Ethical considerations on placebo-controlled vaccine trials in pregnant women / Consideraciones éticas sobre los ensayos de vacunas controlados con placebo en mujeres embarazadas / Considerações éticas sobre estudos de vacina controlada com placebo em gestantes

Abstract Placebo use in clinical trials, whenever a proven effective treatment exists, is one of the most debated topics in contemporary research ethics. This article addresses the ethical framework for placebo use in clinical trials assessing vaccine efficacy in pregnant women. Vaccine trial participants are healthy at the outset and some must be infected during the study to demonstrate the product's efficacy, meaning that placebo-treated participants are under risk of serious and irreversible harm. If effective vaccines exist, such risk precludes placebo use. This interdiction should be extended to any clinical trial of vaccine efficacy in pregnant women, because a demonstration of clinical efficacy in nonpregnant individuals and comparable immunogenic responses in pregnant women are predictors of efficacy in pregnancy as well. Moreover, product effectiveness in real-world use scenarios can be ascertained by observational studies conducted after its inclusion in vaccination campaigns.

Resumen El uso de placebo en ensayos clínicos es uno de los principales temas debatidos sobre la ética en investigación contemporánea cuando existe un tratamiento eficaz probado. Este artículo aborda la ética en el uso de placebo en ensayos clínicos sobre la eficacia de vacuna en mujeres embarazadas. Las participantes en los ensayos de vacunas estaban sanas al inicio del estudio, y algunas fueron vacunadas durante el estudio para demostrar la eficacia del producto. Las participantes tratadas con placebo corren el riesgo de sufrir daños graves e irreversibles. Si existen vacunas efectivas, este riesgo impide el uso de placebo. Este impedimento debe extenderse a cualquier ensayo clínico de eficacia de vacuna en embarazadas, pues la eficacia clínica demostrada en mujeres no embarazadas y las respuestas inmunogénicas comparables con las embarazadas son predictores de eficacia en el embarazo. Además, la efectividad del producto se constata en estudios observacionales realizados tras las campañas de vacunación.

Resumo O uso de placebo em ensaios clínicos, quando um tratamento comprovadamente eficaz existe, é um dos principais tópicos debatidos na ética em pesquisa contemporânea. Este artigo aborda o quadro ético para o uso de placebo em ensaios clínicos que avaliam a eficácia de vacina em gestantes. Participantes em ensaios de vacina são saudáveis no início e alguns devem ser inoculados durante o estudo para demonstrar a eficácia do produto. Ou seja, participantes tratados com placebo estão sob risco de danos graves e irreversíveis. Se existirem vacinas eficazes, esse risco impede o uso de placebo. Essa interdição deve ser estendida a qualquer ensaio clínico de eficácia de vacina em gestantes, pois a demonstração de eficácia clínica em não gestantes e as respostas imunogênicas comparáveis em gestantes também são preditoras de eficácia na gravidez. Ademais, a eficácia do produto em cenários reais de uso pode ser verificada por estudos observacionais realizados após sua inclusão em campanhas de vacinação.

Delivery of acupuncture in clinical trials: Research acupuncturists' perspectives / 中西医结合学报

Delivery of acupuncture in the setting of a clinical trial is a unique practice that diverges significantly from the delivery of acupuncture in a real-world clinical setting. Research acupuncturists, particularly those trained in traditional Chinese medicine (TCM), are often required to set aside valued precepts of traditional care, including diagnosing imbalances, individualizing treatment, and forging a therapeutic relationship with patients. TCM-trained acupuncturists express mixed feelings about participating in clinical trials. Many are eager to play a vital role in the advancement of acupuncture science and appreciate the need for strict protocol adherence to minimize bias. However, the acupuncturist(s) may also have concerns about clinical trial methodology, including but not limited to the delivery of a control condition, e.g., sham acupuncture. Investigators should anticipate certain questions and even a level of resistance to the requirements of research among acupuncturists and be prepared to address them. This manuscript presents a brief review of the subjective experience of the research acupuncturist within the available scientific literature as it pertains to the delivery of active and sham clinical research protocols. Our goals are to better understand the perspectives of acupuncturists who may participate in clinical research, so that their concerns may be addressed in study design and methodology. To that end, we suggest the creation of a novel training program specifically for clinical trial acupuncturists, intended for qualified TCM- and Western-trained practitioners, that would help to standardize the research acupuncturist's role and help to strengthen the design and execution of acupuncture studies. Please cite this article as: Anastasi JK, Capili B, Neumaier J, Hackett L. Delivery of acupuncture in clinical trials: Research acupuncturists' perspectives. J Integr Med. 2023; 21(4):315-319.

Teoría de la complejidad en la atención del paciente con dolor musculoesquelético / Complexity theory in the management of patients with musculoskeletal pain

Los sistemas no lineales no son susceptibles de ser investigados con métodos reduccionistas. En este sentido, la teoría de la complejidad ofrece un enfoque alternativo para cuantificar la importancia de los factores contextuales en el paciente con dolor musculoesquelético. El resultado del uso positivo (placebo) o negativo (nocebo) de factores contextuales en el entorno terapéutico, podría ser responsable de gran parte de un componente inespecífico en la eficacia del tratamiento, afectando directamente la calidad de los resultados relacionados con la salud del paciente (por ejemplo, dolor, funcionalidad o satisfacción). En los últimos años, se ha incrementado la comprensión del valor de estos efectos. A pesar del creciente interés, el conocimiento y el reconocimiento de los efectos terapéuticos, continúan siendo limitados y heterogéneos entre los fisioterapeutas, lo cual reduce su valor traslacional en el campo de la fisioterapia. El propósito de este estudio es presentar el abordaje el paciente con dolor musculoesquelético desde la perspectiva la teoría de la complejidad.

