Factors associated to the presence of headache in patients with influenza infection and its consequences: a 2010-2020 surveillance-based study.

Headache is a common symptom of influenza infection; however, its causes and consequences remain uncertain. In this manuscript, we analyzed which demographic and clinical factors were associated with the presence of headache during the course of influenza infection and whether patients with headache had a different prognosis, evaluated by need of hospitalization, sick leave or school absenteeism. The influence study (NCT05704335) was an observational study that analyzed data routinely collected from the Health Sentinel Network between 2010 and 2020. During the study period, 7832 cases were considered, among which, 5275 (67.4%) reported headache. The presence of headache was independently associated with myalgia (2.753; 95%CI: 2.456-3.087, P < 0.001), asthenia (OR: 1.958; 95%CI: 1.732-2.214, P < 0.001), shivering (OR: 1.925; 95%CI: 1.718-2.156, P < 0.001), nasopharyngeal erythema (OR: 1.505; 95%CI: 1.293-1.753, P < 0.001), fever (OR: 1.469; 95%CI: 1.159-1.861; P = 0.001), sudden onset of symptoms (OR: 1.380; 95%CI: 1.120-1.702, p = 0.004), female sex (OR: 1.134; 95%CI: 1.023-1.257, P = 0.018), and gastrointestinal symptoms (OR: 1.169; 95%CI: 1.039-1.315; P = 0.01). Patients with headache had a sex and age adjusted lower odds of being referred to the hospital (OR: 0.463; 95%CI: 0.264-0.812, P = 0.007) and a higher odd of having a sick leave and/or school absenteeism (absenteeism (OR: 1.342; 95%CI: 1.190-1.514, P < 0.001). In conclusion, the presence of headache seems associated with symptoms caused by the innate immune response. These findings support a headache pathophysiology linked with the innate immune response. Due to the potential negative consequences and its treatable nature, clinicians should systematically evaluate it and, whenever necessary, treat it too.

Description of maternal and neonatal adverse events in pregnant people immunised with COVID-19 vaccines during pregnancy in the CLAP NETWORK of sentinel sites. Nested case-control analysis of the immunization-associated risk: A study protocol.

INTRODUCTION: COVID-19 is associated with higher morbimortality in pregnant people compared with non-pregnant people. At present, the benefits of maternal immunisation are considered to outweigh the risks, and therefore, vaccination is recommended during pregnancy. However, additional information is needed on the safety of the vaccines in this population. METHODS AND ANALYSIS: This a retrospective cohort nested case-control study in pregnant people who attended maternity hospitals from eight Latin American and Caribbean countries. A perinatal electronic clinical history database with neonatal and obstetric information will be used. The proportion of pregnant people immunised with COVID-19 vaccines of the following maternal and neonatal events will be described: preterm infant, small for gestational age, low birth weight, stillbirth, neonatal death, congenital malformations, maternal near miss and maternal death. Moreover, the risk of prematurity, small for gestational age and low birth weight associated with exposure to COVID-19 vaccines will be estimated. Each case will be matched with two groups of three randomly selected controls. Controls will be matched by hospital and mother's age (±3 years) with an additional matching by delivery date and conception time in the first and second control groups, respectively. The estimated required sample size for the main analysis (exposure to any vaccine) concerning 'non-use' is at least 1009 cases (3027 controls) to detect an increased probability of vaccine-associated event risk of 30% and at least 650 cases (1950 controls) to detect 30% protection. Sensitivity and secondary analyses considering country, type of vaccine, exposure windows and completeness of immunisation will be reported. ETHICS: The study protocol was reviewed by the Ethical Review Committee on Research of the Pan American Health Organization. Patient informed consent was waived due to the retrospective design and the utilisation of anonymised data (Ref. No: PAHOERC.0546.01). Results will be disseminated in open access journals.

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

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.

Barriers of Access to Opioid Medicines within the Context of Palliative Care in Latin America: The Perception of Health Professionals.

