The incidence of arthropathy adverse events in efalizumab-treated patients is low and similar to placebo and does not increase with long-term treatment: pooled analysis of data from Phase III clinical trials of efalizumab

A large-scale, pooled analysis of safety data from five Phase III clinical trials (including open-label extensions of two of these studies) and two Phase III open-label clinical trials of efalizumab was conducted to explore whether arthropathy adverse events (AEs) were associated with efalizumab treatment in patients with moderate-to-severe chronic plaque psoriasis. Data from patients who received subcutaneous injections of efalizumab or placebo were stratified for analysis into phases according to the nature and duration of treatment. These included: the ‘first treatment’ phase (0–12-week data from patients who received either efalizumab, 1 mg/kg once weekly, or placebo in the five placebo-controlled studies); the ‘extended treatment’ phase (13–24-week data from seven trials for all efalizumab-treated patients); and the ‘long-term treatment’ phase (data from efalizumab-treated patients who received treatment for up to 36 months in two long-term trials). Descriptive statistics were performed and the incidence of arthropathy AEs per patient-year was calculated using 95% confidence intervals (CIs). During the first treatment phase, a similar proportion of patients had an arthropathy AE in the efalizumab group (3.3%; 58/1740 patients) compared with the placebo group (3.5%; 34/979 patients); the incidence of arthropathy AEs per patient-year was 0.15 in the efalizumab group (95% CI 0.11–0.19) and 0.16 in the placebo group (95% CI 0.11–0.22). Analysis of first treatment phase data from one study (n = 793) showed that the incidence of psoriatic arthropathy per patient-year was lower in efalizumab-treated patients (0.10; 95% CI 0.05–0.18) than in those given placebo (0.17; 95% CI 0.08–0.30). During the extended treatment phase, the incidence of arthropathy remained low (0.17; 95% CI 0.14–0.22). Data from two long-term studies showed that there was no increase in the incidence of arthropathy AEs over time in patients treated with efalizumab for up to 36 months. Patients who had an arthropathy AE during treatment with efalizumab appeared to be more likely to have a history of arthropathy prior to treatment. Efalizumab does not appear to increase the risk of arthropathy AEs compared with placebo

Ab initio alpha-alpha scattering

Processes involving alpha particles and alpha-like nuclei comprise a major part of stellar nucleosynthesis and hypothesized mechanisms for thermonuclear supernovae. In an effort towards understanding alpha processes from first principles, we describe in this letter the first ab initio calculation of alpha-alpha scattering. We use lattice effective field theory to describe the low-energy interactions of nucleons and apply a technique called the adiabatic projection method to reduce the eight-body system to an effective two-cluster system. We find good agreement between lattice results and experimental phase shifts for S-wave and D-wave scattering. The computational scaling with particle number suggests that alpha processes involving heavier nuclei are also within reach in the near future.Comment: 6 pages, 6 figure

Chapter 10: Deciding Whether to Complement a Systematic Review of Medical Tests with Decision Modeling

Limited by what is reported in the literature, most systematic reviews of medical tests focus on “test accuracy” (or better, test performance), rather than on the impact of testing on patient outcomes. The link between testing, test results and patient outcomes is typically complex: even when testing has high accuracy, there is no guarantee that physicians will act according to test results, that patients will follow their orders, or that the intervention will yield a beneficial endpoint. Therefore, test performance is typically not sufficient for assessing the usefulness of medical tests. Modeling (in the form of decision or economic analysis) is a natural framework for linking test performance data to clinical outcomes. We propose that (some) modeling should be considered to facilitate the interpretation of summary test performance measures by connecting testing and patient outcomes. We discuss a simple algorithm for helping systematic reviewers think through this possibility, and illustrate it by means of an example

Lattice QCD at finite temperature: a status report

Karsch F. Lattice QCD at finite temperature: a status report. Zeitschrift für Physik, C: Particles and Fields. 1988;38(1-2):147-155.We analyze the status of numerical simulation of QCD at finite temperature. Emphasis is put on quantitative predictions emerging from lattice calculations that may be tested in heavy ion experiments. Recent results on the chiral phase transition, thermodynamics of the quark gluon plasma phase and various screening lengths are discussed. Presented at the 6th International Conference on Ultra-Relativistic Nucleus-Nucleus Collisions-Quark Matter 1987, 24–28 August 1987, Nordkirchen, Federal Republic of Germany

PIP5KIβ Selectively Modulates Apical Endocytosis in Polarized Renal Epithelial Cells

