Real-World Evidence of Ribociclib Plus Aromatase Inhibitors as First-Line Treatment in Advanced Breast Cancer: The BrasiLEEira Study.

PURPOSE: Cyclin inhibitors plus endocrine therapy represent the reference standard for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) locally advanced or metastatic breast cancer (ABC). Efficacy results on hard end points such as overall survival come from well-designed randomized clinical trials (RCTs). However, a limitation of RCTs is the low external results validity, and their extrapolation to a broader population may not be appropriate. Real-world studies can overcome these limitations, also increasing the reliability of RCTs. MATERIALS AND METHODS: The BrasiLEEira was an observational, longitudinal, retrospective, multicenter study to evaluate the effectiveness and safety of ribociclib plus nonsteroidal aromatase inhibitors in Brazilian women age 18 years or older with HR+/HER2- ABC. The study was approved by the institutional review boards of all 11 hospitals. Data were collected anonymously from medical records using an electronic case report form designed by an independent academic research organization, which conducted the study considering all recommendations of international guidelines. The primary end point was 1-year progression-free survival (PFS) rate. Secondary end points included mortality, dose reduction, and safety. RESULTS: The mean age of 76 patients was 57 years, and 28.9% were Black/Brown. The most prevalent comorbidity was arterial hypertension (34.7%). About 26.0% had endocrine-resistant disease, and 54.1% had more than three metastatic sites. The PFS rate was 77.6%. Three patients died (3.9%). Dose reductions occurred in 37.7% of patients. The most common adverse event was neutropenia (68.4%). CONCLUSION: The high-quality evidence from the BrasiLEEira study corroborates the RCTs' findings, expanding its validity to a broader spectrum and underrepresented population who may benefit from ribociclib treatment.

Effect of ribociclib on productivity losses due to breast cancer in young women in Brazil.

OBJETIVE: To evaluate the effect of ribociclib versus endocrine therapy on productivity losses due to advanced breast cancer. METHODS: Productivity data from the MONALEESA-7 trial, obtained from the results of the application of the Work Productivity and Activity Impairment (WPAI) questionnaire on progression-free survival state (43-month follow-up), were extrapolated to the 10,936 Brazilian prevalent cases of premenopausal women with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer. Productivity loss was determined by quantifying the economic costs of workforce dropout over time in both treatment arms and by discounting the economic costs of absenteeism and presenteeism from workforce retention. A human capital approach was used. RESULTS: Net productivity gains in the ribociclib arm were estimated at USD 4,285,525.00, representing 316,609 added work hours over 43 months and a mean of 2,009 added work weeks per year. CONCLUSIONS: The phase III MONALEESA-7 trial productivity results applied to the Brazilian premenopausal prevalent cases of hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer showed that treatment with ribociclib + endocrine therapy improves workforce participation compared with endocrine therapy alone in premenopausal women with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) metastatic breast cancer, with potential economic gains for the Brazilian society.

Cost-effectiveness of ribociclib for premenopausal or perimenopausal women with HR+/HER2- advanced breast cancer: a Brazilian public health care system perspective.

Introduction: The MONALEESA-7 trial compared ribociclib plus endocrine therapy (ET) with placebo as first-line treatment of advanced luminal/HER2-negative breast cancer (ABC) in premenopausal and perimenopausal women (age <50 years) and showed significant benefits to progression-free survival and overall survival. This study aimed to compare the cost-effectiveness of ribociclib + ET versus ET alone in patients with ABC from the perspective of the Brazilian public national health system. Methods: We calculated the incremental cost-effectiveness ratio (ICER) using a Markov model with progression-free survival, post-progression survival, and death states. We expressed ICER as incremental costs per progression-free life-year (PFLY) and quality-adjusted life-year (QALY) gained in a 10-year time horizon. We used parametric survival distributions fit to MONALEESA-7 data to generate survival distributions for progression-free and post-progression survival. The largest British preference study in breast cancer served as the basis to estimate health-state utilities. We estimated direct costs (ABC treatment, follow-up, monitoring, and adverse events) using Brazilian-specific values from public sources. An expert consensus panel determined the resource patterns required. We applied annual discounts of 5% to costs and QALYs. Results: Ribociclib + ET resulted in an incremental gain of 1.03 PFLYs and 0.80 QALYs at a cost of $37,319.31. The ICER of ribociclib + ET versus ET was $36,379.41 per PFLY gained and $46,590.79 per QALY gained. In deterministic sensitivity analysis, results were primarily affected by the annual discount rate, followed by the cost of ribociclib. In probabilistic sensitivity analysis, simulations agreed with the base-case. Conclusion: Ribociclib increased PFLYs and QALYs in patients with HR+/HER2- ABC when added to ET. Because Brazil does not have a formally defined cost-effectiveness threshold, other domains need to be considered for incorporation decisions, such as disease burden and humanistic impact on this young, economically active population. These findings may be useful in discussions for incorporation of ribociclib into the Brazilian public health system.

