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Purpose To examine the ablation zone, muscle contractions, and temperature increases in both rabbit liver and kidney models in vivo for a custom-made high-frequency irreversible electroporation (H-FIRE) generator. Materials and Methods A total of 18 New Zealand white rabbits were used to investigate five H-FIRE protocols (n = 3 for each protocol) and an IRE protocol (n = 3) for the performance of the designed H-FIRE device in both liver and kidney tissues. The ablation zone was determined by using histological analysis 72 h after treatment. The extent of muscle contractions and temperature change during the application of pulse energy were measured by a commercial accelerometer attached to animals and fiber optic temperature probe inserted into organs with IRE electrodes, respectively. Results All H-FIRE protocols were able to generate visible ablation zones without muscle contractions, for both liver and kidney tissues. The area of ablation zone generated in H-FIRE pulse protocols (e.g., 0.3–1 μs, 2000 V, and 90–195 bursts) appears similar to that of IRE protocol (100 μs, 1000 V, and 90 pulses) in both liver and kidney tissues. No significant temperature increase was noticed except for the protocol with the highest pulse energy (e.g., 1 μs, 2000 V, and 180 bursts). Conclusion Our work serves to complement the current H-FIRE pulse waveforms, which can be optimized to significantly improve the quality of ablation zone in terms of precision for liver and kidney tumors in clinical setting.

This paper designs a parameter-dependent self-adaption integral sliding mode controller which converges the system in a finite time while focusing on an uncertain linear parameter varying (LPV) model of a variant aircraft that has a large-scale variation of the sweep angle and an extension. This design promotes the robustness and L2 performance of the aircraft's speed and altitude during the variant process. According to the longitudinal nonlinear model of a morphing aircraft obtained by the KANE method, the LPV model with the stretch and the sweep angle as the time-varying parameters is derived, and then, the equivalent linear time-invariant (LTI) system is obtained by the linear fractional representation (LFR). Furthermore, the state feedback LFR-H∞ controller has deduced from the linear matrix inequality (LMI) constraints, and then, the existing conditions of the integral sliding mode are obtained from the pole assignment. There are significant uncertainties and disturbances when the linear controller acts on the nonlinear system. Therefore, an adaptive algorithm is introduced to further improve the robustness of the integral sliding mode controller. Moreover, a parameter-dependent Lyapunov function analysis shows that the designed adaptive integral sliding mode control rate can converge the LPV system trajectories to the integral sliding mode surface in a finite time. The comparative simulation results of the nonlinear model of the morphing aircraft indicate the robustness and effectiveness of this approach. The method designed in this paper can be extended to general LPV systems.

Background: Up to 30% of people infected with SARS-CoV-2 report disabling symptoms 2 years after the infection. Over 100 persistent symptoms have been associated with Post-Acute COVID-19 Symptoms (PACS) and/or long-COVID, showing a significant clinical heterogeneity. To develop effective, patient-targeted treatment, a better understanding of underlying mechanisms is needed. Epigenetics has helped elucidating the pathophysiology of several health conditions and it might help unravelling inter-individual differences in patients with PACS and long-COVID. As accumulating research is exploring epigenetic mechanisms in PACS and long-COVID, we systematically summarized the available literature on the topic., Methods: We interrogated five databases (Medline, Embase, Web of Science, Scopus and medXriv/bioXriv) and followed PRISMA and SWiM guidelines to report our results., Results: Eight studies were included in our review. Six studies explored DNA methylation in PACS and/or long-COVID, while two studies explored miRNA expression in long-COVID associated with lung complications. Sample sizes were mostly small and study quality was low or fair. The main limitation of the included studies was a poor characterization of the patient population that made a homogeneous synthesis of the literature challenging. However, studies on DNA methylation showed that mechanisms related to the immune and the autonomic nervous system, and cell metabolism might be implicated in the pathophysiology of PACS and long-COVID., Conclusion: Epigenetic changes might help elucidating PACS and long-COVID underlying mechanisms, aid subgrouping, and point towards tailored treatments. Preliminary evidence is promising but scarce. Biological and epigenetic research on long-COVID will benefit millions of people suffering from long-COVID and has the potential to be transferable and benefit other conditions as well, such as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). We urge future research to employ longitudinal designs and provide a better characterization of included patients.

Purpose: Technology-Based Eye Care Services (TECS) is a tele-ophthalmology program operating in the Veterans' Administration since 2015. This study explores characteristics of the national TECS population, evaluates implementation and sustainability of TECS, and analyzes possible associations and effects of demographic characteristics and social determinants of health (SDOH) on being diagnosed with a vision threatening (VT) disease., Design: Implementation and sustainability of TECS from 2015-2022 was examined along with the sociodemographic characteristics of Veterans served through TECS in 2021., Patients/subjects: Veteran patients seen in TECS nationwide., Main Outcome Measures: Characteristics, disease prevalence and diagnoses, implementation success rate, sustainability rate, preliminary analysis of outcomes and disparity., Methods: Per quarter from 2015-2022, TECS sites were classified as implementing, active, or sustained. Standard Query Language (SQL) was used to determine sociodemographic data and logistic regression models were used to identify risk factors associated with VT eye diagnosis., Results: 21,712 Veterans, 52.1% rural or highly rural, were served by TECS in 2021. The average age was 64.7 years, with females comprising 10.9% of the population served. From 2015-2022, of the 67 TECS sites initiated, 6 were implementing with 51 of 61 initiated sites still operational in the first quarter (Q1) of 2022 (83.6% success rate).Macular degeneration (AMD) and cataracts were more prevalent in rural and highly rural populations (7.6% and 11.3%, and 48.8% and 55.0%, respectively) vs. urban populations; glaucoma and diabetic retinopathy (DR) had the opposite association. The prevalence of any type of VT eye disease was lowest in the Mountains/Central region (0.54%) and highest in the Southeast region (3.2%) of the US. Rural and highly rural residents were 1.3 and 2.5 times as likely, respectively, to be diagnosed with a VT eye disease than urban residents., Conclusions: Implementation and sustainability of TECS has been promising. The data provides key information that can be utilized to improve the deployment of TECS and similar programs, along with the possible future direction of TECS services. Moreover, experience from one national ocular telehealth program clearly illustrates that telemedicine can address eye care disparities in the Veteran population and may be utilized for other vulnerable groups as well., (Copyright © 2024. Published by Elsevier Inc.)

