What guidance exists to support patient partner compensation practices? A scoping review of available policies and guidelines.

BACKGROUND: An integral aspect of patient engagement in research, also known as patient and public involvement, is appropriately recognising patient partners for their contributions through compensation (e.g., coauthorship, honoraria). Despite known benefits to compensating patient partners, our previous work suggested compensation is rarely reported and researchers perceive a lack of guidance on this issue. To address this gap, we identified and summarised available guidance and policy documents for patient partner compensation. METHODS: We conducted this scoping review in accordance with methods suggested by the JBI. We searched the grey literature (Google, Google Scholar) in March 2022 and Overton (an international database of policy documents) in April 2022. We included articles, guidance or policy documents regarding the compensation of patient partners for their research contributions. Two reviewers independently extracted and synthesised document characteristics and recommendations. RESULTS: We identified 65 guidance or policy documents. Most documents were published in Canada (57%, n = 37) or the United Kingdom (26%, n = 17). The most common recommended methods of nonfinancial compensation were offering training opportunities to patient partners (40%, n = 26) and facilitating patient partner attendance at conferences (38%, n = 25). The majority of guidance documents (95%) suggested financially compensating (i.e., offering something of monetary value) patient partners for their research contributions. Across guidance documents, the recommended monetary value of financial compensation was relatively consistent and associated with the role played by patient partners and/or specific engagement activities. For instance, the median monetary value for obtaining patient partner feedback (i.e., consultation) was $19/h (USD) (range of $12-$50/h). We identified several documents that guide the compensation of specific populations, including youth and Indigenous peoples. CONCLUSION: Multiple publicly available resources exist to guide researchers, patient partners and institutions in developing tailored patient partner compensation strategies. Our findings challenge the perception that a lack of guidance hinders patient partner financial compensation. Future efforts should prioritise the effective implementation of these compensation strategies to ensure that patient partners are appropriately recognised. PATIENT OR PUBLIC CONTRIBUTIONS: The patient partner coauthor informed protocol development, identified data items, and interpreted findings.

Economic Evaluations of Chimeric Antigen Receptor T-Cell Therapies for Hematologic and Solid Malignancies: A Systematic Review.

OBJECTIVES: This study aimed to systematically review evidence on the cost-effectiveness of chimeric antigen receptor T-cell (CAR-T) therapies for patients with cancer. METHODS: Electronic databases were searched in October 2022 and updated in September 2023. Systematic reviews, health technology assessments, and economic evaluations that compared costs and effects of CAR-T therapy in patients with cancer were included. Two reviewers independently screened studies, extracted data, synthesized results, and critically appraised studies using the Philips checklist. Cost data were presented in 2022 US dollars. RESULTS: Our search yielded 1809 records, 47 of which were included. Most of included studies were cost-utility analysis, published between 2018 and 2023, and conducted in the United States. Tisagenlecleucel, axicabtagene ciloleucel, idecabtagene vicleucel, ciltacabtagene autoleucel, lisocabtagene maraleucel, brexucabtagene autoleucel, and relmacabtagene autoleucel were compared with various standard of care chemotherapies. The incremental cost-effectiveness ratio (ICER) for CAR-T therapies ranged from $9424 to $4 124 105 per quality-adjusted life-year (QALY) in adults and from $20 784 to $243 177 per QALY in pediatric patients. Incremental cost-effectiveness ratios were found to improve over longer time horizons or when an earlier cure point was assumed. Most studies failed to meet the Philips checklist due to a lack of head-to-head comparisons and uncertainty surrounding CAR-T costs and curative effects. CONCLUSIONS: CAR-T therapies were more expensive and generated more QALYs than comparators, but their cost-effectiveness was uncertain and dependent on patient population, cancer type, and model assumptions. This highlights the need for more nuanced economic evaluations and continued research to better understand the value of CAR-T therapies in diverse patient populations.

Indefinite Anticoagulant Therapy for First Unprovoked Venous Thromboembolism : A Cost-Effectiveness Study.