Effect of ribociclib on productivity losses due to breast cancer in young women in Brazil

ABSTRACT OBJETIVE To evaluate the effect of ribociclib versus endocrine therapy on productivity losses due to advanced breast cancer. METHODS Productivity data from the MONALEESA-7 trial, obtained from the results of the application of the Work Productivity and Activity Impairment (WPAI) questionnaire on progression-free survival state (43-month follow-up), were extrapolated to the 10,936 Brazilian prevalent cases of premenopausal women with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer. Productivity loss was determined by quantifying the economic costs of workforce dropout over time in both treatment arms and by discounting the economic costs of absenteeism and presenteeism from workforce retention. A human capital approach was used. RESULTS Net productivity gains in the ribociclib arm were estimated at USD 4,285,525.00, representing 316,609 added work hours over 43 months and a mean of 2,009 added work weeks per year. CONCLUSIONS The phase III MONALEESA-7 trial productivity results applied to the Brazilian premenopausal prevalent cases of hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer showed that treatment with ribociclib + endocrine therapy improves workforce participation compared with endocrine therapy alone in premenopausal women with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) metastatic breast cancer, with potential economic gains for the Brazilian society.

Cost-effectiveness of ribociclib plus letrozole versus palbociclib plus letrozole or letrozole as monotherapy in first-line treatment of postmenopausal women with HR+/HER2- locally advanced or metastatic breast cancer: a Brazilian private payer perspective.

BACKGROUND: The global burden of breast cancer (BC) is high, especially in advanced stages. CDK 4/6 inhibitors represent a paradigm shift in the treatment of advanced BC HR+/HER2-, given the clinically and statistically significant gain in overall survival associated with this new class of medications. Nevertheless, as an innovation, the incorporation of these drugs impacts healthcare budgets, requiring cost-effectiveness analyses for decision-making. The aim of this study was to evaluate the cost-effectiveness of ribociclib plus letrozole compared with palbociclib plus letrozole or letrozole as monotherapy for first-line treatment of postmenopausal women with HR+/HER2- locally advanced or metastatic BC (aBC) from a Brazilian private healthcare system perspective. METHODS: A model including progression-free survival (PFS), progressed disease, and death health states was used to simulate lifetime costs and outcomes. PFS and overall survival were derived from the MONALEESA-2 trial (lifetime horizon). Healthcare costs included drug acquisition and monitoring, subsequent therapies, adverse events, and end-of-life costs. Effectiveness was measured in quality-adjusted life-years (QALYs). Deterministic and probabilistic sensitivity analyses were performed. RESULTS: The total cost of treatment with ribociclib plus letrozole was USD 72,091.82 versus USD 92,749.64 for palbociclib plus letrozole. Total QALYs were 3.30 and 3.16, respectively. Base-case analysis showed ribociclib as dominant over palbociclib in first-line treatment of women with HR+/HER2- aBC, associated with cost savings and QALY gains. The total cost of treatment with ribociclib plus letrozole was USD 83,058.73 versus USD 29,215.10 for letrozole. Total QALYs were 3.84 and 2.61, respectively. Compared with letrozole, ribociclib plus letrozole was associated with an incremental cost of USD 53,843.64 and an incremental QALY gain of 1.23, with incremental cost-effectiveness ratio of USD 43,826.91 per QALY gained. CONCLUSIONS: As demonstrated by the cost-effectiveness dominance over palbociclib, ribociclib results in savings when used as first-line treatment in postmenopausal women with HR+/HER2- aBC, warranting incorporation in the private healthcare system.

Clinical practice guidelines in Brazil - developing a national programme.

In Brazil, governmental and non-governmental organisations develop practice guidelines (PGs) in order to optimise patient care. Although important improvements have been made over the past years, many of these documents still lack transparency and methodological rigour. In order to conduct a critical analysis and define future steps in PG development in Brazil, we carried out a structured assessment of strengths, weaknesses, opportunities and threats (SWOT analysis) for the development of a national guideline programme. Participants consisted of academia, methodologists, medical societies and healthcare system representatives. In summary, the PG development process has improved in Brazil and current investments in methodological research and capacity-building are ongoing. Despite the centralised processes for public PGs, standardised procedures for their development are not well established and human resources are insufficient in number and capacity to develop the amount of trustworthy documents needed. Brazil's capacity could be strengthened and initial efforts have been made such as the adoption of standards proposed by world-renowned institutions in PG development and enhancement of the involvement of key stakeholders. Further steps involve the alignment between health technology assessment and PG processes for synergy and the development of a national network to promote the interaction between groups involved in the development of PGs. The lessons learned from this paper could be used to foster debate on guideline development, especially for countries facing similar threats on this topic.

