Proarrhythmic proclivity of left-stellate ganglion stimulation in a canine model of drug-induced long-QT syndrome type 1

Background Left-stellate ganglion stimulation (LSGS) can modify regional dispersion of ventricular refractoriness, promote triggered activity, and reduce the threshold for ventricular fibrillation (VF). Sympathetic hyperactivity precipitates torsades de pointes (TdP) and VF in susceptible patients with long-QT syndrome type 1 (LQT1). We investigated the electromechanical effects of LSGS in a canine model of drug-induced LQT1, gaining novel arrhythmogenic insights. Methods In nine mongrel dogs, the left and right stellate ganglia were exposed for electrical stimulation. ECG, left- and right-ventricular endocardial monophasic action potentials (MAPs) and pressures (LVP, RVP) were recorded. The electromechanical window (EMW; Q to LVP at 90% relaxation minus QT interval) was calculated. LQT1 was mimicked by infusion of the KCNQ1/IKs blocker HMR1556. Results At baseline, LSGS and right-stellate ganglion stimulation (RSGS) caused similar heart-rate acceleration and QT shortening. Positive inotropic and lusitropic effects were more pronounced under LSGS than RSGS. IKs blockade prolonged QTc, triggered MAP-early afterdepolarizations (EADs) and rendered the EMW negative, but no ventricular tachyarrhythmias occurred. Superimposed LSGS exaggerated EMW negativity and evoked TdP in 5/9 dogs within 30 s. Preceding extrasystoles originated mostly from the outflow-tracts region. TdP deteriorated into therapy-refractory VF in 4/5 animals. RSGS did not provoke TdP/VF. Conclusions In this model of drug-induced LQT1, LSGS readily induced TdP and VF during repolarization prolongation and MAP-EAD generation, but only if EMW turned from positive to very negative. We postulate that altered mechano-electric coupling can exaggerate regional dispersion of refractoriness and facilitates ventricular ectopy

2001 AAPP Monograph Series

The African American Professors Program (AAPP) at the University of South Carolina is pleased to produce this premier edition of its annual monograph series. It is fitting that the program assume a leadership role in promoting scholarly products that will prove to be useful in future research efforts by faculty and students in higher education. Scholars who have contributed manuscripts for this monograph are to be commended for adding this additional responsibility to their academic workload. Writing across disciplines adds to the intellectual diversity of these papers. From neophytes, relatively speaking, to an array of very experienced individuals, the chapters have been researched and, comprehensively, written. AAPP was created in 1997 under the leadership of Drs. Aretha B. Pigford and Leonard 0. Pellicer, Department of Educational Leadership and Policies. It was designed to address the underrepresentation of African American professors on college and university campuses. Its mission is to expand the pool of these professors in critical academic and research areas. Sponsored by the University of South Carolina, the W. K. Kellogg Foundation, and the South Carolina General Assembly, the program recruits students with bachelor\u27s, master\u27s, and doctoral degrees for disciplines in which African Americans, currently, are underrepresented. An important component of the program is the mentoring experience that is provided. Each student is assigned to a mentor professor who guides the student through a selected academic program and provides various learning experiences. When possible, the mentor serves as chair of the student\u27s doctoral committee. The mentor, also, provides opportunities for the student to team teach, conduct research, and co-author publications. Students have opportunities to attend committee, faculty, and professional meetings, as well as engage in a range of activities that characterize professional life in academia. Scholars enrolled in the program, also, are involved in programmatic and institutional workshops, independent research, and program development. The establishment or genesis of this monograph series is seen as responding to an opportunity to be sensitive to an academic expectation of graduates as they pursue career placement and, also, one that allows for the dissemination of AAPP products to a broader community. We hope that you, likewise, will read this premier monograph of the African American Professors Program with enthusiasm or enlightenment. John McFadden, Ph.D. The Benjamin Elijah Mays Professor Director, African American Professors Program University of South Carolinahttps://scholarcommons.sc.edu/mcfadden_monographs/1005/thumbnail.jp

