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.

Trial of Decompressive Craniectomy for Traumatic Intracranial Hypertension.

BACKGROUND: The effect of decompressive craniectomy on clinical outcomes in patients with refractory traumatic intracranial hypertension remains unclear. METHODS: From 2004 through 2014, we randomly assigned 408 patients, 10 to 65 years of age, with traumatic brain injury and refractory elevated intracranial pressure (>25 mm Hg) to undergo decompressive craniectomy or receive ongoing medical care. The primary outcome was the rating on the Extended Glasgow Outcome Scale (GOS-E) (an 8-point scale, ranging from death to "upper good recovery" [no injury-related problems]) at 6 months. The primary-outcome measure was analyzed with an ordinal method based on the proportional-odds model. If the model was rejected, that would indicate a significant difference in the GOS-E distribution, and results would be reported descriptively. RESULTS: The GOS-E distribution differed between the two groups (P<0.001). The proportional-odds assumption was rejected, and therefore results are reported descriptively. At 6 months, the GOS-E distributions were as follows: death, 26.9% among 201 patients in the surgical group versus 48.9% among 188 patients in the medical group; vegetative state, 8.5% versus 2.1%; lower severe disability (dependent on others for care), 21.9% versus 14.4%; upper severe disability (independent at home), 15.4% versus 8.0%; moderate disability, 23.4% versus 19.7%; and good recovery, 4.0% versus 6.9%. At 12 months, the GOS-E distributions were as follows: death, 30.4% among 194 surgical patients versus 52.0% among 179 medical patients; vegetative state, 6.2% versus 1.7%; lower severe disability, 18.0% versus 14.0%; upper severe disability, 13.4% versus 3.9%; moderate disability, 22.2% versus 20.1%; and good recovery, 9.8% versus 8.4%. Surgical patients had fewer hours than medical patients with intracranial pressure above 25 mm Hg after randomization (median, 5.0 vs. 17.0 hours; P<0.001) but had a higher rate of adverse events (16.3% vs. 9.2%, P=0.03). CONCLUSIONS: At 6 months, decompressive craniectomy in patients with traumatic brain injury and refractory intracranial hypertension resulted in lower mortality and higher rates of vegetative state, lower severe disability, and upper severe disability than medical care. The rates of moderate disability and good recovery were similar in the two groups. (Funded by the Medical Research Council and others; RESCUEicp Current Controlled Trials number, ISRCTN66202560 .).

Hypothermia for Intracranial Hypertension after Traumatic Brain Injury.

BACKGROUND: In patients with traumatic brain injury, hypothermia can reduce intracranial hypertension. The benefit of hypothermia on functional outcome is unclear. METHODS: We randomly assigned adults with an intracranial pressure of more than 20 mm Hg despite stage 1 treatments (including mechanical ventilation and sedation management) to standard care (control group) or hypothermia (32 to 35°C) plus standard care. In the control group, stage 2 treatments (e.g., osmotherapy) were added as needed to control intracranial pressure. In the hypothermia group, stage 2 treatments were added only if hypothermia failed to control intracranial pressure. In both groups, stage 3 treatments (barbiturates and decompressive craniectomy) were used if all stage 2 treatments failed to control intracranial pressure. The primary outcome was the score on the Extended Glasgow Outcome Scale (GOS-E; range, 1 to 8, with lower scores indicating a worse functional outcome) at 6 months. The treatment effect was estimated with ordinal logistic regression adjusted for prespecified prognostic factors and expressed as a common odds ratio (with an odds ratio <1.0 favoring hypothermia). RESULTS: We enrolled 387 patients at 47 centers in 18 countries from November 2009 through October 2014, at which time recruitment was suspended owing to safety concerns. Stage 3 treatments were required to control intracranial pressure in 54% of the patients in the control group and in 44% of the patients in the hypothermia group. The adjusted common odds ratio for the GOS-E score was 1.53 (95% confidence interval, 1.02 to 2.30; P=0.04), indicating a worse outcome in the hypothermia group than in the control group. A favorable outcome (GOS-E score of 5 to 8, indicating moderate disability or good recovery) occurred in 26% of the patients in the hypothermia group and in 37% of the patients in the control group (P=0.03). CONCLUSIONS: In patients with an intracranial pressure of more than 20 mm Hg after traumatic brain injury, therapeutic hypothermia plus standard care to reduce intracranial pressure did not result in outcomes better than those with standard care alone. (Funded by the National Institute for Health Research Health Technology Assessment program; Current Controlled Trials number, ISRCTN34555414.).