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) are comorbid disorders with overlapping symptoms. Research highlights autonomic dysfunction compared to healthy individuals, particularly involving the sympathetic branch. While past reviews focused on neurophysiological assessments, this systematic review summarises biological adrenergic markers, offering deeper insights into the observed sympathetic dysfunction in ME/CFS and FM aiming to identify targetable pathophysiological mechanisms., Methods: A systematic search was performed on PubMed, Web of Science, Embase and Scopus. Studies investigating peripheral biological markers of adrenergic function in patients with ME/CFS or FM compared to healthy controls at baseline were included. Meta-analyses were performed using R statistical software., Results: This meta-analysis of 37 studies, encompassing 543 ME/CFS patients and 651 FM patients, compared with 747 and 447 healthy controls, respectively, revealed elevated adrenaline (SMD = .49 [.31-.67]; Z = 5.29, p < .01) and β1 adrenergic receptor expression (SMD = .79 [.06-1.52]; Z = 2.13; p = .03) in blood of ME/CFS patients at rest. Additionally, patients with ME/CFS had a greater increase in the expression of α2A adrenergic receptor (AR, SMD = .57 [.18-.97]; Z = 2.85, p < .01), β2 AR (SMD = .41 [.02-.81]; Z = 2.04; p = .04) and COMT (SMD = .42 [.03-.81]; Z = 2.11; p = .03) after exercise and an increased response of noradrenaline to an orthostatic test (SMD = .11 [-.47 to -.70]; Z = 2.10; p = .04), both found in blood. FM patients showed no significant differences at baseline but exhibited a diminished adrenaline response to exercise (SMD = -.79 [-1.27 to -.30]; Z = -3.14; p < .01)., Conclusion: This systematic review and meta-analysis revealed adrenergic dysfunction mainly in patients with ME/CFS. Higher baseline adrenaline levels and atypical responses to exercise in ME/CFS indicate that sympathetic dysfunction, underscored by adrenergic abnormalities, is more involved in the pathophysiology of ME/CFS rather than FM., (© 2024 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Introduction: Off-label underdosed direct oral anticoagulants (DOACs) are commonly utilised in Asian patients with atrial fibrillation (AF) since they are prone to bleeding with OACs. However, the efficacy and safety of off-label underdosing DOACs are controversial. This study aimed to compare the effectiveness and safety of off-label underdosed DOACs in Asian patients with AF., Methods: PubMed, Embase, Cochrane library, and ClinicalTrials.gov were searched from 2010 to July 5, 2024, for randomised controlled trials or observational studies that compared off-label DOACs and on-label/warfarin in Asian patients with AF. The primary outcomes included ischaemic stroke or systemic embolism (ISSE) and major bleeding (MB), while secondary outcomes included all-cause death, gastrointestinal bleeding (GIB), intracranial haemorrhage (ICH), and myocardial infarction (MI). Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled using random-effects models., Results: Twenty observational studies were included. Seventeen studies compared off-label underdosed DOACs versus on-label DOACs, whereas five studies compared off-label underdosed DOACs versus warfarin. Off-label underdosed DOACs were associated with higher risk of ISSE (pooled HR [pHR] = 1.17; 95% CI: 1.00-1.38, p = 0.048) and ICH (pHR = 1.27; 95% CI: 1.06-1.52, p = 0.010) versus on-label. Subgroup analysis demonstrated increased ISSE risk with off-label underdosed rivaroxaban compared to on-label (pHR = 1.49; 95% CI: 1.07-2.08). Compared to warfarin, off-label underdosed DOACs were associated with decreased risk of MB (pHR = 0.46; 95% CI: 0.32-0.65, p < 0.001), GIB (pHR = 0.52; 95% CI: 0.29-0.93, p = 0.028), ICH (pHR = 0.60; 95% CI: 0.42-0.86, p = 0.005), and all-cause death (pHR = 0.70; 95% CI: 0.56-0.87, p = 0.001), while illustrating similar ISSE risk., Conclusions: Off-label underdosed DOACs, particularly rivaroxaban, was associated with increased ISSE risk but did not decrease bleeding compared to on-label. Adherence to appropriate DOAC doses should be emphasised to achieve the best clinical outcomes for Asian patients with AF., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Multiple myeloma is a haematological malignancy typically characterised by neoplastic plasma cell infiltration of the bone marrow. Treatment for multiple myeloma consists of multi-line chemotherapy with or without autologous stem cell transplantation and has been rapidly evolving in recent years. However, clinical trials are unable to provide patients and clinicians with long-term prognostic information nor policymakers with the full body of evidence needed to perform economic evaluation of new therapies or make reimbursement decisions. To address these limitations of the available evidence, this study aimed to develop and validate the EpiMAP Myeloma model, a discrete-event simulation model of multiple myeloma disease outcomes and treatment pathways. Risk equations were estimated using the Australian and New Zealand Myeloma & Related Diseases Registry after multiple imputation of missing data. Risk equation coefficients were combined with multiple myeloma patients at diagnosis from the Registry to perform the simulation. The model was validated with 100 bootstraps of an out-of-sample prediction analysis using a 70/30 split of the 4,121 registry patients diagnosed between 2009 and 2023, resulting in 2,884 and 1,237 patients in the training and validation cohorts, respectively. For 90% of the 120 months in the 10-year post-diagnosis period, there was no significant difference in overall survival between the validation and simulated cohorts. These results highlight that the EpiMAP Myeloma model is robust at predicting multiple myeloma disease outcomes and treatment pathways in Australia & New Zealand. In the future, clinicians will be able to use the EpiMAP Myeloma model to provide personalised estimates of life expectancy to patients based on their specific characteristics, disease stage, and response to treatment. Policymakers will also be able to use the model to perform economic evaluation, to forecast the number of patients receiving treatment at different stages, and to determine the downstream impact of listing new, effective therapies., Competing Interests: The authors have declared that no competing interests exist, (Copyright: © 2024 Irving et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Abstract: Patients with hematological malignancies are at high risk of developing hypogammaglobulinemia (HGG) and infections. Immunoglobulin (Ig) is one recommended option to prevent these infections, but it is expensive, and its cost-effectiveness compared with other prevention strategies remains unknown. We conducted a trial-based economic evaluation from the Australian health care system perspective to estimate the 12-month cost-effectiveness of prophylactic Ig vs prophylactic antibiotics in 63 adults with HGG and hematological malignancies participating in the RATIONAL feasibility trial. Two analyses were conducted: (1) cost-utility analysis to assess the incremental cost per quality-adjusted life year (QALY) gained; and (2) cost-effectiveness analysis to assess the incremental cost per serious infection prevented (grade ≥3) and per any infection (any grade) prevented. Over 12 months, the total cost per patient was significantly higher in the Ig group than in the antibiotic group (mean difference, AU$29 140; P < .001). Most patients received IVIg, which was the main cost driver; only 2 patients in the intervention arm received subcutaneous Ig. There were nonsignificant differences in health outcomes. Results showed Ig was more costly than antibiotics and associated with fewer QALYs. The incremental cost-effectiveness ratio of Ig vs antibiotics was AU$111 262 per serious infection prevented, but Ig was more costly and associated with more infections when all infections were included. On average and for this patient population, Ig prophylaxis may not be cost-effective compared with prophylactic antibiotics. Further research is needed to confirm these findings in a larger population and considering longer-term outcomes. The trial was registered at the Australian and New Zealand Clinical Trials Registry as #ACTRN12616001723471., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Medicines are the most frequent health care intervention type; their safe use provides significant benefits, but inappropriate use can cause harm. Systemic primary care approaches can manage serious medication-related problems in a timely manner., Objectives: ACTMed (ACTivating primary care for MEDicine safety) uses information technology and financial incentives to encourage pharmacists to work more closely with general practitioners to reduce the risk of harm, improve patients' experience of care, streamline workflows, and increase the efficiency of medical care., Methods and Analysis: The stepped wedge cluster randomised trial in 42 Queensland primary care practices will assess the effectiveness of the ACTMed intervention. The primary outcome will be the proportion of people at risk of serious medication-related problems - patients with atrial fibrillation, heart failure, cardiovascular disease, type 2 diabetes, or asthma or chronic obstructive pulmonary disease - who experience such problems. We will also estimate the cost per averted serious medication-related problem and the cost per averted potentially preventable medication-related hospitalisation., Ethics Approval: The University of Queensland Human Research Ethics Committee approved the pilot (2021/HE002189) and trial phases of the ACTMed study (2022/HE002136). Access to Patron data was granted by the Patron Data Governance Committee (PAT052ACTMed). Access to linked hospitalisations and deaths data are subject to Public Health Act approval (pending)., Dissemination of Findings: A comprehensive dissemination plan will be co-developed by the researchers, the ACTMed steering committee and consumer advisory group, project partners, and trial site representatives. Aboriginal and Torres Strait Islander communities will be supported in leading community-level dissemination., Trial Registration: Australian New Zealand Clinical Trials Registry (pilot: ACTRN12622000595718; 21 April 2022; full trial: ACTRN12622000574741; 14 April 2022)., (© 2023 The Authors. Medical Journal of Australia published by John Wiley & Sons Australia, Ltd on behalf of AMPCo Pty Ltd.)

