Occurrence, fate, and potential impacts of wood preservatives in the environment: Challenges and environmentally friendly solutions.

Wood preservation has gained global prevalence in recent years, primarily owing to the renewable nature of wood and its capacity to act as a carbon sink. Wood, in its natural form, lacks intrinsic resilience and is prone to decay if left untreated; hence, wood preservatives (WPs) are used to improve wood's longevity. The fate and potential hazards of wood preservatives to human health, ecosystems, and the environment are complex and depend on various aspects, including the type of the preservative compounds, their physicochemical properties, application methods, exposure pathways, environmental conditions, and safety measures and guidelines. The occurrence and distribution of WPs in environmental matrices such as soil and water can result in hazardous pollutants seeping into surface water, groundwater, and soil, posing health hazards, and polluting the environment. Bioremediation is crucial to safeguarding the environment and effectively removing contaminants through hydrolytic and/or photochemical reactions. Phytoremediation, vermicomposting, and sustainable adsorption have demonstrated significant efficacy in the remediation of WPs in the natural environment. Adsorbents derived from biomass waste have been acknowledged for their ability to effectively remove WPs, while also offering cost-efficiency and environmental sustainability. This paper aims to identify wood preservatives' sources and fate in the environment and present a comprehensive overview of the latest advancements in environmentally friendly methods relevant to the removal of the commonly observed contaminants associated with WPs in environmental matrices.

Cancer pain assessment and management: does an institutional approach individualise and reduce cost of care?

OBJECTIVES: To understand individual prescribing and associated costs in patients managed with the Edinburgh Pain Assessment and management Tool (EPAT). METHODS: The EPAT study was a two-arm parallel group cluster randomised (1:1) trial, including 19 UK cancer centres. Study outcome assessments, including pain levels, analgesia and non-pharmacological and anaesthetic interventions, collected at baseline, 3-5 days and, if applicable, 7-10 days after admission. Costs calculated for inpatient length of stay (LoS), medications and complex pain interventions. Analysis accounted for the clustered nature of the trial design. In this post-hoc analysis, healthcare utilisation and costs are presented descriptively. PARTICIPANTS: 10 centres randomised to EPAT (487 patients) and 9 (449 patients) to usual care (UC). MAIN OUTCOME MEASURES: Pharmacological and non-pharmacological management, complex pain interventions, length of hospital stay and costs related to these outcomes. RESULTS: The mean per patient hospital cost was £3866 with EPAT and £4194 with UC, reflecting a mean LoS of 2.9 days and 3.1 days, respectively. Costs were lower for non-opioids, Non-steroidal anti-inflammatories (NSAIDs) and opioids but slightly higher for adjuvants with EPAT than with UC. The mean per-patient opioid costs were £17.90 (EPAT) and £25.80 (UC). Mean per patient costs of all medication were £36 (EPAT) and £40 (UC).Complex pain intervention costs were £117 with EPAT per patient and £90 with UC. Overall mean cost per patient was £4018.3 (95% CI 3698.9 to 4337.8) with EPAT and £4323.8 (95% CI 4060.0 to 4587.7) with UC. CONCLUSIONS: EPAT facilitated personalised medicine and may result in less opioids, more specific treatments, improved pain outcomes and cost savings.

Evaluation of Outcomes Among Patients With Traumatic Intracranial Hypertension Treated With Decompressive Craniectomy vs Standard Medical Care at 24 Months: A Secondary Analysis of the RESCUEicp Randomized Clinical Trial.