2002 AAPP Monograph Series: African American Professors Program

The African American Professors Program (AAPP) at the University of South Carolina is pleased to produce the second edition of its annual monograph series. It is fitting that the program contrives to assume a leadership role in promoting scholarly products that prove to be useful in research endeavors by faculty and students in higher education. Scholars who have contributed manuscripts for this monograph are to be commended for adding this additional responsibility to their academic workload. Writing across disciplines adds to the intellectual diversity of these papers. From neophytes, relatively speaking, to an array of very experienced individuals, the chapters have been researched and comprehensively written. Founded in 1997 through the Department of Educational Leadership and Policies in the College of Education, AAPP was designed to address the underrepresentation of African American professors on college and university campuses. Its mission is to expand the pool of these professors in critical academic and research areas. Sponsored by the University of South Carolina, the W.K. Kellogg Foundation, and the South Carolina General Assembly, the program recruits students with bachelor\u27s, master\u27s, and doctoral degrees for disciplines in which African Americans, currently, are underrepresented. An important component of the program is the mentoring experience that is provided. Each student is assigned to a mentor professor who guides the student through a selected academic program and provides various learning experiences. When possible, the mentor serves as chair of the student\u27s doctoral committee. The mentor, also, provides opportunities for the student to team teach, conduct research, and co-author publications. Students have opportunities to attend committee, faculty, and professional meetings, as well as to engage in a range of activities that characterize professional life in academia. Scholars enrolled in the program also are involved in programmatic and institutional workshops, independent research, and program development. The continuation of this monograph series is seen as responding to an opportunity to be sensitive to an academic expectation of graduates as they pursue career placement and, also, one that allows for the dissemination of AAPP products to a broader community. We hope that you will read this monograph of the African American Professors Program with enthusiasm or enlightenment. John McFadden, Ph.D. The Benjamin Elijah Mays Professor Director, African American Professors Program University of South Carolinahttps://scholarcommons.sc.edu/mcfadden_monographs/1000/thumbnail.jp

Phase 2 Study of Dabrafenib Plus Trametinib in Patients With BRAF V600E-Mutant Metastatic NSCLC:Updated 5-Year Survival Rates and Genomic Analysis

Introduction: Dabrafenib plus trametinib was found to have robust antitumor activity in patients with BRAF V600E-mutant metastatic NSCLC (mNSCLC). We report updated survival analysis of a phase 2 study (NCT01336634) with a minimum of 5-year follow-up and updated genomic data. Methods: Pretreated (cohort B) and treatment-naive (cohort C) patients with BRAF V600E-mutant mNSCLC received dabrafenib 150 mg twice daily and trametinib 2 mg once daily. The primary end point was investigator-assessed overall response rate per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points were duration of response, progression-free survival, overall survival, and safety. Results: At data cutoff, for cohorts B (57 patients) and C (36 patients), the median follow-up was 16.6 (range: 0.5–78.5) and 16.3 (range: 0.4–80) months, overall response rate (95% confidence interval [CI]) was 68.4% (54.8–80.1) and 63.9% (46.2–79.2), median progression-free survival (95% CI) was 10.2 (6.9–16.7) and 10.8 (7.0–14.5) months, and median overall survival (95% CI) was 18.2 (14.3–28.6) and 17.3 (12.3–40.2) months, respectively. The 4- and 5-year survival rates were 26% and 19% in pretreated patients and 34% and 22% in treatment-naive patients, respectively. A total of 17 patients (18%) were still alive. The most frequent adverse event was pyrexia (56%). Exploratory genomic analysis indicated that the presence of coexisting genomic alterations might influence clinical outcomes in these patients; however, these results require further investigation. Conclusions: Dabrafenib plus trametinib therapy was found to have substantial and durable clinical benefit, with a manageable safety profile, in patients with BRAF V600E-mutant mNSCLC, regardless of previous treatment

CT colonography with limited bowel preparation for the detection of colorectal neoplasia in an FOBT positive screening population

Item does not contain fulltextPURPOSE: Aim was to evaluate the accuracy of computed tomography colonography (CTC) for detection of colorectal neoplasia in a Fecal Occult Blood Test (FOBT) positive screening population. METHODS: In three different institutions, consecutive FOBT positives underwent CTC after laxative free iodine tagging bowel preparation followed by colonoscopy with segmental unblinding. Each CTC was read by two experienced observers. For CTC and for colonoscopy the per-polyp sensitivity and per-patient sensitivity and specificity were calculated for detection of carcinomas, advanced adenomas, and adenomas. RESULTS: In total 22 of 302 included FOBT positive participants had a carcinoma (7%) and 137 had an adenoma or carcinoma >/=10 mm (45%). CTC sensitivity for carcinoma was 95% with one rectal carcinoma as false negative finding. CTC sensitivity for advanced adenomas was 92% (95% CI: 88-96) vs. 96% (95% CI: 93-99) for colonoscopy (P = 0.26). For adenomas and carcinomas >/=10 mm the CTC per-polyp sensitivity was 93% (95% CI: 89-97) vs. 97% (95% CI: 94-99) for colonoscopy (P = 0.17). The per-patient sensitivity for the detection of adenomas and carcinomas >/=10 mm was 95% (95% CI: 91-99) for CTC vs. 99% (95% CI: 98-100) for colonoscopy (P = 0.07), while the per-patient specificity was 90% (95% CI: 86-95) and 96% (95% CI: 94-99), respectively (P < 0.001). CONCLUSION: CTC with limited bowel preparation performed in an FOBT positive screening population has high diagnostic accuracy for the detection of adenomas and carcinomas and a sensitivity similar to that of colonoscopy for relevant lesions.1 december 201

Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015: a population-level modelling analysis

