Barriers to access to antihypertensive medicines: insights from the HEARTS initiative in latin American and Caribbean region.

Introduction: Hypertension significantly impacts the global cardiovascular disease burden, presenting a pronounced challenge within Latin America and the Caribbean. The Pan American Health Organization's (PAHO) HEARTS initiative endeavours to meet this challenge by enhancing comprehensive cardiovascular risk management, inclusive of improved access to antihypertensive medications. This study scrutinises the challenges and barriers in accessing these medications, which are crucial for effective hypertension management in these regions. Methods: The research employed a two-phase approach: an initial analysis of National Essential Medicines Lists (NEMLs) from 22 countries involved in the HEARTS initiative for the presence of antihypertensive medications, followed by an in-depth pharmaceutical market analysis in six selected countries to evaluate the availability, pricing, and procurement practices of these medications. Results: The study revealed notable inconsistencies in the inclusion of recommended antihypertensive medications across NEMLs, particularly the lack of fixed-dose combinations (FDCs). The market analysis brought to light significant limitations in medicine registration and substantial variations in pricing, which adversely impact the accessibility and affordability of essential antihypertensive treatments. Furthermore, an examination of procurement practices identified considerable diversity across countries, highlighting potential areas for optimisation, including the use of the PAHO Strategic Fund. Conclusions: The barriers to accessing essential antihypertensive medications in Latin America and the Caribbean are multifaceted, stemming from outmoded NEMLs, limited market availability of advised medications, and disparate procurement processes. Leveraging pooled procurement mechanisms such as the PAHO Strategic Fund, coupled with vital updates to NEMLs, stands to markedly improve both the accessibility and affordability of these treatments.

Treatment of Childhood Brucellosis: A Systematic Review.

BACKGROUND: Proper treatment for brucellosis is crucial to eradicate the infection and prevent complications, but there is a notable gap in evidence for pediatric treatment. This study aims to address this gap by reviewing current literature, analyzing the efficacy and safety of brucellosis treatment in children, and identifying areas that require further investigation. METHODS: A systematic review, following preferred reporting items for systematic reviews and meta-analyses and Cochrane Handbook guidelines, assessed antimicrobial regimens' efficacy and safety for treating human brucellosis in children. Original human studies with clinical outcomes after drug therapy intervention for children up to 10 years were included. Searches were conducted in Medline, Embase, Cochrane Library and LILACS databases for studies indexed until March 6, 2023. Study selection, data extraction, and bias risk assessment were performed by pairs of reviewers. The quality assessment used Joanna Briggs Institute tools and grading of recommendations assessment, development and evaluation system. Data were analyzed using R software. RESULTS: A total of 1773 records were reviewed, yielding 11 eligible studies encompassing 1156 children. All included studies presented an observational design. The most reported treatment approaches included sulfamethoxazole-trimethoprim with rifampicin or aminoglycosides, with summarized failure rates of 2% (95% confidence interval: 0.0-0.49) and 13% (95% confidence interval: 0.06-0.29), respectively (very low certainty of evidence). Adverse events and time to defervescence were not reported. CONCLUSIONS: Sulfamethoxazole-trimethoprim + rifampicin were the most prescribed antibiotics for brucellosis for pediatrics. The study highlights the need for more research with robust designs, and emphasizes uncertainty regarding the efficacy of antimicrobial regimens, emphasizing the importance of further investigations to guide specific treatment protocols for this population.

Efficacy of antibiotic prophylaxis to preventing brucellosis in accidental exposure: A systematic review.

