Using systems thinking-based risk assessment methods to assess hazardous manual tasks: a comparison of Net-HARMS, EAST-BL, FRAM and STPA.

Formal risk assessment is a component of safety management relating to hazardous manual tasks (HMT). Systems thinking approaches are currently gaining interest for supporting safety management. Existing HMT risk assessment methods have been found to be limited in their ability to identify risks across the whole work system; however, systems thinking-based risk assessment (STBRA) methods were not designed for the HMT context and have not been tested in this area. The aim of this study was to compare the performance of four state-of-the-art STBRA methods: Net-HARMS, EAST-BL, FRAM and STPA to determine which would be most useful for identifying HMT risks. Each method was independently applied by one of four analysts to assess the risks associated with a hypothetical HMT system. The outcomes were assessed for alignment with a benchmark analysis. Using signal detection theory (SDT), overall STPA was found to be the best performing method having the highest hit rate, second lowest false alarm rate and highest Matthews Correlation Coefficient of the four methods.Practitioner summary: A comparison of four systems thinking risk assessment methods found that STPA had the highest level of agreement with the benchmark analysis and is the most suitable for practitioners to use to identify the risks associated with HMT systems.

MAA868, a novel FXI antibody with a unique binding mode, shows durable effects on markers of anticoagulation in humans.

A large unmet medical need exists for safer antithrombotic drugs because all currently approved anticoagulant agents interfere with hemostasis, leading to an increased risk of bleeding. Genetic and pharmacologic evidence in humans and animals suggests that reducing factor XI (FXI) levels has the potential to effectively prevent and treat thrombosis with a minimal risk of bleeding. We generated a fully human antibody (MAA868) that binds the catalytic domain of both FXI (zymogen) and activated FXI. Our structural studies show that MAA868 traps FXI and activated FXI in an inactive, zymogen-like conformation, explaining its equally high binding affinity for both forms of the enzyme. This binding mode allows the enzyme to be neutralized before entering the coagulation process, revealing a particularly attractive anticoagulant profile of the antibody. MAA868 exhibited favorable anticoagulant activity in mice with a dose-dependent protection from carotid occlusion in a ferric chloride-induced thrombosis model. MAA868 also caused robust and sustained anticoagulant activity in cynomolgus monkeys as assessed by activated partial thromboplastin time without any evidence of bleeding. Based on these preclinical findings, we conducted a first-in-human study in healthy subjects and showed that single subcutaneous doses of MAA868 were safe and well tolerated. MAA868 resulted in dose- and time-dependent robust and sustained prolongation of activated partial thromboplastin time and FXI suppression for up to 4 weeks or longer, supporting further clinical investigation as a potential once-monthly subcutaneous anticoagulant therapy.

Stochastic online appointment scheduling of multi-step sequential procedures in nuclear medicine.

The increased demand for medical diagnosis procedures has been recognized as one of the contributors to the rise of health care costs in the U.S. in the last few years. Nuclear medicine is a subspecialty of radiology that uses advanced technology and radiopharmaceuticals for the diagnosis and treatment of medical conditions. Procedures in nuclear medicine require the use of radiopharmaceuticals, are multi-step, and have to be performed under strict time window constraints. These characteristics make the scheduling of patients and resources in nuclear medicine challenging. In this work, we derive a stochastic online scheduling algorithm for patient and resource scheduling in nuclear medicine departments which take into account the time constraints imposed by the decay of the radiopharmaceuticals and the stochastic nature of the system when scheduling patients. We report on a computational study of the new methodology applied to a real clinic. We use both patient and clinic performance measures in our study. The results show that the new method schedules about 600 more patients per year on average than a scheduling policy that was used in practice by improving the way limited resources are managed at the clinic. The new methodology finds the best start time and resources to be used for each appointment. Furthermore, the new method decreases patient waiting time for an appointment by about two days on average.

Evaluation of the pharmacodynamics and pharmacokinetics of the PARP inhibitor olaparib: a phase I multicentre trial in patients scheduled for elective breast cancer surgery.