Nonlinear systems are not susceptible to research with a reductionist approach. In this sense, the complexity theory provides an alternative approach to quantify the importance of contextual factors in patients with musculoskeletal pain. The use of positive (placebo) or negative (nocebo) contextual factors in the therapeutic setting could largely account for the non-specific component of treatment efficacy, directly affecting the quality of patients' health-related outcomes (e.g., pain, disability, or satisfaction). In recent years, there has been a better understanding of the effects of contextual factors. However, the knowledge and awareness of them is limited and heterogeneous among physical therapists, reducing their translational value in the field of physiotherapy. The purpose of this essay is to describe the management of patients with musculoskeletal pain from the complexity theory perspective.

A randomized double-blinded placebo-controlled clinical trial of minodronate tablet in postmenopausal Chinese women with osteoporosis / 中华妇产科杂志

Objective:To verify the efficacy and safety of daily oral minodronate in postmenopausal women with established osteoporosis.Methods:In this randomized, double-blinded, placebo-controlled trial, 262 postmenopausal women were enrolled. Patients were randomized to receive daily oral minodronate 1 mg with supplements of 500 mg calcium and 200 U vitamin D 3 ( n=130) or placebo ( n=132) with daily supplements of 500 mg calcium and 200 U vitamin D 3, for 48 weeks. The primary endpoint was the average bone mineral density (BMD) change in the lumbar vertebrae 48 weeks post-treatment. Secondary outcome measures was the incidence of vertebral fractures. Safety assessments included the rate of adverse events. Results:At the end of 48 weeks treatment, the average BMD change rate from baseline were: full analysis set results: (3.52±4.82)% in the minodronate group and (2.00±5.74)% in the placebo group; per-protocol set results: (3.99±5.05)% in the minodronate group and (2.07±6.20)% in the placebo group; the differences were all significant (all P<0.05). Vertebral fracture occured in 3 patients (2.3%, 3/132) in the placebo group, and 1 case (0.8%, 1/130) in the minodronate group ( P>0.05). The incidence of adverse events was 71.5% (93/130) in the minodronate group and 78.0% (103/132) in the placebo group ( P>0.05). Conclusion:Minodronate is effective and safe in the treatment of postmenopausal osteoporosis without severe side effects.

Effects of cinepazide maleate injection on blood pressure in patients with acute ischemic stroke and hypertension / 中华内科杂志

Objective:To investigate the blood pressure change in patients with acute ischemic stroke (AIS) and hypertension treated with cinepazide maleate injection.Methods:This was a subgroup analysis of post-marketing clinical confirmation study of cinepazide maleate injection for acute ischemic stroke: a randomized, double-blinded, multicenter, placebo-parallel controlled trial, which conducted in China from August 2016 to February 2019. Eligible patients fulfilled the inclusive criteria of acute anterior circulation ischemic stroke with National Institutes of Health Stroke Scale (NIHSS) scores of 7-25. The primary endpoints were mean blood pressure of AIS patients treated with cinepazide maleate or control, which were assessed during the treatment period (14 days), and the proportion of the patients with normal blood pressure was analyzed after the treatment period. Furthermore, a subgroup analysis was performed to investigate a possible effect of the history of hypertension on outcomes.Results:This analysis included 809 patients with hypertension. There was no significant difference in patients blood pressure and the proportion of patients with normal blood pressure (60.5% vs. 59.0%, P>0.05) between cinepazide maleate group and control group. Conclusion:Administration of cinepazide maleate injection does not affect the management of clinical blood pressure in patients with AIS.

O uso de placebo no contexto de ensaios clínicos na doença inflamatória intestinal / Placebo use in the context of inflammatory bowel disease clinical trials

ABSTRACT Inflammatory bowel disease comprises two distinct conditions - Crohn's disease and ulcerative colitis - which can be treated with immunomodulators. A non-neglectable proportion of these patients will need biologic therapy, and many patients under biologic treatment will experience either primary or secondary failure. As a consequence, clinical trials evaluating new therapeutic alternatives are being developed. These trials share common features, such as being controlled with placebo. Placebo use in clinical trials is a matter of intense debate. Those who support placebo use highlight the methodologic advantages placebo-controlled trials have. Those against placebo use argue that it would be against ethical principles in clinical research to expose a patient to placebo when a valid therapeutic alternative exists. In this review, we summarize the existing arguments for and against the use of placebo in the context of inflammatory bowel disease research. We finally suggest that it is very likely that in the near future inflammatory bowel disease trials will no longer be controlled with a placebo arm, but instead they will be non-inferiority trials with an active comparator.

RESUMO A doença inflamatória intestinal compreende duas condições distintas: a doença de Crohn e a retocolite ulcerativa, que podem ser tratadas com imunomoduladores. Uma proporção não negligenciável desses pacientes necessitará de terapia biológica e, muitos destes em tratamento biológico, experimentarão falha primária ou secundária. Como consequência, ensaios clínicos avaliando novas alternativas terapêuticas estão sendo desenvolvidos. Estes ensaios partilham características comuns, tais como ser controlado com placebo. O uso de placebo em ensaios clínicos é uma questão de intenso debate. Aqueles que apoiam o uso do placebo destacam as vantagens metodológicas que os ensaios controlados com placebo têm. Aqueles contra o uso de placebo argumentam que seria contra os princípios éticos na investigação clínica expor um paciente ao placebo quando uma alternativa terapêutica válida existe. Nesta revisão, resumimos os argumentos existentes a favor e contra o uso de placebo no contexto da pesquisa de doença inflamatória intestinal. Finalmente, sugerimos que é muito provável que em um futuro próximo os ensaios de doença inflamatória intestinal não serão mais controlados com um braço placebo; em vez disso, serão feitos ensaios de não-inferioridade com um comparador ativo.