Localized synthesis of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] at clathrin coated pits (CCPs) is crucial for the recruitment of adaptors and other components of the internalization machinery, as well as for regulating actin dynamics during endocytosis. PtdIns(4,5)P2 is synthesized from phosphatidylinositol 4-phosphate by any of three phosphatidylinositol 5-kinase type I (PIP5KI) isoforms (α, β or γ). PIP5KIβ localizes almost exclusively to the apical surface in polarized mouse cortical collecting duct cells, whereas the other isoforms have a less polarized membrane distribution. We therefore investigated the role of PIP5KI isoforms in endocytosis at the apical and basolateral domains. Endocytosis at the apical surface is known to occur more slowly than at the basolateral surface. Apical endocytosis was selectively stimulated by overexpression of PIP5KIβ whereas the other isoforms had no effect on either apical or basolateral internalization. We found no difference in the affinity for PtdIns(4,5)P2-containing liposomes of the PtdIns(4,5)P2 binding domains of epsin and Dab2, consistent with a generic effect of elevated PtdIns(4,5)P2 on apical endocytosis. Additionally, using apical total internal reflection fluorescence imaging and electron microscopy we found that cells overexpressing PIP5KIβ have fewer apical CCPs but more internalized coated structures than control cells, consistent with enhanced maturation of apical CCPs. Together, our results suggest that synthesis of PtdIns(4,5)P2 mediated by PIP5KIβ is rate limiting for apical but not basolateral endocytosis in polarized kidney cells. PtdIns(4,5)P2 may be required to overcome specific structural constraints that limit the efficiency of apical endocytosis. © 2013 Szalinski et al

The Impact of Duty Hours on Resident Self Reports of Errors

BACKGROUND: Resident duty hour limitations aim, in part, to reduce medical errors. Residents’ perceptions of the impact of duty hours on errors are unknown. OBJECTIVE: To determine residents’ self-reported contributing factors, frequency, and impact of hours worked on suboptimal care practices and medical errors. DESIGN: Cross-sectional survey. SUBJECTS: 164 Internal Medicine Residents at the University of California, San Francisco. MEASUREMENTS AND RESULTS: Residents were asked to report the frequency and contributing factors of suboptimal care practices and medical errors, and how duty hours impacted these practices and aspects of resident work-life. One hundred twenty-five residents (76%) responded. The most common suboptimal care practices were working while impaired by fatigue and forgetting to transmit information during sign-out. In multivariable models, residents who felt overwhelmed with work (p = 0.02) and who reported spending >50% of their time in nonphysician tasks (p = 0.002) were more likely to report suboptimal care practices. Residents reported work-stress (a composite of fatigue, excessive workload, distractions, stress, and inadequate time) as the most frequent contributing factor to medical errors. In multivariable models, only engaging in suboptimal practices was associated with self-report of higher risk for medical errors (p < 0.001); working more than 80 hours per week was not associated with suboptimal care or errors. CONCLUSION: Our findings suggest that administrative load and work stressors are more closely associated with resident reports of medical errors than the number of hours work. Efforts to reduce resident duty hours may also need to address the nature of residents’ work to reduce errors

Residents' perceptions of a night float system

Background. A Night Float (NF) system has been implemented by many institutions to address increasing concerns about residents' work hours. The purpose of our study was to examine the perceptions of residents towards a NF system. Methods. A 115-item questionnaire was developed to assess residents' perceptions of the NF rotation as compared with a regular call month. The categories included patient care, education, medical errors, and overall satisfaction. Internal Medicine housestaff (post-graduate years 1-3) from three hospital settings at the University of Pittsburgh completed the questionnaire. Results. The response rate was 90% (n = 149). Of these, 74 had completed the NF rotation. The housestaff felt that the quality of patient care was improved because of NF (41% agreed and 18% disagreed). A majority also felt that better care was provided by a rested physician in spite of being less familiar with the patient (46% agreed and 21% disagreed). Most felt that there was less emphasis on education (65%) and more emphasis on service (52%) during NF. Overall, the residents felt more rested during their call months (83%) and strongly supported the 80-hour workweek requirement (77%). Conclusion. Housestaff felt that the overall quality of patient care was improved by a NF system. The perceived improved quality of care by a rested physician coupled with a perceived decrease in the emphasis on education may have significant implications in housestaff training. © 2009 Jasti et al; licensee BioMed Central Ltd