BACKGROUND: Antibiotic prophylaxis to prevent brucellosis after accidental exposure to Brucella is an important topic in public health. This study aimed to systematically review the efficacy of antibiotic prophylaxis following accidental exposure to Brucella in preventing human brucellosis disease. METHODS: The study protocol was registered in PROSPERO (CRD42023456812). The outcomes included the incidence of brucellosis disease, adverse events rate, and antibiotic prophylaxis adherence. A comprehensive literature search, conducted until 20 November, 2023, involved Medline, Embase, Cochrane Library, and LILACS databases. Descriptive analysis and meta-analysis using R software were performed, risk of bias was assessed using JBI Critical appraisal tools, and certainty of evidence was assessed using the GRADE tool. RESULTS: Among 3102 initially identified records, eight studies involving 97 individuals accidentally exposed, all focused on high-risk accidental exposure to Brucella in laboratory settings, were included in the review. All studies reported the prophylactic treatment comprising doxycycline at a dosage of 100 mg twice daily, combined with rifampicin at 600 mg, both administered over 21 days. Prophylaxis adherence was reported in 86% of cases, and incidence of brucellosis post-treatment was 0.01. Adverse events, mainly gastrointestinal, occurred in 26% of cases. Critical appraisal revealed limitations in reporting demographics and clinical information. The certainty of evidence was rated as 'very low,' emphasising the need for caution in interpreting the observed outcomes due to study design constraints and the absence of comparative groups. CONCLUSIONS: PEP is an alternative practice reported in the literature, used in accidents with high-risk exposure to Brucella. The currently available evidence of the efficacy of antibiotic prophylaxis is insufficient to support a recommendation for or against the widespread use of antibiotic prophylaxis, so caution is needed in interpreting results due to the very low certainty of evidence, primarily stemming from case series and lack of comparative groups.

Effectiveness of nirmatrelvir-ritonavir for the treatment of patients with mild to moderate COVID-19 and at high risk of hospitalization: Systematic review and meta-analyses of observational studies.

OBJECTIVE: To assess the effectiveness of nirmatrelvir-ritonavir in the treatment of outpatients with mild to moderate COVID-19 who are at higher risk of developing severe illness, through a systematic review with meta-analyses of observational studies. METHODS: A systematic search was performed, in accordance with the Cochrane search methods, to identify observational studies that met the inclusion criteria. The outcomes of mortality and hospitalization were analyzed. Search was conducted on PubMed, EMBASE, and The Cochrane Library. Two reviewers independently screened references, selected the studies, extracted the data, assessed the risk of bias using ROBINS-I tool and evaluated the quality of evidence using the GRADE tool. This study followed the PRISMA reporting guideline. RESULTS: A total of 16 observational studies were finally included. The results of the meta-analysis showed that in comparison to standard treatment without antivirals, nirmatrelvir-ritonavir reduced the risk of death by 59% (OR = 0.41; 95% CI: 0.35-0.52; moderate certainty of evidence). In addition, a 53% reduction in the risk of hospital admission was observed (OR = 0.47; 95% CI: 0.36-0.60, with very low certainty of evidence). For the composite outcome of hospitalization and/or mortality, there was a 56% risk reduction (OR = 0.44; 95% CI: 0.31-0.64, moderate certainty of evidence). CONCLUSION: The results suggest that nirmatrelvir-ritonavir could be effective in reducing mortality and hospitalization. The results were valid in vaccinated or unvaccinated high-risk individuals with COVID-19. Data from ongoing and future trials may further advance our understanding of the effectiveness and safety of nirmatrelvir-ritonavir and help improve treatment guidelines for COVID-19.

Effectiveness of first-line treatment for relapsing-remitting multiple sclerosis in Brazil: A 16-year non-concurrent cohort study.