OM-85 BV for primary prevention of recurrent airway infections: a pilot randomized, double-blind, placebo-controlled study / OM-85 BV para prevenção primária de infecções recorrentes das vias aéreas: estudo piloto, randomizado, duplo-cego, placebo-controlado

ABSTRACT Objective To compare the frequency of respiratory tract infections in children treated with OM-85 BV and placebo during the 3-month therapy period, and observation for a further 3 months after treatment. Methods A randomized, double-blind, placebo-controlled trial was conducted with 54 children (6 months to 5 years old) with no past history of recurrent respiratory infections attending daycare center. Family members were instructed to administer one capsule per day for 10 consecutive days, for 3 months of OM-85 BV or placebo. Telephone interviews were conducted every 30 days. Results There was no significant difference in the number of respiratory infections between the groups. The mean number of respiratory tract infection in the OM-85 BV Group in the first 3 months was 0.92±0.87, and in the Placebo Group was 0.74±1.02, and at 6 months it was 1.62±1.47 and 1.03±1.34, respectively. Conclusion OM-85 BV was not effective in the primary prevention of respiratory tract infections. Although most authors recommend the use of this immunostimulant in children with a history of recurrent respiratory infections, more studies are needed to define its usefulness in the primary prevention of respiratory infections in healthy children exposed to few risk factors.

RESUMO Objetivo Comparar a frequência de infecções do trato respiratório em crianças tratadas com OM-85 BV e placebo durante o período de terapia de 3 meses, e observação por mais 3 meses após o tratamento. Métodos Foi realizado estudo randomizado, duplo-cego, controlado por placebo com 54 crianças (6 meses a 5 anos) sem história prévia de infecções respiratórias recorrentes, que frequentavam creches. Os membros da família foram instruídos a administrar uma cápsula por dia durante 10 dias consecutivos, durante 3 meses, de OM-85 BV ou placebo. Entrevistas telefônicas foram realizadas a cada 30 dias. Resultados Não houve diferença significativa no número de infecções respiratórias entre os grupos. O número médio de infecções do trato respiratório no Grupo OM-85 BV nos primeiros 3 meses foi de 0,92±0,87 e, no Grupo Placebo, de 0,74±1,02, e aos 6 meses foi de 1,62±1,47 e 1,03±1,34, respectivamente. Conclusão O OM-85 BV não foi eficaz na prevenção primária de infecções do trato respiratório. Embora a maioria dos autores recomende o uso deste imunoestimulante em crianças com história de infecções respiratórias recorrentes, mais estudos são necessários para definir sua utilidade na prevenção primária de infecções respiratórias em crianças saudáveis expostas a poucos fatores de risco.

Actitudes de los médicos familiares mexicanos sobre el uso de placebos en la práctica clínica / Attitudes of Mexican family physicians on the use of placebos in clinical practice

Resumen Introducción: El uso de placebo se ha extendido en la práctica a pesar de ser polémico. En México, la práctica de medicina familiar es predominante institucional y trabaja con un cuadro básico de medicamentos. Objetivo: Determinar la frecuencia y actitud del médico familiar en la utilización de placebos en la práctica clínica. Método: Estudio transversal, observacional, multicéntrico, en 307 médicos familiares con práctica activa, en 27 estados de la República Mexicana. Se usó cuestionario con datos sociodemográficos, preguntas sobre frecuencia de uso y actitudes elaboradas por consenso. Se analizó con chi cuadrada. Resultados: 75 % utilizó placebos (IC 95 % = 69.7-79.4 %); 122 (39.7 %) placebos puros, principalmente agua (p < 0.05), y 220 (71.6 %) placebos impuros, principalmente vitaminas y exámenes de laboratorio. Los usaron más en pacientes con síntomas físicos no explicados médicamente (178, 45.5 %), incluidos 122 (31.2 %) pacientes “sanos preocupados” o con padecimientos crónicos (40, 12.5 %). Motivos de prescripción: 249 (81 %) por el efecto psicológico, cuando demostraron beneficio (176, 57 %), aun cuando implicara engaño (78, 25 %) o evidencia de eficacia insuficiente (57, 19 %). El principal motivo fue por insistencia del paciente. Conclusiones: Se utilizaron más placebos impuros, principalmente en pacientes sanos preocupados y en aquellos con padecimientos crónicos.

Abstract Introduction: The use of placebo has spread in clinical practice despite being controversial. In Mexico, the practice of family medicine is predominantly institutional and works with an essential medications list. Objective: To determine the frequency and family doctor attitude regarding the use of placebos in clinical practice. Method: Cross-sectional, observational, multicenter study of 307 family doctors with active practice in 27 states of the Mexican Republic. A questionnaire was used with sociodemographic data and consensus-developed questions about frequency of use and attitudes. For analysis, the square-chi test was used. Results: 75% used placebos (95% CI=69.7-79.4%); 122 (39.7%) used pure placebos, mainly water (p < 0.05), and 220 (71.6%), impure placebos, mainly vitamins and laboratory tests. They were used more in patients with medically unexplained physical symptoms (178, 45.5%), including 122 (31.2%) “healthy worried” patients, or who had chronic conditions (40, 12.5%). Reasons for prescription: 249 (81%) for the psychological effect, when they showed benefit (176, 57%), even when it implied deceiving (78, 25%) or insufficient evidence of efficacy (57, 19%). The main reason was because of patient insistence. Conclusions: More impure placebos were used, mainly in healthy worried patients and in those with chronic conditions.

