Cancer and central nervous system disorders: protocol for an umbrella review of systematic reviews and updated meta-analyses of observational studies

BACKGROUND: The objective of this study will be to synthesize the epidemiological evidence and evaluate the validity of the associations between central nervous system disorders and the risk of developing or dying from cancer. METHODS/DESIGN: We will perform an umbrella review of systematic reviews and conduct updated meta-analyses of observational studies (cohort and case-control) investigating the association between central nervous system disorders and the risk of developing or dying from any cancer or specific types of cancer. Searches involving PubMed/MEDLINE, EMBASE, SCOPUS and Web of Science will be used to identify systematic reviews and meta-analyses of observational studies. In addition, online databases will be checked for observational studies published outside the time frames of previous reviews. Eligible central nervous system disorders will be Alzheimer's disease, anorexia nervosa, amyotrophic lateral sclerosis, autism spectrum disorders, bipolar disorder, depression, Down's syndrome, epilepsy, Huntington's disease, multiple sclerosis, Parkinson's disease and schizophrenia. The primary outcomes will be cancer incidence and cancer mortality in association with a central nervous system disorder. Secondary outcome measures will be site-specific cancer incidence and mortality, respectively. Two reviewers will independently screen references identified by the literature search, as well as potentially relevant full-text articles. Data will be abstracted, and study quality/risk of bias will be appraised by two reviewers independently. Conflicts at all levels of screening and abstraction will be resolved through discussion. Random-effects meta-analyses of primary observational studies will be conducted where appropriate. Parameters for exploring statistical heterogeneity are pre-specified. The World Cancer Research Fund (WCRF)/American Institute for Cancer Research (AICR) criteria and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach will be used for determining the quality of evidence for cancer outcomes. DISCUSSION: Our study will establish the extent of the epidemiological evidence underlying the associations between central nervous system disorders and cancer and will provide a rigorous and updated synthesis of a range of important site-specific cancer outcomes. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016052762

Cardiovascular and renal outcomes of renin-angiotensin system blockade in adult patients with diabetes mellitus: a systematic review with network meta-analyses

Medications aimed at inhibiting the renin-angiotensin system (RAS) have been used extensively for preventing cardiovascular and renal complications in patients with diabetes, but data that compare their clinical effectiveness are limited. We aimed to compare the effects of classes of RAS blockers on cardiovascular and renal outcomes in adults with diabetes

The pharmacological and non-pharmacological treatment of attention deficit hyperactivity disorder in children and adolescents: A systematic review with network meta-analyses of randomised trials

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed psychiatric disorders in childhood. A wide variety of treatments have been used for the management of ADHD. We aimed to compare the efficacy and safety of pharmacological, psychological and complementary and alternative medicine interventions for the treatment of ADHD in children and adolescents. METHODS AND FINDINGS: We performed a systematic review with network meta-analyses. Randomised controlled trials (≥ 3 weeks follow-up) were identified from published and unpublished sources through searches in PubMed and the Cochrane Library (up to April 7, 2016). Interventions of interest were pharmacological (stimulants, non-stimulants, antidepressants, antipsychotics, and other unlicensed drugs), psychological (behavioural, cognitive training and neurofeedback) and complementary and alternative medicine (dietary therapy, fatty acids, amino acids, minerals, herbal therapy, homeopathy, and physical activity). The primary outcomes were efficacy (treatment response) and acceptability (all-cause discontinuation). Secondary outcomes included discontinuation due to adverse events (tolerability), as well as serious adverse events and specific adverse events. Random-effects Bayesian network meta-analyses were conducted to obtain estimates as odds ratios (ORs) with 95% credibility intervals. We analysed interventions by class and individually. 190 randomised trials (52 different interventions grouped in 32 therapeutic classes) that enrolled 26114 participants with ADHD were included in complex networks. At the class level, behavioural therapy (alone or in combination with stimulants), stimulants, and non-stimulant seemed significantly more efficacious than placebo. Behavioural therapy in combination with stimulants seemed superior to stimulants or non-stimulants. Stimulants seemed superior to behavioural therapy, cognitive training and non-stimulants. Behavioural therapy, stimulants and their combination showed the best profile of acceptability. Stimulants and non-stimulants seemed well tolerated. Among medications, methylphenidate, amphetamine, atomoxetine, guanfacine and clonidine seemed significantly more efficacious than placebo. Methylphenidate and amphetamine seemed more efficacious than atomoxetine and guanfacine. Methylphenidate and clonidine seemed better accepted than placebo and atomoxetine. Most of the efficacious pharmacological treatments were associated with harms (anorexia, weight loss and insomnia), but an increased risk of serious adverse events was not observed. There is lack of evidence for cognitive training, neurofeedback, antidepressants, antipsychotics, dietary therapy, fatty acids, and other complementary and alternative medicine. Overall findings were limited by the clinical and methodological heterogeneity, small sample sizes of trials, short-term follow-up, and the absence of high-quality evidence; consequently, results should be interpreted with caution. CONCLUSIONS: Clinical differences may exist between the pharmacological and non-pharmacological treatment used for the management of ADHD. Uncertainties about therapies and the balance between benefits, costs and potential harms should be considered before starting treatment. There is an urgent need for high-quality randomised trials of the multiple treatments for ADHD in children and adolescents. PROSPERO, number CRD42014015008

