECG in the pre-hospital ECG group was 5 minutes; from pre-hospital ECG to the GMC ED was 34 minutes. Median time from first medical contact (EMS contact) to reperfusion (device activation) was 79 versus 157 minutes (P < 0.001), respectively in pre-hospital ECG vs. transfer groups. Mortality in the two groups at 1 year was 4.1% in the pre-hospital ECG group versus 8.3% in the transfer group (P-value = 0.34). After adjusting for the difference in age between the two groups, the 62% reduction in 1 year mortality associated with having obtained a pre-hospital ECG was still not statistically significant (P-value = 0.19). CONCLUSION: In a rural regional STEMI network, pre-hospital ECGs decreased time from first medical contact to reperfusion by 50% and were associated with an excellent clinical outcome at 1 year. © 2016 Wiley Periodicals, Inc.

The Potential of sGC Modulators for the Treatment of Age-Related Fibrosis: A Mini-Review.

Fibrotic diseases cause high rates of morbidity and mortality, and their incidence increases with age. Despite intense research and development efforts, effective and well-tolerated antifibrotic treatments are scarce. Transforming growth factor-ß signaling, which is widely considered the most important profibrotic factor, causes a pro-oxidant shift in redox homeostasis and a concomitant decrease in nitric oxide (NO) signaling. The NO/cyclic guanosine monophosphate (cGMP) signaling cascade plays a pivotal role in the regulation of cell and organ function in whole-body hemostasis. Increases in NO/cGMP can lead to relaxation of smooth muscle cells triggering vasorelaxation. In addition, there is consistent evidence from preclinical in vitro and in vivo models that increased cGMP also exerts antifibrotic effects. However, most of these findings are descriptive and the molecular pathways are still being investigated. Furthermore, in a variety of fibrotic diseases and also during the natural course of aging, NO/cGMP production is low, and current treatment approaches to increase cGMP levels might not be sufficient. The introduction of compounds that specifically target and stimulate soluble guanylate cyclase (sGC), the so called sGC stimulators and sGC activators, might be able to overcome these limitations and could be ideal tools for investigating antifibrotic mechanisms in vitro and in vivo as they may provide effective treatment strategies for fibrotic diseases. These drugs increase cGMP independently from NO via direct modulation of sGC activity, and have synergistic and additive effects to endogenous NO. This review article describes the NO/cGMP signaling pathway and its involvement in fibrotic remodeling. The classes of sGC modulator drugs and their mode of action are described. Finally, the preclinical in vitro and in vivo findings and antifibrotic effects of cGMP elevation via sGC modulation are reviewed. sGC stimulators and activators significantly attenuate tissue fibrosis in a variety of internal organs and in the skin. Moreover, these compounds seem to have multiple intervention sites and may reduce extracellular matrix formation, fibroblast proliferation, and myofibroblast activation. Thus, sGC stimulators and sGC activators may offer an efficacious and tolerable therapy for fibrotic diseases, and clinical trials are currently underway to assess the potential benefit for patients with systemic sclerosis.

Pre-treatment with P2Y12 inhibitors in ACS patients: who, when, why, and which agent?

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12receptor inhibitor is the mainstay of treatment for acute coronary syndrome (ACS) patients, whether they undergo a percutaneous coronary intervention (PCI) or are managed medically. In recent years, the most appropriate timing for initiation and duration of P2Y12receptor inhibition has been a focus of great interest. Many observational studies and a single prospective trial (CREDO) utilizing clopidogrel had focused on whether pre-treatment with clopidogrel, i.e. its administration upstream of coronary angiography and PCI, is beneficial. Although the rationale for pre-treatment is obvious, large-scale randomized trials supporting a pre-treatment strategy with clopidogrel or with the newer P2Y12inhibitors prasugrel and ticagrelor did not exist. Proponents of a pre-treatment strategy had to rely on their best guess, on non-randomized studies, or on negative studies in which a trend for a benefit had been demonstrated. Recently, however, two randomized trials directly evaluated the value of pre-treatment-one in patients with a non-STE elevation myocardial infarction (NSTEMI)-the Comparison of Prasugrel at the Time of Percutaneous Coronary Intervention or as Pretreatment at the Time of Diagnosis in Patients with Non-ST Elevation Myocardial Infarction (ACCOAST) trial, and a second trial evaluating the use of ticagrelor in ST-elevation myocardial infarction (STEMI) patients, the Administration of Ticagrelor in the Cath Lab or in the Ambulance for New ST-elevation myocardial Infarction to open the Coronary artery (ATLANTIC) trial. Neither of the two trials, however, answered all the questions clinicians have about pre-treatment. And given the recent approval of the intravenous and rapidly acting P2Y12inhibitor cangrelor, the choice of who should receive treatment with a P2Y12inhibitor, which one should be used, and when it should be administered, should be carefully re-evaluated for all patients. This clinical review aims at evaluating the available evidence regarding the value of pre-treatment with the now four available oral and intravenous P2Y12inhibitors that can be administered to patients in whom coronary angiography followed by a possible PCI is planned.

