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Sao Paulo Medical Journal, Volume: 142, Número: 1, Publicado: 2024
  • Chronic pain: A big challenge Editorial

    Zakka, Telma; Papler, Hélio; Pêgo-Fernandes, Paulo Manuel
  • Impact of pre-operative weight loss on non-alcoholic fatty liver disease histopathology and insulin resistance in individuals undergoing bariatric surgery: a propensity matched cross-sectional comparison Original Article

    Maldonado, Fábio Henrique Ribeiro; Mega, Paulo Ferreira; Germano, Carlos Wustemberg; Dias, Luana Leite Castilho; Callejas, Guilherme Hoverter; Gestic, Martinho Antonio; Utrini, Murillo Pimentel; Chaim, Felipe David Mendonça; Callejas-Neto, Francisco; Chaim, Elinton Adami; Cazzo, Everton

    Resumo em Inglês:

    ABSTRACT BACKGROUND: The effect of weight loss (WL) on histopathological aspects of non-alcoholic fatty liver disease (NAFLD) may provide further insights into the dynamics of hepatic recovery after WL. OBJECTIVE: To analyze the effects of pre-operative WL on insulin resistance- and NAFLD-related histology in individuals undergoing bariatric surgery (BS) with or without pre-operative WL. DESIGN AND SETTING: A matched cross-sectional study was conducted at a public university hospital and a private clinic in Campinas, Brazil. METHODS: An analytical, observational, cross-sectional study was conducted using prospectively collected databases of individuals who underwent BS and liver biopsy at either a public tertiary university hospital (with pre-operative WL) or a private clinic (without pre-operative WL). Random electronic matching by gender, age, and body mass index (BMI) was performed and two paired groups of 24 individuals each were selected. RESULTS: Of the 48 participants, 75% were female. The mean age was 37.4 ± 9.6. The mean BMI was 38.9 ± 2.6 kg/m2. Fibrosis was the most common histopathological abnormality (91.7%). Glucose was significantly lower in the WL group (92 ± 19.1 versus 111.8 ± 35.4 mg/dL; P = 0.02). Significantly lower frequencies of macrovesicular steatosis (58.3% versus 95.8%; P = 0.004), microvesicular steatosis (12.5% versus 87.5%; P < 0.001), and portal inflammation (50% versus 87.5%; P = 0.011) were observed in the WL group. CONCLUSION: Pre-operative WL was significantly associated with lower frequencies of macro- and mi- crovesicular steatosis, portal inflammation, and lower glycemia, indicating an association between the recent trajectory of body weight and histological aspects of NAFLD.
  • Translation, cross-cultural adaptation, and validation of health and self-management in diabetes questionnaire (HASMID-10) into Brazilian Portuguese Original Article

    Santos-de-Araújo, Aldair Darlan; Dibai-Filho, Almir Vieira; Pontes-Silva, André; Rêgo, Adriana Sousa; Santos, Dalyla Lima dos; Mendes Júnior, Abraão Albino; Pereira, Fábio Henrique Ferreira; Bacelar, Solange Negreiros de Almeida; Oliveira, Bárbara Emanoele Costa; Tavarez, Rudys Rodolfo de Jesus; Bassi-Dibai, Daniela

    Resumo em Inglês:

    ABSTRACT BACKGROUND: Considering the ability of the health and self-management in diabetes questionnaire (HASMID-10) to verify the impact of self-management on diabetes, we highlight its relevance to scientific research and clinical applicability. However, to date, no study has been conducted to scientifically support its use in other languages. OBJECTIVE: To translate, cross-culturally adapt, and validate the HASMID-10 into the Brazilian Portuguese. DESIGN AND SETTING: A translation, cross-cultural adaptation, and validation study conducted at Ceuma University. METHODS: Study was conducted in accordance with the Guidelines for the Process of Cross-Cultural Adaptation of Self-Report Measures and Consensus-based Standards for the Selection of Health Measurement Instruments. We included participants of both sexes diagnosed with diabetes, aged between 18 and 64 years, and without cognitive deficits or any other limitations that would prevent them from answering the questionnaire. We assessed participants using the problem areas in diabetes (PAID) scale and HASMID-10. We assessed reliability using a test-retest model with a 7-day interval between assessments. We used intraclass correlation coefficient (ICC), 95% confidence interval (CI), standard error of measurement (SEM), minimum detectable difference (MDD), Spearman correlation coefficient, and floor and ceiling effects. RESULTS: Sample comprised 116 participants, most of whom were women, overweight, non-practitioners of physical activity, and nonsmokers. We observed significant correlations (P = 0.006; rho = −0.256) between the HASMID-10 and PAID, adequate reliability (ICC = 0.780) and internal consistency (Cronbach's alpha = 0.796). No ceiling or floor effects were observed. CONCLUSION: HASMID-10 has adequate measurement properties and may be used for Brazilians.
  • Assessing a cut-off point for the diagnosis of abnormal uterine bleeding using the Menstrual Bleeding Questionnaire (MBQ): a validation and cultural translation study with Brazilian women Original Article