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.

A closed testing procedure to select an appropriate method for updating prediction models.

Prediction models fitted with logistic regression often show poor performance when applied in populations other than the development population. Model updating may improve predictions. Previously suggested methods vary in their extensiveness of updating the model. We aim to define a strategy in selecting an appropriate update method that considers the balance between the amount of evidence for updating in the new patient sample and the danger of overfitting. We consider recalibration in the large (re-estimation of model intercept); recalibration (re-estimation of intercept and slope) and model revision (re-estimation of all coefficients) as update methods. We propose a closed testing procedure that allows the extensiveness of the updating to increase progressively from a minimum (the original model) to a maximum (a completely revised model). The procedure involves multiple testing with maintaining approximately the chosen type I error rate. We illustrate this approach with three clinical examples: patients with prostate cancer, traumatic brain injury and children presenting with fever. The need for updating the prostate cancer model was completely driven by a different model intercept in the update sample (adjustment: 2.58). Separate testing of model revision against the original model showed statistically significant results, but led to overfitting (calibration slope at internal validation = 0.86). The closed testing procedure selected recalibration in the large as update method, without overfitting. The advantage of the closed testing procedure was confirmed by the other two examples. We conclude that the proposed closed testing procedure may be useful in selecting appropriate update methods for previously developed prediction models. Copyright © 2016 John Wiley & Sons, Ltd.

Five-Year Mortality and Hospital Costs Associated with Surviving Intensive Care.

RATIONALE: Survivors of critical illness experience significant morbidity, but the impact of surviving the intensive care unit (ICU) has not been quantified comprehensively at a population level. OBJECTIVES: To identify factors associated with increased hospital resource use and to ascertain whether ICU admission was associated with increased mortality and resource use. METHODS: Matched cohort study and pre/post-analysis using national linked data registries with complete population coverage. The population consisted of patients admitted to all adult general ICUs during 2005 and surviving to hospital discharge, identified from the Scottish Intensive Care Society Audit Group registry, matched (1:1) with similar hospital control subjects. Five-year outcomes included mortality and hospital resource use. Confounder adjustment was based on multivariable regression and pre/post within-individual analyses. MEASUREMENTS AND MAIN RESULTS: Of 7,656 ICU patients, 5,259 survived to hospital discharge (5,215 [99.2%] matched to hospital control subjects). Factors present before ICU admission (comorbidities/pre-ICU hospitalizations) were stronger predictors of hospital resource use than acute illness factors. In the 5 years after the initial hospital discharge, compared with hospital control subjects, the ICU cohort had higher mortality (32.3% vs. 22.7%; hazard ratio, 1.33; 95% confidence interval, 1.22-1.46; P < 0.001), used more hospital resources (mean hospital admission rate, 4.8 vs. 3.3/person/5 yr), and had 51% higher mean 5-year hospital costs ($25,608 vs. $16,913/patient). Increased resource use persisted after confounder adjustment (P < 0.001) and using pre/post-analyses (P < 0.001). Excess resource use and mortality were greatest for younger patients without significant comorbidity. CONCLUSIONS: This complete, national study demonstrates that ICU survivorship is associated with higher 5-year mortality and hospital resource use than hospital control subjects, representing a substantial burden on individuals, caregivers, and society.

Effects of Alteplase for Acute Stroke on the Distribution of Functional Outcomes: A Pooled Analysis of 9 Trials.

BACKGROUND: Thrombolytic therapy with intravenous alteplase within 4.5 hours of ischemic stroke onset increases the overall likelihood of an excellent outcome (no, or nondisabling, symptoms). Any improvement in functional outcome distribution has value, and herein we provide an assessment of the effect of alteplase on the distribution of the functional level by treatment delay, age, and stroke severity. METHODS: Prespecified pooled analysis of 6756 patients from 9 randomized trials comparing alteplase versus placebo/open control. Ordinal logistic regression models assessed treatment differences after adjustment for treatment delay, age, stroke severity, and relevant interaction term(s). RESULTS: Treatment with alteplase was beneficial for a delay in treatment extending to 4.5 hours after stroke onset, with a greater benefit with earlier treatment. Neither age nor stroke severity significantly influenced the slope of the relationship between benefit and time to treatment initiation. For the observed case mix of patients treated within 4.5 hours of stroke onset (mean 3 hours and 20 minutes), the net absolute benefit from alteplase (ie, the difference between those who would do better if given alteplase and those who would do worse) was 55 patients per 1000 treated (95% confidence interval, 13-91; P=0.004). CONCLUSIONS: Treatment with intravenous alteplase initiated within 4.5 hours of stroke onset increases the chance of achieving an improved level of function for all patients across the age spectrum, including the over 80s and across all severities of stroke studied (top versus bottom fifth means: 22 versus 4); the earlier that treatment is initiated, the greater the benefit.