Importance: Trials often assess primary outcomes of traumatic brain injury at 6 months. Longer-term data are needed to assess outcomes for patients receiving surgical vs medical treatment for traumatic intracranial hypertension. Objective: To evaluate 24-month outcomes for patients with traumatic intracranial hypertension treated with decompressive craniectomy or standard medical care. Design, Setting, and Participants: Prespecified secondary analysis of the Randomized Evaluation of Surgery With Craniectomy for Uncontrollable Elevation of Intracranial Pressure (RESCUEicp) randomized clinical trial data was performed for patients with traumatic intracranial hypertension (>25 mm Hg) from 52 centers in 20 countries. Enrollment occurred between January 2004 and March 2014. Data were analyzed between 2018 and 2021. Eligibility criteria were age 10 to 65 years, traumatic brain injury (confirmed via computed tomography), intracranial pressure monitoring, and sustained and refractory elevated intracranial pressure for 1 to 12 hours despite pressure-controlling measures. Exclusion criteria were bilateral fixed and dilated pupils, bleeding diathesis, or unsurvivable injury. Interventions: Patients were randomly assigned 1:1 to receive a decompressive craniectomy with standard care (surgical group) or to ongoing medical treatment with the option to add barbiturate infusion (medical group). Main Outcomes and Measures: The primary outcome was measured with the 8-point Extended Glasgow Outcome Scale (1 indicates death and 8 denotes upper good recovery), and the 6- to 24-month outcome trajectory was examined. Results: This study enrolled 408 patients: 206 in the surgical group and 202 in the medical group. The mean (SD) age was 32.3 (13.2) and 34.8 (13.7) years, respectively, and the study population was predominantly male (165 [81.7%] and 156 [80.0%], respectively). At 24 months, patients in the surgical group had reduced mortality (61 [33.5%] vs 94 [54.0%]; absolute difference, -20.5 [95% CI, -30.8 to -10.2]) and higher rates of vegetative state (absolute difference, 4.3 [95% CI, 0.0 to 8.6]), lower or upper moderate disability (4.7 [-0.9 to 10.3] vs 2.8 [-4.2 to 9.8]), and lower or upper severe disability (2.2 [-5.4 to 9.8] vs 6.5 [1.8 to 11.2]; χ27 = 24.20, P = .001). For every 100 individuals treated surgically, 21 additional patients survived at 24 months; 4 were in a vegetative state, 2 had lower and 7 had upper severe disability, and 5 had lower and 3 had upper moderate disability, respectively. Rates of lower and upper good recovery were similar for the surgical and medical groups (20 [11.0%] vs 19 [10.9%]), and significant differences in net improvement (≥1 grade) were observed between 6 and 24 months (55 [30.0%] vs 25 [14.0%]; χ22 = 13.27, P = .001). Conclusions and Relevance: At 24 months, patients with surgically treated posttraumatic refractory intracranial hypertension had a sustained reduction in mortality and higher rates of vegetative state, severe disability, and moderate disability. Patients in the surgical group were more likely to improve over time vs patients in the medical group. Trial Registration: ISRCTN Identifier: 66202560.

Application of Process Hazard Analysis and Inherently Safer Design in Wood Pellet Production.

Wood pellets are a fuel used for heat and power generation. Wood pellets are manufactured from forest residues and byproducts of other sectors in the wood processing industry, such as sawmilling. Wood pellet production generates combustible wood dust, which presents the risk of fire and explosion. The objective of this research was to incorporate the principles of inherently safer design (ISD) for the management of combustible dust hazards associated with wood pellet production. Using bow tie analysis to explicitly consider ISD within process hazard analysis (PHA), ISD barriers were successfully identified, including the use of paved surfaces to store feedstock to minimize rocks entering the process and presenting a risk of ignition sources, the use of reduced-size silos to minimize the inventory and increase the turnover frequency, the removal of unnecessary or hazardous equipment, such as fans, following a redesign, and the relocation of hazardous equipment, such as cyclones, outside and away from personnel. A summary of example-based guidance for combustible dust hazards was collected to support additional ISD implementation within PHA as part of the process safety management (PSM). The research also highlights learnings for conducting virtual PHA workshops, as well as identifying opportunities for incorporating ISD within operating wood processing facilities through the incident investigation and risk assessment elements of PSM.

Effects of Antiplatelet Therapy After Stroke Caused by Intracerebral Hemorrhage: Extended Follow-up of the RESTART Randomized Clinical Trial.

Importance: The Restart or Stop Antithrombotics Randomized Trial (RESTART) found that antiplatelet therapy appeared to be safe up to 5 years after intracerebral hemorrhage (ICH) that had occurred during antithrombotic (antiplatelet or anticoagulant) therapy. Objectives: To monitor adherence, increase duration of follow-up, and improve precision of estimates of the effects of antiplatelet therapy on recurrent ICH and major vascular events. Design, Setting and Participants: From May 22, 2013, through May 31, 2018, this prospective, open, blinded end point, parallel-group randomized clinical trial studied 537 participants at 122 hospitals in the UK. Participants were individuals 18 years or older who had taken antithrombotic therapy for the prevention of occlusive vascular disease when they developed ICH, discontinued antithrombotic therapy, and survived for 24 hours. After initial follow-up ended on November 30, 2018, annual follow-up was extended until November 30, 2020, for a median of 3.0 years (interquartile range [IQR], 2.0-5.0 years) for the trial cohort. Interventions: Computerized randomization that incorporated minimization allocated participants (1:1) to start or avoid antiplatelet therapy. Main Outcomes and Measures: Participants were followed up for the primary outcome (recurrent symptomatic ICH) and secondary outcomes (all major vascular events) for up to 7 years. Data from all randomized participants were analyzed using Cox proportional hazards regression, adjusted for minimization covariates. Results: A total of 537 patients (median age, 76.0 years; IQR, 69.0-82.0 years; 360 [67.0%] male; median time after ICH onset, 76.0 days; IQR, 29.0-146.0 days) were randomly allocated to start (n = 268) or avoid (n = 269 [1 withdrew]) antiplatelet therapy. The primary outcome of recurrent ICH affected 22 of 268 participants (8.2%) allocated to antiplatelet therapy compared with 25 of 268 participants (9.3%) allocated to avoid antiplatelet therapy (adjusted hazard ratio, 0.87; 95% CI, 0.49-1.55; P = .64). A major vascular event affected 72 participants (26.8%) allocated to antiplatelet therapy compared with 87 participants (32.5%) allocated to avoid antiplatelet therapy (hazard ratio, 0.79; 95% CI, 0.58-1.08; P = .14). Conclusions and Relevance: Among patients with ICH who had previously taken antithrombotic therapy, this study found no statistically significant effect of antiplatelet therapy on recurrent ICH or all major vascular events. These findings provide physicians with some reassurance about the use of antiplatelet therapy after ICH if indicated for secondary prevention of major vascular events. Trial Registration: isrctn.org Identifier: ISRCTN71907627.