    Rezende, Gabriela Pravatta; Brito, Luiz Gustavo Oliveira; Gomes, Daniela Angerame Yela; Souza, Leticia Mansano de; Polo, Sergio; Benetti-Pinto, Cristina Laguna

    Resumo em Inglês:

    ABSTRACT BACKGROUND: Abnormal uterine bleeding (AUB) is a common condition, and the Menstrual Bleeding Questionnaire (MBQ) is used for its assessment. OBJECTIVES: To translate, assess the cut-off point for diagnosis, and explore psychometric properties of the MBQ for use in Brazilian Portuguese. DESIGN AND SETTING: Prospective cohort study including 200 women (100 with and 100 without AUB) at a tertiary referral center. METHODS: MBQ translation involved a pilot-testing phase, instrument adjustment, data collection, and back-translation. Cut-off point was obtained using receiver operating curve analysis. Menstrual patterns, impact on quality of life due to AUB, internal consistency, test-retest, responsiveness, and discriminant validity were assessed. For construct validity, the Pictorial Blood Assessment Chart (PBAC) and World Health Organization Quality of Life – abbreviated version (WHOQOL-BREF) were applied. RESULTS: Women with AUB were older, had higher body mass indices, and had a worse quality of life during menstruation. Regarding the MBQ's psychometric variables, Cronbach's alpha coefficient was > 0.70 in all analyses, high intraclass correlation coefficient was found in both groups; no ceiling and floor effects were observed, and construct validity was demonstrated (correlation between MBQ score, PBAC score, and clinical menstrual cycle data). No difference between MBQ and PBAC scores were perceived after the test-retest. Significant differences were found between MBQ and PBAC scores before and after treatment. An MBQ score ≥ 24 was associated with a high probability of AUB; accuracy of 98%. CONCLUSION: The MBQ is a reliable questionnaire for Brazilian women. The cut-off ≥ 24 shows high accuracy to discriminate AUB.
  • Noninvasive mechanical ventilation assistance in amyotrophic lateral sclerosis: a systematic review Original Article

    Cunha-Correia, Carolina da; Gama, Mylana Dandara Pereira; Fontana, Pedro Nogueira; Fantini, Francisca Goreth Malheiro Moraes; Prado, Gilmar Fernandes; Dourado Júnior, Mário Emílio Teixeira; Schwingel, Paulo Adriano

    Resumo em Inglês:

    ABSTRACT BACKGROUND: Respiratory failure is the most common cause of death in patients with amyotrophic lateral sclerosis (ALS), and morbidity is related to poor quality of life (QOL). Non-invasive ventilation (NIV) may be associated with prolonged survival and QOL in patients with ALS. OBJECTIVES: To assess whether NIV is effective and safe for patients with ALS in terms of survival and QOL, alerting the health system. DESIGN AND SETTING: Systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting standards using population, intervention, comparison, and outcome strategies. METHODS: The Cochrane Library, CENTRAL, MEDLINE, LILACS, EMBASE, and CRD databases were searched based on the eligibility criteria for all types of studies on NIV use in patients with ALS published up to January 2022. Data were extracted from the included studies, and the findings were presented using a narrative synthesis. RESULTS: Of the 120 papers identified, only 14 were related to systematic reviews. After thorough reading, only one meta-analysis was considered eligible. In the second stage, 248 studies were included; however, only one systematic review was included. The results demonstrated that NIV provided relief from the symptoms of chronic hypoventilation, increased survival, and improved QOL compared to standard care. These results varied according to clinical phenotype. CONCLUSIONS: NIV in patients with ALS improves the outcome and can delay the indication for tracheostomy, reducing expenditure on hospitalization and occupancy of intensive care unit beds. SYSTEMATIC REVIEW REGISTRATION: PROSPERO database: CRD42021279910 — https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=279910.
  • Sociodemographic, behavioral, obstetric, and healthcare factors associated with low weight at birth: a case-control study Original Article