BACKGROUND: Clinical practice guidelines recommend indefinite anticoagulation for a first unprovoked venous thromboembolism (VTE). OBJECTIVE: To estimate the benefit-harm tradeoffs of indefinite anticoagulation in patients with a first unprovoked VTE. DESIGN: Markov modeling study. DATA SOURCES: Systematic reviews and meta-analyses for the long-term risks and case-fatality rates of recurrent VTE and major bleeding. Published literature for costs, quality of life, and other clinical events. TARGET POPULATION: Patients with a first unprovoked VTE who have completed 3 to 6 months of initial anticoagulant treatment. TIME HORIZON: Lifetime. PERSPECTIVE: Canadian health care public payer. INTERVENTION: Indefinite anticoagulation with direct oral anticoagulants. OUTCOME MEASURES: Recurrent VTE events, major bleeding events, costs in 2022 Canadian dollars (CAD), and quality-adjusted life-years (QALYs). RESULTS OF BASE-CASE ANALYSIS: When compared with discontinuing anticoagulation after initial treatment in a hypothetical cohort of 1000 patients aged 55 years, indefinite anticoagulation prevented 368 recurrent VTE events, which included 14 fatal pulmonary emboli, but induced an additional 114 major bleeding events, which included 30 intracranial hemorrhages and 11 deaths from bleeding. Indefinite anticoagulation cost CAD $16 014 more per person and did not increase QALYs (-0.075 per person). RESULTS OF SENSITIVITY ANALYSIS: Model results were most sensitive to the case-fatality rate of major bleeding and the annual risk for major bleeding during extended anticoagulation. LIMITATION: The model assumed that risks for recurrent VTE and major bleeding measured in clinical trials at 1 year remained constant during extended anticoagulation. CONCLUSION: Clinicians should use shared decision making to incorporate individual patient preferences and values when considering treatment duration for unprovoked VTE. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research.

A systematic assessment of preclinical multilaboratory studies and a comparison to single laboratory studies.

Background: Multicentric approaches are widely used in clinical trials to assess the generalizability of findings, however, they are novel in laboratory-based experimentation. It is unclear how multilaboratory studies may differ in conduct and results from single lab studies. Here, we synthesized the characteristics of these studies and quantitatively compared their outcomes to those generated by single laboratory studies. Methods: MEDLINE and Embase were systematically searched. Screening and data extractions were completed in duplicate by independent reviewers. Multilaboratory studies investigating interventions using in vivo animal models were included. Study characteristics were extracted. Systematic searches were then performed to identify single lab studies matched by intervention and disease. Difference in standardized mean differences (DSMD) was then calculated across studies to assess differences in effect estimates based on study design (>0 indicates larger effects in single lab studies). Results: Sixteen multilaboratory studies met inclusion criteria and were matched to 100 single lab studies. The multicenter study design was applied across a diverse range of diseases, including stroke, traumatic brain injury, myocardial infarction, and diabetes. The median number of centers was four (range 2-6) and the median sample size was 111 (range 23-384) with rodents most frequently used. Multilaboratory studies adhered to practices that reduce the risk of bias significantly more often than single lab studies. Multilaboratory studies also demonstrated significantly smaller effect sizes than single lab studies (DSMD 0.72 [95% confidence interval 0.43-1]). Conclusions: Multilaboratory studies demonstrate trends that have been well recognized in clinical research (i.e. smaller treatment effects with multicentric evaluation and greater rigor in study design). This approach may provide a method to robustly assess interventions and the generalizability of findings between laboratories. Funding: uOttawa Junior Clinical Research Chair; The Ottawa Hospital Anesthesia Alternate Funds Association; Canadian Anesthesia Research Foundation; Government of Ontario Queen Elizabeth II Graduate Scholarship in Science and Technology.

Phlebotomy resulting in controlled hypovolemia to prevent blood loss in major hepatic resections (PRICE-2): study protocol for a phase 3 randomized controlled trial.

INTRODUCTION: Blood loss and red blood cell (RBC) transfusion in liver surgery are areas of concern for surgeons, anesthesiologists, and patients alike. While various methods are employed to reduce surgical blood loss, the evidence base surrounding each intervention is limited. Hypovolemic phlebotomy, the removal of whole blood from the patient without volume replacement during liver transection, has been strongly associated with decreased bleeding and RBC transfusion in observational studies. This trial aims to investigate whether hypovolemic phlebotomy is superior to usual care in reducing RBC transfusions in liver resection. METHODS: This study is a double-blind multicenter randomized controlled trial. Adult patients undergoing major hepatic resections for any indication will be randomly allocated in a 1:1 ratio to either hypovolemic phlebotomy and usual care or usual care alone. Exclusion criteria will be minor resections, preoperative hemoglobin <100g/L, renal insufficiency, and other contraindication to hypovolemic phlebotomy. The primary outcome will be the proportion of patients receiving at least one allogeneic RBC transfusion unit within 30 days of the onset of surgery. Secondary outcomes will include transfusion of other allogeneic blood products, blood loss, morbidity, mortality, and intraoperative physiologic parameters. The surgical team will be blinded to the intervention. Randomization will occur on the morning of surgery. The sample size will comprise 440 patients. Enrolment will occur at four Canadian academic liver surgery centers over a 4-year period. Ethics approval will be obtained at participating sites before enrolment. DISCUSSION: The results of this randomized control trial will provide high-quality evidence regarding the use of hypovolemic phlebotomy in major liver resection and its effects on RBC transfusion. If proven to be effective, this intervention could become standard of care in liver operations internationally and become incorporated within perioperative patient blood management programs. TRIAL REGISTRATION: ClinicalTrials.gov NCT03651154 . Registered on August 29 2018.