Indomethacin for preventing post-endoscopic retrograd cholangiopancreatography pancreatitis by rectal administration: a Meta-analysis of randomized controlled trial / 中国基层医药

Objective@#To assess the effectiveness and safety of indomethacin in preventing post-endoscopic retrograd cholangiopancreatography pancreatitis(PEP) by rectal administration.@*Methods@#Retrieved from PubMed, Cochrane Library, CNKI, VIP, CBM and Wanfang database, randomized blinding placebo-controlled trails about indomethacin for preventing PEP by rectal administration were included from establishment to December 2017 and comprehensively evaluated.Two reviewers independently screened literature according to the inclusion and exclusion criteria, extracted data, assessed the risk bias of included studies, and then Meta-analysis was performed using the RevMan 5.3 software.@*Results@#A total of 8 RCTs involving 3240 patients were included.The results of Meta-analysis showed that indomethacin could reduce the incidence of PEP(OR=0.57, 95% CI: 0.45-0.73, P<0.00 001) and moderate or severe PEP(OR=0.51, 95% CI: 0.30-0.85, P=0.010). The adverse reactions of indomethacin was gastrointestinal bleeding, and there was no statistically significant difference between indomethacin and placebo(OR=0.63, 95% CI: 0.25-1.52, P=0.300).@*Conclusion@#Indomethacin is safe and effective in reducing the incidence of PEP by rectal administration.

Indomethacin for preventing post-endoscopic retrograd cholangiopancreatography pancreatitis by rectal administration: a Meta-analysis of randomized controlled trial / 中国基层医药

Objective To assess the effectiveness and safety of indomethacin in preventing post-endoscopic retrograd cholangiopancreatography pancreatitis (PEP) by rectal administration.Methods Retrieved from PubMed,Cochrane Library,CNKI,VIP,CBM and Wanfang database,randomized blinding placebo-controlled trails about indomethacin for preventing PEP by rectal administration were included from establishment to December 2017 and comprehensively evaluated.Two reviewers independently screened literature according to the inclusion and exclusion criteria,extracted data,assessed the risk bias of included studies,and then Meta-analysis was performed using the RevMan 5.3 software.Results A total of 8 RCTs involving 3240 patients were included.The results of Meta-analysis showed that indomethacin could reduce the incidence of PEP(OR =0.57,95％ CI:0.45-0.73,P ＜ 0.00 001) and moderate or severe PEP(OR =0.51,95 ％ CI:0.30-0.85,P =0.010).The adverse reactions of i ndomethacin was gastrointestinal bleeding,and there was no statistically significant difference between indomethacin and placebo(OR =0.63,95％ CI:0.25-1.52,P =0.300).Conclusion Indomethacin is safe and effective in reducing the incidence of PEP by rectal administration.

Effect of escitalopram in the treatment of alcohol-dependent patients with depression / 中国基层医药

Objective To observe the clinical effect of escitalopram in the treatment of alcohol -dependent patients with depressive symptoms and its influence on social function recovery .Methods From January 2016 to December 2017,80 alcohol -dependent patients with depressive symptoms in the Seventh People ＇s Hospital of Wenzhou were selected and divided into two groups by random digital table method ,with 40 cases in each group.The observation group was treated with escitalopram.The control group was treated with placebo for 2 months.The scores of depression,social dysfunction screening scale , quality of life and incidence of adverse reactions were compared between the two groups.Results After treatment for 1 month and 2 months,the depression scores of the observation group were (15.02 ±2.23)points and (9.02 ±2.12)points,respectively,which were lower than those of the control group[(20.13 ±2.12) points,(15.24 ±2.15) points] ( t ＝10.504,13.029,all P ＜0.05).After treatment for 1 month and 2 months,the scores of the screening scale for social functional defects in the observation group were (2.85 ±1.23)points and (0.89 ±0.52)points,respectively,which were lower than those in the control group [(4.13 ± 1.62)points,(2.52 ±1.16)points]( t＝3.930,8.110,all P＜0.05).The scores of physical health ,mental health, physical life,social function and total quality of life in the observation group were (87.47 ±5.69) points,(84.63 ± 5.21)points,(87.16 ±5.24) points,(85.46 ±5.95) points and (86.12 ±5.95) points,respectively,which were higher than those of the control group [(79.58 ±5.93)points,(76.72 ±7.82)points,(79.28 ±5.57)points,(75.92 ± 5.45) points,(78.46 ±5.85) points] (t＝5.995,5.257,6.435,7.384,5.733,all P＜0.05).There was no statistically significant difference in the incidence of adverse reactions between the two groups(P＞0.05).Conclusion Escitalopram in the treatment of alcohol -dependent patients with depressive symptoms has good effect ,not only helps to improve the depression,but also helps to promote the recovery of social function of the patients ,and the safety is relatively high.