Can Enhanced Techniques Improve the Diagnostic Accuracy of Transvaginal Sonography and Magnetic Resonance Imaging for Rectosigmoid Endometriosis? A Systematic Review and Meta-analysis.

OBJECTIVE: Our aim was to perform a systematic review and meta-analysis of the most commonly used examinations for rectosigmoid lesions of deeply infiltrating endometriosis, transvaginal sonography (TVS) and magnetic resonance imaging (MRI), to compare their diagnostic accuracy and enhanced or non-enhanced techniques. METHODS: A systematic search was performed until March 2018 without time or language restrictions. Eligibility criteria included studies that compared the accuracy of TVS and MRI for diagnosis of rectosigmoid endometriosis. The quality of the studies was assessed by means of Quality Assessment of Diagnostic Accuracy Studies-2 and Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations. Bivariate and hierarchical analysis were performed. The difference in the accuracy of TVS and MRI was tested, and heterogeneity was addressed by means of meta-regression, sensitivity, or subgroup analysis. RESULTS: A total of 1754 studies were screened; 105 studies were eligible, and 11 studies were included in the meta-analysis. Overall pooled sensitivity, specificity, and area under the receiver operating characteristic curve were 0.80, 0.94, and 0.95, respectively. The measures for MRI were 0.82, 0.94, and 0.95, respectively. There was no statistical difference between the accuracy values of TVS and MRI (P = 0.90). The use of bowel preparation and vaginal contrast could enhance the accuracy of MRI. Along with rectosigmoid prevalence, bowel and vaginal contrast explained a significant proportion of the statistical heterogeneity. CONCLUSIONS: Both TVS and MRI showed high diagnostic accuracy for rectosigmoid deeply infiltrating endometriosis lesions. There is no strong evidence suggesting that the two diagnostic methods might differ in specificity or sensitivity, but enhanced techniques may increase the accuracy measures.

Gender Differences in Retention and Promotion Among Generalists Who Graduated From Research-Intensive Fellowships.

BACKGROUND: Generalists who pursue research-intensive fellowships develop research skills and mentor-mentee relationships. Whether gender disparities in retention and promotion exist among this research-trained cohort is understudied. OBJECTIVE: We measured whether disparities exist among graduates of research-intensive fellowships and how mentorship influences them. METHODS: We surveyed generalists (internal medicine, pediatrics, family medicine, combined internal medicine-pediatrics) between July and August 2016 who graduated from research-intensive fellowships. Generalists ("mentees") were asked whether they remained or were promoted, and to name up to 10 influential mentors during or within 5 years of fellowship. Multivariable logistic regression estimated associations between mentee gender and retention and promotion. Next, we separately included 3 network characteristics: (1) mentee degrees (number of mentors reported per mentee); (2) mean mentor betweenness centrality (importance of each mentor within the network); and (3) largest community membership (mentee status in the largest interconnected mentor-mentee group within the network). All models adjusted for generalists' race, specialty, fellowship institution, and publications. RESULTS: One hundred sixty-two graduates (51%) representing 19 institutions responded. In adjusted analyses, compared to men, women were as likely to remain in academic medicine (odds ratio [OR] 1.88; 95% confidence interval [CI] 0.72-4.89; P = .20), but less likely to be promoted within 5 years of fellowship (OR 0.26; 95% CI 0.09-0.80; P = .018). Inclusion of network measures did not alter these associations. CONCLUSIONS: Despite remaining in academic medicine as frequently as their male counterparts, fellowship-trained women were promoted less often. Features of mentors, measured using network analysis, may not explain these observed differences.

Rational use of diagnostic tests for clinical decision making.

OBJECTIVE: To assist clinicians to make adequate interpretation of scientific evidence from studies that evaluate diagnostic tests in order to allow their rational use in clinical practice. METHODS: This is a narrative review focused on the main concepts, study designs, the adequate interpretation of the diagnostic accuracy data, and making inferences about the impact of diagnostic testing in clinical practice. RESULTS: Most of the literature that evaluates the performance of diagnostic tests uses cross-sectional design. Randomized clinical trials, in which diagnostic strategies are compared, are scarce. Cross-sectional studies measure diagnostic accuracy outcomes that are considered indirect and insufficient to define the real benefit for patients. Among the accuracy outcomes, the positive and negative likelihood ratios are the most useful for clinical management. Variations in the study's cross-sectional design, which may add bias to the results, as well as other domains that contribute to decreasing the reliability of the findings, are discussed, as well as how to extrapolate such accuracy findings on impact and consequences considered important for the patient. Aspects of costs, time to obtain results, patients' preferences and values should preferably be considered in decision making. CONCLUSION: Knowing the methodology of diagnostic accuracy studies is fundamental, but not sufficient, for the rational use of diagnostic tests. There is a need to balance the desirable and undesirable consequences of tests results for the patients in order to favor a rational decision-making approach about which tests should be recommended in clinical practice.