Dickkopf-3 regulates prostate epithelial cell acinar morphogenesis and prostate cancer cell invasion by limiting TGF-ß-dependent activation of matrix metalloproteases.

Dickkopf-3 (Dkk-3) is a secreted protein whose expression is downregulated in many types of cancer. Endogenous Dkk-3 is required for formation of acini in 3D cultures of prostate epithelial cells, where it inhibits transforming growth factor (TGF)-ß/Smad signaling. Here, we examined the effects of Dkk-3 on the expression and activity of matrix metalloproteases (MMPs), which mediate the effects of TGF-ß on extracellular matrix disassembly during tissue morphogenesis and promote invasion of tumor cells. Silencing of Dkk-3 in prostate epithelial cells resulted in increased expression and enzyme activity of MMP-2 and MMP-9. Inhibition of MMP-9 partially restored normal acinar morphogenesis in Dkk-3-silenced RWPE-1 prostate epithelial cells. In PC3 prostate cancer cells, Dkk-3 inhibited TGF-ß-dependent migration and invasion. Inhibition was mediated by the Dkk-3 C-terminal cysteine-rich domain (Cys2), which also inhibited TGF-ß-induced expression of MMP9 and MMP13. In contrast, Dkk-3, but not Cys2, increased formation of normal acini in Dkk-3-silenced prostate epithelial cells. These observations highlight a role for Dkk-3 in modulating TGF-ß/MMP signals in the prostate, and suggest that the Dkk-3 Cys2 domain can be used as a basis for therapies that target the tumor promoting effects of TGF-ß signaling in advanced prostate cancer.

Appending Limited Clinical Data to an Administrative Database for Acute Myocardial Infarction Patients: The Impact on the Assessment of Hospital Quality.

BACKGROUND: Hospitals' risk-standardized mortality rates and outlier status (significantly higher/lower rates) are reported by the Centers for Medicare and Medicaid Services (CMS) for acute myocardial infarction (AMI) patients using Medicare claims data. New York now has AMI claims data with blood pressure and heart rate added. OBJECTIVE: The objective of this study was to see whether the appended database yields different hospital assessments than standard claims data. METHODS: New York State clinically appended claims data for AMI were used to create 2 different risk models based on CMS methods: 1 with and 1 without the added clinical data. Model discrimination was compared, and differences between the models in hospital outlier status and tertile status were examined. RESULTS: Mean arterial pressure and heart rate were both significant predictors of mortality in the clinically appended model. The C statistic for the model with the clinical variables added was significantly higher (0.803 vs. 0.773, P<0.001). The model without clinical variables identified 10 low outliers and all of them were percutaneous coronary intervention hospitals. When clinical variables were included in the model, only 6 of those 10 hospitals were low outliers, but there were 2 new low outliers. The model without clinical variables had only 3 high outliers, and the model with clinical variables included identified 2 new high outliers. CONCLUSION: Appending even a small number of clinical data elements to administrative data resulted in a difference in the assessment of hospital mortality outliers for AMI. The strategy of adding limited but important clinical data elements to administrative datasets should be considered when evaluating hospital quality for procedures and other medical conditions.