Background: Different sets of barriers have been identified to explain the difficulties in the access and availability of opioid analgesics in palliative care, particularly in low- and middle-income countries, including Latin America. Objective: To validate a structured questionnaire for the access to opioid medicines and to investigate the perception of health professionals regarding access barriers to opioid analgesics in 17 countries of the Latin American Region. Design: Survey to identify the domains and barriers of access to opioid medicines according to health professionals, including physicians, nurses, and pharmacists affiliated to institutions that provide palliative care in Latin America between August 2019 and October 2020. Results: We analyzed responses from 426 health professionals. The median age was 44 years old (ranging from 23 to 73 years) with an average experience in palliative care of 10 years (range: 1-35), 71.8% were women, and 49.8% were affiliated to specialized health care facilities of urban areas (94.6%). The main barriers perceived to be extremely relevant by the respondents were "belief that patients can develop addiction" and "financial limitations of patients" for the patient's domain and the "appropriate education, instruction, and training of professionals" for health professional's domain. Conclusions: It is necessary to develop strategies to strengthen less-developed health systems of the region to review legal frameworks, ensure integrated palliative care systems, and deploy multidisciplinary strategies for sensitizing, training, and raising the awareness of patients, caregivers and, particularly, health professionals regarding appropriate prescription and rational use of opioid analgesics.

MICEmi: A method to identify cognitive endophenotypes of mental illnesses.

BACKGROUND: Characterizing neurocognitive endophenotypes of mental illnesses (MIs) could be useful for identifying at-risk individuals, increasing early diagnosis, improving disease subtyping, and proposing therapeutic strategies to reduce the negative effects of the symptoms, in addition to serving as a scientific basis to unravel the physiopathology of the disease. However, a standardized algorithm to determine cognitive endophenotypes has not yet been developed. The main objective of this study was to present a method for the identification of endophenotypes in MI research. METHODS: For this purpose, a 14-expert working group used a scoping review methodology and designed a method that includes a scoring template with five criteria and indicators, a strategy for their verification, and a decision tree. CONCLUSIONS: This work is ongoing since it is necessary to obtain external validation of the applicability of the method in future research.

Mortality in Persons With Autism Spectrum Disorder or Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-analysis.

IMPORTANCE: Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are childhood-onset disorders that may persist into adulthood. Several studies have suggested that they may be associated with an increased risk of mortality; however, the results are inconsistent. OBJECTIVE: To assess the risk of mortality among persons with ASD or ADHD and their first-degree relatives. DATA SOURCES: A search of MEDLINE, Embase, Scopus, Web of Science, and PsycINFO (published from inception to April 1, 2021) was supplemented by searching reference lists of the retrieved articles. STUDY SELECTION: Cohort and case-control studies that reported mortality rate ratios (RRs) in persons with ASD or ADHD and/or their first-degree relatives compared with the general population or those without ASD/ADHD were included. DATA EXTRACTION AND SYNTHESIS: Screening, data extraction, and quality assessment were performed by at least 2 researchers independently. A random-effects model was used to meta-analyze individual studies and assessed heterogeneity (I2). MAIN OUTCOMES AND MEASURES: All-cause mortality in association with ASD or ADHD. Secondary outcome was cause-specific mortality. RESULTS: Twenty-seven studies were included, with a total of 642 260 individuals. All-cause mortality was found to be higher for persons with ASD (154 238 participants; 12 studies; RR, 2.37; 95% CI, 1.97-2.85; I2, 89%; moderate confidence) and persons with ADHD (396 488 participants; 8 studies; RR, 2.13; 95% CI, 1.13-4.02; I2, 98%; low confidence) than for the general population. Among persons with ASD, deaths from natural causes (4 studies; RR, 3.80; 95% CI, 2.06-7.01; I2, 96%; low confidence) and deaths from unnatural causes were increased (6 studies; RR, 2.50; 95% CI, 1.49-4.18; I2, 95%; low confidence). Among persons with ADHD, deaths from natural causes were not significantly increased (4 studies; RR, 1.62; 95% CI, 0.89-2.96; I2, 88%; low confidence), but deaths from unnatural causes were higher than expected (10 studies; RR, 2.81; 95% CI, 1.73-4.55; I2, 92%; low confidence). CONCLUSIONS AND RELEVANCE: This systematic review and meta-analysis found that ASD and ADHD are associated with a significantly increased risk of mortality. Understanding the mechanisms of these associations may lead to targeted strategies to prevent avoidable deaths in high-risk groups. The substantial heterogeneity between studies should be explored further.

