Risk of depression, suicide and psychosis with hydroxychloroquine treatment for rheumatoid arthritis: a multinational network cohort study.

OBJECTIVES: Concern has been raised in the rheumatology community regarding recent regulatory warnings that HCQ used in the coronavirus disease 2019 pandemic could cause acute psychiatric events. We aimed to study whether there is risk of incident depression, suicidal ideation or psychosis associated with HCQ as used for RA. METHODS: We performed a new-user cohort study using claims and electronic medical records from 10 sources and 3 countries (Germany, UK and USA). RA patients ≥18 years of age and initiating HCQ were compared with those initiating SSZ (active comparator) and followed up in the short (30 days) and long term (on treatment). Study outcomes included depression, suicide/suicidal ideation and hospitalization for psychosis. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate database-specific calibrated hazard ratios (HRs), with estimates pooled where I2 <40%. RESULTS: A total of 918 144 and 290 383 users of HCQ and SSZ, respectively, were included. No consistent risk of psychiatric events was observed with short-term HCQ (compared with SSZ) use, with meta-analytic HRs of 0.96 (95% CI 0.79, 1.16) for depression, 0.94 (95% CI 0.49, 1.77) for suicide/suicidal ideation and 1.03 (95% CI 0.66, 1.60) for psychosis. No consistent long-term risk was seen, with meta-analytic HRs of 0.94 (95% CI 0.71, 1.26) for depression, 0.77 (95% CI 0.56, 1.07) for suicide/suicidal ideation and 0.99 (95% CI 0.72, 1.35) for psychosis. CONCLUSION: HCQ as used to treat RA does not appear to increase the risk of depression, suicide/suicidal ideation or psychosis compared with SSZ. No effects were seen in the short or long term. Use at a higher dose or for different indications needs further investigation. TRIAL REGISTRATION: Registered with EU PAS (reference no. EUPAS34497; http://www.encepp.eu/encepp/viewResource.htm? id=34498). The full study protocol and analysis source code can be found at https://github.com/ohdsi-studies/Covid19EstimationHydroxychloroquine2.

Comparison of efficacy of extracorporeal magnetic innervation and Kegel exercises for stress urinary incontinence in adult women: study protocol for a randomized controlled trial.

Stress urinary incontinence (SUI) is defined as a complaint of inadvertent loss of urine occurring as a result of an increase in intraabdominal pressure. Strong evidence supports the use of pelvic floor muscle training (PFMT) as the first-line conservative treatment for SUI. Extracorporeal magnetic stimulation (EMS) is a non-invasive, effective, acceptable, and safe therapeutic modality for SUI. Although PFMT and EMS share most of their influences on the pathophysiology of SUI, it is unclear whether one of these routinely used treatment modalities is superior to another in terms of improvement of clinical outcomes or cost-effectiveness. To the best of our knowledge, no randomized controlled trials have so far directly compared PFMT with EMS. Our aim here is to describe a protocol for such a study. This will be a parallel-group, single-blind, randomised controlled trial compliant with the SPIRIT, CONSORT, and TIDieR reporting guidelines. Participants will be women aged 18 to 65 years who have previously given at least one vaginal delivery (at least 12 months before joining the study) who present with symptoms of SUI lasting at least 6 months yet have not previously received treatment for it. In the first study arm, patients will receive an eight-week, high-intensity, home-based Kegel exercises regimen. In the second study arm, the treatment scheme will consist of 2 sessions of EMS per week for a total of eight weeks. The primary outcome will be effectiveness of treatment as measured by the International Consultation on Incontinence Questionnaire Urinary Incontinence-Short Form overall score, eight weeks, three months, and six months after commencement of treatment.

Paving the way for personalised behaviourally based prevention of obesity: systematic search of the literature.