Comparison of Biological and Mechanical Prostheses for Heart Valve Surgery: A Systematic Review of Randomized Controlled Trials.

BACKGROUND: The choice of a mechanical (MP) or biological prosthesis (BP) for patients with valvular heart disease undergoing replacement is still not a consensus. OBJECTIVE: We aimed to determine the clinical outcomes of MP or BP placement in those patients. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) that compared biological prostheses and mechanical prostheses in patients with valvular heart diseases and assessed the outcomes. RCTs were searched in the MEDLINE, EMBASE, LILACS, CENTRAL, SCOPUS and Web of Science (from inception to November 2014) databases. Meta-analyses were performed using inverse variance with random effects models. The GRADE system was used to rate the quality of the evidence. A P-value lower than 0.05 was considered significant. RESULTS: A total of four RCTs were included in the meta-analyses (1,528 patients) with follow up ranging from 2 to 20 years. Three used old generation mechanical and biological prostheses, and one used contemporary prostheses. No significant difference in mortality was found between BP and MP patients (risk ratio (RR = 1.07; 95% CI 0.99-1.15). The risk of bleeding was significantly lower in BP patients than MP patients (RR = 0.64; 95% CI 0.52-0.78); however, reoperations were significantly more frequent in BP patients (RR = 3.60; 95% CI 2.44-5.32). There were no statistically significant differences between BP and MP patients with respect to systemic arterial embolisms and infective endocarditis (RR = 0.93; 95% CI 0.66-1.31, RR = 1.21; CI95% 0.78-1.88, respectively). Results in the trials with modern and old prostheses were similar. CONCLUSIONS: The mortality rate and the risk of thromboembolic events and endocarditis were similar between BP and MP patients. The risk of bleeding was approximately one third lower for BP patients than for MP patients, while the risk of reoperations was more than three times higher for BP patients.

Comparison of Biological and Mechanical Prostheses for Heart Valve Surgery: A Systematic Review of Randomized Controlled Trials / Comparação de Próteses Biológicas e Mecânicas para Cirurgia de Válvula Cardíaca: Revisão Sistemática de Estudos Controlados Randomizados

Abstract Background: The choice of a mechanical (MP) or biological prosthesis (BP) for patients with valvular heart disease undergoing replacement is still not a consensus. Objective: We aimed to determine the clinical outcomes of MP or BP placement in those patients. Methods: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) that compared biological prostheses and mechanical prostheses in patients with valvular heart diseases and assessed the outcomes. RCTs were searched in the MEDLINE, EMBASE, LILACS, CENTRAL, SCOPUS and Web of Science (from inception to November 2014) databases. Meta-analyses were performed using inverse variance with random effects models. The GRADE system was used to rate the quality of the evidence. A P-value lower than 0.05 was considered significant. Results: A total of four RCTs were included in the meta-analyses (1,528 patients) with follow up ranging from 2 to 20 years. Three used old generation mechanical and biological prostheses, and one used contemporary prostheses. No significant difference in mortality was found between BP and MP patients (risk ratio (RR = 1.07; 95% CI 0.99-1.15). The risk of bleeding was significantly lower in BP patients than MP patients (RR = 0.64; 95% CI 0.52-0.78); however, reoperations were significantly more frequent in BP patients (RR = 3.60; 95% CI 2.44-5.32). There were no statistically significant differences between BP and MP patients with respect to systemic arterial embolisms and infective endocarditis (RR = 0.93; 95% CI 0.66-1.31, RR = 1.21; CI95% 0.78-1.88, respectively). Results in the trials with modern and old prostheses were similar. Conclusions: The mortality rate and the risk of thromboembolic events and endocarditis were similar between BP and MP patients. The risk of bleeding was approximately one third lower for BP patients than for MP patients, while the risk of reoperations was more than three times higher for BP patients.