Strengthening therapeutic adherence and pharmacovigilance to antimalarial treatment in Manaus, Brazil: a multicomponent strategy using mHealth.

BACKGROUND: Public health initiatives for improving adherence to primaquine based regimens and enhancing effective pharmacovigilance are needed to support the efforts for malaria elimination in real world conditions. METHODS: A multicomponent patient-oriented strategy using a Smart Safety Surveillance (3S) approach including: (1) educational materials for treatment counselling and identification of warning symptoms of haemolytic anaemia; (2) an mHealth component using Short Message Service (SMS) treatment reminders and (3) development and implementation of follow-up phone surveys three days after treatment completion, using a web-based platform linked to the local information system of malaria. Adherence was measured using the Morisky Medication Adherence Scale. Self-reported events were registered using a structured questionnaire and communicated to the Brazilian Health Regulatory Agency. RESULTS: Educational materials were disseminated to 5594 patients, of whom 1512 voluntarily entered the mHealth component through the local information system; 7323 SMS were sent, and 1062 participants completed a follow-up survey after treatment. The mean age of patients was 37.36 years (SD 13.65), 61.24% were male, 98.54% were infected with. Plasmodium vivax and 95.90% received a short regimen of chloroquine plus primaquine (CQ + PQ 7 days), as per malaria case management guidelines in Brazil. From the 1062 surveyed participants 93.31% were considered adherent to the treatment. Most of the patients (95.20%) reported at least one adverse event. Headache, lack of appetite and nausea/vomiting were the most frequently reported adverse events by 77.31%, 70.90% and 56.78% of the patients respectively. A quarter of the patients reported anxiety or depression symptoms; 57 (5.37%) patients reported 5 to 6 warning symptoms of haemolytic anaemia including jaundice and dark urine in 44 (4.14%). Overall, three patients presenting symptoms of haemolytic anaemia attended a hospital and were diagnosed with G6PD deficiency, and one had haemolysis. All of them recovered. CONCLUSIONS: Under real world conditions, a multicomponent patient-oriented strategy using information and communication technologies allowed health care providers to reinforce treatment adherence and enhance safety surveillance of adverse events associated with regimens using primaquine. Active monitoring through phone surveys also reduced under-reporting of ADRs. This approach is low-cost, scalable and able to support prioritized activities of the national malaria programme.

Smart Safety Surveillance (3S): Multi-Country Experience of Implementing the 3S Concepts and Principles.

INTRODUCTION: The Smart Safety Surveillance (3S) concept is based on the understanding that, when faced with competing pharmacovigilance priorities, countries will have to invest judiciously, by focusing on new priority products, sharing work and resources with other countries when possible and building national competence for those activities that cannot be delegated. METHOD: The 3S principles were applied to Armenia, Brazil, Ethiopia, India, Peru and Thailand using three priority products: bedaquiline, rotavirus vaccine and tafenoquine. A baseline assessment of pharmacovigilance preparedness was used to identify gaps and establish a work plan. The impact was measured by comparing pre and post 3S-intervention outcomes, which included the number and quality of reports (completeness scores) in the WHO global database of Individual Case Safety Reports, VigiBase, and number of structural indicators met. The implementation period was 9-18 months, ranging from March 2018 (earliest started) until May 2020 (latest). RESULT: An increase in adverse drug reaction (ADR) reporting was demonstrated in Armenia (bedaquiline), Brazil (TB and malaria medicines), India (rotavirus vaccine) and Ethiopia (TB medicines). Completeness scores were above 0.5 at baseline in all countries, and reports improved in quality for Brazil (TB), Peru (malaria), Thailand (malaria) and India (immunization). The number of structural indicators met increased by more than double for Ethiopia. Ethiopia and India demonstrated an increased capacity for signal detection and signal evaluation. Armenia, Brazil, Peru and Thailand showed increased capacity to assess risk management plans following the implementation of 3S principles. CONCLUSION: The 3S concept has demonstrated success in different ways across the six countries. Activities focused on three products for a proof of concept of the 3S principles, with the expectation that the project impact will be sustained through strengthened systems, to guide pharmacovigilance activities of other products in the future. It is important to continue monitoring the countries to understand if the gains and successes of the current 3S project are sustainable.