Engaging Patients and Caregivers in an Early Health Economic Evaluation: Discerning Treatment Value Based on Lived Experience.

BACKGROUND: Traditionally, economic evaluations have engaged clinicians and policymakers; however, patients and their caregivers have insight that can ensure that the economic evaluation process appropriately reflects disease consequences and adequately addresses their priorities related to treatment. OBJECTIVE: We aimed to identify patient priorities to inform an early economic evaluation of chimeric antigen receptor T-cell therapy for adults with relapsed or refractory B-cell acute lymphoblastic leukemia. METHODS: We conducted two online group discussions of four participants each, involving patients with experience of hematological cancer and a caregiver. We used an adapted version of the nominal group technique, a consensus-building discussion approach, to generate focused qualitative data. RESULTS: Patients and a caregiver acknowledged both the costs directly related to clinical care, such as the out-of-pocket cost of drugs, and the indirect treatment costs, such as the cost of transport, accommodation, and food. The emotional and physical toll of treatment and the influence of treatment on employment and education were additional costs emphasized by participants. Treatment benefits prioritized by participants included the efficacy of treatment, manageable side effects, improved quality of life, accessibility of treatment, and short treatment duration. CONCLUSIONS: Engaging patients and caregivers in an early economic evaluation could help identify additional costs and benefits of therapies that are not typically recognized in economic evaluations but have the potential to increase the commercial viability of novel therapies. This research also demonstrates how patients and caregivers can be engaged at different levels in the development of early economic evaluation models.

Epidemiology of intravenous immune globulin in septic shock: a retrospective cohort analysis of the Premier Healthcare Database.

PURPOSE: Intravenous immune globulin (IVIG) may improve survival in people with septic shock. Current utilization patterns of IVIG are unknown. We sought to characterize adult patients with septic shock requiring vasopressors who received IVIG, describes IVIG regimens, and evaluate determinants of IVIG use in patients with septic shock. METHODS: We conducted a retrospective database study of adult patients with septic shock admitted to US hospitals in the Premier Healthcare Database (from July 2010 to June 2013). We described the proportion of patients with septic shock receiving IVIG, examined IVIG regimens across sites and employed random-effects multivariable regression techniques to identify predictors of IVIG use. RESULTS: Intravenous immune globulin was administered to 0.3% (n = 685) of patients with septic shock; with a median [interquartile range (IQR)] dose of 1 [0.5-1.8] g·kg-1 for a median [IQR] of 1 [1-2] day. Receipt of IVIG was less likely for Black patients (odds ratio [OR], 0.54; 95% confidence interval [CI] 0.41 to 0.72) and patients without private insurance (Medicare OR, 0.73; 95% CI 0.59 to 0.90; Medicaid OR, 0.41; 95% CI 0.30 to 0.57) and more likely for patients with immunocompromise (OR, 6.83; 95% CI 5.47 to 8.53), necrotizing fasciitis (OR, 9.78; 95% CI 6.97 to 13.72), and toxic shock (OR, 56.9; 95% CI 38.7 to 83.7). CONCLUSIONS: Intravenous immune globulin is used infrequently across the US in patients with septic shock. Regimens of IVIG in septic shock may be less intensive than those associated with a survival benefit in meta-analyses. Observed infrequent use supports apparent clinical equipoise, perhaps secondary to limitations of the primary literature. A clinical trial evaluating the role of IVIG in septic shock is needed.