Targeting rehabilitation to improve outcomes after total knee arthroplasty in patients at risk of poor outcomes: randomised controlled trial.

OBJECTIVE: To evaluate whether a progressive course of outpatient physiotherapy offers superior outcomes to a single physiotherapy review and home exercise based intervention when targeted at patients with a predicted poor outcome after total knee arthroplasty. DESIGN: Parallel group randomised controlled trial. SETTING: 13 secondary and tertiary care centres in the UK providing postoperative physiotherapy. PARTICIPANTS: 334 participants with knee osteoarthritis who were defined as at risk of a poor outcome after total knee arthroplasty, based on the Oxford knee score, at six weeks postoperatively. 163 were allocated to therapist led outpatient rehabilitation and 171 to a home exercise based protocol. INTERVENTIONS: All participants were reviewed by a physiotherapist and commenced 18 sessions of rehabilitation over six weeks, either as therapist led outpatient rehabilitation (progressive goal oriented functional rehabilitation protocol, modified weekly in one-one contact sessions) or as physiotherapy review followed by a home exercise based regimen (without progressive input from a physiotherapist). MAIN OUTCOME MEASURES: Primary outcome was Oxford knee score at 52 weeks, with a 4 point difference between groups considered to be clinically meaningful. Secondary outcomes included additional patient reported outcome measures of pain and function at 14, 26, and 52 weeks post-surgery. RESULTS: 334 patients were randomised. Eight were lost to follow-up. Intervention compliance was more than 85%. The between group difference in Oxford knee score at 52 weeks was 1.91 (95% confidence interval -0.18 to 3.99) points, favouring the outpatient rehabilitation arm (P=0.07). When all time point data were analysed, the between group difference in Oxford knee score was a non-clinically meaningful 2.25 points (0.61 to 3.90, P=0.01). No between group differences were found for secondary outcomes of average pain (0.25 points, -0.78 to 0.28, P=0.36) or worst pain (0.22 points, -0.71 to 0.41, P=0.50) at 52 weeks or earlier time points, or of satisfaction with outcome (odds ratio 1.07, 95% confidence interval 0.71 to 1.62, P=0.75) or post-intervention function (4.64 seconds, 95% confidence interval -14.25 to 4.96, P=0.34). CONCLUSIONS: Outpatient therapist led rehabilitation was not superior to a single physiotherapist review and home exercise based regimen in patients at risk of poor outcomes after total knee arthroplasty. No clinically relevant differences were observed across primary or secondary outcome measures. TRIALS REGISTRATION: Current Controlled Trials ISRCTN23357609 and ClinicalTrials.gov NCT01849445.

A practical method for dealing with missing Glasgow Coma Scale verbal component scores.

OBJECTIVE: The Glasgow Coma Scale (GCS) is used for the assessment of impaired consciousness; however, it is not always possible to test each component, most commonly the verbal component. This affects the derivation of the GCS sum score, which has a role in systems for predicting patient outcome. Imputation of missing scores does not add extra information, but it does allow use of tools for predicting outcome that require complete data. The authors devised a simple and practical tool to employ when verbal component data are missing. They then assessed the tool's utility by application to the GCS-Pupils plus age plus CT findings (GCS-PA CT) prognostic model. METHODS: The authors inspected data from the International Mission for Prognosis and Analysis of Clinical Trials in Traumatic Brain Injury (IMPACT) cohort to characterize the frequency of missing verbal scores. The authors identified a single verbal score to impute for each eye and motor combined sum (EM) score from distributions of verbal scores in a published database of 54,069 patients. The effectiveness of the imputed verbal score was assessed using a dataset containing information from the IMPACT and Corticosteroid Randomisation After Significant Head Injury (CRASH) databases. The authors compared the performance of the prognostic model using actual verbal scores with the performance using imputed verbal scores and assessed the information yield using Nagelkerke's R2 statistic. RESULTS: Verbal data were most commonly missing in patients with no eye opening and with a motor score of 4 or less. The "simple" imputation model that was developed performed as well as a more complex model involving distinct combinations of eye and motor scores. The imputation model consisted of the following: EM scores 2-6, add 1; EM score 7, add 2; EM score 8 or 9, add 4; and EM score 10, add 5 to provide the GCS sum score. Modeling without information about the verbal score reduced the R2 from 32.1% to 31.4% and from 34.9% to 34.0% for predictions of death and favorable outcome at 6 months, respectively, compared with using full verbal score information. CONCLUSIONS: This strategy is particularly valuable for imputation in clinical practice, enabling clinicians to make a rapid and reliable determination of the GCS sum score when the verbal component is not testable. This will support clinical communication and decisions based on estimates of injury severity as well as enable estimation of prognosis. The authors suggest that external validation of their imputation strategy and the performance of the GCS-PA charts should be undertaken in other clinical populations.