Myopericarditis Associated with the Novavax COVID-19 Vaccine (NVX-CoV2373): A Retrospective Analysis of Individual Case Safety Reports from VigiBase

Abstract Background Myocarditis and pericarditis have been associated most notably with mRNA vaccines, but the association with a recently authorized adjuvated vaccine (NVX-CoV2373) is controversial. Objective The aim was to analyze the cases of myocarditis and pericarditis in association with NVX-CoV2373 reported to the World Health Organization (WHO) global database of individual case safety reports (ICSRs) for drug monitoring (VigiBase), applying disproportionality analyses. Patients and methods The main characteristics of the ICSRs reporting myopericarditis with NVX-CoV2373 have been summarized. Reporting odds ratios (RORs) as a measure of disproportionality for reported myopericarditis (November 1967–August 2022) have been calculated for NVX-CoV2373; mRNA and adenoviral vector-based vaccines were also included as a reference. Results In total, 61 ICSRs included NVX-CoV2373. Most of the reports originated in Australia (50; 82.0%); 24 (39.3%) were considered serious. None of them were fatal. The median age of individuals was 35.5 years old, and most were males (38; 62.3%). Chest pain was the most common co-reported event 43 (70.5%). The median induction period was 3 days after immunization. Increased disproportionality for myopericarditis was found for NVX-CoV2373 (ROR 14.47, 95% confidence interval [CI] 11.22–18.67) and mRNA vaccines: BNT162b2 (ROR 17.15, 95% CI 16.88–17.42) and mRNA-1273 (ROR 6.92, 95% CI 6.77–7.08). Higher values were found in males. The adenoviral vector-based vaccine Ad26.COV2.S showed slightly increased disproportionality (ROR 1.83, 95% CI 1.70–1.98), whereas no increased disproportionality was found for ChAdOx1. Conclusions NVX-CoV2373 vaccine showed a similar increased disproportionality as mRNA vaccines. More evidence from controlled studies is necessary; however, a precautionary approach is warranted. Healthcare professionals should be aware of the potential occurrence of myopericarditis with this new vaccine

Perspectiva futura de la farmacoepidemiología en la era del "Big data" y la expansión de las fuentes de información

ABSTRACT The arrival of new drug into the market requires many years of previous research along with the need of continuous evaluation throughout the lifetime of the drug. This warrants pharmacoepidemiological research which may be defined as the study of the use and the effects of drugs in large populations. Nowadays, this type of research seems more feasible thanks to the massive expansion of the information sources and data (e.g: clinical patient registries, electronic medical records). However, there is a risk of information overload, fragmented evidence and given the enthusiasm aroused by the "Big Data", it must be emphasized that its nature is mainly observational, and therefore subject to bias and confusion. The application of epidemiological methods in this scenario seems essential for any analysis. In short, the management and use of these data sources to generate useful information expansion is the next challenge for the application of research methods in modern pharmacoepidemiology.RESUMEN La llegada de nuevos medicamentos al mercado exige muchos años de investigación previa junto con la evaluación continua de sus resultados durante toda la vida del medicamento. Ello justifica la necesidad de la investigación farmacoepidemiológica, entendida como el estudio del uso y los efectos de los medicamentos en grandes poblaciones. En la actualidad, este tipo de investigación parece más factible que nunca, habida cuenta de la expansión que han experimentado de las fuentes de información por la incorporación masiva de datos, (por ejemplo, registros clínicos de pacientes o historia clínica electrónica). No obstante, ante el entusiasmo que suscita el "Big Data", se debe tener en cuenta el riesgo de sobreinformación, de evidencia fragmentada y que su naturaleza mayoritariamente observacional está sujeta a sesgos y confusión. La utilización de los métodos epidemiológicos en este escenario se antoja fundamental para su análisis. En definitiva, el manejo y aprovechamiento de estas fuentes de información en expansión para generar información útil constituye el próximo desafío para la aplicación de los métodos de investigación en la farmacoepidemiología moderna