Background and Objectives: Reduced mobility in patients with amyotrophic lateral sclerosis (ALS) is hypothesized to increase the risk of venous thromboembolism (VTE). A few small, single-center studies have investigated the risk of VTE in patients with ALS. Given the high morbidity and mortality associated with VTE, further understanding of the risk in patients with ALS may inform clinical care. The objective of this study was to investigate the incidence of VTE in patients with ALS compared with controls without ALS., Methods: Patients were identified from a US health insurance claims database, Optum's deidentified Clinformatics Data Mart Database, between 2004 and 2019. ALS cases were defined as patients aged 18 years or older with (1) 2 or more ALS claims at least 27 days apart including at least 1 claim from a neurologist visit or (2) 1 or more ALS claims and a prescription for riluzole or edaravone. Each ALS case was matched on age and sex to 5 controls without ALS. VTE was defined as at least 1 claim for VTE and at least 1 anticoagulant prescription or VTE-related procedure within 7 days before and 30 days after a VTE claim date. Incidence rates were reported per 1,000 person-years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using the Cox proportional hazards model., Results: Among 4,205 ALS cases and 21,025 controls, incident VTE occurred in 132 ALS cases (3.1%) and 244 controls (1.2%). Incidence rates of VTE were 19.9 per 1,000 person-years (95% CI 16.7-23.6) in ALS cases compared with 6.0 per 1,000 person-years (95% CI 5.0-7.1) in controls. ALS cases were about 3 times more likely to develop VTE (HR 3.3, 95% CI 2.6-4.0), with similar results among men and women. The median time to first VTE was 10 months from the initial ALS claim in ALS cases., Discussion: Consistent with previous smaller studies, a higher incidence rate of VTE was observed in a large sample of patients with ALS from across the United States, as compared to matched controls. The markedly increased risk underscores the importance of preventive efforts and careful monitoring for VTE in patients with ALS and may have implications for the management of ALS., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: The intrathecally administered antisense oligonucleotide tofersen reduces synthesis of the superoxide dismutase 1 (SOD1) protein and is being studied in patients with amyotrophic lateral sclerosis (ALS) associated with mutations in SOD1 ( SOD1 ALS)., Methods: In this phase 3 trial, we randomly assigned adults with SOD1 ALS in a 2:1 ratio to receive eight doses of tofersen (100 mg) or placebo over a period of 24 weeks. The primary end point was the change from baseline to week 28 in the total score on the ALS Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) among participants predicted to have faster-progressing disease. Secondary end points included changes in the total concentration of SOD1 protein in cerebrospinal fluid (CSF), in the concentration of neurofilament light chains in plasma, in slow vital capacity, and in handheld dynamometry in 16 muscles. A combined analysis of the randomized component of the trial and its open-label extension at 52 weeks compared the results in participants who started tofersen at trial entry (early-start cohort) with those in participants who switched from placebo to the drug at week 28 (delayed-start cohort)., Results: A total of 72 participants received tofersen (39 predicted to have faster progression), and 36 received placebo (21 predicted to have faster progression). Tofersen led to greater reductions in concentrations of SOD1 in CSF and of neurofilament light chains in plasma than placebo. In the faster-progression subgroup (primary analysis), the change to week 28 in the ALSFRS-R score was -6.98 with tofersen and -8.14 with placebo (difference, 1.2 points; 95% confidence interval [CI], -3.2 to 5.5; P = 0.97). Results for secondary clinical end points did not differ significantly between the two groups. A total of 95 participants (88%) entered the open-label extension. At 52 weeks, the change in the ALSFRS-R score was -6.0 in the early-start cohort and -9.5 in the delayed-start cohort (difference, 3.5 points; 95% CI, 0.4 to 6.7); non-multiplicity-adjusted differences favoring early-start tofersen were seen for other end points. Lumbar puncture-related adverse events were common. Neurologic serious adverse events occurred in 7% of tofersen recipients., Conclusions: In persons with SOD1 ALS, tofersen reduced concentrations of SOD1 in CSF and of neurofilament light chains in plasma over 28 weeks but did not improve clinical end points and was associated with adverse events. The potential effects of earlier as compared with delayed initiation of tofersen are being further evaluated in the extension phase. (Funded by Biogen; VALOR and OLE ClinicalTrials.gov numbers, NCT02623699 and NCT03070119; EudraCT numbers, 2015-004098-33 and 2016-003225-41.)., (Copyright © 2022 Massachusetts Medical Society.)