Resumo Fundamento: A escolha de próteses mecânicas ou biológicas para pacientes com doença de válvula cardíaca ainda não é um consenso. Objetivo: Determinar os desfechos clínicos de próteses mecânicas e biológicas nesses pacientes. Métodos: Conduzimos uma revisão sistemática e metanálise e estudos controlados randomizados (RCTs) que compararam próteses mecânicas e biológicas em pacientes com doenças de válvulas cardíaca, e avaliamos seus resultados. A busca por RCTs foi feita nas bases de dados MEDLINE, EMBASE, LILACS, CENTRAL, SCOPUS e Web of Science (do início a novembro de 2014). As metanálises foram realizadas usando variação inversa com modelos de efeitos aleatórios. Usamos o sistema GRADE para avaliar a qualidade da evidência. Um valor menor que 0,05 foi considerado significativo. Resultados: Um total de quatro RCTs foi incluído na metanálise (1528 pacientes) com acompanhamento de 2 a 20 anos. Em três estudos, foram utilizadas próteses mecânicas e biológicas mais antigas, e em um estudo próteses contemporâneas. Não foi observada diferença de mortalidade entre os pacientes que receberam próteses mecânicas e biológicas (risco relativo, RR = 1,07; IC95% 0,99-1,15). O risco de sangramento foi significativamente mais baixo nos pacientes que receberam próteses biológicas que naqueles com próteses mecânicas (RR = 0,64; IC95% 0,52-0,78). Contudo, as reoparações foram mais frequentes em pacientes com próteses biológicas (RR = 3,60; IC95% 2,44-5,32). Não houve diferenças estatisticamente significativas entre pacientes com próteses biológicas e mecânicas em relação à embolia arterial sistêmica e endocardite infecciosa (RR = 0,93; IC95% 0,66-1,31; RR = 1,21; IC95% 0,78-1,88, respectivamente). Resultados entre os estudos com próteses modernas e antigas foram similares. Conclusões: A taxa de mortalidade e o risco de eventos tromboembólicos e endocardite foram similares entre os pacientes que receberam próteses biológicas e mecânicas. O risco de sangramentos foi aproximadamente um terço menor nos pacientes com próteses biológicas que mecânicas, ao passo que o risco de reoperação foi mais que três vezes maior nos pacientes com próteses biológicas.

Rational use of diagnostic tests for clinical decision making

SUMMARY OBJECTIVE: To assist clinicians to make adequate interpretation of scientific evidence from studies that evaluate diagnostic tests in order to allow their rational use in clinical practice. METHODS: This is a narrative review focused on the main concepts, study designs, the adequate interpretation of the diagnostic accuracy data, and making inferences about the impact of diagnostic testing in clinical practice. RESULTS: Most of the literature that evaluates the performance of diagnostic tests uses cross-sectional design. Randomized clinical trials, in which diagnostic strategies are compared, are scarce. Cross-sectional studies measure diagnostic accuracy outcomes that are considered indirect and insufficient to define the real benefit for patients. Among the accuracy outcomes, the positive and negative likelihood ratios are the most useful for clinical management. Variations in the study's cross-sectional design, which may add bias to the results, as well as other domains that contribute to decreasing the reliability of the findings, are discussed, as well as how to extrapolate such accuracy findings on impact and consequences considered important for the patient. Aspects of costs, time to obtain results, patients' preferences and values should preferably be considered in decision making. CONCLUSION: Knowing the methodology of diagnostic accuracy studies is fundamental, but not sufficient, for the rational use of diagnostic tests. There is a need to balance the desirable and undesirable consequences of tests results for the patients in order to favor a rational decision-making approach about which tests should be recommended in clinical practice.

RESUMO OBJETIVO: Auxiliar os clínicos na interpretação adequada das evidências científicas de estudos que avaliam testes diagnósticos, de modo a permitir seu uso racional na prática clínica. MÉTODOS: Revisão narrativa da literatura dos principais conceitos, desenhos de estudo, interpretação adequada dos dados de acurácia diagnóstica e realização de inferências sobre o impacto do teste diagnóstico na prática clínica. RESULTADOS: A maioria da literatura que avalia o desempenho de testes diagnósticos utiliza como delineamento os estudos transversais. Ensaios clínicos randomizados, avaliando desfechos clínicos, que seriam considerados ideais, são escassos. Os estudos transversais mensuram desfechos de acurácia diagnóstica que são considerados indiretos e insuficientes para definir o real benefício para os pacientes. Dentre os desfechos, as razões de verossimilhança positiva e negativa são as mais úteis para a decisão da conduta clínica. Variações no delineamento transversal do estudo, que podem acrescentar vieses aos resultados, bem como outros domínios que contribuem para diminuir a confiabilidade dos achados, são discutidos, além de como extrapolar tais achados de acurácia em impacto e consequências consideradas importantes para o paciente. Aspectos sobre custos, tempo para a obtenção do resultado, preferências e valores dos pacientes devem, preferencialmente, participar da tomada de decisão. CONCLUSÃO: Conhecer a metodologia dos estudos de acurácia diagnóstica é fundamental, porém não suficiente, para o uso racional de testes diagnósticos. Há a necessidade de se ponderarem as consequências desejáveis e indesejáveis dos resultados dos testes para os pacientes, de modo a favorecer a tomada de decisão racional acerca de qual teste recomendar na prática clínica.

