Comparative efficacy, safety, and cost-effectiveness of abobotulinumtoxinA and onabotulinumtoxinA in children with upper limb spasticity: a systematic literature review, indirect treatment comparison, and economic evaluation.

OBJECTIVE: The objective of this study was to compare clinical- and cost-effectiveness of type A botulinum toxin (BoNT-A) therapies for management of pediatric upper limb spasticity, including AbobotulinumtoxinA (aboBoNT-A) and Onabotulinumtoxin A (onaBoNT-A). METHODS: Systematic literature review and indirect treatment comparisons were conducted of randomized controlled trials reporting efficacy and safety outcomes. Efficacy was characterized by Modified Ashworth Scale (MAS) and Ashworth Scale (AS) up to 16-weeks post-injection. Results were used to inform a cost-effectiveness model with a 1-year time horizon, linking response rates with health-related quality-of-life (HRQoL) outcomes and costs from a UK perspective. Other data sources included in the cost-effectiveness model were drug unit costs, health care resource utilization based on UK physician survey, and HRQoL impacts of adverse events associated with oral anti-spasticity therapies. Results were characterized as cost per quality-adjusted life year and cost per responder. RESULTS: Six studies were included in evidence syntheses. There was a trend towards greater response rate for aboBoNT-A which resulted in improved HRQoL and lower annual costs compared with onaBoNT-A. Safety outcomes were similar across BoNT-A therapies. In cost-effectiveness analysis, aboBoNT-A was an economically dominant therapy with respect to cost per quality-adjusted life year. The cost per responder at 1 year was estimated to be £39,056 for aboBoNT-A vs. £54,831 for onaBoNT-A. LIMITATIONS AND CONCLUSIONS: Based on observed safety and efficacy data, aboBoNT-A is estimated to result in higher treatment response and consequently increased quality-of-life and reduced costs, vs. onaBoNT-A in children with upper limb spasticity. Limitations to the study include study heterogeneity limited details available for onaBoNT-A studies (e.g. use of physical therapy), and limited availability of responder data. Where assumptions were required, they were made to be conservative towards aboBoN-A.

Comprehensive genomic profiling for non-small-cell lung cancer: health and budget impact.

Background: Single-gene tests and hotspot panels targeting specific subsets of biomarkers constitute the Canadian genomic testing landscape for non-small-cell lung cancer (nsclc). However, newer testing options such as comprehensive genomic profiling (cgp) offer improved detection rates and identification of multiple classes of genomic alterations in a single assay, minimizing tissue requirements and turnaround time. The objective of the present analysis was to assess the health and budget impacts of adopting cgp testing for nsclc in Canada. Methods: This study assessed the impact of funding the cgp tests FoundationOne CDx and FoundationOne Liquid (Foundation Medicine, Cambridge, MA, U.S.A.) over a 3-year time horizon using a Canadian societal perspective for Ontario. Conventional testing strategies were summarized into two reference scenarios: a series of single-gene tests only, and reflex single-gene testing followed by a hotspot panel for negative results. Four adoption scenarios for cgp testing were considered: replacing all single-gene and hotspot panel testing, replacing hotspot panel testing only, use after negative single-gene and hotspot testing, and use of FoundationOne Liquid in individuals with insufficient tissue for conventional testing. Results: When cgp testing was assumed to replace all conventional testing with 50% uptake, the budget impact per person per year ranged from $0.71 to $0.87, depending on the reference scenario, with a 3-year gain of 680.9 life-years and 3831 working days over the full cohort. Conclusions: Given the present testing landscape for patients with nsclc in Canada, listing cgp testing could optimize the selection of appropriately targeted treatments, and thus add life-years and productivity for this population, with a minimal budget impact.

Cardiovascular risk profile in individuals initiating treatment for overactive bladder - Challenges and learnings for comparative analysis using linked claims and electronic medical record databases.

