Decisive role of nuclear quantum effects on surface mediated water dissociation at finite temperature

Water molecules adsorbed on inorganic substrates play an important role in several technological applications. In the presence of light atoms in adsorbates, nuclear quantum effects (NQE) influence properties of these systems. In this work, we explore the impact of NQE on the dissociation of water wires on stepped Pt(221) surfaces. By performing ab initio molecular dynamics simulations with van der Waals corrected density functional theory, we note that several competing minima for both intact and dissociated structures are accessible at finite temperatures, making it important to assess whether harmonic estimates of the quantum free energy are sufficient to determine the relative stability of the different states. We perform ab initio path integral molecular dynamics (PIMD) in order to calculate these contributions taking into account conformational entropy and anharmonicities at finite temperatures. We propose that when when adsorption is weak and NQE on the substrate are negligible, PIMD simulations can be performed through a simple partition of the system, resulting in considerable computational savings. We calculate the contribution of NQE to the free energies, including anharmonic terms. We find that they result in an increase of up to 20% of the quantum contribution to the dissociation free energy compared to harmonic estimates. We also find that the dissociation has a negligible contribution from tunneling, but is dominated by ZPE, which can enhance the rate by three orders of magnitude. Finally we highlight how both temperature and NQE indirectly impact dipoles and the redistribution of electron density, causing work function to changes of up to 0.4 eV with respect to static estimates. This quantitative determination of the change in work function provides a possible approach to determine experimentally the most stable configurations of water oligomers on the stepped surfaces

Efficacy and safety of once-monthly Risperidone ISM ® in schizophrenic patients with an acute exacerbation

Funding: This study was funded by Laboratorios Farmacéuticos Rovi, S.A. Madrid, Spain. It was supported also in part by a grant from Center for the Development of Industrial Technology (Expedient No. IDI-20160109).To evaluate the efficacy and safety of Risperidone ISM ® against placebo in patients with acute exacerbation of schizophrenia. A multicenter, randomized, double-blind, placebo-controlled study was conducted between June 2017 and December 2018 (NCT03160521). Eligible patients received once-monthly intramuscular injections of Risperidone ISM ® (75 or 100 mg) or placebo for 12 weeks. The primary efficacy outcome was change in Positive and Negative Syndrome Scale (PANSS) total score from baseline to week 12. The key secondary efficacy outcome was change from baseline in Clinical Global Impressions-Severity of Illness scale (CGI-S) score. Altogether, 438 patients were randomized (1:1:1) and 390 included in the modified ITT efficacy set. The PANSS total score (mean difference, 95% CI) improved significantly from baseline to day 85 with Risperidone ISM ® 75 and 100 mg, with placebo-adjusted differences of −13.0 (95% CI, −17.3 to −8.8); (p < 0.0001), and −13.3 (−17.6 to −8.9); (p < 0.0001), respectively. Significantly improved mean changes were also obtained for CGI-S score from baseline to day 85 for both doses of Risperidone ISM ® compared with placebo −0.7 (−1.0 to −0.5); p < 0.0001, for both doses. The statistically significant improvement for both efficacy outcomes were observed as early as 8 days after first injection. The most frequently reported treatment-emergent adverse events were increased blood prolactin (7.8%), headache (7.3%), hyperprolactinemia (5%), and weight increase (4.8%). Neither new nor unexpected relevant safety information was recorded. Risperidone ISM ® provided rapid and progressive reduction of symptoms in patients with acutely exacerbated schizophrenia without need of oral risperidone supplementation or loading doses. Both doses were safe and well tolerated

Missing Data Frequency and Correlates in Two Randomized Surgical Trials for Urinary Incontinence in Women

INTRODUCTION AND HYPOTHESIS: Missing data is frequently observed in clinical trials; high rates of missing data may jeopardize trial outcome validity. PURPOSE: We determined the rates of missing data over time, by type of data collected and compared demographic and clinical factors associated with missing data among women who participated in two large randomized clinical trials of surgery for stress urinary incontinence, the Stress Incontinence Surgical Treatment Efficacy Trial (SISTEr) and the Trial of Midurethral Sling (TOMUS). METHODS: The proportions of subjects who attended and missed each follow-up visit were calculated. The chi-squared test, Fisher\u27s exact test and t test were used to compare women with and without missing data, as well as the completeness of the data for each component of the composite primary outcome. RESULTS: Data completeness for the primary outcome computation in the TOMUS trial (62.3%) was nearly double that in the SISTEr trial (35.7%). The follow-up visit attendance rate decreased over time. A higher proportion of subjects attended all follow-up visits in the TOMUS trial and overall there were fewer missing data for the period that included the primary outcome assessment at 12 months. The highest levels of complete data for the composite outcome variables were for the symptoms questionnaire (SISTEr 100 %, TOMUS 99.8%) and the urinary stress test (SISTEr 96.1%, TOMUS 96.7%). In both studies, the pad test was associated with the lowest levels of complete data (SISTEr 85.1%, TOMUS 88.3%) and approximately one in ten subjects had incomplete voiding diaries at the time of primary outcome assessment. Generally, in both studies, a higher proportion of younger subjects had missing data. This analysis lacked a patient perspective as to the reasons for missing data that could have provided additional information on subject burden, motivations for adherence and study design. In addition, we were unable to compare the effects of the different primary outcome assessment time-points in an identically designed trial. CONCLUSIONS: Missing visits and data increased with time. Questionnaire data and physical outcome data (urinary stress test) that could be assessed during a visit were least prone to missing data, whereas data for variables that required subject effort while away from the research team (pad test, voiding diary) were more likely to be missing. Older subjects were more likely to provide complete data

A window of opportunity for abatacept in RA: is disease duration an independent predictor of low disease activity/remission in clinical practice?