Despite extensive research, amyotrophic lateral sclerosis (ALS) remains a progressive and invariably fatal neurodegenerative disease. Limited knowledge of the underlying causes of ALS has made it difficult to target upstream biological mechanisms of disease, and therapeutic interventions are usually administered relatively late in the course of disease. Genetic forms of ALS offer a unique opportunity for therapeutic development, as genetic associations may reveal potential insights into disease etiology. Genetic ALS may also be amenable to investigating earlier intervention given the possibility of identifying clinically presymptomatic, at-risk individuals with causative genetic variants. There is increasing evidence for a presymptomatic phase of ALS, with biomarker data from the Pre-Symptomatic Familial ALS (Pre-fALS) study showing that an elevation in blood neurofilament light chain (NfL) precedes phenoconversion to clinically manifest disease. Tofersen is an investigational antisense oligonucleotide designed to reduce synthesis of superoxide dismutase 1 (SOD1) protein through degradation of SOD1 mRNA. Informed by Pre-fALS and the tofersen clinical development program, the ATLAS study (NCT04856982) is designed to evaluate the impact of initiating tofersen in presymptomatic carriers of SOD1 variants associated with high or complete penetrance and rapid disease progression who also have biomarker evidence of disease activity (elevated plasma NfL). The ATLAS study will investigate whether tofersen can delay the emergence of clinically manifest ALS. To our knowledge, ATLAS is the first interventional trial in presymptomatic ALS and has the potential to yield important insights into the design and conduct of presymptomatic trials, identification, and monitoring of at-risk individuals, and future treatment paradigms in ALS., (© 2022. The Author(s).)

Objectives: To identify published economic evaluations of interventions aimed at preventing, diagnosing, or treating food allergies in children., Methods: We examined economic evaluations published from 2000 to 2019. Data analyzed included: food allergy type, study population/setting, intervention/comparator, and economic evaluation details. Quality assessment used reporting and economic modeling checklists. Two reviewers simultaneously undertook article screening, data extraction, and quality assessment., Results: 17 studies were included: 8 peanut allergy (PA) studies, 8 cow's milk allergy (CMA) studies, and 1 egg allergy (EA) study. All PA studies reported incremental costs per quality-adjusted life-year gained for diagnostic strategies, management pathways for peanut exposure, and immunotherapies. Immunotherapies rendered inconsistent cost-effectiveness results. CMA studies reported costs per symptom-free day or probability of developing CMA tolerance. Cost-effectiveness of extensively hydrolyzed casein formula for CMA treatment was consistently demonstrated. Early introduction of cooked egg in first year of life dominated all EA prevention strategies. Quality assessment showed average noncompliance for 3.5 items/study (range 0-11) for modeling methods and 3.4 items/study (range 0-8) for reporting quality. Key quality concerns included limited justification for model choice, evidence base for model parameters, source of utility values, and representation of uncertainty., Conclusion: Recent cost-effectiveness literature of interventions in PA, CMA, and EA is limited and diverse. Interventions for diagnosis and treatment of CMA and prevention of EA were generally cost-effective; however, results for PA were variable and dependent on effectiveness and utility values used. There is a need to expand economic evaluation of interventions for childhood food allergy and to improve methods and reporting., (Copyright © 2021 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Aims: Oral anticoagulant (OAC) is recommended for preventing stroke in atrial fibrillation (AF). However, the OAC utilisation in AF patients with dementia or cognitive impairment (CI) is limited. This study aimed to examine the prevalence of OAC prescriptions in AF patients with dementia/CI and to identify factors associated with OAC treatment within 180 days after dementia/CI diagnosis., Methods: Using The Health Improvement Network database, the annual trends of OAC between 2000 and 2015 were calculated. Multivariable logistic regression was performed to identify factors associated with OAC treatment., Results: The prevalence rate of OAC prescriptions increased from 6.1% in 2000 to 45.9% in 2015. Among OAC users, the proportion of direct oral anticoagulants (DOACs) use increased significantly from 0.1% in 2011 to 33.8% in 2015 (P-trend < 0.001), while the proportion of vitamin K antagonist use decreased by 28.6% from 100% in 2000 to 71.4% in 2015 (P-trend < 0.001). In the multivariable analysis, younger age, very old age, female sex, higher Charlson Comorbidity Index, having a HAS-BLED score ≥3, a history of intracranial bleeding, falls and polypharmacy were significantly associated with lower odds of receiving OAC., Conclusions: In UK primary care, OAC use increased from 2000 to 2015 in AF patients with dementia/CI, with a substantial increase in use of DOACs. Characteristics related to frailty are associated with lower odds of OAC prescription. Given the increasing use of DOACs in patients with dementia/CI, further studies are needed to investigate the safety and effectiveness of DOACs in this important patient group., (© 2020 The British Pharmacological Society.)