For managing overactive bladder (OAB), mirabegron, a ß3 adrenergic receptor agonist, is typically used as second-line pharmacotherapy after antimuscarinics. Therefore, patients initiating treatment with mirabegron and antimuscarinics may differ, potentially impacting associated clinical outcomes. When using observational data to evaluate real-world safety and effectiveness of OAB treatments, residual bias due to unmeasured confounding and/or confounding by indication are important considerations. Falsification analysis, in which clinically irrelevant endpoints are tested as a reference, can be used to assess residual bias. The objective in this study was to compare baseline cardiovascular risk among OAB patients by treatment, and assess the presence of residual bias via falsification analysis of OAB patients treated with mirabegron or antimuscarinics, to determine whether clinically relevant comparisons across groups would be feasible. Linked electronic health record and claims data (Optum/Humedica) for OAB patients in the United States from 2011-2015 were available, with index defined as first date of OAB treatment during this period. Unadjusted characteristics were compared across groups at index and propensity-matching conducted. Falsification endpoints (hepatitis C, shingles, community-acquired pneumonia) were compared between groups using odds ratios (ORs) and 95% confidence intervals (CI). The study identified 10,311 antimuscarinic- and 408 mirabegron-treated patients. Mirabegron patients were predominantly older males, with more comorbidities. The analytic sample included 1,188 antimuscarinic patients propensity-matched to 396 mirabegron patients; after matching, no significant baseline differences remained. Estimates of falsification ORs were 0.7 (CI:0.3-1.7) for shingles, 1.5 (CI:0.3-8.2) for hepatitis C, 0.8 (CI:0.4-1.8) and 0.9 (CI:0.6-1.4) for pneumonia. While propensity matching successfully balanced observed covariates, wide CIs prevented definitive conclusions regarding residual bias. Accordingly, further observational comparisons by treatment group were not pursued. In real-world analysis, bias-detection methods could not confirm that differences in cardiovascular risk in patients receiving mirabegron versus antimuscarinics were fully adjusted for, precluding clinically relevant comparisons across treatment groups.

Contributions of neuroimaging, balance testing, electrophysiology and blood markers to the assessment of sport-related concussion.

OBJECTIVE: To review the diagnostic tests and investigations used in the management of sports concussion, in the adult and paediatric populations, to (a) monitor the severity of symptoms and deficits, (b) track recovery and (c) advance knowledge relating to the natural history and neurobiology of the injury. DESIGN: Qualitative literature review of the neuroimaging, balance testing, electrophysiology, blood marker and concussion literature. INTERVENTION: PubMed and Medline databases were reviewed for investigations used in the management of adult and paediatric concussion, including structural imaging (computerised tomography, magnetic resonance imaging, diffusion tensor imaging), functional imaging (single photon emission computerised tomography, positron emission tomography, functional magnetic resonance imaging), spectroscopy (magnetic resonance spectroscopy, near infrared spectroscopy), balance testing (Balance Error Scoring System, Sensory Organization Test, gait testing, virtual reality), electrophysiological tests (electroencephalography, evoked potentials, event related potentials, magnetoencephalography, heart rate variability), genetics (apolipoprotein E4, channelopathies) and blood markers (S100, neuron-specific enolase, cleaved Tau protein, glutamate). RESULTS: For the adult and paediatric populations, each test has been classified as being: (1) clinically useful, (2) a research tool only or (3) not useful in sports-related concussion. CONCLUSIONS: The current status of the diagnostic tests and investigations is analysed, and potential directions for future research are provided. Currently, all tests and investigations, with the exception of clinical balance testing, remain experimental. There is accumulating research, however, that shows promise for the future clinical application of functional magnetic resonance imaging in sport concussion assessment and management.

Knowledge transfer principles as applied to sport concussion education.

OBJECTIVE: To (a) examine knowledge transfer literature and optimal learning needs as applied to healthcare professionals, coaches and student athletes; (b) apply the practice of knowledge transfer to sport concussion education resources; and (c) identify needs and make recommendations for optimising concussion education. DESIGN: Qualitative literature review of knowledge transfer and concussion education literature. INTERVENTION: Pubmed, Medline, Psych Info and Sport Discus databases were reviewed. 52 journal articles, 20 websites and 2 books were reviewed. RESULTS: The methods in which individuals experience optimal learning varies and should be considered when developing effective concussion education strategies. Physician knowledge and performance are impacted by education outreach, interaction and reminder messages. Educational strategies associated with optimal learning for physio and athletic therapists include problem and evidence-based practice, socialisation and peer-assisted learning. From a coaching perspective, research supports the reflective process as a learning modality. Student athletes have strengths and weaknesses in different areas and so perform differently on activities requiring distinct strategies. Knowing the impact of sport concussion resources on knowledge enhancement and modifying attitudes and behaviours toward concussion requires evaluation strategies. Review of concussion resources using the perspective of knowledge transfer and methods for improvement is discussed. CONCLUSIONS: Knowledge transfer is a relatively new concept in sports medicine and its influence on enhancing concussion education is not well known. The needs and optimal learning styles of target audiences coupled with evaluation need to be a piece of the overall concussion education puzzle to effectively impact knowledge of and attitudes and behaviours towards sport concussion.