Adverse events associated with the use of recommended vaccines during pregnancy: An overview of systematic reviews.

INTRODUCTION: Maternal immunization is aimed at reducing morbidity and mortality in pregnant women and their newborns. Updated evidence synthesis of maternal-fetal outcomes is constantly needed to ensure that the risk-benefit of vaccination during pregnancy remains positive. METHODS: An overview of systematic reviews (OoSRs) was performed. We searched The Cochrane Library, MEDLINE and EMBASE for SRs including recommended vaccines for maternal immunization reporting the following: abortion, stillbirth, chorioamnionitis, congenital anomalies, microcephaly, neonatal death, neonatal infection, preterm birth (PTB), low birth weight (LBW), maternal death and small for gestational age (SGA) from 2010 to April 2019. Quality and overlap of SRs was assessed. RESULTS: Seventeen SRs were identified, eight of them included meta-analysis; quality was high in three SRs, moderate in six SRs, low in two SRs, and critically low in six SRs. Stillbirth and PTB were the most frequently reported outcomes by 15 and 13 SRs, respectively, followed by abortion (9 SRs), congenital anomalies (9 SRs), SGA (8 SRs), neonatal death (8 SRs), LBW (4 SRs), chorioamnionitis (3 SRs), maternal death (1 SR). SRs included mainly observational evidence for influenza and Tdap vaccines (11 SRs and 4 SRs, respectively); limited evidence was found for hepatitis (1 SR), yellow fever (1 SR), and meningococcal (1 SR) vaccines. Most of the SRs found no effect. Eight SRs found benefit/protection of influenza vaccine (for stillbirth, neonatal death, preterm birth, LBW), or Tdap vaccine (for preterm birth and SGA); one found a probable risk (chorioamnionitis/Tdap). The SRs for Hepatitis B, meningococcal and yellow fever vaccines were inconclusive. CONCLUSIONS: Definite risks were not identified for any vaccine and outcome; however better evidence is needed for all outcomes and vaccines. The available evidence in the SRs to support vaccine safety was based mainly on observational data. More RCTs with adequate reporting of maternal-fetal outcomes and larger high-quality observational studies are needed.

Cataracts and statins. A disproportionality analysis using data from VigiBase.

The basis of the association between statin use and cataract has been explored using the World Health Organization (WHO) global database of individual case safety reports (ICSRs) for drug monitoring (VigiBase) through January 2019. The reporting odds ratios (RORs) as a measure of disproportionality for reported cataracts and individual statins have been calculated. Subgroup analyses according statin lipophilicity, sex, and age groups have been performed. Moreover, RORs have been calculated for non-statin lipid lowering drugs. An increased disproportionality have been found for most individual statins lovastatin: [ROR: 14.80, 95% confidence interval (CI): 13.30, 16.46)], atorvastatin (ROR: 3.48, 95% CI 3.19-3.80), pravastatin (ROR: 3.15, 95% CI: 2.54-3.90), rosuvastatin (ROR: 2.90, 95% CI: 2.53-3.31), simvastatin (ROR: 2.27, 95%CI: 1.99-2.60), fluvastatin (ROR: 2.03, 95% CI: 1.33-3.08) and statins (overall) ROR: 3.66, 95% CI:3.46-3.86). Increased disproportionality for cataract and statins (drug-class) have been found regardless of statin lipophilicity, sex and group age (more or less than 65 years old). No disproportionality was found for other lipid-lowering drugs (ezetimibe, fibrates or PCSK9 inhibitors). These findings suggest an increased risk of cataract associated with statins as a drug-class. Further studies to characterize the risk are advised. Benefits and potential harms should be considered before starting treatment with statins.