Introduction: A substantial proportion of hospital admissions and readmissions are directly attributable to preventable medication-related harm. Interventions that reduce these harms could avert significant suffering and healthcare costs., Objectives: The Discharge Medications Reconciliation (DCMedsRec) trial will evaluate a structured medication reconciliation service by community pharmacists post hospital discharge on the risk of 30-day unplanned readmission. Electronic access to the Hospital Discharge Summary via My Health Record will underpin this service., Methods: DCMedsRec is a non-blinded randomised controlled trial of an intervention by community pharmacists within 30 days of hospital discharge in Melbourne, Australia. Patients discharged from hospital will be assessed by a hospital pharmacist for trial eligibility. If eligible, patients will be randomised to either a control or intervention group by sequentially marked sealed envelopes. Intervention patients receive an invitation to the DCMedsRec service at a participating community pharmacy, who will be reimbursed. Control patients will receive usual care. A Number Needed to Treat of 20 will require 293 DCMedsRec interventions to achieve 80% power. With a predicted 30% uptake, a minimum sample of 977 in the intervention arm is required., Outcomes: The primary outcome will be the rate of 30-day unplanned hospital readmission in intervention (DCMedsRec) versus usual care groups. Secondary analyses will evaluate the economic impact of the intervention and a qualitative thematic analysis of the experience and value of the service for both patients and service providers (community pharmacists)., Analysis: An intention-to-treat analysis will be used to assess intervention efficacy and results will be reported using risk ratios with 95% confidence intervals. Cost-effectiveness analysis will compare within-trial costs and outcomes of the DCMedsRec versus usual care from a health-system perspective., Trial Registration and Funding: This trial is registered with the Australian and New Zealand Clinical Trials Register and funded by the Australian Digital Health Agency., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aims: Comparative fracture risk for non-vitamin K antagonist oral anticoagulants (NOACs) and vitamin K antagonists (VKAs) among patients with atrial fibrillation (AF) remains unclear. This study aimed to provide summary relative risk (RR) estimates for associations between NOACs vs. VKAs and fracture risk., Methods and Results: PubMed, EMBASE, and Cochrane Library were searched from 2010 to 26 May 2020. Observational studies investigating the association between NOACs vs. VKAs and fracture risk in patients with AF were included. The adjusted effect estimates were pooled using the DerSimonian-Laird random effects models. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and the Meta-analysis of Observational Studies in Epidemiological (MOOSE) guidelines were followed. Five observational studies comprising 269 922 patients and 4289 fractures were included. Non-vitamin K antagonist oral anticoagulants use was associated with a lower risk of any fractures compared to VKAs use, with moderate heterogeneity [pooled RR = 0.83, 95% confidence interval (CI): 0.75-0.92, P < 0.001, I2 = 73.0%]. When comparing individual NOAC to VKAs, a statistically significant lower risk of any fractures was found for rivaroxaban (pooled RR = 0.79, 95% CI: 0.71-0.88, P < 0.001, I2 = 55.2%) and apixaban (pooled RR = 0.75, 95% CI: 0.60-0.92, P = 0.007, I2 = 54.5%), but not dabigatran (pooled RR = 0.87, 95% CI: 0.74-1.01, P = 0.061, I2 = 74.6%). No differences were observed in all head-to-head comparisons between NOACs., Conclusion: This large meta-analysis suggests that NOACs use was associated with a lower risk of fractures compared with VKAs. Fracture risks were similar between NOACs. These findings may help inform the optimal anticoagulant choice for patients with AF at high risk of fracture., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Purpose: Comparative gastrointestinal bleeding (GIB) risk between rivaroxaban and low-dose aspirin is unknown in patients with atrial fibrillation (AF). This study investigated GIB risk with rivaroxaban vs aspirin among two separate AF cohorts in Hong Kong and the United Kingdom, using a common protocol approach., Methods: This was a population-based cohort study using separate data from the Clinical Data Analysis and Reporting System (CDARS) of the Hong Kong Hospital Authority (2010-2018) and The Health Improvement Network (THIN) database in the United Kingdom (2011-2017). Patients with AF newly prescribed aspirin or rivaroxaban were included. Cox proportional hazards regression was used to compare GIB risks for rivaroxaban vs aspirin, accounting for confounders using propensity score fine stratification approach., Results: In CDARS, 29 213 patients were included; n = 1052 (rivaroxaban), n = 28 161 (aspirin). Crude GIB event rates per 100 patient-years in CDARS were 3.0 (aspirin) and 2.6 (rivaroxaban). No difference in GIB risk was observed between rivaroxaban and aspirin overall (HR = 1.04, 95%CI = 0.76-1.42), and in dose-stratified analyses (HR = 1.21, 95%CI = 0.84-1.74 [20 mg/day]; HR = 0.80, 95%CI = 0.44-1.45 [≤15 mg/day]). In THIN, 11 549 patients were included, n = 3496 (rivaroxaban) and n = 8053 (aspirin). Crude GIB event rates were 1.3 (aspirin) and 2.4 (rivaroxaban) per 100 patient-years. No difference in GIB risk was observed between rivaroxaban and aspirin overall (HR = 1.40, 95%CI = 1.00-1.98) and low-dose rivaroxaban (≤15 mg/day) (HR = 1.00, 95%CI = 0.56-1.30), but increased GIB risk was observed for rivaroxaban 20 mg/day vs aspirin (HR = 1.57, 95%CI = 1.08-2.29)., Conclusion: In patients with AF, GIB risk was comparable between aspirin and rivaroxaban ≤15 mg/day. GIB risk for rivaroxaban 20 mg/day vs aspirin remains uncertain and warrants further investigation., (© 2020 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Captive animal welfare is important for establishments that exhibit species for education, conservation, and research. However, captive animals are often exposed to a number of potential stressors, such as visitors and anthropogenic noise. We aimed to identify the impact of a concert series on the behaviour of Fiordland penguins ( Eudyptes pachyrhynchus ; n = 2), and solitary- ( n = 1) or group- ( n = 4)-housed collared peccaries ( Pecari tajacu ). Animal behaviour, visitor density, and visitor behaviour was monitored pre-concert (afternoons; 16:00-19:00), during the concert (evenings; 19:00-21:00), and post-concert (nights; 21:00-00:00) on concert days (penguin n = 7 days; peccary n = 8 days) and in the same periods on days when there was no concert (penguin n = 8 days; peccary n = 6 days). Fiordland penguins spent more time surface swimming and diving in the pool on concert afternoons and evenings (all p < 0.001), more time in the nest on concert nights ( p < 0.001), preened less on concert afternoons and nights ( p = 0.019), and engaged with their habitat less on concert evenings and nights ( p = 0.002) compared to these periods on days without a concert. The group-housed peccaries slept more in the afternoon and evening ( p ≤ 0.01) and were more vigilant at night ( p = 0.009) on concert days compared to no-concert days. The solitary-housed peccary slept more on concert nights ( p = 0.035), rested more frequently across all time periods on concert days ( p < 0.001), and used the front of the enclosure more across all concert time periods ( p < 0.001) compared to no-concert days. We provide evidence that behaviour was altered on event days; however, we cannot determine the nature of these changes. Further research is needed to understand the impact of music concerts on zoo animal welfare.