RéSUMé: OBJECTIF: L'immunoglobuline intraveineuse (IGIV) peut améliorer la survie chez les personnes atteintes de choc septique. Les pratiques actuelles d'utilisation de l'IGIV sont inconnues. Nous avons cherché à caractériser les patients adultes en état de choc septique et nécessitant des vasopresseurs qui ont reçu de l'IGIV, à décrire les dosages administrés d'IGIV, et à évaluer les causes déterminantes d'une utilisation d'IGIV chez ces patients. MéTHODE: Nous avons réalisé une étude rétrospective de base de données portant sur des patients adultes atteints de choc septique admis dans des hôpitaux américains et inclus dans la base de données Premier Healthcare (de juillet 2010 à juin 2013). Nous avons décrit la proportion de patients en choc septique recevant de l'IGIV, examiné les posologies utilisées d'IGIV à travers les sites et employé des techniques de régression multivariable à effets aléatoires pour identifier les prédicteurs de l'utilisation d'IGIV. RéSULTATS: L'IGIV a été administrée à 0,3 % (n = 685) des patients présentant un choc septique, avec une dose médiane [écart interquartile (ÉIQ)] de 1 [0,5­1,8] g·kg-1 pour une médiane [ÉIQ] de 1 [1­2] jour. L'administration d'IGIV était moins probable chez les patients noirs (rapport de cotes [RC], 0,54; intervalle de confiance [IC] à 95 %, 0,41 à 0,72) et les patients sans assurance privée (RC Medicare, 0,73; IC 95 %, 0,59 à 0,90; RC Medicaid, 0,41; IC 95 %, 0,30 à 0,57) et plus probable chez les patients immunodéprimés (RC, 6,83; IC 95 %, 5,47 à 8,53), atteints de fasciite nécrosante (RC, 9,78; IC 95 %, 6,97 à 13,72), et en choc toxique (RC, 56,9; IC 95 %, 38,7 à 83,7). CONCLUSION: L'IGIV est rarement utilisée aux États-Unis chez les patients en choc septique. Les dosages d'IGIV utilisés en cas de choc septique pourraient être moins intensifs que ceux associés à un effet bénéfique en matière de survie dans les méta-analyses. L'utilisation peu fréquente observée appuie une équivalence clinique apparente, peut-être secondaire aux limites de la littérature princeps. Une étude clinique évaluant le rôle de l'IGIV dans le choc septique est nécessaire.

Stakeholder engagement in economic evaluation: Protocol for using the nominal group technique to elicit patient, healthcare provider, and health system stakeholder input in the development of an early economic evaluation model of chimeric antigen receptor T-cell therapy.

INTRODUCTION: Chimeric antigen receptor T-cell (CAR-T) therapy is a class of immunotherapy. An economic evaluation conducted at an early stage of development of CAR-T therapy for treatment of adult relapsed or refractory acute lymphoblastic leukaemia could provide insight into factors contributing to the cost of treatment, the potential clinical benefits, and what the health system can afford. Traditionally, stakeholders are engaged in certain parts of health technology assessment processes, such as in the identification and selection of technologies, formulation of recommendations, and implementation of recommendations; however, little is known about processes for stakeholder engagement during the conduct of the assessment. This is especially the case for economic evaluations. Stakeholders, such as clinicians, policy-makers, patients, and their support networks, have insight into factors that can enhance the validity of an economic evaluation model. This research outlines a specific methodology for stakeholder engagement and represents an avenue to enhance health economic evaluations and support the use of these models to inform decision making for resource allocation. This protocol may inform a tailored framework for stakeholder engagement processes in future economic evaluation model development. METHODS AND ANALYSIS: We will involve clinicians, healthcare researchers, payers, and policy-makers, as well as patients and their support networks in the conduct and verification of an early economic evaluation of a novel health technology to incorporate stakeholder-generated knowledge. Three stakeholder-specific focus groups will be conducted using an online adaptation of the nominal group technique to elicit considerations from each. This study will use CAR-T therapy for adults with relapsed or refractory B-cell acute lymphoblastic leukaemia as a basis for investigating broader stakeholder engagement processes. ETHICS AND DISSEMINATION: This study received ethics approval from the Ottawa Hospital Research Institute Research Ethics Board (REB 20200320-01HT) and the results will be shared via conference presentations, peer-reviewed publications, and ongoing stakeholder engagement.

Implementation of the Canadian Cardiovascular Society guidelines for perioperative risk assessment and management: an interrupted time series study.

