High Temperature Electron Localization in dense He Gas

We report new accurate mesasurements of the mobility of excess electrons in high density Helium gas in extended ranges of temperature $[(26\leq T\leq 77) K ]$ and density $[ (0.05\leq N\leq 12.0) {atoms} \cdot {nm}^{-3}]$ to ascertain the effect of temperature on the formation and dynamics of localized electron states. The main result of the experiment is that the formation of localized states essentially depends on the relative balance of fluid dilation energy, repulsive electron-atom interaction energy, and thermal energy. As a consequence, the onset of localization depends on the medium disorder through gas temperature and density. It appears that the transition from delocalized to localized states shifts to larger densities as the temperature is increased. This behavior can be understood in terms of a simple model of electron self-trapping in a spherically symmetric square well.Comment: 23 pages, 13 figure

Mobility of O2−_2^- ions in supercritical Ar: Experiment and Molecular Dynamics Simulations

A new analysis and new Molecular Dynamics (MD) simulations of the measurements of the mobility $\mu_{i}$ of O$_{2}^{-}$ ions in dense supercritical Ar gas are reported. $\mu_{i}$ shows a marked dependence on the distance from the critical temperature $T_{c}.$ A mobility defect appears as a function of the gas density and its maximum value occurs below the critical density. The locus of points of maximum mobility defect in the $P-T$ plane appears on the extrapolation of the coexistence curve into the single-phase region. MD simulations quantitatively reproduce the mobility defect near $T_{c}.$Comment: 7 pages, 6 figures, submitted to International Journal of Mass Spectrometry, issue in honor of E. Illenberge

Chemical exposure and infant leukaemia: development of an adverse outcome pathway (AOP) for aetiology and risk assessment research

Infant leukaemia (<1 year old) is a rare disease of an in utero origin at an early phase of foetal development. Rearrangements of the mixed-lineage leukaemia (MLL) gene producing abnormal fusion proteins are the most frequent genetic/molecular findings in infant B cell-acute lymphoblastic leukaemia. In small epidemiological studies, mother/foetus exposures to some chemicals including pesticides have been associated with infant leukaemia; however, the strength of evidence and power of these studies are weak at best. Experimental in vitro or in vivo models do not sufficiently recapitulate the human disease and regulatory toxicology studies are unlikely to capture this kind of hazard. Here, we develop an adverse outcome pathway (AOP) based substantially on an analogous disease\u2014secondary acute leukaemia caused by the topoisomerase II (topo II) poison etoposide\u2014and on cellular and animal models. The hallmark of the AOP is the formation of MLL gene rearrangements via topo II poisoning, leading to fusion genes and ultimately acute leukaemia by global (epi)genetic dysregulation. The AOP condenses molecular, pathological, regulatory and clinical knowledge in a pragmatic, transparent and weight of evidence-based framework. This facilitates the interpretation and integration of epidemiological studies in the process of risk assessment by defining the biologically plausible causative mechanism(s). The AOP identified important gaps in the knowledge relevant to aetiology and risk assessment, including the specific embryonic target cell during the short and spatially restricted period of susceptibility, and the role of (epi)genetic features modifying the initiation and progression of the disease. Furthermore, the suggested AOP informs on a potential Integrated Approach to Testing and Assessment to address the risk caused by environmental chemicals in the future

Risk factors for Luminal A ductal carcinoma in situ (DCIS) and invasive breast cancer in the Carolina Breast Cancer Study