Activators and stimulators of soluble guanylate cyclase counteract myofibroblast differentiation of prostatic and dermal stromal cells.

BACKGROUND: Fibrotic diseases encompass numerous systemic and organ-specific disorders characterized by the development and persistence of myofibroblasts. TGFß1 is considered the key inducer of fibrosis and drives myofibroblast differentiation in cells of diverse histological origin by a pro-oxidant shift in redox homeostasis associated with decreased nitric oxide (NO)/cGMP signaling. Thus, enhancement of NO/cGMP represents a potential therapeutic strategy to target myofibroblast activation and therefore fibrosis. METHODS: Myofibroblast differentiation was induced by TGFß1 in human primary prostatic (PrSCs) and normal dermal stromal cells (NDSCs) and monitored by α smooth muscle cell actin (SMA) and IGF binding protein 3 (IGFBP3) mRNA and protein levels. The potential of enhanced cGMP production by the sGC stimulator BAY 41-2272 or the sGC activator BAY 60-2770 to inhibit and revert myofibroblast differentiation in vitro was analyzed. Moreover, potential synergisms of BAY 41-2272 or BAY 60-2770 and inhibition of cGMP degradation by the PDE5 inhibitor vardenafil were investigated. RESULTS: BAY 41-2272 and BAY 60-2770 at doses of 30µM significantly inhibited induction of SMA and IGFBP3 levels in PrSCs and reduced myofibroblast marker levels in TGFß1-predifferentiated cells. At lower concentrations (3 and 10µM) only BAY 41-2272 but not BAY 60-2770 significantly inhibited and reverted myofibroblast differentiation. In NDSCs both substances significantly inhibited differentiation at all concentrations tested. Attenuation of SMA expression was more pronounced in NDSCs whereas reduction of IGFBP3 levels by BAY 41-2272 appeared more efficient in PrSCs. Moreover, administration of BAY 41-2272 or BAY 60-2770 enhanced the efficiency of the PDE5 inhibitor vardenafil to inhibit and revert myofibroblast differentiation in vitro. CONCLUSIONS: Increase of cGMP by sGC stimulation/activation significantly inhibited and reverted myofibroblast differentiation. This effect was even more pronounced when a combination treatment with a PDE5 inhibitor was applied. Thus, enhancement of NO/cGMP-signaling by sGC stimulation/activation is a promising strategy for the treatment of fibrotic diseases. Whereas, in NDSCs BAY 60-2770 and BAY 41-2272 exerted similar effects on myofibroblast differentiation, higher potency of BAY 41-2272 was observed in PrSCs, indicating phenotypical differences between fibroblasts form different organs that should be taken into account in the search for antifibrotic therapies.

Contemporary use of platelet function and pharmacogenomic testing among patients with acute myocardial infarction undergoing percutaneous coronary intervention in the United States.

BACKGROUND: Although platelet function and pharmacogenomic testing have been studied in clinical trials, their adoption into contemporary practice is unknown. METHODS: We studied patterns of platelet function and pharmacogenomic testing among 10,048 patients with acute myocardial infarction treated with percutaneous coronary intervention at 226 US hospitals in the TRANSLATE-ACS observational study between April 2010 and October 2012, excluding those receiving research protocol-mandated testing. Inverse probability-weighted propensity adjustment was used to compare 1-year bleeding and major adverse cardiac event risks between patients with and without testing. RESULTS: Overall, 337 (3.4%) patients underwent predischarge platelet function testing, whereas 85 (0.9%) underwent pharmacogenomic testing; 82% and 93% of hospitals never performed any platelet function or pharmacogenomic testing, respectively. Patients undergoing testing were more likely to be on an adenosine diphosphate receptor inhibitor preadmission or to have percutaneous coronary intervention of a previously treated lesion. Tested patients were more likely than nontested patients to be switched from clopidogrel to prasugrel/ticagrelor (25.7% vs 9.7%, P < .001) and were more likely to be on prasugrel/ticagrelor 6 months postdischarge (33.8% vs 25.1%, P < .001). No significant differences in 1-year bleeding and major adverse cardiac event risks were observed between tested and nontested patients (adjusted hazard ratios 1.06 [95% CI 0.68-1.65] and 1.21 [95% CI 0.94-1.54], respectively). CONCLUSIONS: Platelet function and pharmacogenomic testing are rarely performed in contemporary myocardial infarction patients in the United States. When tested, patients were more likely to be treated with higher-potency adenosine diphosphate receptor inhibitors, yet no significant differences in longitudinal outcomes were observed.