BACKGROUND: Relapsing-remitting multiple sclerosis (RRMM) is a chronic, progressive, inflammatory and immune-mediated disease that affects the central nervous system and is characterized by episodes of neurological dysfunction followed by a period of remission. The pharmacological strategy aims to delay the progression of the disease and prevent relapse. Interferon beta and glatiramer are commonly used in the Brazilian public health system and are available to patients who meet the guideline criteria. The scenario of multiple treatments available and in development brings the need for discussion and evaluation of the technologies already available before the incorporation of new drugs. This study analyses the effectiveness of first-line treatment of RRMS measured by real-world evidence data, from the Brazilian National Health System (SUS). METHODS AND FINDINGS: We conducted a non-concurrent national cohort between 2000 and 2015. The study population consisted of 22,722 patients with RRMS using one of the following first-line drugs of interest: glatiramer or one of three presentations of interferon beta. Kaplan-Meier analysis was used to estimate the time to treatment failure. A univariate and multivariate Cox proportional hazard model was used to evaluate factors associated with treatment failure. In addition, patients were propensity score-matched (1:1) in six groups of comparative first-line treatments to evaluate the effectiveness among them. The analysis indicated a higher risk of treatment failure in female patients (HR = 1.08; P = 0,01), those with comorbidities at baseline (HR = 1.20; P<0,0001), in patients who developed comorbidities after starting treatment (i.e., rheumatoid arthritis-HR = 1.65; P<0,0001), those exclusive SUS patients (HR = 1.31; P<0,0001) and among patients using intramuscular interferon beta (IM ßINF-1a) (28% to 60% compared to the other three treatments; P<0,0001). Lower risk of treatment failure was found among patients treated with glatiramer. CONCLUSIONS: This retrospective cohort suggests that glatiramer is associated with greater effectiveness compared to the three presentations of interferon beta. When evaluating beta interferons, the results suggest that the intramuscular presentation is not effective in the treatment of multiple sclerosis.

Prevalence of self-reported dengue infections in Manaus Metropolitan Region: a cross-sectional study.

INTRODUCTION: Dengue is an endemic and epidemic disease in Brazil, with a high burden of disease. Amazonas State has a high risk of transmission. This study aimed to assess the self-reported prevalence of dengue in adults living in Manaus Metropolitan Region. METHODS: A cross-sectional study was conducted with adults living in Manaus Metropolitan Region in 2015. We performed a three-phase probabilistic sampling to collect participants' clinical and sociodemographic data. Self-reported dengue infection in the previous year was the primary outcome. Descriptive statistics and Poisson regression analysis with robust variance were used to calculate the prevalence ratio (PR) of dengue infections with 95% confidence intervals (95% CIs). Multilevel analysis including city and neighborhood variables was calculated. All analyses considered the complex sampling. RESULTS: Among the 4,001 participants, dengue in the previous year was self-reported by 7.0% (95% CI 6.3%-7.8%). Dengue was more frequent in women(PR 1.51; 95% CI 1.06-2.13), elderly participants (≥60 years old, PR 2.54; 95% CI 1.19-5.45), White and Asian participants (PR, 1.57; 95% CI, 1.11-2.23), and individuals who had not received endemic agent visits (PR, 2.28; 95% CI, 1.31-3.99). After multilevel analysis, sex was no longer a significant variable, with the remaining associations still significant. CONCLUSIONS: Seven out of 100 inhabitants of Manaus Metropolitan Region reported dengue in the previous year. Dengue was predominantly observed in women, elderly individuals, White and Asian individuals, and individuals who did not receive endemic agent visits. The setting plays an important role in dengue infections.

Prevalence of self-reported dengue infections in Manaus Metropolitan Region: a cross-sectional study

Abstract INTRODUCTION: Dengue is an endemic and epidemic disease in Brazil, with a high burden of disease. Amazonas State has a high risk of transmission. This study aimed to assess the self-reported prevalence of dengue in adults living in Manaus Metropolitan Region. METHODS: A cross-sectional study was conducted with adults living in Manaus Metropolitan Region in 2015. We performed a three-phase probabilistic sampling to collect participants' clinical and sociodemographic data. Self-reported dengue infection in the previous year was the primary outcome. Descriptive statistics and Poisson regression analysis with robust variance were used to calculate the prevalence ratio (PR) of dengue infections with 95% confidence intervals (95% CIs). Multilevel analysis including city and neighborhood variables was calculated. All analyses considered the complex sampling. RESULTS: Among the 4,001 participants, dengue in the previous year was self-reported by 7.0% (95% CI 6.3%-7.8%). Dengue was more frequent in women(PR 1.51; 95% CI 1.06-2.13), elderly participants (≥60 years old, PR 2.54; 95% CI 1.19-5.45), White and Asian participants (PR, 1.57; 95% CI, 1.11-2.23), and individuals who had not received endemic agent visits (PR, 2.28; 95% CI, 1.31-3.99). After multilevel analysis, sex was no longer a significant variable, with the remaining associations still significant. CONCLUSIONS: Seven out of 100 inhabitants of Manaus Metropolitan Region reported dengue in the previous year. Dengue was predominantly observed in women, elderly individuals, White and Asian individuals, and individuals who did not receive endemic agent visits. The setting plays an important role in dengue infections.