Effect of escitalopram in the treatment of alcohol－dependent patients with depression / 中国基层医药

Objective@#To observe the clinical effect of escitalopram in the treatment of alcohol-dependent patients with depressive symptoms and its influence on social function recovery.@*Methods@#From January 2016 to December 2017, 80 alcohol-dependent patients with depressive symptoms in the Seventh People's Hospital of Wenzhou were selected and divided into two groups by random digital table method, with 40 cases in each group.The observation group was treated with escitalopram.The control group was treated with placebo for 2 months.The scores of depression, social dysfunction screening scale, quality of life and incidence of adverse reactions were compared between the two groups.@*Results@#After treatment for 1 month and 2 months, the depression scores of the observation group were (15.02±2.23)points and (9.02±2.12)points, respectively, which were lower than those of the control group[(20.13±2.12)points, (15.24±2.15)points](t=10.504, 13.029, all P<0.05). After treatment for 1 month and 2 months, the scores of the screening scale for social functional defects in the observation group were (2.85±1.23)points and (0.89±0.52)points, respectively, which were lower than those in the control group[(4.13±1.62)points, (2.52±1.16)points](t=3.930, 8.110, all P<0.05). The scores of physical health, mental health, physical life, social function and total quality of life in the observation group were (87.47±5.69)points, (84.63±5.21)points, (87.16±5.24)points, (85.46±5.95)points and (86.12±5.95)points, respectively, which were higher than those of the control group[(79.58±5.93)points, (76.72±7.82)points, (79.28±5.57)points, (75.92±5.45)points, (78.46±5.85)points](t=5.995, 5.257, 6.435, 7.384, 5.733, all P<0.05). There was no statistically significant difference in the incidence of adverse reactions between the two groups(P>0.05).@*Conclusion@#Escitalopram in the treatment of alcohol-dependent patients with depressive symptoms has good effect, not only helps to improve the depression, but also helps to promote the recovery of social function of the patients, and the safety is relatively high.

Cost-effectiveness analysis of abiraterone, docetaxel or placebo plus androgen deprivation therapy for hormone-sensitive advanced prostate cancer / Análise de custo-efetividade da adição de abiraterona ou quimioterapia ao tratamento do câncer de próstata metastático hormônio-sensível

ABSTRACT Objective To evaluate the cost-effectiveness of the addition of chemotherapy or abiraterone to androgen deprivation. Methods We developed an analytical model to determine the cost-effectiveness of the addition of docetaxel or abiraterone versus androgen deprivation therapy alone. Direct and indirect costs were included in the model. The effects were expressed in Quality-Adjusted Life Years adjusted for side effects. Results Compared to androgen deprivation therapy alone, the addition of chemotherapy and of abiraterone generated 0.492 and 0.999, respectively, in Quality-Adjusted Life Years. Abiraterone led to a Quality-Adjusted Life Years gain of 0.506 compared to docetaxel. The incremental costs per Quality-Adjusted Life Years were R$ 133.649,22 for docetaxel, R$ 330.828,70 for abiraterone and R$ 571.379,42 for abiraterone compared to docetaxel, respectively. Conclusion The addition of chemotherapy to androgen deprivation therapy is more cost-effective than the addition of abiraterone to androgen deprivation therapy. However, discounts on abiraterone cost might improve cost-effectiveness.

RESUMO Objetivo Avaliar a relação custo-efetividade da adição de quimioterapia ou abiraterona à terapia de privação hormonal. Métodos Um modelo analítico foi desenvolvido para determinar a relação custo-efetividade da adição de docetaxel ou abiraterona comparada à terapia de privação hormonal isolada. Custos diretos e indiretos foram incluídos no modelo. Os efeitos foram expressos em Anos de Vida Ajustados para Qualidade corrigidos pelos efeitos colaterais de cada terapia. Resultados A adição de quimioterapia e de abiraterona à terapia de privação hormonal aumentou os Anos de Vida Ajustados para Qualidade em 0,492 e 0,999, respectivamente, em comparação à terapia de privação hormonal isolada. A abiraterona promoveu ganho de Anos de Vida Ajustados para Qualidade de 0,506 em relação ao docetaxel. O custo incremental por Anos de Vida Ajustados para Qualidade foi R$ 133.649,22 para o docetaxel, R$ 330.828,70 para a abiraterona e R$ 571.379,42 para a abiraterona comparada ao docetaxel. Conclusão A adição de quimioterapia à terapia de privação hormonal é mais custo-efetiva que a adição de abiraterona à terapia de privação hormonal. Contudo, descontos no custo da abiraterona poderiam tornar esse tratamento mais custo-efetivo.

Atosiban efficacy and safety in pregnant women with threatened preterm delivery: systematic review of the literature with network meta-analysis / Eficacia y seguridad de atosiban en mujeres gestantes con diagnóstico de amenaza de parto pretérmino: revisión sistemática de la literatura con metaanálisis en red

ABSTRACT Objective: To assess the efficacy and safety of atosiban in pregnant women with risk of preterm delivery as compared to nifedipine, indomethacin, terbutaline, fenoterol and placebo. Materials and methods: A systematic literature review was carried out in eight electronic databases, including Medline, Central, and Embase, using free and standardized search terms. Outcomes assessment included time delay until delivery, neonatal mortality, ratio of adverse maternal events, and ratio of neonatal complications. The quality of the evidence was evaluated per study and for the body of evidence and, whenever feasible, the information was synthesized into a meta-analysis. Alternatively, a narrative summary was presented. Results: Eleven studies were included. Atosiban did not show any statistically significant differences in terms of delaying delivery versus other uterine contraction inhibitors. The neonatal mortality was lower compared to indomethacin (RR = 0.21; 95% CI: 0.05 to 0.92), and the percentage of total maternal adverse events was lower compared to fenoterol (RR = 0.16; 95% CI: 0.08 to 0.31), nifedipine (RR = 0.48; 95% CI: 0.3 to 0.78), and terbutaline (RR = 0.44; 95% CI: 0.28 to 0.71). Conclusions: Atosiban has similar efficacy for delivery delay in patients with risk of preterm delivery as compared to other agents (moderate certainty), showing some advantages regarding neonatal mortality (low certainty) versus indomethacin, and compared to fenoterol, nifedipine and terbutaline in terms of maternal adverse events (moderate certainty).