Purpose Invasive breast cancers are thought to arise from in situ lesions, but some ductal carcinoma in situ (DCIS) are indolent with low likelihood of progressing to invasive carcinoma. Comparison of risk factor associations between DCIS and invasive disease may elucidate which factors influence early versus late stages of carcinogenesis. Therefore, we determined whether there were differences in risk factor profiles for screen-detected DCIS and invasive breast cancer among Luminal A lesions. Methods We conducted a case-control analysis using data from the Carolina Breast Cancer Study (1993-2001). Analyses were restricted to Luminal A tumors and screen-detected tumors among mammography-eligible women, to limit confounding by mode of detection (N = 108 DCIS; N = 203 invasive). Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between risk factors and lesion type. Results In stratified analyses, we observed qualitative differences in the direction of association for ever smoking, obese BMI, high waist-To-hip-ratio (WHR), and ?10 years of oral contraceptive use between DCIS and invasive disease. Breastfeeding was inversely associated with invasive disease and was not associated with DCIS. Interaction tests for risk factor associations between Luminal A DCIS and invasive breast cancer were not statistically significant (p>0.05). Conclusions Among Luminal A tumors, established breast cancer risk factors may exert stronger effects on progression of early lesions to invasive disease, with lesser effects on risk of DCIS

Confirming the bidirectional nature of the association between severe hypoglycemic and cardiovascular events in type 2 diabetes: Insights from Exscel

OBJECTIVE We sought to confirm a bidirectional association between severe hypoglycemic events (SHEs) and cardiovascular (CV) event risk and to characterize individuals at dual risk. RESEARCH DESIGN AND METHODS In a post hoc analysis of 14,752 Exenatide Study of Cardiovascular Event Lowering (EXSCEL) participants, we examined time-dependent associations between SHEs and subsequent major adverse cardiac events (CV death, nonfatal myocardial infarction [MI] or stroke), fatal/nonfatal MI, fatal/nonfatal stroke, hospitalization for acute coronary syndrome (hACS), hospitalization for heart failure (hHF), and all-cause mortality (ACM), as well as time-dependent associations between nonfatal CV events and subsequent SHEs. RESULTS SHEs were uncommon and not associated with once-weekly exenatide therapy (hazard ratio 1.13 [95% CI 0.94–1.36], P 5 0.179). In fully adjusted models, SHEs were associated with an increased risk of subsequent ACM (1.83 [1.38–2.42], P < 0.001), CV death (1.60 [1.11–2.30], P 5 0.012), and hHF (2.09 [1.37–3.17], P 5 0.001), while nonfatal MI (2.02 [1.35–3.01], P 5 0.001), nonfatal stroke (2.30 [1.25–4.23], P 5 0.007), hACS (2.00 [1.39–2.90], P < 0.001), and hHF (3.24 [1.98–5.30], P < 0.001) were all associated with a subsequent increased risk of SHEs. The elevated bidirectional time-dependent hazards linking SHEs and a composite of all CV events were approximately constant over time, with those individuals at dual risk showing higher comorbidity scores compared with those without. CONCLUSIONS These findings, showing greater risk of SHEs after CV events as well as greater risk of CV events after SHEs, validate a bidirectional relationship between CV events and SHEs in patients with high comorbidity scores

Clinical Outcomes in Patients with Type 2 Diabetes Mellitus and Peripheral Artery Disease: Results from the EXSCEL Trial

Background: Recent trials have identified anti-diabetes mellitus agents that lower major adverse cardiovascular event (MACE) rates, although some increase rates of lower-extremity amputation (LEA). Patients with peripheral artery disease (PAD) have greater incidence of diabetes mellitus and risk for LEA, prompting this investigation of clinical outcomes in patients with diabetes mellitus and PAD in the EXSCEL trial (Exenatide Study of Cardiovascular Event Lowering). Methods: EXSCEL evaluated the effects of once-weekly exenatide (a GLP-1 [glucagon-like peptide-1] receptor agonist) versus placebo on the rates of the primary composite MACE end point (cardiovascular death, myocardial infarction, or stroke) among patients with type 2 diabetes mellitus. In this post hoc analysis, we assessed the association of baseline PAD with rates of MACE, LEA, and the effects of exenatide versus placebo in patients with and without PAD. Results: EXSCEL included 2800 patients with PAD (19% of the trial population). These individuals had higher unadjusted and adjusted rates of MACE compared with patients without PAD (13.6% versus 11.4%, respectively) as well as a higher adjusted hazard ratio (adjusted hazard ratio, 1.13 [95% CI, 1.00-1.27]; P=0.047). Patients with PAD had higher all-cause mortality (adjusted hazard ratio 1.38 [95% CI, 1.20-1.60]; P<0.001) and more frequent LEA (adjusted hazard ratio 5.48 [95% CI, 4.16-7.22]; P<0.001). Patients treated with exenatide or placebo had similar rates of MACE and LEA, regardless of PAD status. Conclusions: EXSCEL participants with PAD had higher rates of all-cause mortality and LEA compared with those without PAD. There were no differences in MACE or LEA rates with exenatide versus placebo. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT01144338