Intuitive vs Deliberative Approaches to Making Decisions About Life Support: A Randomized Clinical Trial.

Importance: Patients with serious illnesses are often encouraged to actively deliberate about the desirability of life support. Yet it is unknown whether deliberation changes the substance or quality of such decisions. Objective: To identify differences in decisions about life support interventions and goals of care made intuitively vs deliberatively by patients with serious illnesses. Design, Setting, and Participants: Randomized clinical trial in which patients were asked to express treatment preferences in a series of clinical scenarios. Participants were 199 hospitalized patients aged 60 years and older with serious oncologic, cardiac, and pulmonary illnesses treated in a large, urban academic hospital from July 1, 2015, through March 15, 2016. Interventions: Patients in the intuitive group were subjected to a cognitive load and instructed to answer each question immediately based on gut instinct. Patients in the deliberative group were not cognitively loaded, were instructed to think carefully about their answers, and were required to explain their answers. Main Outcomes and Measures: Choices regarding life support (4 scenarios) and goals of care (1 scenario), concordance of these choices with patients' valuations of health states that could follow from them, and decisional uncertainty. Results: Of 199 patients, 132 (66%) were male and the mean (SD) age was 67.2 (5.0) years. Similar proportions of patients in the intuitive group (n = 97) and the deliberative group (n = 102) said they would accept a feeding tube for chronic aspiration (42% vs 44%, respectively; difference, -2%; 95% CI, -16% to 12%; P = .79), antibiotics for life-threatening infection in the event of terminal illness (39% vs 43%, respectively; difference, -4%; 95% CI, -18% to 10%; P = .57), a trial of mechanical ventilation (59% vs 60%, respectively; difference,-1%; 95% CI, -15% to 13%; P = .88), and a tracheostomy tube (37% vs 41%, respectively; difference, -4%; 95% CI, -22% to 13%; P = .64). Patients in the deliberative group were slightly more likely than patients in the intuitive group to choose a palliative approach to treatment in the event of serious illness (45% vs 30%, respectively; difference, 15%; 95% CI, 1%-29%; P = .04). Across scenarios, decisional uncertainty was similar between the 2 groups (all P > .05), and intuitive decisions were either equally or more closely aligned with patients' health state valuations than deliberative decisions. Conclusions and Relevance: In this study, encouraging hospitalized patients with serious illnesses to deliberate on end-of-life decisions did not change the content or improve the quality of these decisions. It is important to evaluate whether decision aids and structured communication interventions improve seriously ill patients' choices. Trial Registration: ClinicalTrials.gov Identifier: NCT02487810.

The Overt and Hidden Use of Animal-Derived Products in Alternative Methods for Skin Sensitisation: A Systematic Review.

In vitro methods that can replace animal testing in the identification of skin sensitisers are now a reality. However, as cell culture and related techniques usually rely on animal-derived products, these methods may be failing to address the complete replacement of animals in safety assessment. The objective of this study was to identify the animal-derived products that are used as part of in vitro methods for skin sensitisation testing. Thus, a systematic review of 156 articles featuring 83 different in vitro methods was carried out and, from this review, the use of several animal-derived products from different species was identified, with the use of fetal bovine serum being cited in most of the methods (78%). The use of sera from other animals, monoclonal antibodies and animal proteins were also variously mentioned. While non-animal alternatives are available and methods free of animal-derived products are emerging, most of the current methods reported used at least one animal-derived product, which raises ethical and technical concerns. Therefore, to deliver technically and ethically better in vitro methods for the safety assessment of chemicals, more effort should be made to replace products of animal origin in existing methods and to avoid their use in the development of new method protocols.

Contributors to Intensive Care Unit Clinicians' Predictions of Patient Outcomes: A Qualitative Analysis.

BACKGROUND: Information about a critically ill patient's prognosis is important to the shared decision-making process. The factors that physicians and nurses consider when generating their prognoses are not well understood. OBJECTIVE: To explore the factors that intensive care unit clinicians consider when prognosticating for their patients. METHODS: Intensive care unit clinicians (physicians and nurses) were asked to predict 6-month survival and describe the patient-related factors that they considered in their prognoses. The reported factors were tallied and compared with predictions of 6-month survival or death and with correct and incorrect predictions. RESULTS: Physicians and nurses completed 254 and 286 surveys, respectively, for 303 patients. Of 23 factors identified, the 3 most frequently reported were acute conditions, medical history and comorbid conditions, and trajectory. For patients predicted to be alive at 6 months, physicians commonly mentioned the factors procedures and age; nurses mentioned behavior patterns, previous experiences, and social support. For patients predicted to be dead at 6 months, both groups commonly mentioned cancer. Factors with the highest ratios of correct to incorrect predictions reported by physicians were procedures and definitive treatment; those reported by nurses were procedures, behavior patterns, and current functional status. CONCLUSIONS: Intensive care unit clinicians use various patient factors to inform their prognoses. Clinicians use different factors when predicting survival than when predicting death. Some factors are reported more frequently for correct predictions than for incorrect predictions.