Use of instrumental variables in the analysis of generalized linear models in the presence of unmeasured confounding with applications to epidemiological research.

A major, often unstated, concern of researchers carrying out epidemiological studies of medical therapy is the potential impact on validity if estimates of treatment are biased due to unmeasured confounders. One technique for obtaining consistent estimates of treatment effects in the presence of unmeasured confounders is instrumental variables analysis (IVA). This technique has been well developed in the econometrics literature and is being increasingly used in epidemiological studies. However, the approach to IVA that is most commonly used in such studies is based on linear models, while many epidemiological applications make use of non-linear models, specifically generalized linear models (GLMs) such as logistic or Poisson regression. Here we present a simple method for applying IVA within the class of GLMs using the generalized method of moments approach. We explore some of the theoretical properties of the method and illustrate its use within both a simulation example and an epidemiological study where unmeasured confounding is suspected to be present. We estimate the effects of beta-blocker therapy on one-year all-cause mortality after an incident hospitalization for heart failure, in the absence of data describing disease severity, which is believed to be a confounder.

Functional abnormalities in symptomatic concussed athletes: an fMRI study.

Our aim was to quantify with functional magnetic resonance imaging (fMRI) changes in brain activity in concussed athletes and compare the results with those of normal control subjects. Regional brain activations associated with a working memory task were obtained from a group of concussed athletes (15 symptomatic, 1 asymptomatic) and eight matched control subjects, using blood oxygen level dependent (BOLD) fMRI. The average percent signal change from baseline to working memory condition in each region of interest was computed. Symptomatic concussed athletes demonstrated task-related activations in some but not all the regions of interest, even when they performed as well as the control subjects. Furthermore, several concussed athletes had additional increases in activity outside the regions of interest, not seen in the control group. Quantitative analysis of BOLD signals within regions of interest revealed that, in general, concussed athletes had different BOLD responses compared to the control subjects. The task-related activation pattern of the one symptom-free athlete was comparable to that of the control group. We also repeated the study in one athlete whose symptoms had resolved. On the first study, when he was still symptomatic, less task-related activations were observed. On follow-up, once his symptoms had disappeared, the task-related activations became comparable to those of the control group. These results demonstrate the potential of fMRI, in conjunction with the working memory task, to identify an underlying pathology in symptomatic concussed individuals with normal structural imaging results.

Snowblading injuries in Eastern Canada.

OBJECTIVES: To evaluate injury patterns of snowbladers and compare them with those of skiers and snowboarders. To determine possible effects of helmet use in these sports on injury to the head and neck. METHODS: This prospective case series observational study was conducted by collecting the injury reports from the ski patrol during the 1999-2000 season at Mont Tremblant ski resort, Quebec. All participants in downhill winter sports who presented themselves to the ski patrol with traumatic injury related to their sport were included. A concussion was defined as any loss of consciousness, amnesia, confusion, disorientation, vertigo, or headache that resulted from injury. The ski patroller reported helmet use on the accident report at the time of injury. RESULTS: Snowbladers present with a unique pattern of injury compared with skiers and snowboarders. The incidence of leg, knee, and ankle/foot injuries were 20.5%, 25.6%, and 10.3% respectively. Concussions represented 11% of all injuries. There was no increase in other injury, including neck injury, related to helmet use. CONCLUSIONS: Unique injury patterns in snowbladers warrant reconsideration of equipment design. Concussion is a common injury on the ski slope. Although the effects of helmet use on concussion rate are inconclusive based on this study, helmet use did not increase the rate of neck injury, even when adjusted for age.

Evidence-based review of sport-related concussion: basic science.

The evidence base for sport-related concussive brain injury is reviewed in this paper. In the past, pathophysiological understanding of this common condition has been extrapolated from studies of severe brain trauma. More recent scientific study demonstrates that this approach is unsatisfactory, and the clinical features of concussion represent a predominantly functional brain injury rather than manifest by structural or neuropathological damage. Such understanding of this condition remains incomplete at this stage.