Evading the CKM Hierarchy: Intrinsic Charm in B Decays

We show that the presence of intrinsic charm in the hadrons' light-cone wave functions, even at a few percent level, provides new, competitive decay mechanisms for B decays which are nominally CKM-suppressed. For example, the weak decays of the B-meson to two-body exclusive states consisting of strange plus light hadrons, such as B\to\pi K, are expected to be dominated by penguin contributions since the tree-level b\to s u\bar u decay is CKM suppressed. However, higher Fock states in the B wave function containing charm quark pairs can mediate the decay via a CKM-favored b\to s c\bar c tree-level transition. Such intrinsic charm contributions can be phenomenologically significant. Since they mimic the amplitude structure of ``charming'' penguin contributions, charming penguins need not be penguins at all.Comment: 28 pages, 6 figures, published version. References added, minor change

Exploring the Possible Impact of Unbalanced Open-Label Drop-In of Glucose-Lowering Medications on EXSCEL Outcomes

Background: EXSCEL (Exenatide Study of Cardiovascular Event Lowering) assessed the impact of once-weekly exenatide 2 mg versus placebo in patients with type 2 diabetes mellitus, while aiming for glycemic equipoise. Consequently, greater drop-in of open-label glucose-lowering medications occurred in the placebo group. Accordingly, we explored the potential effects of their unbalanced use on major adverse cardiovascular events (MACE), defined as cardiovascular death, nonfatal myocardial infarction or nonfatal stroke, and all-cause mortality (ACM), given that some of these agents are cardioprotective. Methods: Cox hazard models were performed by randomized treatment for drug classes where >5% open-label drop-in glucose-lowering medication occurred, and for glucagon-like peptide-1 receptor agonists (GLP-1 RAs; 3.0%) using three methodologies: drop-in visit right censoring, inverse probability for treatment weighting (IPTW), and applying drug class risk reductions. Results: Baseline glucose-lowering medications for the 14 752 EXSCEL participants (73.1% with previous cardiovascular disease) did not differ between treatment groups. During median 3.2 years follow-up, open-label drop-in occurred in 33.4% of participants, more frequently with placebo than exenatide (38.1% versus 28.8%), with metformin (6.1% versus 4.9%), sulfonylurea (8.7% versus 6.9%), dipeptidyl peptidase-4 inhibitors (10.6% versus 7.5%), SGLT-2i (10.3% versus 8.1%), GLP-1 RA (3.4% versus 2.4%), and insulin (13.8% versus 9.4%). The MACE effect size was not altered meaningfully by right censoring, but the favorable HR for exenatide became nominally significant in the sulfonylurea and any glucose-lowering medication groups, while the ACM HR and p-values were essentially unchanged. IPTW decreased the MACE HR from 0.91 (P=0.061) to 0.85 (P=0.008) and the ACM HR from 0.86 (P=0.016) to 0.81 (P=0.012). Application of literature-derived risk reductions showed no meaningful changes in MACE or ACM HRs or P values, although simulations of substantially greater use of drop-in cardioprotective glucose-lowering agents demonstrated blunting of signal detection. Conclusions: EXSCEL-observed HRs for MACE and ACM remained robust after right censoring or application of literature-derived risk reductions, but the exenatide versus placebo MACE effect size and statistical significance were increased by IPTW. Effects of open-label drop-in cardioprotective medications need to be considered carefully when designing, conducting, and analyzing cardiovascular outcome trials of glucose-lowering agents under the premise of glycemic equipoise. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01144338