09-23-1969 Correspondence from Harlan to Black

Dear Hugo: I am in favor of expediting consideration of this case as proposed in your memorandum. As presently advised however -- and certainly pending reciept of a response -- I would not favor a summary disposition of the case on the merits

10-28-1969 Correspondence from Harlan to Burger

Supplementing my earlier letter of today, I thought it might be convenient for you and the Brethren to have in unitary form the per curiam -order that would result from the proposals made in that letter. The following would eventuate

Blueprint for the Dissemination of Evidence-Based Practices in Health Care

Proposes strategies for better dissemination of best practices through quality improvement campaigns, including campaigns aligned with adopting organizations' goals, practical implementation tools and guides, and networks to foster learning opportunities

FLIP (Flice-like inhibitory protein) suppresses cytoplasmic double-stranded-RNA-induced apoptosis and NF-κB and IRF3-mediated signaling

<p>Abstract</p> <p>Background</p> <p>Cytoplasmic viral double-stranded RNA (dsRNA) is detected by a class of ubiquitous cytoplasmic RNA helicases, retinoic acid inducible gene-I (RIG-I) and melanoma differentiation antigen-5 (MDA5), which initiate a signaling cascade via their common adaptor called interferon-β (IFN-β) promoter stimulator-1 (IPS-1). This leads to the production of proinflammatory and antiviral cytokines, the type I Interferons, via mainly nuclear factor kappa B (NF-κB) and interferon response factor-3 (IRF3) transcription factors. Fas-associated death domain (FADD) protein, receptor-interacting protein (RIP1), caspase-8 and tumor necrosis factor receptor (TNFR)-associated death domain (TRADD) protein, all traditionally associated with death receptor signaling, are also involved in RIG-I/MDA5 signaling pathway. We previously showed that FLIP (Flice-like inhibitory protein), also designated as <it>cflar </it>(CASP8 and FADD-like apoptosis regulator), negatively regulates lipopolysaccharide (LPS)-induced toll-like receptor 4 (TLR4) signaling in endothelial cells and mouse embryonic fibroblasts (MEFs) and protected against TLR4-mediated apoptosis.</p> <p>Results</p> <p>In this study, we investigated the role of FLIP in cellular response to cytoplasmic polyinosinic:polycytidylic acid, poly(I:C), a synthetic analog of dsRNA. <it>C</it>onsistent with the previously described role of FADD in RIG-I/MDA5-mediated apoptosis, we found that FLIP^-/-MEFs were more susceptible to killing by cytoplasmic poly(I:C). However, FLIP^-/-MEFs also exhibited markedly increased expression of NF-κB-and IRF3- dependent genes in response to cytoplasmic poly(I:C). Importantly, reconstitution of FLIP in FLIP^-/-MEFs reversed the hyper-activation of IRF3- and NF-κB-mediated gene expression. Further, we found that caspase-8 catalytic activity was not required for cytoplasmic poly(I:C)-mediated NF-κB and IRF3 signaling.</p> <p>Conclusions</p> <p>These results provide evidence for a crucial dual role for FLIP in antiviral responses to cytoplasmic dsRNA: it protects from cytoplasmic dsRNA-mediated cell death while down-regulating IRF3-and NF-κB-mediated gene expression. Since the pathogenesis of several viral infections involves a heightened and dysregulated cytokine response, a possible therapy could involve modulating FLIP levels.</p

Investigation of 89 candidate gene variants for effects on all-cause mortality following acute coronary syndrome