Association of Anorexia Nervosa With Risk of Cancer: A Systematic Review and Meta-analysis.

Importance: Anorexia nervosa is recognized as an important cause of morbidity in young people. However, the risk of cancer in people with anorexia nervosa remains uncertain. Objective: To evaluate the association of anorexia nervosa with the risk of developing or dying of cancer. Data Sources: MEDLINE, Scopus, Embase, and Web of Science from database inception to January 9, 2019. Study Selection: Published observational studies in humans examining the risk of cancer in people with anorexia nervosa compared with the general population or those without anorexia nervosa. Studies needed to report incidence or mortality rate ratios (RRs). Data Extraction and Synthesis: Screening, data extraction, and methodological quality assessment were performed by at least 2 researchers independently. A random-effects model was used to synthesize individual studies. Heterogeneity (I2) was assessed and 95% prediction intervals (PIs) were calculated. Main Outcomes and Measures: All cancer incidence and cancer mortality associated with anorexia nervosa. Secondary outcomes were site-specific cancer incidence and mortality. Results: Seven cohort studies published in 10 articles (42 602 participants with anorexia nervosa) were included. Anorexia nervosa was not associated with risk of developing any cancer (4 studies in women; RR, 0.97; 95% CI, 0.89-1.06; P = .53; I2, 0%; 95% PI, 0.80-1.18; moderate confidence). Anorexia nervosa was associated with decreased breast cancer incidence (5 studies in women; RR, 0.60; 95% CI, 0.50-0.80; P < .001; I2, 0%; 95% PI, 0.44-0.83; high confidence). Conversely, anorexia nervosa was associated with increased risk of developing lung cancer (3 studies in women; RR, 1.50; 95% CI, 1.06-2.12; P = .001; I2, 0%; 95% PI, 0.19-16.46; low confidence) and esophageal cancer (2 studies in women; RR, 6.10; 95% CI, 2.30-16.18; P < .001; I2, 0%; low confidence). Conclusions and Relevance: Among people with anorexia nervosa, risk of developing cancer did not differ compared with the general population, but a significantly reduced risk of breast cancer was observed. Understanding the mechanisms underlying these associations could have important preventive potential.

Trends in attention-deficit hyperactivity disorder medication use: a retrospective observational study using population-based databases.

BACKGROUND: The use of medications to treat attention deficit hyperactivity disorder (ADHD) has increased, but the prevalence of ADHD medication use across different world regions is not known. Our objective was to determine regional and national prevalences of ADHD medication use in children and adults, with a specific focus on time trends in ADHD medication prevalence. METHODS: We did a retrospective, observational study using population-based databases from 13 countries and one Special Administrative Region (SAR): four in Asia and Australia, two in North America, five in northern Europe, and three in western Europe. We used a common protocol approach to define study populations and parameters similarly across countries and the SAR. Study populations consisted of all individuals aged 3 years or older between Jan 1, 2001, and Dec 31, 2015 (dependent on data availability). We estimated annual prevalence of ADHD medication use with 95% CI during the study period, by country and region and stratified by age and sex. We reported annual absolute and relative percentage changes to describe time trends. FINDINGS: 154·5 million individuals were included in the study. ADHD medication use prevalence in 2010 (in children aged 3-18 years) varied between 0·27% and 6·69% in the countries and SAR assessed (0·95% in Asia and Australia, 4·48% in North America, 1·95% in northern Europe, and 0·70% in western Europe). The prevalence of ADHD medication use among children increased over time in all countries and regions, and the absolute increase per year ranged from 0·02% to 0·26%. Among adults aged 19 years or older, the prevalence of any ADHD medication use in 2010 varied between 0·003% and 1·48% (0·05% in Asia and Australia, 1·42% in North America, 0·47% in northern Europe, and 0·03% in western Europe). The absolute increase in ADHD medication use prevalence per year ranged from 0·0006% to 0·12%. Methylphenidate was the most commonly used ADHD medication in most countries. INTERPRETATION: Using a common protocol and data from 13 countries and one SAR, these results show increases over time but large variations in ADHD medication use in multiple regions. The recommendations of evidence-based guidelines need to be followed consistently in clinical practice. Further research is warranted to describe the safety and effectiveness of ADHD medication in the short and long term, and to inform evidence-based guidelines, particularly in adults. FUNDING: None.