Decompressive craniectomy following traumatic brain injury: developing the evidence base.

In the context of traumatic brain injury (TBI), decompressive craniectomy (DC) is used as part of tiered therapeutic protocols for patients with intracranial hypertension (secondary or protocol-driven DC). In addition, the bone flap can be left out when evacuating a mass lesion, usually an acute subdural haematoma (ASDH), in the acute phase (primary DC). Even though, the principle of "opening the skull" in order to control brain oedema and raised intracranial pressure has been practised since the beginning of the 20th century, the last 20 years have been marked by efforts to develop the evidence base with the conduct of randomised trials. This article discusses the merits and challenges of this approach and provides an overview of randomised trials of DC following TBI. An update on the RESCUEicp study, a randomised trial of DC versus advanced medical management (including barbiturates) for severe and refractory post-traumatic intracranial hypertension is provided. In addition, the rationale for the RESCUE-ASDH study, the first randomised trial of primary DC versus craniotomy for adult head-injured patients with an ASDH, is presented.

Alteplase for acute ischemic stroke: outcomes by clinically important subgroups in the Third International Stroke Trial.

BACKGROUND AND PURPOSE: Our aim was to identify whether particular subgroups of patients had an unacceptably high risk of symptomatic intracranial hemorrhage or low chance of benefit when treated with alteplase (recombinant tissue-type plasminogen activator). METHODS: Third International Stroke Trial was an international randomized trial of the intravenous (IV) recombinant plasminogen activator alteplase (0.9 mg/kg) versus control in 3035 (1515 versus 1520) patients. We analyzed the effect of recombinant tissue-type plasminogen activator on 6-month functional outcome, early death, and symptomatic intracranial hemorrhage (both ≤7 days). We tested for any differences in treatment effect between subgroups by a test of interaction. Our 13 protocol prespecified subgroups were time to randomization, age, sex, stroke subtype, atrial fibrillation, early ischemic change (clinician and expert panel), prior antiplatelet use, stroke severity, diastolic and systolic blood pressure at randomization, center's thrombolysis experience, and trial phase. Analyses were adjusted for key baseline prognostic factors. RESULTS: There were no significant interactions in the subgroups analyzed that were consistent across all 3 outcomes. Treatment with recombinant tissue-type plasminogen activator increased the odds of symptomatic intracranial hemorrhage by a greater amount in patients taking prior antiplatelets than those who were not (P=0.019 for test of interaction), but had no clear detrimental effect on functional outcome at 6 months in this group (P=0.781 for test of interaction). CONCLUSIONS: Among the types of patient in the Third International Stroke Trial, this secondary analysis did not identify any subgroups for whom treatment should be avoided. Given the limitations of the analysis, we found no clear evidence to avoid treatment in patients with prior ischemic stroke, diabetes mellitus, or hypertension. CLINICAL TRIAL REGISTRATION URL: http://www.controlled-trials.com. Unique identifier: ISRCTN25765518. http://www.controlled-trials.com/ISRCTN25765518.

Integrated collaborative care for comorbid major depression in patients with cancer (SMaRT Oncology-2): a multicentre randomised controlled effectiveness trial.