Metabolite identification using an ion mobility enhanced data-independent acquisition strategy and automated data processing.

RATIONALE: Liquid chromatography/mass spectrometry is an essential tool for efficient and reliable quantitative and qualitative analysis and underpins much of contemporary drug metabolism and pharmacokinetics. Data-independent acquisition methods such as MSE have reduced the potential to miss metabolites, but do not formally generate quadrupole-resolved product ion spectra. The addition of ion mobility separation to these approaches, for example, in High-Definition MSE (HDMSE ) has the potential to reduce the time needed to set up an experiment and maximize the chance that all metabolites present can be resolved and characterized. We compared High-Definition Data-Dependent Acquisition (HD-DDA), MSE and HDMSE approaches using automated software processing with Mass-MetaSite and WebMetabase. METHODS: Metabolite identification was performed on incubations of glucagon-like peptide-1 (7-37) (GLP-1) and verapamil hydrochloride. The HD-DDA, MSE and HDMSE experiments were conducted on a Waters ACQUITY UPLC I-Class LC system with a VION IMS quadrupole time-of-flight (QTOF) mass spectrometer operating under UNIFI control. All acquired data were processed using MassMetaSite able to read data from UNIFI 1.9.4. WebMetabase was used to review the detected chromatographic peaks and the spectral data interpretations. RESULTS: A comparison of outcomes obtained for MSE and HDMSE data demonstrated that the same structures were proposed for metabolites of both verapamil and GLP-1. The ratio of structurally matched to mismatched product ions found by MassMetaSite was slightly greater for HDMSE than for MSE , and HD-DDA, thus improving confidence in the structures proposed through the addition of ion mobility based data acquisitions. CONCLUSIONS: HDMSE data acquisition is an effective approach for the elucidation of metabolite structures for both small molecules and peptides, with excellent accuracy and quality, requiring minimal tailoring for the compound under investigation.

Zoledronate in the prevention of Paget's (ZiPP): protocol for a randomised trial of genetic testing and targeted zoledronic acid therapy to prevent SQSTM1-mediated Paget's disease of bone.

INTRODUCTION: Paget's disease of bone (PDB) is characterised by increased and disorganised bone remodelling affecting one or more skeletal sites. Complications include bone pain, deformity, deafness and pathological fractures. Mutations in sequestosome-1 (SQSTM1) are strongly associated with the development of PDB. Bisphosphonate therapy can improve bone pain in PDB, but there is no evidence that treatment alters the natural history of PDB or prevents complications. The Zoledronate in the Prevention of Paget's disease trial (ZiPP) will determine if prophylactic therapy with the bisphosphonate zoledronic acid (ZA) can delay or prevent the development of PDB in people who carry SQSTM1 mutations. METHODS AND ANALYSIS: People with a family history of PDB aged >30 years who test positive for SQSTM1 mutations are eligible to take part. At the baseline visit, participants will be screened for the presence of bone lesions by radionuclide bone scan. Biochemical markers of bone turnover will be measured and questionnaires completed to assess pain, health-related quality of life (HRQoL), anxiety and depression. Participants will be randomised to receive a single intravenous infusion of 5 mg ZA or placebo and followed up annually for between 4 and 8 years at which point baseline assessments will be repeated. The primary endpoint will be new bone lesions assessed by radionuclide bone scan. Secondary endpoints will include changes in biochemical markers of bone turnover, pain, HRQoL, anxiety, depression and PDB-related skeletal events. ETHICS AND DISSEMINATION: The study was approved by the Fife and Forth Valley Research Ethics Committee on 22 December 2008 (08/S0501/84). Following completion of the trial, a manuscript will be submitted to a peer-reviewed journal. The results of this trial will inform clinical practice by determining if early intervention with ZA in presymptomatic individuals with SQSTM1 mutations can prevent or slow the development of bone lesions with an adverse event profile that is acceptable. TRIAL REGISTRATION NUMBER: ISRCTN11616770.

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial.