Frontal-to-Parietal Top-Down Causal Streams along the Dorsal Attention Network Exclusively Mediate Voluntary Orienting of Attention

Previous effective connectivity analyses of functional magnetic resonance imaging (fMRI) have revealed dynamic causal streams along the dorsal attention network (DAN) during voluntary attentional control in the human brain. During resting state, however, fMRI has shown that the DAN is also intrinsically configured by functional connectivity, even in the absence of explicit task demands, and that may conflict with effective connectivity studies. To resolve this contradiction, we performed an effective connectivity analysis based on partial Granger causality (pGC) on event-related fMRI data during Posner's cueing paradigm while optimizing experimental and imaging parameters for pGC analysis. Analysis by pGC can factor out exogenous or latent influences due to unmeasured variables. Typical regions along the DAN with greater activation during orienting than withholding of attention were selected as regions of interest (ROIs). pGC analysis on fMRI data from the ROIs showed that frontal-to-parietal top-down causal streams along the DAN appeared during (voluntary) orienting, but not during other, less-attentive and/or resting-like conditions. These results demonstrate that these causal streams along the DAN exclusively mediate voluntary covert orienting. These findings suggest that neural representations of attention in frontal regions are at the top of the hierarchy of the DAN for embodying voluntary attentional control

Anti-tumour activity and toxicity of the new prodrug9-aminocamptothecin glucuronide (9ACG) in mice

Cancer chemotherapy is limited by the modest therapeutic index of most antineoplastic drugs. Some glucuronide prodrugs may display selective anti-tumour activity against tumours that accumulate β-glucuronidase. We examined the toxicity and anti-tumour activity of 9-aminocamptothecin glucuronide, a new glucuronide prodrug of 9-aminocamptothecin, to evaluate its potential clinical utility. 9-aminocamptothecin glucuronide was 25–60 times less toxic than 9-aminocamptothecin to five human cancer cell lines. β-glucuronidase activated 9-aminocamptothecin glucuronide to produce similar cell killing as 9-aminocamptothecin or topotecan. The in vivo toxicity of 9-aminocamptothecin glucuronide in BALB/c mice was dose-, route-, sex- and age-dependent. 9-aminocamptothecin glucuronide was significantly less toxic to female than to male mice but the difference decreased with age. 9-aminocamptothecin glucuronide and 9-aminocamptothecin produced similar inhibition (∼80%) of LS174T human colorectal carcinoma tumours. 9-aminocamptothecin glucuronide cured a high percentage of CL1-5 human lung cancer xenografts with efficacy that was similar to or greater than 9-aminocamptothecin, irinotecan and topotecan. The potent anti-tumour activity of 9-aminocamptothecin glucuronide suggests that this prodrug should be further evaluated for cancer treatment

Preconditioning Involves Selective Mitophagy Mediated by Parkin and p62/SQSTM1

Autophagy-dependent mitochondrial turnover in response to cellular stress is necessary for maintaining cellular homeostasis. However, the mechanisms that govern the selective targeting of damaged mitochondria are poorly understood. Parkin, an E3 ubiquitin ligase, has been shown to be essential for the selective clearance of damaged mitochondria. Parkin is expressed in the heart, yet its function has not been investigated in the context of cardioprotection. We previously reported that autophagy is required for cardioprotection by ischemic preconditioning (IPC). In the present study, we used simulated ischemia (sI) in vitro and IPC of hearts to investigate the role of Parkin in mediating cardioprotection ex vivo and in vivo. In HL-1 cells, sI induced Parkin translocation to mitochondria and mitochondrial elimination. IPC induced Parkin translocation to mitochondria in Langendorff-perfused rat hearts and in vivo in mice subjected to regional IPC. Mitochondrial depolarization with an uncoupling agent similarly induced Parkin translocation to mitochondria in cells and Langendorff-perfused rat hearts. Mitochondrial loss was blunted in Atg5-deficient cells, revealing the requirement for autophagy in mitochondrial elimination. Consistent with previous reports indicating a role for p62/SQSTM1 in mitophagy, we found that depletion of p62 attenuated mitophagy and exacerbated cell death in HL-1 cardiomyocytes subjected to sI. While wild type mice showed p62 translocation to mitochondria and an increase in ubiquitination, Parkin knockout mice exhibited attenuated IPC-induced p62 translocation to the mitochondria. Importantly, ablation of Parkin in mice abolished the cardioprotective effects of IPC. These results reveal for the first time the crucial role of Parkin and mitophagy in cardioprotection