BACKGROUND: Medical conditions are often complicated by major depression, with consequent additional impairment of quality of life. We aimed to compare the effectiveness of an integrated treatment programme for major depression in patients with cancer (depression care for people with cancer) with usual care. METHODS: SMaRT Oncology-2 is a parallel-group, multicentre, randomised controlled effectiveness trial. We enrolled outpatients with major depression from three cancer centres and their associated clinics in Scotland, UK. Participants were randomly assigned in a 1:1 ratio to the depression care for people with cancer intervention or usual care, with stratification (by trial centre) and minimisation (by age, primary cancer, and sex) with allocation concealment. Depression care for people with cancer is a manualised, multicomponent collaborative care treatment that is delivered systematically by a team of cancer nurses and psychiatrists in collaboration with primary care physicians. Usual care is provided by primary care physicians. Outcome data were collected up until 48 weeks. The primary outcome was treatment response (≥50% reduction in Symptom Checklist Depression Scale [SCL-20] score, range 0-4) at 24 weeks. Trial statisticians and data collection staff were masked to treatment allocation, but participants could not be masked to the allocations. Analyses were by intention to treat. This trial is registered with Current Controlled Trials, number ISRCTN40568538. FINDINGS: 500 participants were enrolled between May 12, 2008, and May 13, 2011; 253 were randomly allocated to depression care for people with cancer and 247 to usual care. 143 (62%) of 231 participants in the depression care for people with cancer group and 40 (17%) of 231 in the usual care group responded to treatment: absolute difference 45% (95% CI 37-53), adjusted odds ratio 8·5 (95% CI 5·5-13·4), p<0·0001. Compared with patients in the usual care group, participants allocated to the depression care for people with cancer programme also had less depression, anxiety, pain, and fatigue; and better functioning, health, quality of life, and perceived quality of depression care at all timepoints (all p<0·05). During the study, 34 cancer-related deaths occurred (19 in the depression care for people with cancer group, 15 in the usual care group), one patient in the depression care for people with cancer group was admitted to a psychiatric ward, and one patient in this group attempted suicide. None of these events were judged to be related to the trial treatments or procedures. INTERPRETATION: Our findings suggest that depression care for people with cancer is an effective treatment for major depression in patients with cancer. It offers a model for the treatment of depression comorbid with other medical conditions. FUNDING: Cancer Research UK and Chief Scientist Office of the Scottish Government.

Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials.

BACKGROUND: Alteplase is effective for treatment of acute ischaemic stroke but debate continues about its use after longer times since stroke onset, in older patients, and among patients who have had the least or most severe strokes. We assessed the role of these factors in affecting good stroke outcome in patients given alteplase. METHODS: We did a pre-specified meta-analysis of individual patient data from 6756 patients in nine randomised trials comparing alteplase with placebo or open control. We included all completed randomised phase 3 trials of intravenous alteplase for treatment of acute ischaemic stroke for which data were available. Retrospective checks confirmed that no eligible trials had been omitted. We defined a good stroke outcome as no significant disability at 3-6 months, defined by a modified Rankin Score of 0 or 1. Additional outcomes included symptomatic intracranial haemorrhage (defined by type 2 parenchymal haemorrhage within 7 days and, separately, by the SITS-MOST definition of parenchymal type 2 haemorrhage within 36 h), fatal intracranial haemorrhage within 7 days, and 90-day mortality. FINDINGS: Alteplase increased the odds of a good stroke outcome, with earlier treatment associated with bigger proportional benefit. Treatment within 3·0 h resulted in a good outcome for 259 (32·9%) of 787 patients who received alteplase versus 176 (23·1%) of 762 who received control (OR 1·75, 95% CI 1·35-2·27); delay of greater than 3·0 h, up to 4·5 h, resulted in good outcome for 485 (35·3%) of 1375 versus 432 (30·1%) of 1437 (OR 1·26, 95% CI 1·05-1·51); and delay of more than 4·5 h resulted in good outcome for 401 (32·6%) of 1229 versus 357 (30·6%) of 1166 (OR 1·15, 95% CI 0·95-1·40). Proportional treatment benefits were similar irrespective of age or stroke severity. Alteplase significantly increased the odds of symptomatic intracranial haemorrhage (type 2 parenchymal haemorrhage definition 231 [6·8%] of 3391 vs 44 [1·3%] of 3365, OR 5·55, 95% CI 4·01-7·70, p<0·0001; SITS-MOST definition 124 [3·7%] vs 19 [0·6%], OR 6·67, 95% CI 4·11-10·84, p<0·0001) and of fatal intracranial haemorrhage within 7 days (91 [2·7%] vs 13 [0·4%]; OR 7·14, 95% CI 3·98-12·79, p<0·0001). The relative increase in fatal intracranial haemorrhage from alteplase was similar irrespective of treatment delay, age, or stroke severity, but the absolute excess risk attributable to alteplase was bigger among patients who had more severe strokes. There was no excess in other early causes of death and no significant effect on later causes of death. Consequently, mortality at 90 days was 608 (17·9%) in the alteplase group versus 556 (16·5%) in the control group (hazard ratio 1·11, 95% CI 0·99-1·25, p=0·07). Taken together, therefore, despite an average absolute increased risk of early death from intracranial haemorrhage of about 2%, by 3-6 months this risk was offset by an average absolute increase in disability-free survival of about 10% for patients treated within 3·0 h and about 5% for patients treated after 3·0 h, up to 4·5 h. INTERPRETATION: Irrespective of age or stroke severity, and despite an increased risk of fatal intracranial haemorrhage during the first few days after treatment, alteplase significantly improves the overall odds of a good stroke outcome when delivered within 4·5 h of stroke onset, with earlier treatment associated with bigger proportional benefits. FUNDING: UK Medical Research Council, British Heart Foundation, University of Glasgow, University of Edinburgh.