BACKGROUND: Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy. METHODS: RESTART was a prospective, randomised, open-label, blinded-endpoint, parallel-group trial at 122 hospitals in the UK that assessed whether starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. For this prespecified subgroup analysis, consultant neuroradiologists masked to treatment allocation reviewed brain CT or MRI scans performed before randomisation to confirm participant eligibility and rate features of the intracerebral haemorrhage and surrounding brain. We followed participants for primary (recurrent symptomatic intracerebral haemorrhage) and secondary (ischaemic stroke) outcomes for up to 5 years (reported elsewhere). For this report, we analysed eligible participants with intracerebral haemorrhage according to their treatment allocation in primary subgroup analyses of cerebral microbleeds on MRI and in exploratory subgroup analyses of other features on CT or MRI. The trial is registered with the ISRCTN registry, number ISRCTN71907627. FINDINGS: Between May 22, 2013, and May 31, 2018, 537 participants were enrolled, of whom 525 (98%) had intracerebral haemorrhage: 507 (97%) were diagnosed on CT (252 assigned to start antiplatelet therapy and 255 assigned to avoid antiplatelet therapy, of whom one withdrew and was not analysed) and 254 (48%) underwent the required brain MRI protocol (122 in the start antiplatelet therapy group and 132 in the avoid antiplatelet therapy group). There were no clinically or statistically significant hazards of antiplatelet therapy on recurrent intracerebral haemorrhage in primary subgroup analyses of cerebral microbleed presence (2 or more) versus absence (0 or 1) (adjusted hazard ratio [HR] 0·30 [95% CI 0·08-1·13] vs 0·77 [0·13-4·61]; pinteraction=0·41), cerebral microbleed number 0-1 versus 2-4 versus 5 or more (HR 0·77 [0·13-4·62] vs 0·32 [0·03-3·66] vs 0·33 [0·07-1·60]; pinteraction=0·75), or cerebral microbleed strictly lobar versus other location (HR 0·52 [0·004-6·79] vs 0·37 [0·09-1·28]; pinteraction=0·85). There was no evidence of heterogeneity in the effects of antiplatelet therapy in any exploratory subgroup analyses (all pinteraction>0·05). INTERPRETATION: Our findings exclude all but a very modest harmful effect of antiplatelet therapy on recurrent intracerebral haemorrhage in the presence of cerebral microbleeds. Further randomised trials are needed to replicate these findings and investigate them with greater precision. FUNDING: British Heart Foundation.

Effect of Alendronic Acid on Fracture Healing: A Multicenter Randomized Placebo-Controlled Trial.

There is a concern that bisphosphonates may impair fracture healing because of their inhibitory effects on bone turnover. Here we evaluated the effects of early bisphosphonate therapy on fracture healing and functional outcome following a fracture of the distal radius. The fracture and bisphosphonates (FAB) trial was a double-blind, randomized, placebo-controlled trial involving 15 trauma centers in the United Kingdom. We enrolled 421 bisphosphonate-naive patients aged ≥50 years with a radiographically confirmed fracture of the distal radius and randomized them in a 1:1 ratio to receive alendronic acid 70 mg once weekly (n = 215) or placebo (n = 206) within 14 days of the fracture. The primary outcome measure was the proportion of fractures that had radiologically united at 4 weeks as assessed by an observer, blinded to treatment allocation. Secondary outcomes included the Disabilities of the Arm Shoulder and Hand (DASH) questionnaire, range of wrist movement and grip strength, pain and analgesia requirements, and the rate of malunion. The mean ± SD age of participants was 63 ± 8.5 years and 362 (86%) were female. At 4 weeks, 48 of 202 (23.8%) fractures had united in the alendronic acid group compared with 52 of 187 (27.8%) in the placebo group (observed absolute proportion difference 4.0%; 95% CI, -4.7% to 12.8%; p = 0.36). The absolute proportion difference between groups based on imputed data was 4.5% (95% CI, -4.7% to 13.8%; p = 0.30). There was no significant difference in the proportion of fractures that had united at any other time point and no differences in the DASH score, pain at the fracture site, grip strength, or any other clinical outcome. We conclude that among patients aged 50 years and above with a distal radius fracture, early administration of alendronic acid does not adversely affect fracture union or clinical outcome. These findings suggest bisphosphonate therapy can be safely commenced early after fracture if clinically indicated. © 2019 American Society for Bone and Mineral Research.

The REstart or STop Antithrombotics Randomised Trial (RESTART) after stroke due to intracerebral haemorrhage: statistical analysis plan for a randomised controlled trial.

BACKGROUND: For adults surviving stroke due to spontaneous (non-traumatic) intracerebral haemorrhage (ICH) who had taken an antithrombotic (i.e. anticoagulant or antiplatelet) drug for the prevention of vaso-occlusive disease before the ICH, it is unclear whether starting antiplatelet therapy modifies the risks of recurrent ICH, major haemorrhagic events, major occlusive vascular events, or a composite of all major vascular events compared to avoiding antiplatelet therapy. METHODS/DESIGN: The REstart or STop Antithrombotics Randomised Trial (RESTART) is an investigator-led, parallel group, open, assessor-blind, randomised trial comparing starting versus avoiding antiplatelet therapy for adults surviving antithrombotic-associated ICH. Recruitment began on 22 May 2013 and ended on 31 May 2018. Follow-up ended on 30 November 2018. This update to the protocol describes the statistical analysis plan (version 1.7, finalised on 25 January 2019). Database lock and un-blinding occurred on 29 January 2019, after which the un-masked trial statistician conducted the final analyses according to this statistical analysis plan. DISCUSSION: Final results of RESTART will be analysed and disseminated in May 2019. TRIAL REGISTRATION: ISRCTN registry 71907627 . Prospectively registered on 25 April 2013.