Evidence-Based review of sport-related concussion: clinical science.

The clinical nature of sport-related concussion is discussed in this paper. Particularly highlighted are the difficulties with definition, injury severity grading, classification, and understanding of clinical symptoms. In addition, the well-recognized sequelae of concussion including the motor and convulsive manifestations are discussed in detail. Where possible, an evidence-based approach is adopted to assist the understanding of the literature in this complex area.

New frontiers in diagnostic imaging in concussive head injury.

Concussed athletes may have documented incapacitating postconcussive symptoms, neuropsychological deficits, and consequent important changes in their lives and sport, yet the majority of neuroimaging attempts reveal few findings to account for these signs and symptoms. In this paper, we explore new techniques in the neuroimaging of concussion including diffusion-weighted magnetic resonance imaging and functional brain imaging technology.

Recommendations for grading of concussion in athletes.

Mild sports-related concussions, in which there is no loss of consciousness, account for >75% of all sports-related brain injury. Universal agreement on concussion definition and severity grading does not exist. Grading systems represent expertise of clinicians and researchers yet scientific evidence is lacking. Most used loss of consciousness and post-traumatic amnesia as markers for grading concussion. Although in severe head injury these parameters may have been proven important for prognosis, no study has done the same for sport-related concussion. Post-concussion symptoms are often the main features to help in the diagnosis of concussion in sport. Neuropsychological testing is meant to help physicians and health professionals to have objective indices of some of the neurocognitive symptoms. It is the challenge of physicians, therapists and coaches involved in the care of athletes to know the symptoms of concussion, recognise them when they occur and apply basic neuropsychological testing to help detect this injury. It is, therefore, recommended to be familiar with one grading system and use it consistently, even though it may not be scientifically validated. Then good clinical judgement and the ability to recognise post-concussion signs and symptoms will assure that an athlete never returns to play while symptomatic.

Fate and transport of copper-based crop protectants in plasticulture runoff and the impact of sedimentation as a best management practice.

The fate and distribution of copper-based crop protectants, applied to plasticulture tomato fields to protect against disease, were investigated in a greenhouse-scale simulation of farming conditions in a coastal environment. Following rainfall, 99% of the applied copper was found to remain on the fields sorbed to the soil and plants; most of the soil-bound copper was found sorbed to the top 2.5 cm of soil between the plasticulture rows. Of the copper leaving the agricultural fields, 82% was found in the runoff with the majority, 74%. sorbed to the suspended solids. The remaining copper, 18%, leached through the soil and entered the groundwater with 10% in the dissolved phase and 8% sorbed to suspended solids. Although only 1% copper was found to leave the field, this was sufficient to cause high copper concentrations (average 2102+/-433 microg/L total copper and 189+/-139 microg/L dissolved copper) in the runoff. Copper concentrations in groundwater samples were also high (average 312+/-198 microg/L total copper and 216+/-99 microg/L dissolved copper). Sedimentation, a best management practice for reducing copper loadings. was found to reduce the total copper concentrations in runoff by 90% to a concentration of 245+/-127 microg/L; however, dissolved copper concentrations remained stable, averaging 139+/-55 microg/L. Total copper concentrations were significantly reduced by the effective removal of suspended solids with sorbed copper.

Outbreak of Salmonella indiana associated with egg mayonnaise sandwiches at an acute NHS hospital.

An outbreak of Salmonella indiana infection in December 2000 affected 17 staff, relatives and patients at an acute NHS Hospital in Swansea. Epidemiological investigation identified egg mayonnaise sandwiches as the vehicle of infection. It was not possible to definitively determine the source of the infection or how the prepared sandwiches became contaminated. The most likely explanation was a pasteurisation failure of a batch of the egg roll used to make these sandwiches. Sandwiches are the most frequently identified vehicle of infection in foodborne outbreaks of salmonella infection in hospitals in England and Wales. The process of sandwich preparation has inherent risks because it involves considerable handling of food, which is consumed without further cooking. Care is required in all stages of preparation including the sourcing of materials used to produce the sandwiches. NHS Trusts should review their Hazard Analysis Critical Control Point plans for sandwich production.