    Cluzeni, Viviane Tazinasso; Wendt, Guilherme Welter; Ferreto, Lirane Elize Defante; Lucio, Léia Carolina; Risso-Pascotto, Claudicéia

    Resumo em Inglês:

    ABSTRACT BACKGROUND: Understanding social determinants is crucial for implementing preventive strategies, especially for low birth weight (LBW)—a public health issue that severely increases the risk of morbimortality in children. OBJECTIVE: This study aimed to identify the factors associated with LBW among newborns, assisted by the Brazilian Unified Health System. DESIGN AND SETTING: It analyzed data from newborns and their mothers. The sample was selected by convenience from users of the public health system in Francisco Beltrão (Paraná, Brazil). METHODS: Cases (n = 26) were babies weighing ≤ 2,500 g and controls (n = 52) > 2,500 g. All babies were assessed and paired by sex and date of birth in a 1:2 proportion. Statistical power was computed a posteriori, revealing a power of 87% (α = 0.05). RESULTS: Strong and significant differences were found in the bivariate analysis, in which the number of current smokers or those who quit during pregnancy was higher among mothers of babies with LBW. Moreover, the gestational weeks were lower among these cases. Logistic regression models indicated that the gestational week (odds ratio [OR] = 0.17, 95% confidence interval [CI]:0.05–0.54) and fathers’ educational level (high school or above; OR = 0.22, 95% CI:0.06–0.99) were related to lower chances of low birth weight. CONCLUSIONS: Our findings confirm previous investigations on LBW's multi-causality, showing that the gestational week could reduce up to 82% chances of a baby being born with ≤ 2,500 g. Its association with paternal education underlines the importance of comprehensive policies to protect newborns.
  • Quality of life of older adults in Family Health Strategy: a cross-sectional study Original Article

    Batista, Ilaise Brilhante; Mota, Annah Thereza; Blanco, Ana Luiza; Marinho, Jéssica da Silva; Guimarães, Maria Sortênia Alves; Ribeiro, Andréia Queiroz; Nunes, Daniella Pires

    Resumo em Inglês:

    ABSTRACT BACKGROUND: With the increase in the older adult population, it is essential to identify the living and health conditions that can impact the quality of life of these individuals. OBJECTIVES: To identify the domains and factors associated with the quality of life of older adults under the Family Health Strategy program. DESIGN AND SETTING: This was a cross-sectional analytical study was conducted in the municipality of Palmas, Tocantins, Brazil. METHODS: We assessed 449 older adults enrolled in the Family Health Strategy program. Data were collected between April and July, 2018. World Health Organization Quality of Life Assessment (WHOQOL-OLD) was used to assess the quality of life (QoL) and multiple linear regression was used to estimate the factors associated with QoL. RESULTS: The QoL domain with the highest score was death and dying (mean = 70.4), and the lowest score was for sensory functions (mean = 61.0 points). The factors associated with QoL were single marital status (β = -4.55; P = 0.014), level of independence for daily living activities (β = 4.92; P < 0.001), self-assessment of regular health (β = 5.35; P < 0.001), and poor health (β = -8.67; P < 0.001). CONCLUSION: The death and dying domain of QoL presented the highest score. Marital status, impairment in daily activities, and health self-assessment were associated with QoL.
  • Oral health of an indigenous population in northeastern Brazil: a cross-sectional Study of the Fulni-ô ethnic group Original Article

    Koike, Bruna Del Vechio; Valões, Rosangela Maria Pereira; Cazal, Claudia; Pereira, Vanessa Cardoso; Fraga, Carlos Alberto de Carvalho; Carmo, Rodrigo Feliciano do; Pereira, Meireane Firmino; Guimarães, Manoel Pereira; Souza, Carlos Dornels Freire de; Armstrong, Anderson da Costa

    Resumo em Inglês:

    ABSTRACT BACKGROUND: There is a lack of studies evaluating the oral health of traditional indigenous communities in Brazil. OBJECTIVES: Thus, the objective of this study was to describe the oral health characteristics of the indigenous Fulni-ô ethnic group in Northeast Brazil. DESIGN AND SETTING: A cross-sectional observational investigation was conducted within the Project on Atherosclerosis among Indigenous Populations. METHODS: This study included participants of both sexes from the Fulni-ô ethnic group. The participants included in this investigation underwent a comprehensive oral health evaluation by a registered and experienced dentist to assess oral health and identify potentially malignant oral lesions. Participants with suspicious lesions were referred for biopsy. Shapiro-Wilk, Mann-Whitney, and Student’s t-tests were used, and measures of central tendency and dispersion were described. Statistical significance was 5%. RESULTS: A total of 104 individuals were included in this study. The prevalence of the use of tobacco derivatives was 94.0%, with similarities between sexes. The prevalence of oral changes in this study population was 84.4%. Fifty-one individuals who underwent oral reassessment were referred for oral lesion biopsy. CONCLUSIONS: This study demonstrated a high prevalence of oral alterations in the Fulni-ô population. Histopathological analyses indicated the presence of mild oral epithelial dysplasia in five cases.
  • Awareness of stroke among patients with chronic kidney disease on hemodialysis: a cross-sectional study Original Article

    Gomes, Orlando Vieira; Guimarães, Manoel Pereira; Barbosa, Bárbara Maria Batista; Marinho, Christielle Lidianne Alencar; Nicacio, Jandir Mendonça; Barreira, Matheus Pereira; Rodrigues, Mateus de Sousa; Santana, Leonardo Fernandes e; Elihimas Júnior, Ubiracé Fernando; Schwingel, Paulo Adriano

    Resumo em Inglês:

    ABSTRACT BACKGROUND: Stroke is a major cause of mortality worldwide. Renal dysfunction is an important risk factor for stroke. Brazilian studies on stroke knowledge are generally population based. Studies stratifying stroke knowledge according to comorbidities are rare. Scientific data are essential to guide the awareness of stroke. OBJECTIVE: To assess stroke knowledge in patients with chronic kidney disease (CKD) on hemodialysis. DESIGN AND SETTING: Cross-sectional analytical study of patients with CKD on hemodialysis in north-eastern Brazil. METHODS: A self-administered questionnaire survey on stroke awareness was administered to patients with CKD on hemodialysis between April and November 2022. The chi-square test and other descriptive statistics were used. Univariate and multivariate analyses were performed using logistic regression. RESULTS: A total of 197 patients were included in the analysis. The Brazilian acronym for stroke was used by 53.5% of the participants. Less than 10.0% of the sample showed optimal decision-making ability regarding stroke. Of the participants, 29.9% knew at least one risk factor and one symptom; however, this was considered as having below the minimum capacity because they did not know the emergency service call number. In the analysis adjusted for income and education, females (odds ratio [OR], 0.40%; 95% confidence interval [CI], 0.20-0.82), older patients (OR, 0.24%; 95% CI, 0.09-0.63) and having at most one comorbidity (OR, 0.48%; 95% CI, 0.23-0.98) were factors for lower levels of knowledge or ideal decision-making capacity against stroke. CONCLUSIONS: Patients on hemodialysis, especially women and older people, have little knowledge about stroke.
  • Potentially inappropriate medications with older people in intensive care and associated factors: a historic cohort study Original Article

    Sichieri, Karina; Trevisan, Danilo Donizetti; Barbosa, Ricardo Luís; Secoli, Silvia Regina

    Resumo em Inglês:

    ABSTRACT BACKGROUND: The epidemiology of potentially inappropriate medications (PIMs) in critical care units remains limited, especially in terms of the factors associated with their use. OBJECTIVE: To estimate the incidence and factors associated with PIMs use in intensive care units. DESIGN AND SETTING: Historical cohort study was conducted in a high-complexity hospital in Brazil. METHODS: A retrospective chart review was conducted on 314 patients aged ≥ 60 years who were admitted to intensive care units (ICUs) at a high-complexity hospital in Brazil. The dates were extracted from a “Patient Safety Project” database. A Chi-square test, Student’s t-test, and multivariable logistic regression analyses were performed to assess which factors were associated with PIMs. The statistical significance was set at 5%. RESULTS: According to Beers’ criteria, 12.8% of the identified drugs were considered inappropriate for the elderly population. The incidence rate of PIMs use was 45.8%. The most frequently used PIMs were metoclopramide, insulin, antipsychotics, non-steroidal anti-inflammatory drugs, and benzodiazepines. Factors associated with PIMs use were the number of medications (odds ratio [OR] = 1.17), length of hospital stay (OR = 1.07), and excessive potential drug interactions (OR = 2.43). CONCLUSIONS: Approximately half of the older adults in ICUs received PIM. Patients taking PIMs had a longer length of stay in the ICU, higher numbers of medications, and higher numbers of potential drug interactions. In ICUs, the use of explicit methods combined with clinical judgment can contribute to the safety and quality of medication prescriptions.
  • Habitual physical activity and sedentary behavior as predictors of dynapenia in older adults: a cross-sectional study Original Article

    Santos, Lucas dos; Almeida, Cláudio Bispo de; Valença Neto, Paulo da Fonseca; Silva, Rizia Rocha; Santos, Isaac Costa; Casotti, Cezar Augusto

    Resumo em Inglês:

    ABSTRACT BACKGROUND: Dynapenia is a risk factor of mortality. Therefore, the development of low-cost and easy-to-apply tools is essential to optimize the health surveillance actions of older people. OBJECTIVES: To compare the time spent on habitual physical activity (HPA) and sedentary behavior (SB) among dynapenic and non-dynapenic older adults and ascertain the predictive ability of these behaviors on outcome. DESIGN AND SETTING: A cross-sectional population epidemiological survey was conducted involving 208 older adults. METHODS: HPA and SB were quantified using the International Physical Activity Questionnaire, and dynapenia was identified by handgrip strength (women: 18.37 kgf; men: 26.75 kgf). RESULTS: The prevalence was 24.50%. In both sexes, dynapenic individuals reported a HPA median time of 70.00 minutes/week (min/wk), while non-dynapenic women and men reported HPA median times of 240.00 and 280.00 min/wk, respectively (P < 0.05). For SB among dynapenic individuals, a median of 388.75 min/day was observed in women and 428.57 min/d in men. In contrast, non-dynapenic women and men had 291.42 and 274.28 min/day in SB (P < 0.05), respectively. The best cutoff HPA to discriminate the outcome was 150.00 min/wk in women (sensitivity: 73.30%; specificity: 60.67%) and 140.00 min/wk in men (sensitivity, 71.43%; specificity, 61.54%). The best cutoff SB was 381.43 min/day in women (sensitivity, 53.30%; specificity, 84.80%) and 351.43 min/day in men (sensitivity, 71.43%; specificity, 73.85%). CONCLUSION: Older individuals with dynapenia spent less time on HPA and more time in SB. Furthermore, HPA was found to be a better discriminator of dynapenic individuals, and SB better discriminated non-dynapenic individuals.
  • Dietary patterns and socioeconomic, demographic, and health-related behaviors during pregnancy. A cross-sectional study Original Article

    Oliveira, Tatiane Irene de; Santos, Lais dos; Höfelmann, Doroteia Aparecida

    Resumo em Inglês:

    ABSTRACT BACKGROUND: The identification and understanding of dietary factors and other characteristics that influence gestational weight gain can contribute to the formulation of strategies to promote healthy eating habits before and during pregnancy. OBJECTIVE: To investigate the association between dietary patterns, sociodemographic and obstetric characteristics, and health-related behaviors in pregnant women. DESIGN AND SETTING: A cross-sectional study was conducted on women undergoing prenatal care in the Unified Health System of Colombo, Paraná, Brazil, from February 2018 to September 2019. METHOD: A weekly food frequency questionnaire was administered, and dietary patterns were identified through factor analysis. Median regression models were constructed to identify the associations between dietary pattern scores and variables. RESULTS: Complete data were obtained from 495 pregnant women. Three dietary patterns were identified: 1) “healthy,” with higher factor loadings for the weekly consumption of raw vegetables, cooked vegetables, and fresh fruits; 2) “Western,” including soft drinks or artificial juice, candies, milk, and dairy products, and processed cold meat; and 3) “traditional,” beans and meat. Pregnant women aged 30 years or older (coefficient [Coef.] 0.86, 95% confidence interval [CI] 0.38–1.33) with moderate/intense physical activity (Coef. 0.32, 95% CI 0.02–0.62) had higher adherence to the “healthy” pattern. Adolescents and smokers adhered more to the “traditional” pattern (Coef. 0.17, 95% CI 0.01–0.33). CONCLUSION: Age, smoking status, and physical activity were associated with dietary patterns in pregnant women.
  • Cervical Intraepithelial Neoplasia grade 2 biopsy: Do p16INK4a and Ki-67 biomarkers contribute to the decision to treat? A cross-sectional study Original Article