Therapeutic hypothermia to reduce intracranial pressure after traumatic brain injury: the Eurotherm3235 RCT.

BACKGROUND: Traumatic brain injury (TBI) is a major cause of disability and death in young adults worldwide. It results in around 1 million hospital admissions annually in the European Union (EU), causes a majority of the 50,000 deaths from road traffic accidents and leaves a further ≈10,000 people severely disabled. OBJECTIVE: The Eurotherm3235 Trial was a pragmatic trial examining the effectiveness of hypothermia (32-35 °C) to reduce raised intracranial pressure (ICP) following severe TBI and reduce morbidity and mortality 6 months after TBI. DESIGN: An international, multicentre, randomised controlled trial. SETTING: Specialist neurological critical care units. PARTICIPANTS: We included adult participants following TBI. Eligible patients had ICP monitoring in place with an ICP of > 20 mmHg despite first-line treatments. Participants were randomised to receive standard care with the addition of hypothermia (32-35 °C) or standard care alone. Online randomisation and the use of an electronic case report form (CRF) ensured concealment of random treatment allocation. It was not possible to blind local investigators to allocation as it was obvious which participants were receiving hypothermia. We collected information on how well the participant had recovered 6 months after injury. This information was provided either by the participant themself (if they were able) and/or a person close to them by completing the Glasgow Outcome Scale - Extended (GOSE) questionnaire. Telephone follow-up was carried out by a blinded independent clinician. INTERVENTIONS: The primary intervention to reduce ICP in the hypothermia group after randomisation was induction of hypothermia. Core temperature was initially reduced to 35 °C and decreased incrementally to a lower limit of 32 °C if necessary to maintain ICP at < 20 mmHg. Rewarming began after 48 hours if ICP remained controlled. Participants in the standard-care group received usual care at that centre, but without hypothermia. MAIN OUTCOME MEASURES: The primary outcome measure was the GOSE [range 1 (dead) to 8 (upper good recovery)] at 6 months after the injury as assessed by an independent collaborator, blind to the intervention. A priori subgroup analysis tested the relationship between minimisation factors including being aged < 45 years, having a post-resuscitation Glasgow Coma Scale (GCS) motor score of < 2 on admission, having a time from injury of < 12 hours and patient outcome. RESULTS: We enrolled 387 patients from 47 centres in 18 countries. The trial was closed to recruitment following concerns raised by the Data and Safety Monitoring Committee in October 2014. On an intention-to-treat basis, 195 participants were randomised to hypothermia treatment and 192 to standard care. Regarding participant outcome, there was a higher mortality rate and poorer functional recovery at 6 months in the hypothermia group. The adjusted common odds ratio (OR) for the primary statistical analysis of the GOSE was 1.54 [95% confidence interval (CI) 1.03 to 2.31]; when the GOSE was dichotomised the OR was 1.74 (95% CI 1.09 to 2.77). Both results favoured standard care alone. In this pragmatic study, we did not collect data on adverse events. Data on serious adverse events (SAEs) were collected but were subject to reporting bias, with most SAEs being reported in the hypothermia group. CONCLUSIONS: In participants following TBI and with an ICP of > 20 mmHg, titrated therapeutic hypothermia successfully reduced ICP but led to a higher mortality rate and worse functional outcome. LIMITATIONS: Inability to blind treatment allocation as it was obvious which participants were randomised to the hypothermia group; there was biased recording of SAEs in the hypothermia group. We now believe that more adequately powered clinical trials of common therapies used to reduce ICP, such as hypertonic therapy, barbiturates and hyperventilation, are required to assess their potential benefits and risks to patients. TRIAL REGISTRATION: Current Controlled Trials ISRCTN34555414. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 45. See the NIHR Journals Library website for further project information. The European Society of Intensive Care Medicine supported the pilot phase of this trial.

Simplifying the use of prognostic information in traumatic brain injury. Part 1: The GCS-Pupils score: an extended index of clinical severity.