The objective of the study was to examine whether disease duration independently predicts treatment response among biologic-naive patients with rheumatoid arthritis (RA) initiating abatacept in clinical practice. Using the Corrona RA registry (February 2006-January 2015), biologic-naive patients with RA initiating abatacept with 12-month (+/-3 months) follow-up and assessment of disease activity (Clinical Disease Activity Index [CDAI]) at initiation and at 12 months were identified. The primary outcome was mean change in CDAI (DeltaCDAI) from baseline to 12 months. Secondary outcomes at 12 months included achievement of low disease activity (LDA; CDAI 10 years, n = 79). Increased disease duration was associated with older age (p = 0.047), and the median number of prior conventional disease-modifying antirheumatic drugs used was lowest in the 0- to 2-year duration group (p \u3c 0.001). Mean DeltaCDAI (SE) ranged from -10.22 (1.19) for 0-2 years to -4.63 (1.38) for \u3e 10 years. In adjusted analyses, shorter disease duration was significantly associated with greater mean DeltaCDAI (p = 0.015) and greater likelihood of achieving LDA (p = 0.048). In biologic-naive patients with RA initiating abatacept, earlier disease (shorter disease duration) was associated with greater DeltaCDAI and likelihood of achieving LDA

A window of opportunity for abatacept in RA: is disease duration an independent predictor of low disease activity/remission in clinical practice

The objective of the study was to examine whether disease duration independently predicts treatment response among biologic-naive patients with rheumatoid arthritis (RA) initiating abatacept in clinical practice. Using the Corrona RA registry (February 2006-January 2015), biologic-naive patients with RA initiating abatacept with 12-month (+/-3 months) follow-up and assessment of disease activity (Clinical Disease Activity Index [CDAI]) at initiation and at 12 months were identified. The primary outcome was mean change in CDAI (DeltaCDAI) from baseline to 12 months. Secondary outcomes at 12 months included achievement of low disease activity (LDA; CDAI 10 years, n = 79). Increased disease duration was associated with older age (p = 0.047), and the median number of prior conventional disease-modifying antirheumatic drugs used was lowest in the 0- to 2-year duration group (p \u3c 0.001). Mean DeltaCDAI (SE) ranged from -10.22 (1.19) for 0-2 years to -4.63 (1.38) for \u3e 10 years. In adjusted analyses, shorter disease duration was significantly associated with greater mean DeltaCDAI (p = 0.015) and greater likelihood of achieving LDA (p = 0.048). In biologic-naive patients with RA initiating abatacept, earlier disease (shorter disease duration) was associated with greater DeltaCDAI and likelihood of achieving LDA

Use of peptide antibodies to probe for the mitoxantrone resistance-associated protein MXR/BCRP/ABCP/ABCG2

AbstractRecent studies have characterized the ABC half-transporter associated with mitoxantrone resistance in human cancer cell lines. Encoded by the ABCG2 gene, overexpression confers resistance to camptothecins, as well as to mitoxantrone. We developed four polyclonal antibodies against peptides corresponding to four different epitopes on the mitoxantrone resistance-associated protein, ABCG2. Three epitopes localized on the cytoplasmic region of ABCG2 gave rise to high-affinity antibodies, which were demonstrated to be specific for ABCG2. Western blot analysis of cells with high levels of ABCG2 showed a single major band of the expected 72-kDa molecular size of ABCG2 under denaturing conditions. Immunoblot analysis performed under non-reducing conditions and after treatment with cross-linking reagents demonstrated a molecular weight shift from 72 kDa to several bands of 180 kDa and higher molecular weight, suggesting detection of dimerization products of ABCG2. Evidence of N-linked glycosylation was also obtained using tunicamycin and N-glycosidase F. Finally, both by light, fluorescence and electron microscopic immunohistochemical staining, we demonstrate cytoplasmic and predominantly plasma membrane localization of ABCG2 in cell lines with high levels of expression. Plasma membrane staining was observed on the surface of the chorionic villi in placenta. These results support the hypothesis that ABCG2 is an ABC half-transporter that forms dimers in the plasma membrane, functioning as an ATP-dependent outward pump for substrate transport

BMQ

BMQ: Boston Medical Quarterly was published from 1950-1966 by the Boston University School of Medicine and the Massachusetts Memorial Hospitals