Objective: To determine risks of embolic events, bleeding, and mortality with direct oral anticoagulants (DOACs) vs warfarin in people with atrial fibrillation (AF) and dementia., Design: New-user retrospective cohort study using The Health Improvement Network database., Setting and Participants: A population-based sample comprising people with AF and dementia prescribed DOACs or warfarin from August 2011 to September 2017., Methods: Risk of ischemic stroke (IS), ischemic stroke/transient ischemic attack/systemic embolism (IS/TIA/SE), all-cause mortality, intracranial bleeding (ICB), gastrointestinal bleeding (GIB), and other bleeding were compared for DOACs vs warfarin using propensity score-adjusted Poisson regression. Incidence rate ratios (IRRs) and absolute risk differences (ARDs) were calculated., Results: Overall, 2399 people with AF and dementia initiated DOACs (42%) or warfarin (58%). Before propensity score adjustment, patients who initiated DOACs were older and had more comorbidities. After adjustment, DOAC initiators demonstrated similar risks of IS, TIA, or SE; IS alone; and other bleeding but reduced ICB risk (IRR 0.27, 95% CI 0.08, 0.86; ARD -5.2, 95% CI -6.5, -1.0, per 1000 person-years) compared with warfarin. Increased risk of GIB (IRR 2.11, 95% CI 1.30, 3.42; ARD 14.8, 95% CI 4.0, 32.4, per 1000 person-years) and all-cause mortality (IRR 2.06, 95% CI 1.60, 2.65; ARD 53.0, 95% CI 30.2, 82.8, per 1000 person-years) were observed in DOAC initiators compared with warfarin., Conclusions and Implications: Among people with AF and dementia, initiating treatment with DOACs compared with warfarin was associated with similar risks of IS, TIA, or SE and IS alone. DOAC-treated patients demonstrated reduced ICB risk but increased GIB and all-cause mortality risks. We cannot exclude the possible impact of residual confounding from channeling of DOACs toward older and sicker people, particularly for the outcome of all-cause mortality. Further safety data are urgently needed to confirm findings., (Copyright © 2019 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Tofersen is an antisense oligonucleotide that mediates the degradation of superoxide dismutase 1 (SOD1) messenger RNA to reduce SOD1 protein synthesis. Intrathecal administration of tofersen is being studied for the treatment of amyotrophic lateral sclerosis (ALS) due to SOD1 mutations., Methods: We conducted a phase 1-2 ascending-dose trial evaluating tofersen in adults with ALS due to SOD1 mutations. In each dose cohort (20, 40, 60, or 100 mg), participants were randomly assigned in a 3:1 ratio to receive five doses of tofersen or placebo, administered intrathecally for 12 weeks. The primary outcomes were safety and pharmacokinetics. The secondary outcome was the change from baseline in the cerebrospinal fluid (CSF) SOD1 concentration at day 85. Clinical function and vital capacity were measured., Results: A total of 50 participants underwent randomization and were included in the analyses; 48 participants received all five planned doses. Lumbar puncture-related adverse events were observed in most participants. Elevations in CSF white-cell count and protein were reported as adverse events in 4 and 5 participants, respectively, who received tofersen. Among participants who received tofersen, one died from pulmonary embolus on day 137, and one from respiratory failure on day 152; one participant in the placebo group died from respiratory failure on day 52. The difference at day 85 in the change from baseline in the CSF SOD1 concentration between the tofersen groups and the placebo group was 2 percentage points (95% confidence interval [CI], -18 to 27) for the 20-mg dose, -25 percentage points (95% CI, -40 to -5) for the 40-mg dose, -19 percentage points (95% CI, -35 to 2) for the 60-mg dose, and -33 percentage points (95% CI, -47 to -16) for the 100-mg dose., Conclusions: In adults with ALS due to SOD1 mutations, CSF SOD1 concentrations decreased at the highest concentration of tofersen administered intrathecally over a period of 12 weeks. CSF pleocytosis occurred in some participants receiving tofersen. Lumbar puncture-related adverse events were observed in most participants. (Funded by Biogen; ClinicalTrials.gov number, NCT02623699; EudraCT number, 2015-004098-33.)., (Copyright © 2020 Massachusetts Medical Society.)

Background: Whether oral anticoagulation (OAC) can prevent dementia or cognitive impairment (CI) in patients with atrial fibrillation (AF) remains unclear., Objective: The purpose of this study was to investigate the risk of dementia/CI among AF patients with and without OAC treatment., Methods: We conducted a retrospective cohort study using United Kingdom (UK) primary care data (2000-2017). Participants with newly diagnosed AF without a history of dementia/CI were identified. Inverse probability of treatment weights based on propensity scores and Cox regression were used to compare the dementia outcomes., Results: Among 84,521 patients with AF, 35,245 were receiving OAC treatment and 49,276 received no OAC treatment; of these patients, 29,282 were receiving antiplatelets. Over a mean follow-up of 5.9 years, 5295 patients developed dementia/CI. OAC treatment was associated with a lower risk of dementia/CI compared to no OAC treatment (hazard ratio [HR] 0.90; 95% confidence interval 0.85-0.95; P <.001) or antiplatelets (HR 0.84; 95% confidence interval 0.79-0.90; P <.001). No significant difference in dementia risk was observed for direct oral anticoagulants (DOACs) vs warfarin (HR 0.89; 95% confidence interval 0.70-1.14; P = .373), whereas dual therapy (OAC plus an antiplatelet agent) was associated with a higher risk of dementia/CI compared with no treatment (HR 1.17; 95% confidence interval 1.05-1.31; P = .006)., Conclusion: OAC use was associated with a lower risk of dementia/CI compared to non-OAC and antiplatelet treatment among AF patients. The evidence for DOAC on cognitive function is insufficient, and further studies including randomized clinical trials are warranted., (Copyright © 2020 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Pathological and genetic evidence implicates toxic effects of aggregated α-synuclein in the pathophysiology of neuronal dysfunction and degeneration in Parkinson's disease. Immunotherapy targeting aggregated α-synuclein is a promising strategy for delaying disease progression., Objective: This study (NCT02459886) evaluated the safety, tolerability, and pharmacokinetics of BIIB054, a human-derived monoclonal antibody that preferentially binds to aggregated α-synuclein, in healthy volunteers and participants with Parkinson's disease., Methods: A total of 48 healthy volunteers (age 40-65, 19 women) and 18 Parkinson's disease participants (age 47-75, 5 women, Hoehn and Yahr stage ≤2.5) were in the study. Volunteers were enrolled into 6 single-dose cohorts of BIIB054 (range 1-135 mg/kg) or placebo, administered intravenously; Parkinson's disease participants received a single dose of BIIB054 (15 or 45 mg/kg) or placebo. All participants were evaluated for 16 weeks with clinical, neuroimaging, electrocardiogram, and laboratory assessments. Serum and cerebrospinal fluid BIIB054 concentrations were measured. BIIB054/α-synuclein complexes were measured in plasma., Results: Most adverse events were mild and assessed by investigators as unrelated to the study drug. Pharmacokinetic parameters for volunteers and the Parkinson's disease participants were similar. BIIB054 serum exposure and maximum concentrations were dose proportional during the dose range studied. In volunteers and the Parkinson's disease participants, the serum half-life of BIIB054 was 28 to 35 days; the cerebrospinal fluid-to-serum ratio ranged from 0.13% to 0.56%. The presence of BIIB054/α-synuclein complexes in plasma was confirmed; all Parkinson's disease participants showed almost complete saturation of the BIIB054/α-synuclein complex formation., Conclusions: BIIB054 has favorable safety, tolerability, and pharmacokinetic profiles in volunteers and Parkinson's disease participants, supporting further clinical development. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society., (© 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.)