PURPOSE: The Canadian Cardiovascular Society (CCS) guidelines for patients undergoing non-cardiac surgery address the lack of standardized management for patients at risk of perioperative cardiovascular complications. Our interdisciplinary group evaluated the implementation of these guidelines. METHODS: We used an interrupted time series design to evaluate the effect of implementation of the CCS guidelines, using routinely collected hospital data. The study population consisted of elective, non-cardiac surgery patients who were: i) inpatients following surgery and ii) age ≥ 65 or age 45-64 yr with a Revised Cardiac Risk Index ≥ 1. Outcomes included adherence to troponin I (TnI) monitoring (primary) and adherence to appropriate consultant care for patients with elevated TnI (secondary). Exploratory outcomes included cost measures and clinical outcomes such as length of stay. RESULTS: We included 1,421 patients (706 pre- and 715 post-implementation). We observed a 67% absolute increase (95% confidence interval, 55 to 80; P < 0.001) in adherence to TnI testing following the implementation of the guidelines. In patients who had elevated TnI following guideline implementation (n = 64), the majority (85%) received appropriate follow-up care in the form of a general medicine or cardiology consult, all received at least one electrocardiogram, and half received at least one advanced cardiac test (e.g., cardiac perfusion scan, or percutaneous intervention). CONCLUSIONS: Our study showed the ability to implement and adhere to the CCS guidelines. Large-scale multicentre evaluations of CCS guideline implementation are needed to gain a better understanding of potential effects on clinically relevant outcomes.

RéSUMé: OBJECTIF: Les lignes directrices de la Société canadienne de cardiologie (SCC) concernant les patients subissant une chirurgie non cardiaque ont été conçues pour pallier l'absence de standardisation dans la prise en charge des patients à risque de complications cardiovasculaires périopératoires. Notre groupe interdisciplinaire a évalué la mise en œuvre de ces lignes directrices. MéTHODE: Nous avons utilisé une méthodologie de série chronologique interrompue pour évaluer l'effet de la mise en œuvre des lignes directrices de la SCC, à l'aide des données hospitalières habituellement recueillies. La population à l'étude se composait de patients de chirurgies non cardiaques non urgentes qui étaient : i) hospitalisés après leur chirurgie et ii) âgés de ≥ 65 ans ou de 45 à 64 ans avec un Indice de risque cardiaque révisé ≥ 1. Les critères d'évaluation comprenaient l'observance du monitorage de la troponine I (TnI) (critère d'évaluation primaire) et l'observance des soins spécialisés appropriés aux patients présentant un taux élevé de TnI (critère secondaire). Les critères exploratoires comprenaient des mesures de coûts et des résultats cliniques tels que la durée de séjour. RéSULTATS: Nous avons inclus 1421 patients (706 avant et 715 après la mise en œuvre). Nous avons observé une augmentation absolue de 67 % (intervalle de confiance de 95 %, 55 à 80; P < 0,001) de l'observance des tests de la TnI suite à la mise en œuvre des lignes directrices. Parmi les patients présentant un taux élevé de TnI suite à la mise en œuvre des lignes directrices (n = 64), la majorité (85%) a reçu des soins de suivi appropriés sous la forme d'une consultation en médecine générale ou en cardiologie; tous ont subi au moins un électrocardiogramme, et la moitié ont passé au moins un examen cardiaque subséquent (p. ex., évaluation de la perfusion myocardique par scintigraphie ou cathétérisme percutané). CONCLUSION: Notre étude a montré qu'il est possible de mettre en œuvre et d'adhérer aux nouvelles lignes directrices de la SCC. Des évaluations multicentriques à grande échelle portant sur la mise en œuvre des lignes directrices de la SCC sont nécessaires pour mieux comprendre ses effets potentiels sur les devenirs cliniquement pertinents.

Patient Participation in Clinical Trials of Oncology Drugs and Biologics Preceding Approval by the US Food and Drug Administration.