Olaparib (AZD2281) is an oral poly(ADP-ribose) polymerase (PARP) inhibitor with antitumour activity in cancer patients with BRCA1/2 germline mutations and in patients with homologous recombination deficiency. In this dose-finding study, patients were randomized to olaparib 10, 30, 100, 200 or 400 mg (capsule formulation) twice daily for the 4-5 days preceding breast cancer surgery. The primary objective was to identify an effective biological dose of olaparib for future trials. Secondary endpoints included evaluation of PARP-1 inhibition dose/exposure-response, and safety. Olaparib plasma pharmacokinetics (PK) and the pharmacodynamics (PD) in tumour and peripheral blood mononuclear cells (PBMCs) were evaluated. Population PK/PD modelling was performed on pooled data from this study and a previously reported study. Sixty patients were randomized (n = 12, each dose). Dose-dependent increases in exposure to olaparib were observed, but at ~50 % lower plasma exposure levels than seen in advanced disease studies. The mean maximal extent of PARP inhibition in PBMCs and tumour tissue was 50.6 % and 70.0 %, respectively, and was similar to inhibitory levels reported previously. No PARP inhibition-dose relationship was observed. Due to the unexpectedly low olaparib exposure, we were unable to determine an effective biological dose. Common adverse events included procedural pain (n = 31 patients), nausea, asthenia, malaise and increased blood creatinine (n = 6, each); these were of mild-to-moderate intensity, and all were manageable. Despite low olaparib exposure, PARP inhibition was consistent with previous reports. Reasons for the inter-study differences in exposure are unclear. The tolerability profile of olaparib was consistent with previous studies.

Radiology leadership during a disaster event.

The trauma of a mass casualty event in Fort Hood, TX very quickly impacted the imaging departments of 3 healthcare facilities in central Texas. In the aftermath,there was an opportunity to reflect and learn. When a mass casualty event or disaster takes place, radiology administration needs to be visible, lead staff, manage media attention and law enforcement presence,all while maintaining a high level of quality patient care. Issues of particular concern are training, coping mechanisms, and the impact of leadership. Military and civilian healthcare facilities have different capabilities in terms of training and operations when it comes to managing such an event.

Pharmacokinetic profile of the fulvestrant loading dose regimen in postmenopausal women with hormone receptor-positive advanced breast cancer.

PURPOSE: Fulvestrant is at least as effective as anastrozole in the treatment of postmenopausal women with advanced breast cancer whose disease has previously progressed or recurred on antiestrogen therapy. Pharmacokinetic data have shown that, at the approved dose (250 mg/month), it takes approximately 3-6 months for fulvestrant to reach steady-state levels. Theoretically, a more rapid attainment of steady state might reduce the number of early progressions. A pharmacokinetic model simulating plasma concentrations expected to be achieved with a fulvestrant loading dose (LD) regimen suggested that steady state might be achieved earlier with the LD. The aim of this study was to characterize the pharmacokinetics of the fulvestrant LD regimen. This pharmacokinetic substudy was conducted within a phase III trial, EFECT (Evaluation of Fulvestrant versus Exemestane Clinical Trial), comparing fulvestrant with exemestane in postmenopausal women with hormone-sensitive advanced breast cancer whose disease had progressed or recurred following nonsteroidal aromatase inhibitor treatment. PATIENTS AND METHODS: Patients received fulvestrant intramuscularly using a LD regimen of 500 mg on day 0, 250 mg on days 14 and 28, and then 250 mg each month thereafter. Blood samples were collected throughout the first month and on day 28 of each subsequent month. Plasma fulvestrant concentrations were determined by highperformance liquid chromatography-mass spectrometry, and pharmacokinetic parameters were estimated with nonlinear mixed-effects modeling. RESULTS: Thirty-seven patients receiving fulvestrant were enrolled into the pharmacokinetic substudy, and 269 fulvestrant plasma concentrations were recorded. Maximum fulvestrant concentration (19.7 ng/mL) was observed at an average of 12 days within the first month and maintained at 12-15 ng/mL throughout the remainder of the dosing period. CONCLUSION: Steady-state plasma levels were attained within the first month of treatment with fulvestrant LD, in line with the predictions of the pharmacokinetic model.

Alkoxy- and amidocarbonylation of functionalised aryl and heteroaryl halides catalysed by a Bedford palladacycle and dppf: a comparison with the primary Pd(II) precursors (PhCN)2PdCl2 and Pd(OAc)2.

The versatility of a Bedford-type palladacycle , namely [{Pd(micro-Cl){kappa2-P,C-P(OC6H(2)-2,4-tBu2)(OC6H(3)-2,4-tBu2)2}}2], as a primary Pd source, in combination with the ligand bis-1,1'-(diphenylphosphino)ferrocene (dppf) has been established in carbonylation reactions of aryl and heteroaryl bromides with methanol, piperidine and related nucleophiles. Palladacycle has been compared with other primary Pd sources, e.g. (PhCN)2PdCl2 and Pd(OAc)2. The efficacy of the carbonylation processes appear to be linked to the [Pd] concentration, substrate : catalyst ratio, CO pressure and reaction temperature. In amidocarbonylation, double carbonylation is observed for certain organohalides. In the case of 2,5-dibromopyridine, regioselective amination (Hartwig-Buchwald type) also occurs as a side-reaction.