Objective: Glasgow Coma Scale (GCS) scores and pupil responses are key indicators of the severity of traumatic brain damage. The aim of this study was to determine what information would be gained by combining these indicators into a single index and to explore the merits of different ways of achieving this. Methods: METHODS Information about early GCS scores, pupil responses, late outcomes on the Glasgow Outcome Scale, and mortality were obtained at the individual patient level by reviewing data from the CRASH (Corticosteroid Randomisation After Significant Head Injury; n = 9,045) study and the IMPACT (International Mission for Prognosis and Clinical Trials in TBI; n = 6855) database. These data were combined into a pooled data set for the main analysis. Methods of combining the Glasgow Coma Scale and pupil response data varied in complexity from using a simple arithmetic score (GCS score [range 3-15] minus the number of nonreacting pupils [0, 1, or 2]), which we call the GCS-Pupils score (GCS-P; range 1-15), to treating each factor as a separate categorical variable. The content of information about patient outcome in each of these models was evaluated using Nagelkerke's R2. Results: Separately, the GCS score and pupil response were each related to outcome. Adding information about the pupil response to the GCS score increased the information yield. The performance of the simple GCS-P was similar to the performance of more complex methods of evaluating traumatic brain damage. The relationship between decreases in the GCS-P and deteriorating outcome was seen across the complete range of possible scores. The additional 2 lowest points offered by the GCS-Pupils scale (GCS-P 1 and 2) extended the information about injury severity from a mortality rate of 51% and an unfavorable outcome rate of 70% at GCS score 3 to a mortality rate of 74% and an unfavorable outcome rate of 90% at GCS-P 1. The paradoxical finding that GCS score 4 was associated with a worse outcome than GCS score 3 was not seen when using the GCS-P. Conclusions: A simple arithmetic combination of the GCS score and pupillary response, the GCS-P, extends the information provided about patient outcome to an extent comparable to that obtained using more complex methods. The greater range of injury severities that are identified and the smoothness of the stepwise pattern of outcomes across the range of scores may be useful in evaluating individual patients and identifying patient subgroups. The GCS-P may be a useful platform onto which information about other key prognostic features can be added in a simple format likely to be useful in clinical practice.

Simplifying the use of prognostic information in traumatic brain injury. Part 2: Graphical presentation of probabilities.

OBJECTIVE Clinical features such as those included in the Glasgow Coma Scale (GCS) score, pupil reactivity, and patient age, as well as CT findings, have clear established relationships with patient outcomes due to neurotrauma. Nevertheless, predictions made from combining these features in probabilistic models have not found a role in clinical practice. In this study, the authors aimed to develop a method of displaying probabilities graphically that would be simple and easy to use, thus improving the usefulness of prognostic information in neurotrauma. This work builds on a companion paper describing the GCS-Pupils score (GCS-P) as a tool for assessing the clinical severity of neurotrauma. METHODS Information about early GCS score, pupil response, patient age, CT findings, late outcome according to the Glasgow Outcome Scale, and mortality were obtained at the individual adult patient level from the CRASH (Corticosteroid Randomisation After Significant Head Injury; n = 9045) and IMPACT (International Mission for Prognosis and Clinical Trials in TBI; n = 6855) databases. These data were combined into a pooled data set for the main analysis. Logistic regression was first used to model the combined association between the GCS-P and patient age and outcome, following which CT findings were added to the models. The proportion of variability in outcomes "explained" by each model was assessed using Nagelkerke's R2. RESULTS The authors observed that patient age and GCS-P have an additive effect on outcome. The probability of mortality 6 months after neurotrauma is greater with increasing age, and for all age groups the probability of death is greater with decreasing GCS-P. Conversely, the probability of favorable recovery becomes lower with increasing age and lessens with decreasing GCS-P. The effect of combining the GCS-P with patient age was substantially more informative than the GCS-P, age, GCS score, or pupil reactivity alone. Two-dimensional charts were produced displaying outcome probabilities, as percentages, for 5-year increments in age between 15 and 85 years, and for GCS-Ps ranging from 1 to 15; it is readily seen that the movement toward combinations at the top right of the charts reflects a decreasing likelihood of mortality and an increasing likelihood of favorable outcome. Analysis of CT findings showed that differences in outcome are very similar between patients with or without a hematoma, absent cisterns, or subarachnoid hemorrhage. Taken in combination, there is a gradation in risk that aligns with increasing numbers of any of these abnormalities. This information provides added value over age and GCS-P alone, supporting a simple extension of the earlier prognostic charts by stratifying the original charts in the following 3 CT groupings: none, only 1, and 2 or more CT abnormalities. CONCLUSIONS The important prognostic features in neurotrauma can be brought together to display graphically their combined effects on risks of death or on prospects for independent recovery. This approach can support decision making and improve communication of risk among health care professionals, patients, and their relatives. These charts will not replace clinical judgment, but they will reduce the risk of influences from biases.

Pain Management in Cancer Center Inpatients: A Cluster Randomized Trial to Evaluate a Systematic Integrated Approach-The Edinburgh Pain Assessment and Management Tool.