Study Objective: To determine the cost-effectiveness of 3 clinical decision rules in comparison to Australian and New Zealand usual care: the Children's Head Injury Algorithm for the Prediction of Important Clinical Events (CHALICE), the Pediatric Emergency Care Applied Research Network (PECARN), and the Canadian Assessment of Tomography for Childhood Head Injury (CATCH)., Methods: A decision analytic model was constructed from the Australian health care system perspective to compare costs and outcomes of the 3 clinical decision rules compared with Australian and New Zealand usual care. The study involved multicenter recruitment from 10 Australian and New Zealand hospitals; recruitment was based on the Australian Pediatric Head Injury Rules Study involving 18,913 children younger than 18 years and with a head injury, and with Glasgow Coma Scale score 13 to 15 on presentation to emergency departments (EDs). We determined the cost-effectiveness of the 3 clinical decision rules compared with usual care., Results: Usual care, CHALICE, PECARN, and CATCH strategies cost on average AUD $6,390, $6,423, $6,433, and $6,457 per patient, respectively. Usual care was more effective and less costly than all other strategies and is therefore the dominant strategy. Probabilistic sensitivity analyses showed that when simulated 1,000 times, usual care dominated all clinical decision rules in 61%, 62%, and 60% of simulations (CHALICE, PECARN, and CATCH, respectively). The difference in cost between all rules was less than $36 (95% confidence interval -$7 to $77) and the difference in quality-adjusted life-years was less than 0.00097 (95% confidence interval 0.0015 to 0.00044). Results remained robust under sensitivity analyses., Conclusion: This evaluation demonstrated that the 3 published international pediatric head injury clinical decision rules were not more cost-effective than usual care in Australian and New Zealand tertiary EDs. Understanding the usual care context and the likely cost-effectiveness is useful before investing in implementation of clinical decision rules or incorporation into a guideline., (Copyright © 2018 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Background: People with Alzheimer's disease (AD) are less likely to use oral anticoagulants than people without AD., Objective: We investigated incidence and prevalence of warfarin and direct oral anticoagulant (DOAC) use, and determined predictors of DOAC and warfarin initiation in older people with AD and the general population., Methods: Australian Pharmaceutical Benefits Scheme data for 356,000 people aged ≥65 years dispensed warfarin or DOACs during July 2013-June 2017 were analyzed. Changes in annual incidence and prevalence were estimated using Poisson regression. Predictors of DOAC versus warfarin initiation were estimated using multivariable logistic regression separately for people with AD and the general population., Results: Oral anticoagulant prevalence increased from 8% in people with AD and 9% in the general population to 12% in both groups from 2013/2014 to 2016/2017. DOAC prevalence increased (from 2.4% to 7.8% in people with AD, 3.2% to 7.7% in the general population) while warfarin prevalence declined (6.6% to 4.5%, 7.0% to 4.3%, correspondingly). The incidence of warfarin use decreased by 45-55%. In people with AD, women were less likely to initiate DOACs than men, whereas presence of arrhythmias or pain/inflammation increased likelihood of initiating DOACs. Age ≥85 years, cardiovascular diseases, gastric acid disorder, diabetes, and end-stage renal disease were associated with lower odds of DOAC initiation in the general population., Conclusion: DOAC introduction has coincided with increased anticoagulation rates in people with AD. Rates are now similar in older people with AD and the general population. Compared to previous years, DOACs are now more likely to be initiated, particularly for those aged ≥85 years.

Atrial fibrillation (AF) is a documented risk factor for dementia. However, it is unclear whether oral anticoagulant (OAC) treatment can reduce the development of dementia or cognitive impairment. We conducted a systematic review and meta-analysis of the association between OAC use and subsequent dementia development in AF patients by searching databases from their inception to February 2018 without language restriction. Six studies (one randomized controlled trial and five observational studies) met the inclusion criteria. The pooled adjusted risk ratios (RRs) suggested a protective effect of OAC use in reducing dementia risk (RR 0.79 [95% CI: 0.67 - 0.93], I 2  = 59.7%; P = 0.005). Further, high percentage of time in therapeutic range (TTR) was associated with a decreased risk of dementia (RR 0.38 [95% CI 0.22-0.64], I 2  = 81.8%; P < 0.001). Our results support the hypothesis that AF-related dementia may be due to silent brain infarcts and micro-embolism that could be prevented by OAC use. Future studies with prospective follow-up with direct comparison of vitamin K antagonists and direct oral anticoagulants are needed., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: The advent of hospital electronic medical records (EMRs) with electronic prescribing provides considerable opportunity for pharmacoepidemiological research. However, validity of EMR prescribing data for research purposes is not well established. Validity concerns the percentage of cases in which medications and characteristics (name, type, formulation, dose) are true when verified with an independent data source. This study evaluated the validity of EMR discharge prescription data within the Eastern Health hospital network in Melbourne, Australia., Methods: A random sample of patients were selected who had a diagnosis of atrial fibrillation (AF) and were prescribed at least five medications. Prescription records from 2012 to 2015 were compared with pharmacy dispensing and hospital medical records (reference standards). Medication name, dose, directions and route of administration were compared. Discrepancies between data sources were categorized as omissions, additions, discrepancies in dose, medication form or route of administration or discrepancies in reordering. Sensitivities and 95% confidence intervals (CIs) for intended medication exposure were estimated for therapeutic classes., Results: A total of 5724 prescription orders for 479 patients for whom reference standards were available were included. There were 163 discrepancies (2.8%) between prescription records and reference standards. Additions were the most common data discrepancy ( n = 65; ~1.1% of total prescriptions evaluated), followed by discrepancies in reordering ( n = 34; 0.59%). Sensitivities for intended patient exposure to a medication for each therapeutic class at the first level of the Anatomical Therapeutic Chemical (ATC) classification system were between 97% and 100%. The genitourinary system and sex hormone level of the ATC system demonstrated the lowest sensitivity, (97.3%; 95% CI 92.0%-100%) and the cardiovascular system level demonstrated the highest sensitivity (99.9%; 95% CI 99.7%-100%)., Conclusion: EMR discharge prescription records for patients with AF are a valid information source for conducting pharmacoepidemiological research within Eastern Health in Melbourne, Australia. Further studies in different regions, countries and patient cohorts are required to establish validity of hospital EMR prescription records for pharmacoepidemiological research., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest.

Background: Differences in management and outcomes of oral anticoagulant (OAC) use may exist for people with and without dementia or cognitive impairment (CI)., Objective: To systematically review the prevalence and safety and effectiveness outcomes of OAC use in people with and without dementia or CI., Methods: MEDLINE, EMBASE, and CINAHL were searched for studies reporting prevalence or safety and effectiveness outcomes of OAC use for people with and without dementia, published between 2000 to September 2017. Study selection, data extraction, and quality assessment were performed by two reviewers., Results: studies met pre-specified inclusion criteria (21 prevalence studies, 6 outcomes studies). People with dementia had 52% lower odds of receiving OAC compared to people without dementia. Mean OAC prevalence was 32% for people with dementia, compared to 48% without dementia. There was no difference in the composite outcome of embolic events, myocardial infarction, and all-cause death between dementia and non-dementia groups (adjusted hazard ratio (HR) 0.72, 95% CI, 0.45-1.14, p = 0.155). Bleeding rate was lower for people without dementia (HR 0.56, 95% CI, 0.37-0.85). Adverse warfarin events were more common for residents of long-term care with dementia (adjusted incidence rate ratio 1.48, 95% CI, 1.20-1.82). Community-dwelling people with dementia treated with warfarin had poorer anticoagulation control than those without dementia (mean time in therapeutic range (TTR) % ±SD, 38±26 (dementia), 61±27 (no dementia), p < 0.0001)., Conclusion: A lower proportion of people with dementia received oral anticoagulation compared with people without dementia. People with dementia had higher bleeding risk and poorer anticoagulation control when treated with warfarin.