The long-term costs for treating multiple sclerosis in a 16-year retrospective cohort study in Brazil.

BACKGROUND: Multiple Sclerosis (MS) is a disease that appreciably impacts on the quality of life of patients and is associated with high expenditure. MS is a chronic multifactorial disease, characterized by inflammation, demyelination and axonal loss. The Brazilian public health system provides pharmacological treatment as well as hospital and outpatient care for patients with relapsing-remitting and secondary progressive multiple sclerosis. However, we are not aware of any previous publications assessing total direct medical costs in patients with a long follow-up within the Brazilian healthcare system. Consequently, the objective is to analyze public spending on patients with MS to guide stakeholders in future investment and disinvestment decisions. METHODS AND FINDINGS: We retrospectively analyzed public Brazilian spending on patients with MS between 2000 and 2015 using the patient-centered registry of all patients in the public health system (SUS) obtained through deterministic-probabilistic record linkage of the Outpatient Information System, Hospital Information System and Mortality Information Systems in Brazil. Descriptive data analysis and a multiple linear regression model was performed to evaluate the associations between the mean annual cost per patient and the clinical and demographic variables. The suitability of the model was verified from a residue analysis and the level of significance adopted was 5%. RESULTS: 28,401 patients were identified and subsequently 23,082 patients were analyzed. The majority of the patients were female (73.3%), lived in the southeast region (58.9%), had a mean age of 36.8 (± 12.2) years and started treatment using one of the interferons beta (78.9%). The total direct medical cost spending in the sixteen years of the follow-up was US $ 2,308,393,465.60, and the mean annual expenditure per patient was US $ 13,544.40 (± 4,607.05). In the best fit model (p <0.001), approximately 40% of the variability of the mean annual cost per patient was explained by the region of residence; medication used (intention to treat); if the patient was a non-exclusive user of medicines, i.e., used SUS for other procedures other than high-cost medicines; year of treatment start; and presence of events (death; Relapse; change of treatment and/or comorbidity). CONCLUSIONS: In the public health system of Brazil, disease modifying therapies currently represent almost all of the total direct costs of multiple sclerosis treatment. Around the world, new and emerging health technologies to treat of MS impose a challenge to health budgets, highlighting the need for cost-effectiveness studies comparing these technologies to those already available. Our regression model may help in this process, and calls attention to the need to access the real world performance of new therapies available in SUS, with the potential for disinvestment and/ or price reductions if needed.

The Assessment for Disinvestment of Intramuscular Interferon Beta for Relapsing-Remitting Multiple Sclerosis in Brazil.