Trazodone utilization among the elderly in Spain. A population based study.

INTRODUCTION: Trazodone was authorized for the treatment of depression in the 1970s. Several additional therapeutic uses have been proposed due to its heterogeneous mechanism. This study aims to determine the use of trazodone in the elderly in Spain. METHODS: A nationwide, longitudinal and descriptive analysis was conducted using data from patients aged >65 years with a first prescription of trazodone during the period 2002-2011. Information on dose, comorbidities and relevant co-medication was gathered from the Spanish Primary Care database BIFAP. Incidence rates of trazodone use per 10,000 person-years were calculated by sex and age. RESULTS: A total of 11,766 patients receiving a first prescription of trazodone were included. The incidence rate of trazodone use was 47.2 (95% CI: 46.33-48.04) per 10,000 person-years. An increasing trend in the use of trazodone was observed (5-fold increase in 2011 as compared to 2002). The most common therapeutic indications were: depression (21.41%), Alzheimer/dementia (20.36%), sleep disorders (16.22%), and anxiety disorder (8.91%). The median dose was 100mg/day. The use of trazodone concomitantly with interacting medicines was frequent: anti-hypertensives (53.60%), and CNS depressors (59.32%). CONCLUSIONS: Trazodone use is increasing in elderly patients, and a high proportion of use in non-approved indications was observed. Trazodone is not being used at high doses, but interacting medicines were frequent, and it may pose additional risks for elderly patients.

Risk of mortality among children, adolescents, and adults with autism spectrum disorder or attention deficit hyperactivity disorder and their first-degree relatives: a protocol for a systematic review and meta-analysis of observational studies.

BACKGROUND: Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are childhood onset neurodevelopmental disorders that may persist into adulthood. ASD and ADHD tend to run in families and may have a significant negative impact on the health and longevity of those with the disorder and their relatives. The aim of this study will be to analyze the risk of mortality among children, adolescents, and adults with ASD or ADHD and their first-degree relatives. METHODS/DESIGN: We will conduct a systematic review and meta-analysis of observational studies. Searches of PubMed/MEDLINE, EMBASE, PsycINFO, SCOPUS, and ISI Web of Science will be used to identify epidemiological studies. Eligible studies will be observational studies reporting study-specific data for all-cause mortality or cause-specific mortality in children, adolescents, or adults with ASD or ADHD and/or their first-degree relatives. Cohort studies and case-control studies will be included. The primary outcome will be all-cause mortality. The secondary outcome will be cause-specific mortality. 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 risk of bias/methodological quality will be appraised by two reviewers independently. The methodological quality of epidemiological studies will be appraised using the Newcastle-Ottawa Scale (NOS). Conflicts at all levels of screening and abstraction will be resolved through discussion. Random-effects meta-analyses of primary studies will be conducted where appropriate. Subgroup analyses for exploring statistical heterogeneity, if feasible, will include gender, age group, ethnicity, comorbidities, classification of cause of death, and relevant study characteristics. DISCUSSION: Our study will establish the extent of the epidemiological evidence underlying the risk of mortality among children, adolescents, and adults with ASD or ADHD and their first-degree relatives. We anticipate that our findings will be of interest to patients, their families, caregivers, healthcare professionals, scientists, and policy makers. Implications for future epidemiological research will be discussed. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017059955 .

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.

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.

[Future Perspective of Pharmacoepidemiology in the "Big Data Era" and the Growth of Information Sources]. / Perspectiva futura de la farmacoepidemiología en la era del "Big data" y la expansión de las fuentes de información.

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.

[Utilization of hormone replacement therapy in Spain: Trends in the period 2000-2014]. / Uso del tratamiento hormonal sustitutivo en España: tendencias en el período 2000-2014.