Trial Steering Committees in randomised controlled trials: A survey of registered clinical trials units to establish current practice and experiences.

BACKGROUND: The Medical Research Council Guidelines for Good Clinical Practice outlines a three-committee trial oversight structure--the day-to-day Trial Management Group, the Data Monitoring Committee and the Trial Steering Committee. In this model, the Trial Steering Committee is the executive committee that oversees the trial and considers the recommendations from the Data Monitoring Committee. There is yet to be in-depth consideration establishing the Trial Steering Committee's role and functionality. METHODS: A survey to establish Trial Steering Committee's current practices, role and the use and opinion on the Medical Research Council guidelines was undertaken within UK Clinical Research Collaborative registered Clinical Trials Units. RESULTS: Completed surveys were obtained from 38 of 47 fully and partially registered Units. Individual items in the survey were analysed and reported spanning current Trial Steering Committee practices including its role, requirement and experience required for membership; methods to identify members; and meeting frequency. Terms (a document describing the committee's remit, objectives and functionality) were obtained and analysed from 21 of 33 Units with documents in place at their Unit. A total of 20 responders suggested aspects of the current Medical Research Council Guidelines that need improvement. CONCLUSION: We present the first survey reporting on practices within UK Clinical Research Collaborative registered Clinical Trials Units on the experience and remits of Trial Steering Committees. We have identified a widespread adoption of Medical Research Council Guidelines for Trial Steering Committees in the United Kingdom, but limitations in this existing provision have been identified that need to be addressed.

Integrated collaborative care for major depression comorbid with a poor prognosis cancer (SMaRT Oncology-3): a multicentre randomised controlled trial in patients with lung cancer.

BACKGROUND: The management of depression in patients with poor prognosis cancers, such as lung cancer, creates specific challenges. We aimed to assess the efficacy of an integrated treatment programme for major depression in patients with lung cancer compared with usual care. METHODS: Symptom Management Research Trials (SMaRT) Oncology-3 is a parallel-group, multicentre, randomised controlled trial. We enrolled patients with lung cancer and major depression from three cancer centres and their associated clinics in Scotland, UK. Participants were randomly assigned in a 1:1 ratio to the depression care for people with lung cancer treatment programme or usual care by a database software algorithm that used stratification (by trial centre) and minimisation (by age, sex, and cancer type) with allocation concealment. Depression care for people with lung cancer is a manualised, multicomponent collaborative care treatment that is systematically delivered by a team of cancer nurses and psychiatrists in collaboration with primary care physicians. Usual care is provided by primary care physicians. The primary outcome was depression severity (on the Symptom Checklist Depression Scale [SCL-20], range 0-4) averaged over the patient's time in the trial (up to a maximum of 32 weeks). Trial statisticians and data collection staff were masked to treatment allocation, but patients and clinicians could not be masked to the allocations. Analyses were by intention to treat. This trial is registered with Current Controlled Trials, number ISRCTN75905964. FINDINGS: 142 participants were recruited between Jan 5, 2009, and Sept 9, 2011; 68 were randomly allocated to depression care for people with lung cancer and 74 to usual care. 43 (30%) of 142 patients had died by 32 weeks, all of which were cancer-related deaths. No intervention-related serious adverse events occurred. 131 (92%) of 142 patients provided outcome data (59 in the depression care for people with lung cancer group and 72 in the usual care group) and were included in the intention-to-treat primary analysis. Average depression severity was significantly lower in patients allocated to depression care for people with lung cancer (mean score on the SCL-20 1·24 [SD 0·64]) than in those allocated to usual care (mean score 1·61 [SD 0·58]); difference -0·38 (95% CI -0·58 to -0·18); standardised mean difference -0·62 (95% CI -0·94 to -0·29). Self-rated depression improvement, anxiety, quality of life, role functioning, perceived quality of care, and proportion of patients achieving a 12-week treatment response were also significantly better in the depression care for people with lung cancer group than in the usual care group. INTERPRETATION: Our findings suggest that major depression can be treated effectively in patients with a poor prognosis cancer; integrated depression care for people with lung cancer was substantially more efficacious than was usual care. Larger trials are now needed to estimate the effectiveness and cost-effectiveness of this care programme in this patient population, and further adaptation of the treatment will be necessary to address the unmet needs of patients with major depression and even shorter life expectancy. FUNDING: Cancer Research UK and Chief Scientist Office of the Scottish Government.