In Brazil, inclusion and exclusion of health technologies within the Unified Health System (SUS) is the responsibility of the National Committee for Health Technology Incorporation (CONITEC). A recent Cochrane systematic review demonstrated that intramuscular interferon beta 1a (IFN-ß-1a-IM) was inferior to the other beta interferons (IFN-ßs) for multiple sclerosis (MS). As a result, CONITEC commissioned an analysis to review possible disinvestment within SUS. The objective of this paper is to describe the disinvestment process for IFN-ß-1a-IM in Brazil. The first assessment comprised a literature review and mixed treatment comparison meta-analysis. The outcome of interest was the proportion of relapse-free patients in 2 years. This analysis confirmed the inferiority of IFN-ß-1a-IM. Following this, CONITEC recommended disinvestment, with the decision sent for public consultation. More than 3000 contributions were made on CONITEC's webpage, most of them against the preliminary decision. As a result, CONITEC commissioned a study to assess the effectiveness of IFN-ß-1a-IM among Brazilian patients in routine clinical care. The second assessment involved an 11-year follow-up of a non-concurrent cohort of 12,154 MS patients developed by deterministic-probabilistic linkage of SUS administrative databases. The real-world assessment further demonstrated that IFN-ß-1a-IM users had a statistically higher risk of treatment failure, defined as treatment switching or relapse treatment or death, with the assessment showing that IFN-ß-1a-IM was inferior to the other IFN-ßs and to glatiramer acetate in both direct and indirect analysis. In the drug ranking with 40,000 simulations, IFN-ß-1a-IM was the worst option, with a success rate of only 152/40,000. Following this, CONITEC decided to exclude the intramuscular presentation of IFN-ß from the current MS treatment guidelines, giving patients who are currently on this treatment the option of continuing until treatment failure. In conclusion, we believe this is the first example of this new disinvestment process in action, providing an exemplar for other treatments in Brazil as well as other countries.

Diretriz metodológica para estudos de avaliação econômica de tecnologias em saúde no Brasil / Methodological guidelines for economic evaluation studies of health technologies in Brazil

Objetivos: Resumir os principais pontos da Diretriz de Avaliação Econômica em Saúde (AES) do Ministério da Saúde. Métodos: As diretrizes para AES no Brasil foram desenvolvidas por intermédio de múltiplas rodadas de trabalho iterativas por grupo multidisciplinar de especialistas em economia da saúde e foram submetidas à consulta pública. Resultados: O problema deve ser definido por meio de uma questão de pesquisa estruturada. O estudo pode ser baseado em dados primários ou em modelagem, em que o primeiro aumenta a validade interna dos resultados e o segundo, a capacidade de generalização do estudo. Quando o trabalho for baseado em modelagem e focado em doença crônica, o modelo de Markov pode ser usualmente empregado, quando não houver necessidades que apontem para simulação de eventos discretos (como competição dos indivíduos por recursos escassos) ou modelos de transmissão dinâmica (em vacinação e/ou doenças infecciosas com alta transmissão entre indivíduos). O horizonte temporal preferencial é o de tempo de vida, e a taxa de desconto padrão é de 5% para custo e efetividade. Os custos devem representar a perspectiva do Sistema Único de Saúde (SUS), podendo ser estimados por macrocusteio ou microcusteio. Sempre que possível, os resultados devem ser apresentados no formato de custo por ano de vida salvo ajustado para qualidade, para facilitar comparações com outros estudos. Análises de sensibilidade devem ser extensamente empregadas, de forma a avaliar o impacto da incerteza nos resultados produzidos. Conclusões: Espera-se que, com a padronização da metodologia proposta na Diretriz, a produção de AES no país tenha incremento na sua qualidade e reprodutibilidade.

Objectives: To summarize the main points from the Brazilian's Ministry of Health Economic Evaluations (HEE) guideline. Methods: The guideline was developed through multiple rounds of iterative work, conducted by a multidisciplinary team of specialists in health economics, and where submitted to public consultation. Results: The decision problem should be defined through a structured research question. The study can be either primary data or model-based; in the first case, there is greater internal validity, while the second generates a superior generalizability. When the study is model-based and focused on a chronic disease, a Markov model can be usually employed, except for situations that points towards the need of a discrete event simulation (such as competition of individuals for scarce resources) or a dynamic transition model (for example, vaccination models and infectious diseases with high transmission rates between individuals). The preferred time horizon is the lifetime one, and the default discount rate is 5% for both costs and effectiveness. Costs should represent the Unified Health System (SUS) perspective and can be estimated through either gross-costing or micro-costing. Results should be presented as costs per quality adjusted life years (QALYs) whenever possible, to facilitate comparison with other studies. Sensitivity analyses should be widely employed, in order to evaluate the impact of uncertainty in the results produced by the model. Conclusions: It is expected that, with the standardization proposed in this guideline, the HEE production in Brazil has gains in quality and reproducibility.