RESUMEN Objetivo: evaluar la eficacia y seguridad de atosiban en gestantes con amenaza de parto pretérmino comparado con nifedipino, indometacina, terbutalina, fenoterol y placebo. Materiales y métodos: se realizó una revisión sistemática de la literatura en ocho bases de datos electrónicas (Medline, Central, Embase, entre otras), mediante términos de búsqueda libres y estandarizados. Los desenlaces evaluados incluyeron tiempo de retardo del parto, mortalidad neonatal, proporción de eventos adversos maternos y proporción de complicaciones neonatales. Se evaluó la calidad de la evidencia por estudio y para el cuerpo de evidencia, y se sintetizó la información mediante metaanálisis, cuando fue posible; de lo contrario, se resumió de forma narrativa. Resultados: se incluyeron once estudios. Atosiban no mostró diferencias estadísticamente significativas en retardo del parto contra otros uteroinhibidores. Mostró menor mortalidad neonatal que la indometacina (RR = 0,21; IC 95 %: 0,05 a 0,92), y menor proporción de eventos adversos maternos totales que el fenoterol (RR = 0,16; IC 95 %: 0,08 a 0,31), el nifedipino (RR = 0,48; IC 95 %: 0,3 a 0,78) y la terbutalina (RR = 0,44; IC 95 %: 0,28 a 0,71). Conclusiones: atosiban tiene una eficacia similar para retardar el parto ante la amenaza de un parto pretérmino con otros comparadores (certeza moderada), con ventajas frente a indometacina en mortalidad neonatal (certeza baja) y frente a fenoterol, nifedipino y terbutalina en eventos adversos maternos (certeza moderada).

Advances in CDK4/6 inhibitors in HR+ and HER2- advanced breast cancer / 肿瘤

In the comprehensive treatment of breast cancer, endocrine therapy has become one of the effective methods for hormone receptorpositive (HR+) breast cancer. However, the effectiveness of endocrine therapy has been limited by primary resistance and acquired resistance as its long-term application. The clinical trials associated with cyclin-dependent protein kinases (CDKs) inhibitors have proven that the CDK4/6 inhibitors have an effect in reversing the resistance of endocrine therapy for the patients with HR+ and human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer, and have significance advantage in progression free survival. CDK4/6 inhibitors can regulate cell cycle mainly by the CDK4/6-cyclin D-retinoblastoma (RB) pathway, which is also a key downstream target of estrogen receptor (ER) signal. Therefore, inhibiting the activity of CDK4/6 can restore cell cycle control and further block tumor cell proliferation. This review describes the efficacy, safety and pharmacokinetics of three CDK4/6 inhibitors (palbociclib, ribociclib and abemaciclib) in clinical trials of HR+ and HER2- advanced breast cancer. This article also reviews the latest research results about CDK4/6 inhibitors stimulating the immune response and blocking the distant metastasis of triplenegative breast cancer cell lines.

Auriculoterapia verdadeira e placebo para enfermeiros estressados: ensaio clínico randomizado / Experimental and placebo auriculotherapy for stressed nurses: randomized controlled trial / Auriculoterapia verdadera y placebo para enfermeros estresados: ensayo clínico randomizado

RESUMO Objetivo Comparar a eficácia da auriculoterapia verdadeira e placebo com pontos sham no tratamento de estresse em enfermeiros de um hospital beneficente em São Paulo. Método Ensaio clínico controlado randomizado, simples-cego. A amostra foi constituída de 168 enfermeiros que apresentaram níveis médio e alto de estresse pela Lista de Sintomas de Stress (LSS) e foram randomizados em 3 grupos: Auriculoterapia (G1), Placebo (G2) e Controle (G3). Os grupos 1 e 2 receberam 12 sessões, 2 vezes por semana. Os pontos utilizados no Grupo 1 foram: Shenmen e Tronco Cerebral; no Grupo 2 foram: Ouvido Externo e Bochecha. Os três grupos foram avaliados no início, após oito, 12 sessões e follow-up (15 dias). Resultados O grupo 1 conseguiu 43% de redução e 1,81 de índice d de Cohen (alto efeito), apresentando diferença estatística a partir de oito sessões, com manutenção no follow-up (p<0,001), segundo Análise de Variâncias. Já o grupo 2 atingiu 26% de redução, com d de Cohen de 0,86 (grande efeito), conseguindo diferença após 12 sessões (p<0,001), com manutenção no follow-up (p<0,05), comparativamente ao G3, que não obteve redução em nenhum momento. Conclusão A auriculoterapia verdadeira conseguiu maior redução de estresse entre enfermeiros, mas não houve diferença estatística entre os dois grupos de intervenção. Registro Brasileiro de Ensaios Clínicos: RBR-req2792

ABSTRACT Objective To compare the efficacy of experimental auriculotherapy and placebo auriculotherapy with sham points for the treatment of stress in nurses of a charity hospital in São Paulo. Method Randomized, single-blind, controlled trial. The sample consisted of 168 nurses with medium and high stress levels according to the List of Stress Symptoms (LSS). The participants were randomized to three groups: Auriculotherapy (G1), Placebo (G2) and Control (G3). Groups 1 and 2 received 12 sessions, twice a week. The points used in Group 1 were: Shenmen and Brainstem; in Group 2 the points were: External Ear and Face Area. The three groups were evaluated at baseline, after eight sessions, 12 sessions and in a follow-up (after 15 days). Results Group 1 achieved a 43% reduction and a 1.81 Cohen d index (high effect), presenting statistical difference after eight sessions, maintained in the follow-up evaluation (p <0.001), according to Analysis of Variance. Group 2 achieved a 26% reduction, with Cohen's d index of 0.86 (great effect), achieving a difference after 12 sessions (p<0.001), maintained in the follow-up (p <0.05). The G3 did not present stress reduction. Conclusion Experimental auriculotherapy achieved greater stress reduction among nurses, but there was no statistical difference between the two intervention groups. Brazilian Registry of Clinical Trials: RBR-req2792