Effect of alteplase within 6 hours of acute ischemic stroke on all-cause mortality (third International Stroke Trial).

BACKGROUND AND PURPOSE: Prompt thrombolytic therapy with intravenous alteplase reduces disability after acute ischemic stroke. In an exploratory analysis, we examined whether long-term survival varied by baseline characteristics after alteplase. METHODS: In this open-treatment, international, randomized, controlled trial, ischemic stroke patients were randomly allocated <6 hours of onset to intravenous alteplase (0.9 mg/kg) plus standard care (n=1515) or standard care alone (n=1520). We followed patients to death, censoring when last known to be alive. We grouped patients by delay to randomization, and good or poor predicted prognosis (calculated from baseline National Institutes of Health Stroke Scale [NIHSS] score and age). We present absolute mortality differences between treated and control groups at 7 days, 6 months, and 18 months poststroke. RESULTS: Alteplase was not associated with a significant increase in mortality within 18 months (0.6% [95% confidence interval (CI), -2.9% to +4.2] P=0.72] in all patients with complete vital status (99.9%, 3034/3035). In patients randomized <3 hours of stroke, 18-month mortality was lower in the alteplase-treated group than the control group (40.6% [95% CI, 42.6-52.7] versus 47.8% [95% CI, 35.5-45.3]; P=0.0434]. The difference in 18-month mortality between alteplase-treated and control patients was greater in patients who were randomized early (<3 hours) compared with late (3-6 hours; +9% [95% CI, 1-17]; P=0.0317). Alteplase led to a greater improvement in 18-month survival in patients with a poor prognosis than in patients with a good prognosis (+8% [95% CI, 2-14]; P=0.0091). CONCLUSIONS: These exploratory analyses of the third International Stroke Trial (IST-3) trial support improving acute stroke patients' access to earlier alteplase treatment, treatment of patients with poor prognosis, and further randomized controlled trials in minor stroke to replicate these findings. CLINICAL TRIAL REGISTRATION URL: http://www.controlled-trials.com. Unique identifier: ISRCTN25765518.

Targeting recombinant tissue-type plasminogen activator in acute ischemic stroke based on risk of intracranial hemorrhage or poor functional outcome: an analysis of the third international stroke trial.

BACKGROUND AND PURPOSE: Intravenous recombinant tissue-type plasminogen activator (r-tPA), despite a risk of early symptomatic intracranial hemorrhage (sICH), is of net clinical benefit to acute stroke patients. We tested if predictive models could identify patients least likely to be harmed by sICH or those who gained no net benefit. METHODS: We used the Third International Stroke Trial (IST-3) trial data set, an international, multicenter, open treatment randomized trial of 0.9 mg/kg r-tPA versus control in 3035 patients with acute ischemic stroke. We compared the discrimination and calibration of previously developed predictive models for ICH and poststroke poor outcome and developed a new model using variables selected by systematic review. We calculated the absolute and relative risk reduction of death or dependency with r-tPA in patients at a low, medium, or high predicted risk of sICH or poor functional outcome. RESULTS: Prediction models for sICH or poor outcome (Hemorrhage After Thrombolysis [HAT]; Sugar, Early Infarct Signs, Dense Artery, Age, National Institutes of Health (NIH) Stroke Score (SEDAN); Glucose Race Age Sex Pressure Stroke Severity [GRASPS]; Stroke Thrombolytic Predictive Instrument; Dense Artery, Rankin Score, Age, Glucose, Onset to Treatment Time, NIHSS [DRAGON]; Totaled Health Risks in Vascular Events [THRIVE]; our new model; and a model with National Institutes of Health Stroke Scale and age) had similar area under receiver operator characteristic curves (AUROCC) to predict sICH (P for difference >0.05). The simplest model (with covariates National Institutes of Health Stroke Scale and age) predicted both sICH (AUROCC, 0.63; 95% CI, 0.58-0.68) and poststroke poor functional outcome (AUROCC, 0.80; 95% CI, 0.77-0.82) similarly to complex models. There was no evidence that the effect of r-tPA in patients at high predicted risk of sICH or poor functional outcome after stroke was less than in those at lower risk. CONCLUSIONS: There is a clinically relevant net positive effect of r-tPA in patients with acute stroke at a high predicted risk of sICH or poor functional outcome. CLINICAL TRIAL REGISTRATION URL: http://www.controlled-trials.com. Unique identifier: ISRCTN25765518.

Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial.

BACKGROUND: The balance of risk and benefit from early neurosurgical intervention for conscious patients with superficial lobar intracerebral haemorrhage of 10-100 mL and no intraventricular haemorrhage admitted within 48 h of ictus is unclear. We therefore tested the hypothesis that early surgery compared with initial conservative treatment could improve outcome in these patients. METHODS: In this international, parallel-group trial undertaken in 78 centres in 27 countries, we compared early surgical haematoma evacuation within 12 h of randomisation plus medical treatment with initial medical treatment alone (later evacuation was allowed if judged necessary). An automatic telephone and internet-based randomisation service was used to assign patients to surgery and initial conservative treatment in a 1:1 ratio. The trial was not masked. The primary outcome was a prognosis-based dichotomised (favourable or unfavourable) outcome of the 8 point Extended Glasgow Outcome Scale (GOSE) obtained by questionnaires posted to patients at 6 months. Analysis was by intention to treat. This trial is registered, number ISRCTN22153967. FINDINGS: 307 of 601 patients were randomly assigned to early surgery and 294 to initial conservative treatment; 298 and 291 were followed up at 6 months, respectively; and 297 and 286 were included in the analysis, respectively. 174 (59%) of 297 patients in the early surgery group had an unfavourable outcome versus 178 (62%) of 286 patients in the initial conservative treatment group (absolute difference 3·7% [95% CI -4·3 to 11·6], odds ratio 0·86 [0·62 to 1·20]; p=0·367). INTERPRETATION: The STICH II results confirm that early surgery does not increase the rate of death or disability at 6 months and might have a small but clinically relevant survival advantage for patients with spontaneous superficial intracerebral haemorrhage without intraventricular haemorrhage. FUNDING: UK Medical Research Council.

Formal and informal prediction of recurrent stroke and myocardial infarction after stroke: a systematic review and evaluation of clinical prediction models in a new cohort.

BACKGROUND: The objective of this study was to: (1) systematically review the reporting and methods used in the development of clinical prediction models for recurrent stroke or myocardial infarction (MI) after ischemic stroke; (2) to meta-analyze their external performance; and (3) to compare clinical prediction models to informal clinicians' prediction in the Edinburgh Stroke Study (ESS). METHODS: We searched Medline, EMBASE, reference lists and forward citations of relevant articles from 1980 to 19 April 2013. We included articles which developed multivariable clinical prediction models for the prediction of recurrent stroke and/or MI following ischemic stroke. We extracted information to assess aspects of model development as well as metrics of performance to determine predictive ability. Model quality was assessed against a pre-defined set of criteria. We used random-effects meta-analysis to pool performance metrics. RESULTS: We identified twelve model development studies and eleven evaluation studies. Investigators often did not report effective sample size, regression coefficients, handling of missing data; typically categorized continuous predictors; and used data dependent methods to build models. A meta-analysis of the area under the receiver operating characteristic curve (AUROCC) was possible for the Essen Stroke Risk Score (ESRS) and for the Stroke Prognosis Instrument II (SPI-II); the pooled AUROCCs were 0.60 (95% CI 0.59 to 0.62) and 0.62 (95% CI 0.60 to 0.64), respectively. An evaluation among minor stroke patients in the ESS demonstrated that clinicians discriminated poorly between those with and those without recurrent events and that this was similar to clinical prediction models. CONCLUSIONS: The available models for recurrent stroke discriminate poorly between patients with and without a recurrent stroke or MI after stroke. Models had a similar discrimination to informal clinicians' predictions. Formal prediction may be improved by addressing commonly encountered methodological problems.

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.