Background: Infections due to antibiotic-resistant bacteria are threatening modern health care. However, estimating their incidence, complications, and attributable mortality is challenging. We aimed to estimate the burden of infections caused by antibiotic-resistant bacteria of public health concern in countries of the EU and European Economic Area (EEA) in 2015, measured in number of cases, attributable deaths, and disability-adjusted life-years (DALYs). Methods: We estimated the incidence of infections with 16 antibiotic resistance–bacterium combinations from European Antimicrobial Resistance Surveillance Network (EARS-Net) 2015 data that was country-corrected for population coverage. We multiplied the number of bloodstream infections (BSIs) by a conversion factor derived from the European Centre for Disease Prevention and Control point prevalence survey of health-care-associated infections in European acute care hospitals in 2011–12 to estimate the number of non-BSIs. We developed disease outcome models for five types of infection on the basis of systematic reviews of the literature. Findings: From EARS-Net data collected between Jan 1, 2015, and Dec 31, 2015, we estimated 671 689 (95% uncertainty interval [UI] 583 148–763 966) infections with antibiotic-resistant bacteria, of which 63·5% (426 277 of 671 689) were associated with health care. These infections accounted for an estimated 33 110 (28 480–38 430) attributable deaths and 874 541 (768 837–989 068) DALYs. The burden for the EU and EEA was highest in infants (aged <1 year) and people aged 65 years or older, had increased since 2007, and was highest in Italy and Greece. Interpretation: Our results present the health burden of five types of infection with antibiotic-resistant bacteria expressed, for the first time, in DALYs. The estimated burden of infections with antibiotic-resistant bacteria in the EU and EEA is substantial compared with that of other infectious diseases, and has increased since 2007. Our burden estimates provide useful information for public health decision-makers prioritising interventions for infectious diseases

Pervasive melt percolation reactions in ultra-depleted refractory harzburgites at the Mid-Atlantic Ridge, 15° 20′N : ODP Hole 1274A

Author Posting. © The Authors, 2006. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Contributions to Mineralogy and Petrology 153 (2007): 303-319, doi:10.1007/s00410-006-0148-6.ODP Leg 209 Site 1274 mantle peridotites are highly refractory in terms of lack of residual clinopyroxene, olivine Mg# (up to 0.92) and spinel Cr# (~0.5), suggesting high degree of partial melting (>20%). Detailed studies of their microstructures show that they have extensively reacted with a pervading intergranular melt prior to cooling in the lithosphere, leading to crystallization of olivine, clinopyroxene and spinel at the expense of orthopyroxene. The least reacted harzburgites are too rich in orthopyroxene to be simple residues of low-pressure (spinel field) partial melting. Cu-rich sulfides that precipitated with the clinopyroxenes indicate that the intergranular melt was generated by no more than 12% melting of a MORB mantle or by more extensive melting of a clinopyroxene-rich lithology. Rare olivine-rich lherzolitic domains, characterized by relics of coarse clinopyroxenes intergrown with magmatic sulfides, support the second interpretation. Further, coarse and intergranular clinopyroxenes are highly depleted in REE, Zr and Ti. A two-stage partial melting/melt-rock reaction history is proposed, in which initial mantle underwent depletion and refertilization after an earlier high pressure (garnet field) melting event before upwelling and remelting beneath the present-day ridge. The ultra-depleted compositions were acquired through melt re-equilibration with residual harzburgites.Funding for this research was provided by Centre National de la Recherche Scientifique-Institut National des Sciences de l’Univers (Programme Dynamique et Evolution de la Terre Interne)

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

The effect of temperature on growth and competition between Sphagnum species

Peat bogs play a large role in the global sequestration of C, and are often dominated by different Sphagnum species. Therefore, it is crucial to understand how Sphagnum vegetation in peat bogs will respond to global warming. We performed a greenhouse experiment to study the effect of four temperature treatments (11.2, 14.7, 18.0 and 21.4°C) on the growth of four Sphagnum species: S. fuscum and S. balticum from a site in northern Sweden and S. magellanicum and S. cuspidatum from a site in southern Sweden. In addition, three combinations of these species were made to study the effect of temperature on competition. We found that all species increased their height increment and biomass production with an increase in temperature, while bulk densities were lower at higher temperatures. The hollow species S. cuspidatum was the least responsive species, whereas the hummock species S. fuscum increased biomass production 13-fold from the lowest to the highest temperature treatment in monocultures. Nutrient concentrations were higher at higher temperatures, especially N concentrations of S. fuscum and S. balticum increased compared to field values. Competition between S. cuspidatum and S. magellanicum was not influenced by temperature. The mixtures of S. balticum with S. fuscum and S. balticum with S. magellanicum showed that S. balticum was the stronger competitor, but it lost competitive advantage in the highest temperature treatment. These findings suggest that species abundances will shift in response to global warming, particularly at northern sites where hollow species will lose competitive strength relative to hummock species and southern species