RESUMEN Objetivo Comparar la efectividad de la auriculoterapia verdadera y placebo con puntos sham en el tratamiento de estrés en enfermeros de un hospital benéfico en São Paulo. Método Ensayo clínico controlado aleatorizado, simple ciego. La muestra estuvo constituida de 168 enfermeros que presentaron niveles mediano y alto de estrés por el Inventario de Síntomas de Estrés (ISE) y fueron randomizados en 3 grupos: Auriculoterapia (G1), Placebo (G2) y Control (G3). Los grupos 1 y 2 recibieron 12 sesiones, 2 veces por semana. Los puntos utilizados en el Grupo 1 fueron: Shenmen y Tronco Cerebral; en el Grupo 2, fueron: Oído Externo y Mejilla. Los tres grupos fueron evaluados en el inicio, después de ocho, 12 sesiones y follow-up (15 días). Resultados El grupo 1 logró el 43% de reducción y 1,81 de índice d de Cohen (alto efecto), presentando diferencia estadística a partir de ocho sesiones, con mantenimiento en el follow-up (p<0,001), según el Análisis de Varianzas. En el caso del grupo 2, este alcanzó el 26% de reducción, con d de Cohen de 0,86 (gran efecto), obteniendo diferencia después de 12 sesiones (p<0,001), con mantenimiento en el follow-up (p<0,05), comparativamente con el G3, que no logró reducción en ningún momento. Conclusión La auriculoterapia verdadera consiguió mayor reducción de estrés entre enfermeros, pero no hubo diferencia estadística entre ambos grupos de intervención. Registro Brasileño de Ensayos Clínicos: RBR-req2792

Houpu Paiqi mixture in treatment of functional dyspepsia:a multicenter randomized controlled study / 中华消化杂志

Objective To evaluate the efficacy and safety of Houpu Paiqi mixture in treatment of functional dyspepsia (FD)with abdominal distension symptom.Methods From July 2014 to June 2015 , in nine centers,a total of 162 FD patients with abdominal distension symptom and met Rome Ⅲpostprandial distress syndrome (PDS)diagnostic criteria were enrolled.All patients were randomly divided into trial group and control group,81 patients in either group.The patients of trial group and control group took Houpu Paiqi mixture or placebo,respectively,25 mL per time,twice daily,and both the courses of treatment were two weeks.Before and after the treatment,the improvement of main symptoms,total clinical efficacy rate and efficacy of traditional medicine between two groups were compared.Chi square test,Fisher exact probability method and Wilcoxon test were performed for statistical analysis.Results According to the results of per-protocol (PP)analysis,the total efficacy rate of trial group and control group was 69.4% (50/72)and 59.2% (42/71),respectively,and there was no statistically significant difference in total efficacy rate between the two groups (χ2 =1 .650,P =0.199 ). And there was no statistically significant difference in the improvement of PDS main symptoms(postprandial fullnessand early satiety)between the two groups (56.3% ±27.9% vs 54.4% ±32.1%,t =0.606,P =0.727 ).For those with baseline symptom score over 14,median early satiety score of trial group after the treatment was 0,which was lower than that of control group,and the difference was statistically significant (Z =-2.370,P =0.018).The total efficacy rate of traditional medicine of trial group was 80.8% (59/73 )and that of control group was 72.0% (54/75 ),and the difference was not statistically significant (χ2 = 0.676,P =0.411 ).Conclusion Houpu Paiqi mixture has certain efficacy in FD with abdominal distension,and could be used for the treatment of PDS-predominant FD.

Effectiveness of Traditional Chinese Acupuncture versus Sham Acupuncture: a Systematic Review / Efetividade da Acupuntura Tradicional Chinesa versus Sham Acupuntura: revisão sistemática / Eficacia de la Acupuntura Tradicional China frente a la Acupuntura Sham: una revisión sistemática

ABSTRACT Objective: to identify and synthesize the evidence from randomized clinical trials that tested the effectiveness of traditional Chinese acupuncture in relation to sham acupuncture for the treatment of hot flashes in menopausal women with breast cancer. Method: systematic review guided by the recommendations of the Cochrane Collaboration. Citations were searched in the following databases: MEDLINE via PubMed, Web of Science, CENTRAL, CINAHL, and LILACS. A combination of the following keywords was used: breast neoplasm, acupuncture, acupuncture therapy, acupuncture points, placebos, sham treatment, hot flashes, hot flushes, menopause, climacteric, and vasomotor symptoms. Results: a total of 272 studies were identified, five of which were selected and analyzed. Slight superiority of traditional acupuncture compared with sham acupuncture was observed; however, there were no strong statistical associations. Conclusions: the evidence gathered was not sufficient to affirm the effectiveness of traditional acupuncture compared with sham acupuncture.

RESUMO Objetivo: identificar e sintetizar as evidências oriundas de ensaios clínicos randomizados que testaram a efetividade da acupuntura tradicional chinesa em relação à sham acupuntura para o tratamento dos fogachos em mulheres com câncer de mama no climatério. Método: revisão sistemática guiada pelas recomendações da Colaboração Cochrane. A busca foi realizada nas bases de dados: MEDLINE via PubMed, Web of Science, CENTRAL Cochrane, CINAHL e LILACS. Adotou-se a combinação dos descritores: breast neoplasm, acupuncture, acupuncture therapy, acupuncture points, placebos, sham treatment, hot flashes, hot flushes, menopause, climacteric, vasomotor symptoms. Resultados: foram identificados 272 estudos, sendo 5 selecionados e analisados. Foi observada discreta superioridade da acupuntura tradicional em relação à sham, entretanto, sem fortes associações estatísticas. Conclusões: as evidências obtidas não foram suficientes para afirmar quanto à efetividade da acupuntura tradicional em relação à sham.