Importance: Several studies have estimated the financial inputs for successful drug development. Such analyses do not capture the large investment that patient study participants commit to drug development. Objective: To estimate the volume of patients required to achieve a first US Food and Drug Administration (FDA) approval for a new anticancer drug or biologic therapy. Design, Setting, and Participants: This cohort study included a random sample of prelicense oncology drugs and biologics with a trial site in the United States that were launched into clinical efficacy testing between January 1, 2006, and December 31, 2010. Drugs and biologics were identified using ClinicalTrials.gov registration records. Total patient enrollment was captured over an 8-year span, and each intervention was classified based on whether it received FDA approval and was deemed as having intermediate or substantial value according to the American Society of Clinical Oncology Value Framework (ASCO-VF) score. Secondarily, the association between patient numbers and intervention characteristics was tested. Data were analyzed in February 2020. Main Outcomes and Measure: The prespecified primary outcome was the number of patients enrolled in prelicense trials per FDA approval. Results: A total of 120 drugs and biologics were included in our study, with 84 (70.0%) targeted agents, 20 (16.7%) immunotherapies, and 71 (59.2%) novel agents. A total of 13 drugs and biologics (10.8%; 95% CI, 5.3%-16.8%) in our sample gained FDA approval within 8 years, of which 1 (7.7%) was deemed of intermediate value and 3 (23.1%) were deemed of substantial value using ASCO-VF scoring. Overall, 158 810 patients were enrolled in 1335 trials testing these drugs and biologics, 47 913 (30.2%) in trials that led to FDA approval and 110 897 (69.8%) in trials that did not. An estimated 12 217 (95% CI, 7970-22 215) patient study participants contributed to prelicense trials per FDA approval. The estimated number of patients needed to produce a single FDA-approved drug or biologic of intermediate or substantial ASCO-VF clinical value was 39 703 (95% CI, 19 391-177 991). Conclusions and Relevance: The results of this cohort study make visible the substantial patient investment required for prelicense oncology drug development. Such analyses can be used to devise policies that maximize the clinical impact of research on a per-patient basis.

Accommodating quality and service improvement research within existing ethical principles.

BACKGROUND: Quality and service improvement (QSI) research employs a broad range of methods to enhance the efficiency of healthcare delivery. QSI research differs from traditional healthcare research and poses unique ethical questions. Since QSI research aims to generate knowledge to enhance quality improvement efforts, should it be considered research for regulatory purposes? Is review by a research ethics committee required? Should healthcare providers be considered research participants? If participation in QSI research entails no more than minimal risk, is consent required? The lack of consensus on answers to these questions highlights the need for ethical guidance. MAIN BODY: Three distinct approaches to classifying QSI research in accordance with existing ethical principles and regulations can be found in the literature. In the first approach, QSI research is viewed as distinct from other types of healthcare research and does not require regulation. In the second approach, QSI research falls within regulatory guidelines but is exempt from research ethics committee review. In the third approach, QSI research is deemed to be part of the learning healthcare system and, as such, is subject to a different set of ethical principles entirely. In this paper, we critically assess each of these views. CONCLUSION: While none of these approaches is entirely satisfactory, we argue that use of the ethical principles governing research provides the best means of addressing the numerous questions posed by QSI research.

Antipsychotics for treatment of delirium in hospitalised non-ICU patients.