We have identified in the literature variants in 64 genes that may be involved in gene-obesity-behaviour interactions. Personalisation of behaviourally based preventive approaches against obesity seems feasible, however obesity genomics is still in the discovery phase of translational research and abundant replication studies are needed before these largely pioneering findings can be extended to practice and population impact. Automation of search algorithms and development of more efficient tools for knowledge synthesis of genomic research into gene-obesity-behaviour interactions might facilitate the advent of widely available personalised prevention approaches. Our future efforts shall therefore concentrate on developing such tools, as well as a research repository dedicated to the use of public health genomics for obesity control.

Five-year cumulative incidence of obesity in adults in Croatia: the CroHort study.

The objective of this paper was to evaluate the 5-year incidence of obesity on a sample of 3229 adults and investigate the potential effect of several sociodemographic and lifestyle habits on weight change and obesity incidence in these individuals. The average annual rate of increase in the prevalence of obese adults between 2003 and 2008 was 10.60% for men and 11.08% for women. Analysis showed that development of obesity in 5-year period in women in Croatia is significantly positively associated with frequent consumption of "hidden" fats of animal origin and significantly negative with each higher education level. No significant predictor of obesity has been found in men. Obesity remains a serious health problem for the Croatian population; the alarming rates of excess body weight continue to increase. Preventive measures should urgently be undertaken.

Prevalence and five-year cumulative incidence of abdominal obesity in Croatian women of childbearing age: the CroHort study.

Generalised obesity is increasing in prevalence globally, however trends in abdominal obesity are less well known. In 2003, 1,999 women of childbearing age participated in the Croatian Adult Health Survey, of whom 598 (29.9%) participated in the second cycle in 2008. For 2008, the prevalence of abdominal obesity using the International Diabetes Federation (IDF) criterion (waist circumference > or = 80 cm) was estimated at 70.3% (95% CI 61.8% to 75.7%), whereas the prevalence of abdominal obesity using the National Cholesterol Education Program, Adult Treatment Panel III (NCEP ATP III) criterion (waist circumference > or = 88 cm) was estimated at 48.6% (42.6% to 54.7%). The preceding five-year cumulative incidence was 54.3% (44.5% to 64.2%) and 35.2% (28.0% to 42.4%) using the IDF and NCEP ATP III criteria, respectively. The burden of abdominal obesity is high and rapidly increasing in Croatian women of childbearing age, the key population subgroup for obesity control.

Obesity--new threat to Croatian longevity.

The aim of this study was to examine the association of weight gain and life expectancy at birth in Croatia. Mean body mass index was based on the data from the Croatian Adult Health Survey 2003. Birth rate and mortality data needed for life expectancy calculation were supplied by the Central Bureau of Statistics. The results suggest that the increase in mean body mass index value (1.31 kg m(-2) for women and 1.41 kg m(-2) for men) will shorten life expectancy at birth for one year. Obesity, if unchecked, might have a negative effect on life expectancy in Croatia. Despite widespread knowledge about how to reduce the severity of the problem, observed trends in obesity in Croatia continue to worsen. These trends threaten to diminish the health and life expectancy of current and future generations.

Social conditioning of health behaviors among adults in Croatia: the CroHort study.

The aim of this study was to examine the social conditioning of health behaviors of adults in Croatia, based on the data from Croatian Adult Health Survey 2003. This cross-sectional study on a representative random sample of 9070 Croatian adults showed that obesity was significantly and socially conditioned in women, whereas for men the indication of social conditioning has not reached a statistically significant level. Health behaviors were socially conditioned in both sexes. Men's living habits were more irregular than those of women. Compared with women, men consumed more cured meat products, consumed alcohol excessivelly and smoked cigarettes more often, whereas they ate less fruits and vegetables. Health promotion strategies based on the behavioral correlates of overweight and obesity are needed to prevent excess weight gain in the Croatian population. While for men a unique educational model is applicable, women require more specialized programs, adapted to their social background.

Characteristics of people with the perceived stress in croatia: the CroHort study.