Stimulation of the soluble guanylate cyclase (sGC) inhibits fibrosis by blocking non-canonical TGFß signalling.

OBJECTIVES: We have previously described the antifibrotic role of the soluble guanylate cyclase (sGC). The mode of action, however, remained elusive. In the present study, we describe a novel link between sGC signalling and transforming growth factor ß (TGFß) signalling that mediates the antifibrotic effects of the sGC. METHODS: Human fibroblasts and murine sGC knockout fibroblasts were treated with the sGC stimulator BAY 41-2272 or the stable cyclic guanosine monophosphate (cGMP) analogue 8-Bromo-cGMP and stimulated with TGFß. sGC knockout fibroblasts were isolated from sGCI(fl/fl) mice, and recombination was induced by Cre-adenovirus. In vivo, we studied the antifibrotic effects of BAY 41-2272 in mice overexpressing a constitutively active TGF-ß1 receptor. RESULTS: sGC stimulation inhibited TGFß-dependent fibroblast activation and collagen release. sGC knockout fibroblasts confirmed that the sGC is essential for the antifibrotic effects of BAY 41-2272. Furthermore, 8-Bromo-cGMP reduced TGFß-dependent collagen release. While nuclear p-SMAD2 and 3 levels, SMAD reporter activity and transcription of classical TGFß target genes remained unchanged, sGC stimulation blocked the phosphorylation of ERK. In vivo, sGC stimulation inhibited TGFß-driven dermal fibrosis but did not change p-SMAD2 and 3 levels and TGFß target gene expression, confirming that non-canonical TGFß pathways mediate the antifibrotic sGC activity. CONCLUSIONS: We elucidated the antifibrotic mode of action of the sGC that increases cGMP levels, blocks non-canonical TGFß signalling and inhibits experimental fibrosis. Since sGC stimulators have shown excellent efficacy and tolerability in phase 3 clinical trials for pulmonary arterial hypertension, they may be further developed for the simultaneous treatment of fibrosis and vascular disease in systemic sclerosis.

Assessing hospital performance for acute myocardial infarction: how should emergency department transfers be attributed.

BACKGROUND: The Centers for Medicare and Medicaid Services publicly reports risk-standardized mortality rates (RSMRs) to assess quality of care for hospitals that treat acute myocardial infarction patients, and the outcomes for inpatient transfers are attributed to transferring hospitals. However, emergency department (ED) transfers are currently ignored and therefore attributed to receiving hospitals. METHODS: New York State administrative data were used to develop a statistical model similar to the one used by Centers for Medicare and Medicaid Services to risk-adjust hospital 30-day mortality rates. RSMRs were calculated and outliers were identified when ED transfers were attributed to: (1) the transferring hospital and (2) the receiving hospital. Differences in hospital outlier status and RSMR tertile between the 2 attribution methods were noted for hospitals performing and not performing percutaneous coronary interventions (PCIs). RESULTS: Although both methods of attribution identified 3 high outlier non-PCI hospitals, only 2 of those hospitals were identified by both methods, and each method identified a different hospital as a third outlier. Also, when transfers were attributed to the referring hospital, 1 non-PCI hospital was identified as a low outlier, and no non-PCI hospitals were identified as a low outlier with the other attribution method. About one sixth of all hospitals changed their tertile status. Most PCI hospitals (89%) that changed status moved to a higher (worse RSMR) tertile, whereas the majority of non-PCI hospitals (68%) that changed status were moved to a lower (better) RSMR tertile when ED transfers were attributed to the referring hospital. CONCLUSIONS: Hospital quality assessments for acute myocardial infarction are affected by whether ED transfers are assigned to the transferring or receiving hospital. The pros and cons of this choice should be considered.