BACKGROUND: Many candidate genes have been reported to be risk factors for acute coronary syndrome (ACS), but their impact on clinical prognosis following ACS is unknown. METHODS: We examined the association of putative genetic risk factors with 3-year post-ACS mortality in 811 ACS survivors at university-affiliated hospitals in Kansas City, Missouri. Through a systematic literature search, we first identified genetic variants reported as susceptibility factors for atherosclerosis or ACS. Restricting our analysis to whites, so as to avoid confounding from racial admixture, we genotyped ACS cases for 89 genetic variants in 72 genes, and performed individual Kaplan-Meier survival analyses. We then performed Cox regression to create multivariate risk prediction models that further minimized potential confounding. RESULTS: Of 89 variants tested, 16 were potentially associated with mortality (P < 0.1 for all), of which 6 were significantly associated (P < 0.05) with mortality following ACS. While these findings are not more than what would be expected by chance (P = 0.28), even after Bonferroni correction and adjustment for traditional cardiac risk factors, the IRS1 972Arg variant association (P = 0.001) retained borderline statistical significance (P < 0.1). CONCLUSION: With the possible exception of IRS1, we conclude that multiple candidate genes were not associated with post-ACS mortality in our patient cohort. Because of power limitations, the 16 gene variants with P values < 0.1 may warrant further study. Our data do not support the hypothesis that the remaining 73 genes have substantial, clinically significant association with mortality after an ACS

Contemporary evidence: baseline data from the D2B Alliance

© 2008 Bradley et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Acute Reperfusion Therapy in ST-elevation Myocardial Infarction from 1994-2003

Background—Appropriate utilization of acute reperfusion therapy is not a national performance measure for ST-elevation myocardial infarction at this time, and the extent of its contemporary use among ideal patients is unknown. Methods—From the National Registry of Myocardial Infarction, we identified 238,291 patients enrolled from June 1994 to May 2003 who were ideally suited for acute reperfusion therapy with fibrinolytic therapy or primary percutaneous coronary intervention. We determined rates of not receiving therapy across 3 time periods (June 1994–May 1997, June 1997–May 2000, June 2000– May 2003) and evaluated factors associated with underutilization. Results—The proportion of ideal patients not receiving acute reperfusion therapy decreased by one-half throughout the past decade (time period 1: 20.6%; time period 2: 11.4%; time period 3: 11.6%; P\u3c0.001). Utilization remained significantly lower in key subgroups in the most recent time period: those without chest pain (OR, 0.29; 95% CI, 0.27–0.32); those presenting 6 to 12 hours after symptom onset (OR, 0.57; 95% CI, 0.52–0.61); those 75 years or older (OR, 0.63 compared with patients \u3c55 years old; 95% CI, 0.58–0.68); women (OR, 0.88; 95% CI, 0.84–0.93); and non-whites (OR, 0.90; 95% CI, 0.83–0.97). Conclusions—Utilization of acute reperfusion therapy in ideal patients has improved over the last decade, but more than 10% remain untreated. Measuring and improving its use in this cohort represents an important opportunity to improve care

Depressive symptoms in younger women and men with acute myocardial infarction:Insights from the VIRGO Study

BACKGROUND: Depression was recently recognized as a risk factor for adverse medical outcomes in patients with acute myocardial infarction (AMI). The degree to which depression is present among younger patients with an AMI, the patient profile associated with being a young AMI patient with depressive symptoms, and whether relevant sex differences exist are currently unknown. METHODS AND RESULTS: The Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients (VIRGO) study enrolled 3572 patients with AMI (67.1% women; 2:1 ratio for women to men) between 2008 and 2012 (at 103 hospitals in the United States, 24 in Spain, and 3 in Australia). Information about lifetime history of depression and depressive symptoms experienced over the past 2 weeks (Patient Health Questionnaire; a cutoff score ≥10 was used for depression screening) was collected during index AMI admission. Information on demographics, socioeconomic status, cardiovascular risk, AMI severity, perceived stress (14‐item Perceived Stress Scale), and health status (Seattle Angina Questionnaire, EuroQoL 5D) was obtained through interviews and chart abstraction. Nearly half (48%) of the women reported a lifetime history of depression versus 1 in 4 in men (24%; P<0.0001). At the time of admission for AMI, more women than men experienced depressive symptoms (39% versus 22%, P<0.0001; adjusted odds ratio 1.64; 95% CI 1.36 to 1.98). Patients with more depressive symptoms had higher levels of stress and worse quality of life (P<0.001). Depressive symptoms were more prevalent among patients with lower socioeconomic profiles (eg, lower education, uninsured) and with more cardiovascular risk factors (eg, diabetes, smoking). CONCLUSIONS: A high rate of lifetime history of depression and depressive symptoms at the time of an AMI was observed among younger women compared with men. Depressive symptoms affected those with more vulnerable socioeconomic and clinical profiles