BACKGROUND: Guidelines suggest limited and cautious use of antipsychotics for treatment of delirium where nonpharmacological interventions have failed and symptoms remain distressing or dangerous, or both. It is unclear how well these recommendations are supported by current evidence. OBJECTIVES: Our primary objective was to assess the efficacy of antipsychotics versus nonantipsychotics or placebo on the duration of delirium in hospitalised adults. Our secondary objectives were to compare the efficacy of: 1) antipsychotics versus nonantipsychotics or placebo on delirium severity and resolution, mortality, hospital length of stay, discharge disposition, health-related quality of life, and adverse effects; and 2) atypical vs. typical antipsychotics for reducing delirium duration, severity, and resolution, hospital mortality and length of stay, discharge disposition, health-related quality of life, and adverse effects. SEARCH METHODS: We searched MEDLINE, Embase, Cochrane EBM Reviews, CINAHL, Thomson Reuters Web of Science and the Latin American and Caribbean Health Sciences Literature (LILACS) from their respective inception dates until July 2017. We also searched the Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment Database, Web of Science ISI Proceedings, and other grey literature. SELECTION CRITERIA: We included randomised and quasi-randomised trials comparing 1) antipsychotics to nonantipsychotics or placebo and 2) typical to atypical antipsychotics for the treatment of delirium in adult hospitalised (but not critically ill) patients. DATA COLLECTION AND ANALYSIS: We examined titles and abstracts of identified studies to determine eligibility. We extracted data independently in duplicate. Disagreements were settled by further discussion and consensus. We used risk ratios (RR) with 95% confidence intervals (CI) as a measure of treatment effect for dichotomous outcomes, and between-group standardised mean differences (SMD) with 95% CI for continuous outcomes. MAIN RESULTS: We included nine trials that recruited 727 participants. Four of the nine trials included a comparison of an antipsychotic to a nonantipsychotic drug or placebo and seven included a comparison of a typical to an atypical antipsychotic. The study populations included hospitalised medical, surgical, and palliative patients.No trial reported on duration of delirium. Antipsychotic treatment did not reduce delirium severity compared to nonantipsychotic drugs (standard mean difference (SMD) -1.08, 95% CI -2.55 to 0.39; four studies; 494 participants; very low-quality evidence); nor was there a difference between typical and atypical antipsychotics (SMD -0.17, 95% CI -0.37 to 0.02; seven studies; 542 participants; low-quality evidence). There was no evidence antipsychotics resolved delirium symptoms compared to nonantipsychotic drug regimens (RR 0.95, 95% CI 0.30 to 2.98; three studies; 247 participants; very low-quality evidence); nor was there a difference between typical and atypical antipsychotics (RR 1.10, 95% CI 0.79 to 1.52; five studies; 349 participants; low-quality evidence). The pooled results indicated that antipsychotics did not alter mortality compared to nonantipsychotic regimens (RR 1.29, 95% CI 0.73 to 2.27; three studies; 319 participants; low-quality evidence) nor was there a difference between typical and atypical antipsychotics (RR 1.71, 95% CI 0.82 to 3.35; four studies; 342 participants; low-quality evidence).No trial reported on hospital length of stay, hospital discharge disposition, or health-related quality of life. Adverse event reporting was limited and measured with inconsistent methods; in those reporting events, the number of events were low. No trial reported on physical restraint use, long-term cognitive outcomes, cerebrovascular events, or QTc prolongation (i.e. increased time in the heart's electrical cycle). Only one trial reported on arrhythmias and seizures, with no difference between typical or atypical antipsychotics. We found antipsychotics did not have a higher risk of extrapyramidal symptoms (EPS) compared to nonantipsychotic drugs (RR 1.70, 95% CI 0.04 to 65.57; three studies; 247 participants; very-low quality evidence); pooled results showed no increased risk of EPS with typical antipsychotics compared to atypical antipsychotics (RR 12.16, 95% CI 0.55 to 269.52; two studies; 198 participants; very low-quality evidence). AUTHORS' CONCLUSIONS: There were no reported data to determine whether antipsychotics altered the duration of delirium, length of hospital stay, discharge disposition, or health-related quality of life as studies did not report on these outcomes. From the poor quality data available, we found antipsychotics did not reduce delirium severity, resolve symptoms, or alter mortality. Adverse effects were poorly or rarely reported in the trials. Extrapyramidal symptoms were not more frequent with antipsychotics compared to nonantipsychotic drug regimens, and no different for typical compared to atypical antipsychotics.

An assessment of Prostate Cancer Research International: Active Surveillance (PRIAS) criteria for active surveillance of clinically low-risk prostate cancer patients.

INTRODUCTION: Active surveillance is a strategy to delay or prevent treatment of indolent prostate cancer. The Prostate Cancer Research International: Active Surveillance (PRIAS) criteria were developed to select patients for prostate cancer active surveillance. The objective of this study was to compare pathological findings from PRIAS-eligible and PRIAS-ineligible clinically low-risk prostate cancer patients. METHODS: A D'Amico low-risk cohort of 1512 radical prostatectomy patients treated at The Ottawa Hospital or Memorial Sloan Kettering Cancer Centre between January 1995 and December 2007 was reviewed. Pathological outcomes (pT3 tumours, Gleason sum ≥7, lymph node metastases, or a composite) and clinical outcomes (prostate-specific antigen [PSA] recurrence, secondary cancer treatments, and death) were compared between PRIAS-eligible and PRIAS-ineligible cohorts. RESULTS: The PRIAS-eligible cohort (n=945) was less likely to have Gleason score ≥7 (odds ratio [OR] 0.61; 95% confidence interval [CI] 0.49-0.75), pT3 (OR 0.41; 95% CI 0.31-0.55), nodal metastases (OR 0.37; 95% CI 0.10-1.31), or any adverse feature (OR 0.56; 95% CI 0.45-0.69) compared to the PRIAS-ineligible cohort. The probability of any adverse pathology in the PRIAS-eligible cohort was 41% vs. 56% in the PRIAS-ineligible cohort. At median follow-up of 3.7 years, 72 (4.8%) patients had a PSA recurrence, 24 (1.6%) received pelvic radiation, and 13 (0.9%) received androgen deprivation. No difference was detected for recurrence-free and overall survival between groups (recurrence hazard ratio [HR] 0.71; 95% CI 0.46-1.09 and survival HR 0.72; 95% CI 0.36-1.47). CONCLUSIONS: Low-risk prostate cancer patients who met PRIAS eligibility criteria are less likely to have higher-risk cancer compared to those who did not meet at least one of these criteria.

