Regionalization of ST-segment elevation acute coronary syndromes care: putting a national policy in proper perspective.

A uniform policy for regionalization of ST-segment elevation myocardial infarction (STEMI) care raises several concerns. Transferring all STEMI patients to obtain primary percutaneous coronary intervention (PCI) may be less effective than transferring only high-risk STEMI patients. Delays in time to treatment >60 min associated with transferring patients for primary PCI may result in increased mortality for the average patient as compared with providing immediate fibrinolytic therapy at their initial hospital; yet more than 95% of patients transferred for primary PCI in the U.S. exceed this 60-min benchmark. Superior outcomes associated with treatment at higher-volume regional STEMI centers are inconsistent among centers, and there is no direct evidence that patients will benefit by a transfer to a high-volume hospital from a low-volume hospital. Published data suggest as many as 800 PCI patients would need to be transferred to a high-volume PCI hospital to avoid a single death at a low-volume PCI hospital. Although European randomized trial data suggest transferring patients with STEMI for primary PCI may be superior to immediate fibrinolytic therapy, these findings are unlikely to generalize to the U.S. health care system given size, geography, and organization. ST segment elevation myocardial infarction care regionalization would require a massive redistribution of health care resources, depriving several hospitals of advanced cardiac care facilities, expertise, and associated revenue. Clearer evidence of the benefits and discussion of potential harms are needed before adopting a national STEMI regionalization policy.     

Spontaneous perforation of the ureter diagnosed on technetium 99m DTPA excretory urography

A case of nontraumatic rupture of the ureter secondary to a nonopaque calculus is presented. Because of the inherent high image contrast caused by the leak of technetium 99m-DTPA-labeled urine, the technetium 99m DTPA excretory urogram is seen as an alternative to the intravenous urogram or contrast-enhanced computed tomography in selected cases of suspected ureteral rupture.     

Cardiac glycosides. 7. Sugar stereochemistry and cardiac glycoside activity

Digitoxigenin alpha-L-, beta-L-, alpha-D-, and beta-D-glucosides; alpha-L-, beta-L-, alpha-D-, and beta-D-mannosides; and alpha-L- and beta-L-rhamnosides were stereoselectively synthesized from the corresponding sugar tetrabenzyl trichloroacetimidates. The Na+,K+-ATPase receptor inhibitory activities of these glycosides (as a measure of receptor binding) were compared with those of digitoxigenin, digitoxigenin 6'-hydroxy-beta-D-digitoxoside, digitoxigenin beta-D-galactoside, and digitoxigenin beta-D-digitoxoside. The observed activities reveal that a given sugar substituent may have a role in binding of some glycoside stereoisomers, but not others. With alpha-L- and possibly beta-L-rhamnosides, the 5'-CH3 and 4'-OH appear to have a predominant role in binding to the Na+,K+-ATPase receptor. Addition of a 6'-OH to form the corresponding mannosides dramatically disrupts the effect of both the 5'-CH3 and 4'-OH in prompting receptor binding of the alpha-L isomer. However, with the beta-L isomer, some influence of 4'-OH, 3'-OH, and 2'-OH binding remains. With beta-D-glycosides, binding via the "5'-CH3 site" appears to be of little importance and addition of a 6'-OH diminishes activity only slightly. With these beta-D-glycosides, an equatorial 4'-OH, axial 3'-OH, and equatorial 2'-OH groups appear to contribute to binding.     

Sociodemographic Patterns of Exclusive,Dual, and Polytobacco Use Among U.S. High School Students: A Comparison of Three Nationally Representative Surveys