Avaliação da efetividade dos programas de prevenção da obesidade em adolescentes: revisão sistemática e metanálise / Evaluation of the effectieness of prevention programs for obesity in adolescents: systematic review and metanalysis

OBJETIVOS: Identificar, descrever e avaliar a efetividade dos programas de prevenção da obesidade para adolescentes. MÉTODOS: Revisão sistemática, com busca estruturada em nove bases de dados. Foram considerados elegíveis ensaios clínicos randomizados (ECR) e estudos quase-experimentais que relataram a experiência desses programas quando comparado a um controle, sendo o tempo de acompanhamento de no mínimo um ano. Os desfechos dos estudos deveriam incluir medidas relativas à obesidade, a partir das quais metanálises foram realizadas. Foi realizada descrição dos componentes dos programas. RESULTADOS: Dentre 1.614 estudos identificados, 13 atenderam aos critérios de inclusão. As metanálises realizadas para a diferença de média dos desfechos escore Z do IMC, IMC e prevalência de sobrepeso e obesidade foram -0,01, 0,01 e -0,01, respectivamente. A descrição dos programas revelou elementos motivacionais, de educação, de incentivo à alimentação saudável e atividade física e de envolvimento da família. A metanálise realizada mostrou redução do percentual de gordura corporal (diferença média: -2,18). CONCLUSÕES: Observou-se relevância no desfecho percentual de gordura corporal. A descrição mostrou que os programas avaliados possuem amplo leque de intervenções.

OBJECTIVES: To identify, describe and evaluate the effectiveness of obesity prevention programs for adolescents. METHODS: Systematic review with structured search in nine databases. Randomized controlled trials (RCT) and quasi-experimental studies that reported the experience of these programs when compared to a control were eligible, and the follow-up of at least one year. The studies’ outcomes should include measures relating to obesity, from which meta-analyzes would be carried out. It was performed description of programs. RESULTS: Of 1614 identified studies, 13 met the inclusion criteria. Metaanalyzes performed for the mean difference of the Z score outcomes of BMI, BMI and the prevalence of overweight and obesity were -0.01, 0.01 and -0.01, respectively. The description of the programs revealed elements, such as: motivational, education, to encourage healthy eating and physical activity and family involvement. The meta-analysis showed a reduction in body fat percentage (mean difference: -2.18). CONCLUSIONS: There was significance in the outcome percentage of body fat. The description showed that the evaluated programs have wide range of interventions.

Inteligência avaliativa em rede: construindo consenso em Avaliação de Tecnologias em Saúde / /Assessment intelligence network: consensus building in Health Technology Assessment / /Redes de inteligencia evaluativa: la construcción de un consenso sobre laEvaluación de Tecnologías en Salud

A Avaliação de Tecnologias em Saúde (ATS) é um campo multidisciplinar de estudo, que busca analisar as implicações clínicas, sociais, éticas e econômicas do desenvolvimento, difusão e uso da tecnologia em saúde. O processo de definição de diretrizes metodológicas em ATS exige a construção de consenso entre um amplo conjunto de experts e tomadores de decisão na elaboração de um documento com robustez científica. No Brasil, a partir de 2008 com a criação da Rede Brasileira de Avaliação de Tecnologias em Saúde(REBRATS), a elaboração de diretrizes em ATS passou a ser realizada por meio de um processo colaborativo no âmbito da rede. Este processo tem contribuído não apenas para a padronização metodológica em ATS, mas também para a estruturação da inteligência avaliativa em rede no Brasil. Este artigo tem por objetivo discutir a estrutura e a dinâmica desta inteligência avaliativa, bem com sua evolução ao longo do tempo...