Patients' perceptions and ICU clinicians predictions of quality of life following critical illness.

PURPOSE: To determine how patients perceive their quality of life (QOL) six months following critical illness and to measure clinicians' discriminative accuracy of predicting this outcome. MATERIALS AND METHODS: This prospective cohort study of intensive care unit (ICU) survivors asked patients to report their QOL strictly at six months compared to one month before their critical illness as better, the same, or worse. ICU physicians and nurses made six-month QOL predictions for these patients. RESULTS: Of 162 critical illness survivors, 33% (n = 53) of patients reported six-month QOL as better, 33% (n = 54) the same, and 34% (n = 55) worse. Abnormal cognition and inability to return to primary pastime or original place of residence (p < .05 for all) were associated with worse self-reported QOL at six months in multivariable regression. Predictions of patient perceptions of QOL at six months were pessimistic and had low discriminative accuracy for both physicians (sensitivity 56%, specificity 53%) and nurses (sensitivity 49%, specificity 57%). CONCLUSIONS: Among survivors of critical illness, one-third each reported their six-month post-ICU QOL as better, the same, or worse. Self-reported six-month QOL was associated with six-month function. ICU clinicians should use caution in predicting self-reported QOL, as discriminative accuracy was poor in this cohort.

Viscosupplementation for Hip Osteoarthritis: A Systematic Review and Meta-Analysis of the Efficacy on Pain and Disability, and the Occurrence of Adverse Events.

OBJECTIVE: To assess the efficacy of viscosupplementation (hyaluronic acid [HA]) on the pain and disability caused by hip osteoarthritis, and to determine the occurrence of adverse events. DATA SOURCES: PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov database, and specific journals up to March 2017. STUDY SELECTION: Randomized controlled trials (RCTs) comparing HA with any other intra-articular injection. DATA EXTRACTION: Performed according to Cochrane/Grades of Recommendation, Assessment, Development, and Evaluation criteria. Two authors extracted data and assessed the risk of bias and quality of evidence. A random-effects meta-analysis was conducted. DATA SYNTHESIS: Eight RCTs were retrieved (n=807): 4 comparing HA to placebo; 3 to platelet-rich plasma (PRP); 3 to methylprednisolone; and 1 to mepivacaine. Some RCTs had 3 arms. There is very low evidence that HA is not superior to placebo for pain at 3 months (standardized mean difference [SMD]=-.06; 95% CI, -.38 to .25; P=.69), and high evidence that it is not superior in adverse events (risk ratio [RR]=1.21; 95% CI, .79-1.86; P=.38). There is low evidence that HA is not superior to PRP for pain at 1 month. There is very low evidence that HA is not superior to PRP for pain at 6 and 12 months (mean difference in visual analog scale [in cm]: -.05 [95% CI, -.81 to .71], 1.0 [95% CI, -1.5 to 3.50], and .81 [95% CI, -1.11 to 2.73], respectively). There is high evidence that HA is no different from methylprednisolone for pain at 1 month (SMD=.02; 95% CI, -.18 to .22; P=.85). There is low evidence that HA is no different from methylprednisolone for Outcome Measures in Rheumatoid Arthritis Clinical Trials-Osteoarthritis Research Society International Responders Index at 1 month (RR=.44; 95% CI, .10-1.95; P=.28). There is high evidence that HA is no different from methylprednisolone for adverse events (RR=1.21; 95% CI, .79-1.87; P=.38). CONCLUSIONS: We do not recommend viscosupplementation for hip osteoarthritis. Compared with placebo, data show scarce evidence of its efficacy up to 3 months, and suggest no difference at 6 months. However, future RCTs could present HA as an alternative to methylprednisolone for short-term symptom relief.

Long-acting muscarinic antagonists vs. long-acting ß 2 agonists in COPD exacerbations: a systematic review and meta-analysis.