    Ferreira, Amanda Leal; Dibe, Nasle Domingues; Paiva, Bruna Rodrigues de; Portari, Elyzabeth Avvad; Dock, Dione Corrêa de Araújo; Ferreira, Nilma Valéria Caldeira; Gomes Junior, Saint Clair; Russomano, Fábio Bastos; Andrade, Cecília Vianna de

    Resumo em Inglês:

    ABSTRACT BACKGROUND: Managing cervical intraepithelial neoplasia grade 2 (CIN2) is challenging, considering the CIN2 regression rate, perinatal risks associated with excisional procedures, and insufficient well-established risk factors to predict progression. OBJECTIVES: To determine the ability of p16INK4a and Ki-67 staining in biopsies diagnosed with CIN2 to identify patients with higher-grade lesions (CIN3 or carcinoma). DESIGN AND SETTING: Cross-sectional study conducted at a referral center for treating uterine cervical lesions. METHODS: In 79 women, we analyzed the correlation of p16INK4a and Ki-67 expression in CIN2 biopsies with the presence of a higher-grade lesions, as determined via histopathology in surgical specimens from treated women or via two colposcopies and two cytological tests during follow-up for untreated women with at least a 6-month interval. The expression of these two biomarkers was verified by at least two independent pathologists and quantified using digital algorithms. RESULTS: Thirteen (16.8%) women with CIN2 biopsy exhibited higher-grade lesions on the surgical excision specimen or during follow-up. p16INK4a expression positively and negatively predicted the presence of higher-grade lesions in 17.19% and 86.67% patients, respectively. Ki-67 expression positively and negatively predicted the presence of higher-grade lesions in 40% and 88.24% patients, respectively. CONCLUSIONS: Negative p16INK4a and Ki67 immunohistochemical staining can assure absence of a higher-grade lesion in more than 85% of patients with CIN2 biopsies and can be used to prevent overtreatment of these patients. Positive IHC staining for p16INK4a and Ki-67 did not predict CIN3 in patients with CIN2 biopsies.
  • What is an “ongoing” clinical trial? An analysis of different sources revealed heterogeneous definitions of when a clinical trial starts and ends: a meta-research study Short Communication

    Pacheco, Rafael Leite; Martimbianco, Ana Luiza Cabrera; Riera, Rachel

    Resumo em Inglês:

    ABSTRACT BACKGROUND: Although the concept of an “ongoing study” seems self-explanatory, it is difficult to determine whether a trial is underway. OBJECTIVE: To analyze the definitions of “ongoing clinical trial” across different clinical trial registries, methodological guidelines, and other sources. DESIGN AND SETTING: This meta-research study was conducted at the Universidade Federal de São Paulo (UNIFESP), Brazil. METHODS: We performed a cross-sectional analysis of relevant clinical trial registry databases, methodological guidelines for conducting systematic reviews, and other sources that would define or regulate clinical trials. RESULTS: We identified various heterogeneous definitions used by eligible sources at both the start and end of a clinical trial. The starting criteria used were as follows: when the team is planning the protocol, when permission is given to conduct the study, or when the first participant is enrolled. Some sources used the time at which the last outcome data was collected as a criterion to determine the end of the trial. The International Committee of Medical Journal Editors stated that a study is still “ongoing” during the analysis process. Several sources use a vague definition or present no clear criteria for defining the start or end of a study. CONCLUSION: The concept of “ongoing clinical trials” lacks a transparent and homogeneous definition across relevant sources. A consensus on this concept is important to facilitate the evaluation of available evidence and conduct research synthesis. Further efforts are necessary to determine the best definition for the start and end of a clinical trial.
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