Daily sedation interruption versus no daily sedation interruption for critically ill adult patients requiring invasive mechanical ventilation.

BACKGROUND: Daily sedation interruption (DSI) is thought to limit drug bioaccumulation, promote a more awake state, and thereby reduce the duration of mechanical ventilation. Available evidence has shown DSI to either reduce, not alter, or prolong the duration of mechanical ventilation. OBJECTIVES: The primary objective of this review was to compare the total duration of invasive mechanical ventilation for critically ill adult patients requiring intravenous sedation who were managed with DSI versus those with no DSI. Our other objectives were to determine whether DSI influenced mortality, intensive care unit (ICU) and hospital lengths of stay, adverse events, the total doses of sedative drug administered, and quality of life. SEARCH METHODS: We searched, from database inception to February 2014, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 1); MEDLINE (OvidSP); EMBASE (OvidSP); CINAHL (EBSCOhost); Latin American and Caribbean Health Sciences Literature (LILACS); Web of Science Science Citation Index; Database of Abstracts of Reviews of Effects (DARE); the Health Technology Assessment Database (HTA Database); trial registration websites, and reference lists of relevant articles. We did not apply language restrictions. The reference lists of all retrieved articles were reviewed for additional, potentially relevant studies. SELECTION CRITERIA: We included randomized controlled trials that compared DSI with sedation strategies that did not include DSI in mechanically ventilated, critically ill adults. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and three authors assessed risk of bias. We contacted study authors for additional information as required. We combined data in forest plots using random-effects modelling. A priori subgroups and sensitivity analyses were performed. MAIN RESULTS: Nine trials were used in the analysis (n = 1282 patients). These trials were found to be predominantly at low risk of bias. We did not find strong evidence of an effect of DSI on the total duration of ventilation. Pooled data from nine trials demonstrated a 13% reduction in the geometric mean, with relatively wide confidence intervals (CI) indicating imprecision (95% CI 26% reduction to 2% increase, moderate quality evidence). Similarly, we did not find strong evidence of an effect on ICU length of stay (-10%, 95% CI -20% to 3%, n = 9 trials, moderate quality evidence) or hospital length of stay (-6%, 95% CI -18% to 8%, n = 8 trials, moderate quality evidence). Heterogeneity for these three outcomes was moderate and statistically significant. The risk ratio for ICU mortality was 0.96 (95% CI 0.77 to 1.21, n = 7 trials, moderate quality evidence), for rate of accidental endotracheal tube removal 1.07 (95% CI 0.55 to 2.12, n = 6 trials, moderate quality evidence), for catheter removal 1.48 (95% CI 0.76 to 2.90, n = 4 trials), and for incidence of new onset delirium 1.02 (95% CI 0.91 to 1.13, n = 3 trials, moderate quality evidence). Differences in the doses of any drug used or quality of life score (Short Form (SF)-36) did not reach statistical significance. Tracheostomy was performed less frequently in the DSI group (RR 0.73, 95% CI 0.57 to 0.92, n = 6 trials, moderate quality evidence). Sensitivity analysis of unlogged data resulted in similar findings. Post hoc analysis to further explain heterogeneity, based on study country of origin, showed that studies conducted in North America resulted in a reduction in the duration of mechanical ventilation (-21%, 95% CI -33% to -5%, n = 5 trials). AUTHORS' CONCLUSIONS: We have not found strong evidence that DSI alters the duration of mechanical ventilation, mortality, length of ICU or hospital stay, adverse event rates, drug consumption, or quality of life for critically ill adults receiving mechanical ventilation compared to sedation strategies that do not include DSI. We advise that caution should be applied when interpreting and applying the findings as the overall effect of treatment is always < 1 and the upper limit of the CI is only marginally higher than the no-effect line. These results should be considered unstable rather than negative for DSI given the statistical and clinical heterogeneity identified in the included trials.