OBJECTIVE: To determine whether long-acting muscarinic antagonists (LAMAs) provide superior therapeutic effects over long-acting ß2 agonists (LABAs) for preventing COPD exacerbations. METHODS: This was a systematic review and meta-analysis of randomized clinical trials involving patients with stable, moderate to severe COPD according to the Global Initiative for Chronic Obstructive Lung Disease criteria, treated with a LAMA (i.e., tiotropium bromide, aclidinium, or glycopyrronium), followed for at least 12 weeks and compared with controls using a LABA in isolation or in combination with a corticosteroid. RESULTS: A total of 2,622 studies were analyzed for possible inclusion on the basis of their title and abstract; 9 studies (17,120 participants) were included in the analysis. In comparison with LABAs, LAMAs led to a greater decrease in the exacerbation rate ratio (relative risk [RR] = 0.88; 95% CI: 0.84-0.93]; a lower proportion of patients who experienced at least one exacerbation (RR = 0.90; 95% CI: 0.87-0.94; p < 0.00001); a lower risk of exacerbation-related hospitalizations (RR = 0.78; 95% CI: 0.69-0.87; p < 0.0001); and a lower number of serious adverse events (RR = 0.81; 95% CI: 0.67-0.96; p = 0.0002). The overall quality of evidence was moderate for all outcomes. CONCLUSIONS: The major findings of this systematic review and meta-analysis were that LAMAs significantly reduced the exacerbation rate (exacerbation episodes/year), as well as the number of exacerbation episodes, of hospitalizations, and of serious adverse events.

Long-acting muscarinic antagonists vs. long-acting β 2 agonists in COPD exacerbations: a systematic review and meta-analysis / Antagonistas muscarínicos de longa duração vs. β 2 -agonistas de longa duração em exacerbações da DPOC: revisão sistemática e meta-análise

ABSTRACT Objective: To determine whether long-acting muscarinic antagonists (LAMAs) provide superior therapeutic effects over long-acting β2 agonists (LABAs) for preventing COPD exacerbations. Methods: This was a systematic review and meta-analysis of randomized clinical trials involving patients with stable, moderate to severe COPD according to the Global Initiative for Chronic Obstructive Lung Disease criteria, treated with a LAMA (i.e., tiotropium bromide, aclidinium, or glycopyrronium), followed for at least 12 weeks and compared with controls using a LABA in isolation or in combination with a corticosteroid. Results: A total of 2,622 studies were analyzed for possible inclusion on the basis of their title and abstract; 9 studies (17,120 participants) were included in the analysis. In comparison with LABAs, LAMAs led to a greater decrease in the exacerbation rate ratio (relative risk [RR] = 0.88; 95% CI: 0.84-0.93]; a lower proportion of patients who experienced at least one exacerbation (RR = 0.90; 95% CI: 0.87-0.94; p < 0.00001); a lower risk of exacerbation-related hospitalizations (RR = 0.78; 95% CI: 0.69-0.87; p < 0.0001); and a lower number of serious adverse events (RR = 0.81; 95% CI: 0.67-0.96; p = 0.0002). The overall quality of evidence was moderate for all outcomes. Conclusions: The major findings of this systematic review and meta-analysis were that LAMAs significantly reduced the exacerbation rate (exacerbation episodes/year), as well as the number of exacerbation episodes, of hospitalizations, and of serious adverse events.

RESUMO Objetivo: Determinar se long-acting muscarinic antagonists (LAMAs, antagonistas muscarínicos de longa duração) são superiores a long-acting β2 agonists (LABAs, β2-agonistas de longa duração) na prevenção de exacerbações da DPOC. Métodos: Revisão sistemática e meta-análise de ensaios clínicos controlados aleatórios com pacientes com DPOC estável, de moderada a grave, conforme os critérios da Global Initiative for Chronic Obstructive Lung Disease, tratados com LAMA (brometo de tiotrópio, aclidínio ou glicopirrônio), acompanhados durante pelo menos 12 semanas e comparados a controles que usaram LABA isoladamente ou com um corticosteroide. Resultados: Foram analisados 2.622 estudos para possível inclusão com base em seu título e resumo; 9 estudos (17.120 participantes) foram incluídos na análise. Em comparação com LABAs, LAMAs resultaram em maior diminuição da razão da taxa de exacerbações [risco relativo (RR) = 0,88; IC95%: 0,84-0,93]; menor proporção de pacientes que apresentaram pelo menos uma exacerbação (RR = 0,90; IC95%: 0,87-0,94; p < 0,00001); menor risco de hospitalizações em virtude de exacerbação da doença (RR = 0,78; IC95%: 0,69-0,87; p < 0,0001) e menor número de eventos adversos sérios (RR = 0,81; IC95%: 0,67-0,96; p = 0,0002). A qualidade geral das evidências foi moderada para todos os desfechos. Conclusões: O principal achado desta revisão sistemática e meta-análise foi que LAMAs reduziram significativamente a taxa de exacerbações (episódios de exacerbação/ano), os episódios de exacerbação, as hospitalizações e os eventos adversos sérios.