Purpose Pain is suboptimally managed in patients with cancer. We aimed to compare the effect of a policy of adding a clinician-delivered bedside pain assessment and management tool (Edinburgh Pain Assessment and management Tool [EPAT]) to usual care (UC) versus UC alone on pain outcomes. Patients and Methods In a two-arm, parallel group, cluster randomized (1:1) trial, we observed pain outcomes in 19 cancer centers in the United Kingdom and then randomly assigned the centers to either implement EPAT or to continue UC. The primary outcome was change in the percentage of study participants in each center with a clinically significant (≥ 2 point) improvement in worst pain (using the Brief Pain Inventory Short Form) from admission to 3 to 5 days after admission. Secondary outcomes included quality of analgesic prescribing and opioid-related adverse effects. Results Ten centers were randomly assigned to EPAT, and nine were assigned to UC. We enrolled 1,921 patients and obtained outcome data from 93% (n = 1,795). Participants (mean age, 60 years; 49% women) had a variety of cancer types. For centers randomly assigned to EPAT, the percentage of participants with a clinically significant improvement in worst pain increased from 47.7% to 54.1%, and for those randomly assigned to continue UC, this percentage decreased from 50.6% to 46.4%. The absolute difference was 10.7% (95% CI, 0.2% to 21.1%; P = .046) and it increased to 15.4% (95% CI, 5.8% to 25.0%; P = .004) when two centers that failed to implement EPAT were excluded. EPAT centers had greater improvements in prescribing practice and in the Brief Pain Inventory Short Form pain subscale score. Other pain and distress outcomes and opioid adverse effects did not differ between EPAT and UC. Conclusion A systematic integrated approach improves pain outcomes for inpatients in cancer centers without increasing opioid adverse effects.

The REstart or STop Antithrombotics Randomised Trial (RESTART) after stroke due to intracerebral haemorrhage: study protocol for a randomised controlled trial.

BACKGROUND: For adults surviving stroke due to spontaneous (non-traumatic) intracerebral haemorrhage (ICH) who had taken an antithrombotic (i.e. anticoagulant or antiplatelet) drug for the prevention of vaso-occlusive disease before the ICH, it is unclear whether starting antiplatelet drugs results in an increase in the risk of recurrent ICH or a beneficial net reduction of all serious vascular events compared to avoiding antiplatelet drugs. METHODS/DESIGN: The REstart or STop Antithrombotics Randomised Trial (RESTART) is an investigator-led, randomised, open, assessor-blind, parallel-group, randomised trial comparing starting versus avoiding antiplatelet drugs for adults surviving antithrombotic-associated ICH at 122 hospital sites in the United Kingdom. RESTART uses a central, web-based randomisation system using a minimisation algorithm, with 1:1 treatment allocation to which central research staff are masked. Central follow-up includes annual postal or telephone questionnaires to participants and their general (family) practitioners, with local provision of information about adverse events and outcome events. The primary outcome is recurrent symptomatic ICH. The secondary outcomes are: symptomatic haemorrhagic events; symptomatic vaso-occlusive events; symptomatic stroke of uncertain type; other fatal events; modified Rankin Scale score; adherence to antiplatelet drug(s). The magnetic resonance imaging (MRI) sub-study involves the conduct of brain MRI according to a standardised imaging protocol before randomisation to investigate heterogeneity of treatment effect according to the presence of brain microbleeds. Recruitment began on 22 May 2013. The target sample size is at least 720 participants in the main trial (at least 550 in the MRI sub-study). DISCUSSION: Final results of RESTART will be analysed and disseminated in 2019. TRIAL REGISTRATION: ISRCTN71907627 ( www.isrctn.com/ISRCTN71907627 ). Prospectively registered on 25 April 2013.

Dealing with missing standard deviation and mean values in meta-analysis of continuous outcomes: a systematic review.

BACKGROUND: Rigorous, informative meta-analyses rely on availability of appropriate summary statistics or individual participant data. For continuous outcomes, especially those with naturally skewed distributions, summary information on the mean or variability often goes unreported. While full reporting of original trial data is the ideal, we sought to identify methods for handling unreported mean or variability summary statistics in meta-analysis. METHODS: We undertook two systematic literature reviews to identify methodological approaches used to deal with missing mean or variability summary statistics. Five electronic databases were searched, in addition to the Cochrane Colloquium abstract books and the Cochrane Statistics Methods Group mailing list archive. We also conducted cited reference searching and emailed topic experts to identify recent methodological developments. Details recorded included the description of the method, the information required to implement the method, any underlying assumptions and whether the method could be readily applied in standard statistical software. We provided a summary description of the methods identified, illustrating selected methods in example meta-analysis scenarios. RESULTS: For missing standard deviations (SDs), following screening of 503 articles, fifteen methods were identified in addition to those reported in a previous review. These included Bayesian hierarchical modelling at the meta-analysis level; summary statistic level imputation based on observed SD values from other trials in the meta-analysis; a practical approximation based on the range; and algebraic estimation of the SD based on other summary statistics. Following screening of 1124 articles for methods estimating the mean, one approximate Bayesian computation approach and three papers based on alternative summary statistics were identified. Illustrative meta-analyses showed that when replacing a missing SD the approximation using the range minimised loss of precision and generally performed better than omitting trials. When estimating missing means, a formula using the median, lower quartile and upper quartile performed best in preserving the precision of the meta-analysis findings, although in some scenarios, omitting trials gave superior results. CONCLUSIONS: Methods based on summary statistics (minimum, maximum, lower quartile, upper quartile, median) reported in the literature facilitate more comprehensive inclusion of randomised controlled trials with missing mean or variability summary statistics within meta-analyses.