Evolución del uso de medicamentos ansiolíticos e hipnóticos en España durante el período 2000-2011

Background: For years, anxiolytics and hypnotics have been one of the most prescribed drug classes in most developed countries. The main aim of this study is to explore the pattern of use of anxiolytic and hypnotic drugs during the period 2000-2011, comparing their growth with that of five european countries. Method: We performed an ecological and descriptive study of anxiolytics and hypnotics consumption in Spain. Consumption data were obtained from the databases of medications dispensed in community pharmacies and charged through official prescriptions to the totality of the Spanish National Health System. Annual and total-period consumptions were expressed in defined daily doses (DDD) per 1000 inhabitants per day (DDD/1000 person/day) by each treatment subgroup, active substance and attending the plasma half-life of the medication. Approximate comparisons were also made with some European countries. Results: The use of anxiolytics and hypnotics drugs was 56.7 DDD/1000 person/day in 2000 and 82.9 DDD/1000 person/day in 2011 (a +46.1% increase across the period). Lorazepam and alprazolam were the most used anxiolytics (20.5 and 15.6 DDD/1000 person/day in 2011, respectively), whereas lormetazepam was among the hypnotics (18.3 DDD/1000 person/day in 2011). In relative terms, hypnotics´ lormetazepam and zolpidem increased their use by 103.3% and 85.1%, respectively; while anxiolytics´ lorazepam and hydroxyzine increased 75.1% and 72.8%, respectively. In Spain (period 2003-2010), the total increase in the consumption of anxiolytics and hypnotics was +34.3%, with 24.0% for Portugal, 4.0% for Italy, but a reduction of -6.1% for France. Conclusions: A considerable increase in anxiolytics and hypnotics´ consumption has occurred in Spain during the last decade, being the growth higher than that reported in other European countries.Fundamentos: Los ansiolíticos y los hipnóticos han sido durante años uno de los grupos farmacológicos más prescritos en la mayoría de países desarrollados. El objetivo principal del presente trabajo fue explorar el patrón de uso de ansiolíticos e hipnóticos en España durante el período 2000-2011 y comparar su incremento con el de cinco países europeos. Método: Estudio ecológico descriptivo del consumo en España a partir de datos de medicamentos dispensados en oficina de farmacia y facturados a través de receta oficial con cargo al Sistema Nacional de Salud. El consumo anual y total se expresó en dosis diarias definidas por 1.000 habitantes y día (DDD/1.000 hab/día) en cada subgrupo terapéutico, principio activo y atendiendo a la semivida plasmática. También se establecieron comparaciones aproximativas con otros países. Resultados: El uso de ansiolíticos e hipnóticos fue de 56,7 DDD/1.000 hab/día en el año 2000 y 82,9 DDD/1.000 hab/día en el año 2011 (incremento del 46,1% en el período). Lorazepam y alprazolam fueron los ansiolíticos más consumidos (20,5 y 15,6 DDD/1.000 hab/día en 2011, respectivamente), mientras que lormetazepam lo fue del grupo de los hipnóticos (18,3 DDD/1.000 hab./día en 2011). En términos relativos, lormetazepam y zolpidem fueron los hipnóticos que más incrementaron su uso (103,3% y 85,1%, respectivamente) mientras que lorazepam e hidroxicina lo fueron entre los ansiolíticos (75,1% y 72,8%, respectivamente). En España (período 2003-2010), el incremento total en el consumo de ansiolíticos e hipnóticos fue de +34,3%, siendo del +24,0% para Portugal, +4,0% para Italia y -6,1% para Francia. Conclusiones: Durante el período estudiado, el consumo de ansiolíticos e hipnóticos se incrementó en España, siendo el incremento superior incluso al reportado en otros países europeos