BACKGROUND AND OBJECTIVE: The objective of the study was to describe the trends of utilization, supply and prevalence of hormone replacement therapy (HRT) in Spain during the period 2000-2014. METHODS: Annual prevalence of HRT use including the 95% CI was calculated for women aged≥40 using individual data from the national population-based database BIFAP. Annual and total-period consumptions were expressed in defined daily doses (DDD) per 1,000 inhabitants per day and were obtained from the databases of medications dispensed in community pharmacies and charged through official prescriptions to the Spanish National Health System. RESULTS: In the year 2000, overall HRT consumption was 33.12 DDDs/1000 inhabitans/day: 19.81 for oestrogen only, 6.88 for tibolone and 6.44 for combined oestrogen and progestagen. In 2014 overall HRT consumption was 5.32 DDDs/1000 inhabitans/day: 1.08 for oestrogen only, 1.61 for tibolone and 2.62 for combinations of oestrogen and progestagen. The marketed presentations of HRT decreased by 46.9%. Prevalence of HRT use in women aged≥40 in BIFAP was 7.19% (95% CI 6.97-7.40) in 2001 and 0.21% (95% CI 0.20-0.22) in 2014. Women aged 40-45 registered the highest prevalence of use in 2014: 0.71% (95% CI 0.66-0.76). CONCLUSIONS: A sharp decline in the consumption and prevalence of HRT has been observed in Spain since the publication of the Women's Health Initiative and Million Women Study and the regulatory measures taken restricting conditions of use, showing a similar trend to that of other western countries.

Cardiovascular and Renal Outcomes of Renin-Angiotensin System Blockade in Adult Patients with Diabetes Mellitus: A Systematic Review with Network Meta-Analyses.

BACKGROUND: 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. METHODS AND FINDINGS: Eligible trials were identified by electronic searches in PubMed/MEDLINE and the Cochrane Database of Systematic Reviews (1 January 2004 to 17 July 2014). Interventions of interest were angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and direct renin (DR) inhibitors. The primary endpoints were cardiovascular mortality, myocardial infarction, and stroke-singly and as a composite endpoint, major cardiovascular outcome-and end-stage renal disease [ESRD], doubling of serum creatinine, and all-cause mortality-singly and as a composite endpoint, progression of renal disease. Secondary endpoints were angina pectoris and hospitalization for heart failure. In all, 71 trials (103,120 participants), with a total of 14 different regimens, were pooled using network meta-analyses. When compared with ACE inhibitor, no other RAS blocker used in monotherapy and/or combination was associated with a significant reduction in major cardiovascular outcomes: ARB (odds ratio [OR] 1.02; 95% credible interval [CrI] 0.90-1.18), ACE inhibitor plus ARB (0.97; 95% CrI 0.79-1.19), DR inhibitor plus ACE inhibitor (1.32; 95% CrI 0.96-1.81), and DR inhibitor plus ARB (1.00; 95% CrI 0.73-1.38). For the risk of progression of renal disease, no significant differences were detected between ACE inhibitor and each of the remaining therapies: ARB (OR 1.10; 95% CrI 0.90-1.40), ACE inhibitor plus ARB (0.97; 95% CrI 0.72-1.29), DR inhibitor plus ACE inhibitor (0.99; 95% CrI 0.65-1.57), and DR inhibitor plus ARB (1.18; 95% CrI 0.78-1.84). No significant differences were showed between ACE inhibitors and ARBs with respect to all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, angina pectoris, hospitalization for heart failure, ESRD, or doubling serum creatinine. Findings were limited by the clinical and methodological heterogeneity of the included studies. Potential inconsistency was identified in network meta-analyses of stroke and angina pectoris, limiting the conclusiveness of findings for these single endpoints. CONCLUSIONS: In adults with diabetes, comparisons of different RAS blockers showed similar effects of ACE inhibitors and ARBs on major cardiovascular and renal outcomes. Compared with monotherapies, the combination of an ACE inhibitor and an ARB failed to provide significant benefits on major outcomes. Clinicians should discuss the balance between benefits, costs, and potential harms with individual diabetes patients before starting treatment. REVIEW REGISTRATION: PROSPERO CRD42014014404.