PurposeThis study examines sociodemographic patterns of exclusive/dual/polytobacco use among U.S. high school students using multiple national surveys.MethodsUsing three national youth surveys (Population Assessment of Tobacco and Health [PATH] Wave 4 [2016–2017], 2017 Youth Risk Behavior Survey, and 2017 National Youth Tobacco Survey), we classified tobacco products into four groups: (1) electronic nicotine delivery systems (ENDS), (2) conventional cigarettes (CCs), (3) other combustible tobacco products, and (4) smokeless tobacco products. We created 16 categories of non/exclusive/dual/polytobacco use within the past 30 days using the four product groups and calculated weighted population prevalence by sex and race/ethnicity (all surveys) and parental education and income (PATH), based on variable availability.ResultsThe results from 9,331, 12,407, and 9,699 high school students in PATH, Youth Risk Behavior Survey, and National Youth Tobacco Survey, respectively, largely agreed and pointed to similar conclusions. ENDS was the most prevalent exclusive use product (3.8%–5.2% across surveys), with CCs falling to second or third (1.2%–2.0% across surveys). By sex, exclusive, dual, and poly smokeless tobacco product use were more common for males, whereas exclusive CC use was more common for females. By race/ethnicity, non-Hispanic Whites had a higher prevalence of exclusive ENDS use and ENDS/CC dual use than non-Hispanic Blacks. As income and parental education levels increased from low to high, the prevalence of exclusive CC use decreased, whereas the prevalence of exclusive ENDS use increased.ConclusionUnderstanding sociodemographic patterns of tobacco use can help identify groups who may be at greater risk for tobacco-related health outcomes.     

A framework for considering the risk‐benefit trade‐off in designing noninferiority trials using composite outcome approaches

When a new treatment regimen is expected to have comparable or slightly worse efficacy to that of the control regimen but has benefits in other domains such as safety and tolerability, a noninferiority (NI) trial may be appropriate but is fraught with difficulty in justifying an acceptable NI margin that is based on both clinical and statistical input. To overcome this, we propose to utilize composite risk‐benefit outcomes that combine elements from domains of importance (eg, efficacy, safety, and tolerability). The composite outcome itself may be analyzed using a superiority framework, or it can be used as a tool at the design stage of a NI trial for selecting an NI margin for efficacy that balances changes in risks and benefits. In the latter case, the choice of NI margin may be based on a novel quantity called the maximum allowable decrease in efficacy (MADE), defined as the marginal difference in efficacy between arms that would yield a null treatment effect for the composite outcome given an assumed distribution for the composite outcome. We observe that MADE: (1) is larger when the safety improvement for the experimental arm is larger, (2) depends on the association between the efficacy and safety outcomes, and (3) depends on the control arm efficacy rate. We use a numerical example for power comparisons between a superiority test for the composite outcome vs a noninferiority test for efficacy using the MADE as the NI margin, and apply the methods to a TB treatment trial.     

Expression of adhesion molecules in B-cell chronic lymphocytic leukaemia: an analysis in lymphoid compartments--peripheral blood, bone marrow and lymph node

The trafficking or homing of different lymphoid subsets to particular microenvironment is mediated by specific cell adhesion molecules (CAMs) expressed on lymphocytes and endothelial cells. B-cell chronic lymphocytic leukaemia (B-CLL) or Non-Hodgkin's lymphoma of small lymphocytic, B-cell type are monoclonal expansions of mature lymphocytes. The relative distribution of the tumor lymphocytes among various lymphoid compartments vary from patient to patient. Very few studies underlying this issue are available. To this effect, we have analysed the expression of LFA-1; VLA-4, ICAM-1; CD44H and CD44v6 (haematopoietic and variant form respectively) on freshly isolated lymphocytes obtained from bone marrow (BM), peripheral blood (PB) and lymph node (LN) by flow cytometry. Overall, we find strong expression of CD44H, low to moderate expression of LFA-1, negative to low expression of VLA-4 and lack of expression of CD44v6. ICAM-1 expression was observed only in patients with prominent lymphadenopathy. Higher expression of CD44H in PB lymphoid cells relative to that of BM lymphoid cells correlated with higher PB lymphocytosis (p < 0.001). Proliferating cell nuclear antigen expression in LN sections correlated inversely with VLA-4 expression on BM and PB lymphoid cells (p < 0.05). There was no significant correlation between expression of CAMs and bcl-2 protein.     