Health Technology Assessment (HTA) is a multidisciplinary field of study that seeks to analyze healthtechnologies development, diffusion and use and their clinical, social, economic and ethical implications.The defining process of HTA methodological guidelines requires consensus building among a broad range ofexperts and decision makers in the elaboration of a scientific robust document. In Brazil, since the creationof the Brazilian Network for Health Technology Assessment (REBRATS) in 2008, the elaboration of HTAguidelines has been performed through a collaborative process between network members. This processhas contributed not only to the HTA methodological standardization, but also to structure an assessmentintelligence network in Brazil. This article aims to discuss the structure and dynamics of this evaluativeintelligence and how it has improved over time...

La Evaluación de Tecnologías (HTA) es un campo multidisciplinar de estudio que busca analizar lascaracterísticas clínicas, el desarrollo social, ético y económico, la difusión y el uso de la tecnología en la salud.El proceso de definición de directrices metodológicas en ATS requiere el consenso entre una amplia gamade expertos y tomadores de decisiones en la elaboración de un documento con solidez científica. En Brasil,a partir de 2008 con la creación de la Red Brasileña de Evaluación de Tecnologías Sanitarias (REBRATS)la elaboración de directrices sobre ATS ahora se lleva a cabo a través de un proceso de colaboración dentrode la red. Este proceso ha contribuido no sólo a la estandarización metodológica en ATS, sino también aestructurar la red de inteligencia evaluativa en Brasil. Este artículo tiene como objetivo discutir la estructuray dinámica de esta inteligencia de evaluación, así como su evolución en el tiempo...

Rituximab, fludarabine, and cyclophosphamide versus fludarabine and cyclophosphamide for treatment of chronic lymphocytic leukemia: A systematic review with meta-analysis.

BACKGROUND: Chronic lymphocytic leukemia (CLL) is a disease of the lymphoid system, in which the most common therapy is fludarabine plus cyclophosphamide (FC). The addition of rituximab to FC has been used, a combination known as FCR. OBJECTIVES: To perform a systematic review with meta-analysis of clinical trials between 2000 and 2012 comparing FC and FCR in patients with CLL. MATERIAL AND METHODS: Electronic databases were searched using keywords related to the objectives of this review. The outcomes examined were progression-free survival and complete remission. RESULTS: The progression-free survival and the overall survival showed significant difference between the two regimens, with complete remission being more frequent in FCR-treated patients (odds ratio=2.58; 95% CI: 2.13-3.13). Patients treated with FCR showed significantly higher neutropenia and serious adverse reactions. CONCLUSION: Despite the favorable results of the FCR regimen on outcomes including complete remission, progression-free survival, and overall survival, there is a lack of methodological rigor and appropriate analyses in many of these studies, and thus, there is a need for further studies examining the effect of rituximab in CLL patients.

Pubertal timing in girls and depression: a systematic review.

BACKGROUND: Because the incidence of depression increases after puberty, it is possible that pubertal timing in girls influences the onset of depression. Our objective was to assess the effect of early and late puberty in girls on the incidence of depression. METHODS: We systematically searched relevant databases for controlled studies that assessed the impact of pubertal timing in girls on the incidence of depression or depressive symptoms. The last search was completed in August 2013. Two authors selected the studies, extracted the data, and assessed the quality of the evidence. Meta-analyses of the adjusted and unadjusted results were calculated using random effects. RESULTS: Four cohort studies were included (n=8055 participants). Early puberty significantly increased the risk of new cases of depression in the unadjusted meta-analysis (RR=1.33; CI 95%: 1.02, 1.73) but not in the adjusted estimate of two of the included studies (RR=1.48; CI 95%: 0.69, 2.28). For late puberty, no significant associations were found (unadjusted RR=1.28; CI 95%: 0.87, 1.88). Two studies assessed the effect of early puberty on depressive symptoms and found positive associations. The quality of the available evidence was rated as very low. LIMITATIONS: The polled results had wide confidence intervals, and the available evidence was of very low quality. CONCLUSIONS: The available evidence supports little confidence regarding the impact of pubertal timing on the onset of depression in girls but suggests that early puberty in girls may increase the risk of depression. Further higher quality studies are needed to clarify the association between pubertal timing and the incidence of depression in girls and women.