Pharmacokinetics of midazolam in neonates undergoing extracorporeal membrane oxygenation.

BACKGROUND: Although the pharmacokinetics of midazolam in critically ill children has been described, there are no such reports in extracorporeal membrane oxygenation. METHODS: The pharmacokinetics of midazolam and 1-hydroxy midazolam after continuous infusion (50-250 microg. kg(-1). h(-1)) were determined in 20 neonates undergoing extracorporeal membrane oxygenation. Patients were randomized into two groups: group 1 (n = 10) received midazolam extracorporeally (into the circuit), and group 2 received drug via central or peripheral access. Blood samples for determination of plasma concentrations were taken at baseline, 2, 4, 6, 12, 18, and 24 h, then every 12 h. Population pharmacokinetic analysis and model building was conducted using WinNonMix (Pharsight Corporation, Mountain View, CA). The 1-hydroxy midazolam/midazolam metabolic ratio was determined as a surrogate marker of cytochrome P450 3A activity. RESULTS: The parameter estimates (n = 19) were based on a one-compartment model with time-dependent change in volume of distribution. Volume (mean +/- standard error) expanded monoexponentially from the onset of extracorporeal membrane oxygenation to a maximum value, 0.8 l +/- 0.5 and 4.1 +/- 0.5 l/kg, respectively. Consequently, plasma half-life was substantially prolonged (median [range]) from onset to steady-state: 6.8 (2.2-39.8) and 33.3 (7.4-178) h, respectively. Total body clearance was determined as (mean +/- standard error) 1.4 +/- 0.15 ml. kg-1. min-1. The median metabolic ratio was 0.17 (0.03-0.9). No significant differences were observed between the two groups with respect to parameter estimates. Simulations of plasma concentration profiles revealed excess levels at conventional doses. CONCLUSIONS: These results reveal significantly increased volume of distribution and plasma half-life in neonates receiving extracorporeal membrane oxygenation. Altered kinetics may reflect sequestration of midazolam by components of the extracorporeal membrane oxygenation circuit.

In vitro neuronal and vascular responses to 5-hydroxytryptamine: modulation by 4-methylthioamphetamine, 4-methylthiomethamphetamine and 3,4-methylenedioxymethamphetamine.

4-Methylthioamphetamine and 4-methylthiomethamphetamine are thioarylethylamines structurally related to 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy'). This study compared effects of these agents and MDMA on 5-hydroxytryptamine (5-HT) signalling systems in the brain and vasculature in vitro. Both 4-methylthioamphetamine and 4-methylthiomethamphetamine (100 micro M) reduced the rate of specific high affinity [3H]5-HT reuptake in isolated rat brain synaptosomes to 14% and 10% of control, respectively. The concentration required for half-maximal inhibition (IC(50)) of [3H]5-HT reuptake by 4-methylthioamphetamine (0.27 micro M) was significantly lower (P<0.005) than that for inhibition by MDMA (1.28 micro M) and that for inhibition by 4-methylthiomethamphetamine (0.89 micro M). Both 4-MTA and 4-MTMA caused a significant release of preloaded [3H]5-HT from synaptosomes, but were significantly less effective than MDMA at the concentrations tested (1-100 micro M). In isolated rat aorta, a 15-min preincubation with 4-methylthioamphetamine or 4-methylthiomethamphetamine significantly reduced the maximal contraction (E(max)) induced by 5-HT to 71% or 91% of control (P<0.05 in each case), respectively. In addition, 4-methylthiomethamphetamine (100 micro M), but not 4-methylthioamphetamine, significantly increased the concentration of 5-HT required for half-maximal contraction (EC(50)) from 4.13 to 20.08 micro M (P<0.0001). In contrast, MDMA did not significantly alter the E(max) or the EC(50) of 5-HT-induced aortic contraction. It is concluded that both 4-methylthioamphetamine and 4-methylthiomethamphetamine are potent inhibitors of [3H]5-HT reuptake in the brain. Furthermore, unlike MDMA, they both directly inhibit 5-HT-mediated vascular contraction. These results suggest that these compounds may be potentially more harmful than MDMA in the context of human misuse.