Purpose: Trials of the direct oral anticoagulants (DOACs) dabigatran, rivaroxaban and apixaban provide the basis for prescribing for the prevention of stroke and systemic embolism in atrial fibrillation (AF). The objective of this study was to assess the representativeness of the three pivotal DOAC randomized controlled trials of dabigatran, rivaroxaban and apixaban for unselected hospitalized patients with AF., Methods: A cross-sectional study was undertaken. All patients discharged with AF between 2012 and 2015 from a large public hospital network in Melbourne, Australia, were identified. Inclusion and exclusion criteria from the DOAC trials were applied. The proportions of hospitalized patients with AF who would have been eligible for the dabigatran (RE-LY), rivaroxaban (ROCKET-AF) and apixaban (ARISTOTLE) trials were estimated, as was pooled eligibility for all three trials. Characteristics of eligible and ineligible patients were compared., Results: For the 4734 patients, application of the inclusion and exclusion criteria resulted in 60.5, 52.6 and 35.8% eligibility for the trials of apixaban, dabigatran and rivaroxaban, respectively. Pooled eligibility across all three trials demonstrated that 33.4% of the patients would have been eligible for all three trials but 36.7% ineligible for any trial. Ineligible patients who met exclusion criteria were older and experienced more comorbidities., Conclusions: The apixaban and dabigatran trials may be the most representative of hospitalized patients with AF. The DOAC trial results can readily be extrapolated to, and guide prescribing for, at least two thirds of patients discharged from a large metropolitan health service in Australia.

Purpose: Percutaneous pericardial access (EpiAcc) assists ventricular tachycardia/premature ventricular complex (VT/PVC) ablation by permitting epicardial mapping and ablation outside the vicinity of the coronary venous system. We sought to determine whether expanding indications and growing operator experience have led to increased rates of EpiAcc., Methods: We reviewed the frequency of EpiAcc procedures performed during VT/PVC ablation between 2007 and 2014 to identify temporal trends in the procedure., Results: There were 758 patients undergoing 880 VT/PVC ablation procedures (average 95 patients per year; 110 procedures per year) during the study period. EpiAcc for ablation was utilized in 170 patients (181 procedures). The average age at the time of EpiAcc was 55 ± 16 years and 129 (76.0 %) patients were male. The rate of EpiAcc was 22.9 % in males and 15.4 % in females (P = 0.008). The absolute number of EpiAcc procedures increased from 2007 (6 procedures) to 2014 (27 procedures). Similarly, the proportion of patients undergoing EpiAcc increased from 8.6 % of procedures in 2007 to 24.5 % in 2014 (P < 0.0001). While EpiAcc use became more frequent, the rate of epicardial ablation among those who underwent EpiAcc remained stable (approximately 70 %)., Conclusions: Percutaneous pericardial access has been used with increasing frequency as part of VT/PVC ablations without an increase in the rate of epicardial ablation. This growing utilization may lay the foundation for novel epicardial strategies as new technologies emerge. The frequency of percutaneous pericardial access in VT/PVC ablation appears to be greater in males, reasons for which are undefined.

Much remains unknown about the genetic status and population connectivity of high-elevation and high-latitude freshwater invertebrates, which often persist near snow and ice masses that are disappearing due to climate change. Here we report on the conservation genetics of the meltwater stonefly Lednia tumana (Ricker) of Montana, USA, a cold-water obligate species. We sequenced 1530 bp of mtDNA from 116 L. tumana individuals representing "historic" (>10 yr old) and 2010 populations. The dominant haplotype was common in both time periods, while the second-most-common haplotype was found only in historic samples, having been lost in the interim. The 2010 populations also showed reduced gene and nucleotide diversity and increased genetic isolation. We found lower genetic diversity in L. tumana compared to two other North American stonefly species, Amphinemura linda (Ricker) and Pteronarcys californica Newport. Our results imply small effective sizes, increased fragmentation, limited gene flow, and loss of genetic variation among contemporary L. tumana populations, which can lead to reduced adaptive capacity and increased extinction risk. This study reinforces concerns that ongoing glacier loss threatens the persistence of L. tumana, and provides baseline data and analysis of how future environmental change could impact populations of similar organisms.

Background: Rapid drug desensitization (RDD) is used to address hypersensitivity reactions to chemotherapeutics and monoclonal antibodies, allowing patients to be treated with optimal pharmacological agents. RDD protocols are tailored to each individual patient's reaction and needs, and protect against anaphylaxis, but overall risks, costs, and benefits have not been determined., Objective: We investigated the safety, efficacy, costs, and life expectancy of patients in a large population undergoing RDD., Methods: We analyzed 2177 RDD procedures performed in 370 patients with cancer, vasculitis, and hematological and connective tissue diseases who presented 402 reactions. A subgroup of carboplatin allergic patients with ovarian cancer treated with RDD was analyzed for costs and life expectancy and compared with a nonallergic control group., Results: RDD allowed all patients to receive safely the full dose of the medication to which they were reactive. A gradual increase in the fraction of outpatient desensitizations from 81% to 98% was achieved through risk stratification. Of the 2177 desensitizations, 93% had no or mild reactions whereas 7% had moderate to severe reactions, which did not preclude the completion of the treatment, and there were no deaths. Overall health costs in the carboplatin allergic group were not higher than those in the nonallergic group treated with standard of care. Administration of carboplatin through RDD was as effective as standard administration with a nonsignificant increase in life expectancy in desensitized patients as compared with nonallergic, nondesensitized controls., Conclusions: RDD is cost effective and safe for allergic patients with cancer and chronic disease to remain on first line therapy., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Rationale, Aims and Objectives: The implementation of automated dispensing cabinets (ADCs) in healthcare facilities appears to be increasing, in particular within Australian hospital emergency departments (EDs). While the investment in ADCs is on the increase, no studies have specifically investigated the impacts of ADCs on medication selection and preparation error rates in EDs. Our aim was to assess the impact of ADCs on medication selection and preparation error rates in an ED of a tertiary teaching hospital., Methods: Pre intervention and post intervention study involving direct observations of nurses completing medication selection and preparation activities before and after the implementation of ADCs in the original and new emergency departments within a 377-bed tertiary teaching hospital in Australia. Medication selection and preparation error rates were calculated and compared between these two periods. Secondary end points included the impact on medication error type and severity., Results: A total of 2087 medication selection and preparations were observed among 808 patients pre and post intervention. Implementation of ADCs in the new ED resulted in a 64.7% (1.96% versus 0.69%, respectively, P = 0.017) reduction in medication selection and preparation errors. All medication error types were reduced in the post intervention study period. There was an insignificant impact on medication error severity as all errors detected were categorised as minor., Conclusion: The implementation of ADCs could reduce medication selection and preparation errors and improve medication safety in an ED setting., (© 2015 John Wiley & Sons, Ltd.)