RESUMEN Objetivo: Identificar y sintetizar la evidencia de un ensayo clínico aleatorizado que examinó la eficacia de la acupuntura tradicional en relación a la acupuntura sham para el tratamiento de sofocos en las mujeres menopáusicas con cáncer de mama. Método: Revisión sistemática guiada por las recomendaciones de la Colaboración Cochrane. Las referencias bibliográficas se buscaron en las siguientes bases de datos: MEDLINE vía PubMed, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL y LILACS. Se utilizó una combinación de las siguientes palabras clave: breast neoplasm, acupuncture, acupuncture therapy, acupuncture points, placebos, sham treatment, hot flashes, hot flushes, menopause, climacteric, vasomotor symptoms. Resultados: Se identificó un total de 272 estudios, cinco de los cuales fueron seleccionados y analizados. Se encontró una ligera superioridad de la acupuntura tradicional comparada con la acupuntura sham; sin embargo, no se encontraron asociaciones estadísticas fuertes. Conclusiones: La evidencia obtenida no fue suficiente para confirmar la eficacia de la acupuntura tradicional comparada con la acupuntura sham.

El uso de placebo en ensayos clínicos de fase III en Brasil / The use of placebos in phase III clinical trials in Brazil

El Consejo Federal de Medicina de Brasil (CFM) -órgano normativo y fiscalizador del ejercicio ético de la medicina- prohibió, en 2008, la participación de médicos brasileños en investigaciones que utilizaran placebo para enfermedades con tratamiento eficaz y efectivo, en contraposición a la Declaración de Helsinki, que permite su uso en condiciones metodológicamente justificadas. Con el objetivo de verificar si la normativa ética del CFM modificó el uso de placebo en ensayos clínicos de fase III en Brasil, se analizaron varias características de sus registros en el ClinicalTrials.gov, en los períodos de 2003 a 2007 y de 2009 a 2013. Se concluye que: a) la normativa promulgada por el CFM en 2008 fue ineficaz y prevaleció la posición adoptada por la Declaración de Helsinki; b) el patrocinio de ensayos con placebo por parte de la industria farmacéutica multinacional fue significativo; c) predominaron las investigaciones de fármacos para enfermedades crónicas, y fueron poco significativas para las enfermedades postergadas, de importancia para Brasil.

In 2008, Brazil's Federal Council of Medicine [Conselho Federal de Medicina] (CFM) - regulatory and supervisory agency on the ethical practice of medicine - banned the participation of Brazilian doctors in studies using placebos for diseases with efficient and effective treatment. This position differs with the Helsinki Declaration, which allows the use of placebos in methodologically justified conditions. To ascertain whether the CMF's ethical regulation modified the use of placebos in phase III clinical trials in Brazil, characteristics of the records in ClinicalTrials.gov were researched in the periods from 2003 to 2007 and from 2009 to 2013. The conclusions reached were: a) the regulations issued by the CFM in 2008 were ineffective and the position adopted by the Helsinki Declaration prevails; b) there was significant sponsorship by the multinational pharmaceutical industry of trials with placebos; c) the research was predominantly on new drugs for chronic diseases, with little study done of the neglected diseases which are of great importance to Brazil.

Intervenciones Placebo Para Incrementar el Rendimiento Deportivo: un Tema Revisitado / Placebo Interventions to Enhance Sports Performance: Revisiting an Issue / Intervenções Placebo para Aumentar o Rendimento Esportivo: um Tema Revisitado

Las intervenciones psicológicas para incrementar el rendimiento de los deportistas han ganado gran popularidad. En este artículo se realizó una revisión de la utilización de intervenciones placebo para potenciar el rendimiento deportivo, a partir de la cual se concluyó que el contexto de aplicación, los rasgos de personalidad del deportista y el ritual de intervención han sido propuestos como los factores más relevantes a tomar en consideración. Se estima que, a pesar de las limitaciones, las intervenciones placebo constituyen alternativas eficaces que tienen distintos modos de aplicación. La utilización de vías conscientes y no-conscientes para activar el efecto placebo se materializa en el empleo de las potencialidades que brindan tanto la sugestión verbal como el priming.

Psychological interventions aimed at enhancing the performance of athletes have become increasingly popular. This article reviews the use of placebo interventions to enhance sports performance and finds that the context of application, the athlete's personality traits, and the intervention ritual are usually the most relevant factors to consider. The article proposes that, despite their limitations, placebo interventions are effective alternatives that can be applied in different ways. The use of both conscious and unconscious means to activate the placebo effect takes the form of verbal suggestion and priming.

As intervenções psicológicas para aumentar o rendimento dos esportistas têm ganhado grande popularidade. Neste artigo, realizou-se uma revisão da utilização de intervenções placebo para potencializar o rendimento esportivo, a partir da qual se concluiu que o contexto de aplicação, os traços de personalidade do esportista e o ritual de intervenção foram propostos como fatores mais relevantes a considerar. Estima-se que, apesar das limitações, as intervenções placebo constituem alternativas eficazes que têm diferentes modos de aplicação. A utilização de vias conscientes e não conscientes para ativar o efeito placebo se materializa no emprego das potencialidades que oferecem tanto a sugestão verbal quanto o priming.