Nucleoside analogs plus ritonavir in stable antiretroviral therapy-experienced HIV-infected children: a randomized controlled trial. Pediatric AIDS Clinical Trials Group 338 Study Team

CONTEXT: Although protease inhibitors are used routinely in adults with human immunodeficiency virus (HIV) infection, the role of these drugs in the treatment of clinically stable HIV-infected children is not clear. OBJECTIVE: To evaluate the safety, tolerance, and virologic response produced by a change in antiretroviral therapy in HIV-infected children who were clinically and immunologically stable while receiving previous therapy. DESIGN: The Pediatric AIDS Clinical Trials Group 338, a multicenter, phase 2, randomized, open-label controlled trial conducted from February 6 to April 30, 1997 (patient entry period); patients were followed up for 48 weeks. SETTING: Pediatric HIV research clinics in the United States and Puerto Rico. PATIENTS: Two hundred ninety-seven antiretroviral-experienced, protease inhibitor-naive, clinically stable HIV-infected children aged 2 to 17 years. INTERVENTIONS: Children were randomized to receive zidovudine, 160 mg/m2 3 times per day, plus lamivudine, 4 mg/kg 2 times per day (n = 100); the same regimen plus ritonavir, 350 mg/m2 2 times per day (n = 100); or ritonavir, 350 mg/m2 2 times per day, and stavudine, 4 mg/kg 2 times per day (n = 97). MAIN OUTCOME MEASURE: Plasma HIV-1 RNA levels at study weeks 12 and 48, compared among the 3 treatment groups. RESULTS: At study week 12, 12% of patients in the zidovudine-lamivudine group had undetectable plasma HIV RNA levels (<400 copies/mL) compared with 52% and 54% of patients in the 2- and 3-drug ritonavir-containing groups, respectively (P<.001). Through study week 48, 70% of children continued receiving their ritonavir-containing regimen. At study week 48, 42% of children receiving ritonavir plus 2 nucleosides compared with 27% of those receiving ritonavir and a single nucleoside had undetectable HIV RNA levels (P = .04); however, similar proportions in each group continuing initial therapy had HIV RNA levels of less than 10000 copies/mL (58% vs 48%, respectively; P = .19). CONCLUSIONS: In our study, change in antiretroviral therapy to a ritonavir-containing regimen was associated with superior virologic response at study week 12 compared with change to a dual nucleoside analog regimen. More children receiving ritonavir in combination with 2 compared with 1 nucleoside analog had undetectable HIV RNA levels at study week 48.     

GLI inhibitor GANT-61 diminishes embryonal and alveolar rhabdomyosarcoma growth by inhibiting Shh/AKT-mTOR axis

Rhabdomyosarcoma (RMS) typically arises from skeletal muscle. Currently, RMS in patients with recurrent and metastatic disease have no successful treatment. The molecular pathogenesis of RMS varies based on cancer sub-types. Some embryonal RMS but not other sub-types are driven by sonic hedgehog (Shh) signaling pathway. However, Shh pathway inhibitors particularly smoothened inhibitors are not highly effective in animals. Here, we show that Shh pathway effectors GLI1 and/or GLI2 are over-expressed in the majority of RMS cells and that GANT-61, a specific GLI1/2 inhibitor dampens the proliferation of both embryonal and alveolar RMS cells-derived xenograft tumors thereby blocking their growth. As compared to vehicle-treated control, about 50% tumor growth inhibition occurs in mice receiving GANT-61 treatment. The proliferation inhibition was associated with slowing of cell cycle progression which was mediated by the reduced expression of cyclins D1/2/3 & E and the concomitant induction of p21. GANT-61 not only reduced expression of GLI1/2 in these RMS but also significantly diminished AKT/mTOR signaling. The therapeutic action of GANT-61 was significantly augmented when combined with chemotherapeutic agents employed for RMS therapy such as temsirolimus or vincristine. Finally, reduced expression of proteins driving epithelial mesenchymal transition (EMT) characterized the residual tumors.     

Multimodality Imaging of Submitral Left Ventricular Aneurysm

Submitral left ventricular aneurysms are a rare nonischemic aneurysm thought to be developmental in origin. These aneurysms invariably occur at the site of posterior mitral annulus and lead to mitral valve incompetence. We hereby describe a case of a 30‐year‐old adult with a rare form of submitral left ventricular aneurysm involving whole of the posterior mitral annulus. Multimodality imaging with two‐dimensional echocardiography, three‐dimensional echocardiography, computed tomography and invasive left ventriculography helped the patient to undergo successful resection of the aneurysm along with mitral valve replacement.