This study aimed to assess levels of stress in Croatian adult population using PSS, in a population study (Croatian Adult Cohort Health Study - CroHort). Our results show that the levels of stress were 17.46 (SD = 6.73) for men and 18.32 (SD = 6.46) for women in Croatia. The lowest levels of stress experienced men living in urban area while women living in rural area had the highest level. Men and women who had university degree had significantly lower level of stress. The lowest levels of stress experienced participants who had much better financial condition than average. In men, stress was associated to weak heart, lower back pain, poor financial condition of the household and high alcohol consumption. In women, stress was associated to poor mental health, poor social functioning, poorer financial condition of the household, higher age, lower education, low monthly income of the household and poor general health.

The CroHort study: cardiovascular behavioral risk factors in adults, school children and adolescents, hospitalized coronary heart disease patients, and cardio rehabilitation groups in Croatia.

Based on repeated measurement of health behaviors the CroHort Study showed that health behavior explains a great deal more of class inequalities in mortality than observed in previous studies. These include decreasing prevalence of smoking and increase in obesity, hypertension and diabetes mellitus. The lowest prevalence of health risks was recorded among children and adolescents, followed by general adult population from the CroHort Study. Hospitalized coronary heart disease patients had higher risks prevalence than general population, while the highest prevalence of risks was recorded among patients in cardiac rehabilitation program. The higher levels of stress were associated to lower financial conditions, poorer social functioning and poorer mental health for both men and women. Higher levels of stress were also associated with heart problems, higher alcohol consumption in men while in women stress was associated to poorer general health, higher age and lower levels of education.

[Visceral obesity]. / Visceralna debljina.

Some studies indicate that visceral obesity may be a better predictor of morbidity and mortality related to cardiovascular diseases and type 2 diabetes than general obesity measured by the body mass index. A causal relationship seems to exist between the accumulation of visceral fat and occurence of cardiovascular diseases and type 2 diabetes. Assessment of cardiometabolic risk comprises information on intra-abdominal obesity, as well as traditional risk factors. Visceral fat acts as a large endocrine gland, excreting cytokines and adipokines which leads to insulin resistance and proinflammatory state, whereas subcutaneous fat may act as a protective metabolic sink. Of anthropometric measures, waist circumference seems to best correlate with visceral fat.

Risk of hydroxychloroquine alone and in combination with azithromycin in the treatment of rheumatoid arthritis: a multinational, retrospective study.

BACKGROUND: Hydroxychloroquine, a drug commonly used in the treatment of rheumatoid arthritis, has received much negative publicity for adverse events associated with its authorisation for emergency use to treat patients with COVID-19 pneumonia. We studied the safety of hydroxychloroquine, alone and in combination with azithromycin, to determine the risk associated with its use in routine care in patients with rheumatoid arthritis. METHODS: In this multinational, retrospective study, new user cohort studies in patients with rheumatoid arthritis aged 18 years or older and initiating hydroxychloroquine were compared with those initiating sulfasalazine and followed up over 30 days, with 16 severe adverse events studied. Self-controlled case series were done to further establish safety in wider populations, and included all users of hydroxychloroquine regardless of rheumatoid arthritis status or indication. Separately, severe adverse events associated with hydroxychloroquine plus azithromycin (compared with hydroxychloroquine plus amoxicillin) were studied. Data comprised 14 sources of claims data or electronic medical records from Germany, Japan, the Netherlands, Spain, the UK, and the USA. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate calibrated hazard ratios (HRs) according to drug use. Estimates were pooled where the I 2 value was less than 0·4. FINDINGS: The study included 956 374 users of hydroxychloroquine, 310 350 users of sulfasalazine, 323 122 users of hydroxychloroquine plus azithromycin, and 351 956 users of hydroxychloroquine plus amoxicillin. No excess risk of severe adverse events was identified when 30-day hydroxychloroquine and sulfasalazine use were compared. Self-controlled case series confirmed these findings. However, long-term use of hydroxychloroquine appeared to be associated with increased cardiovascular mortality (calibrated HR 1·65 [95% CI 1·12-2·44]). Addition of azithromycin appeared to be associated with an increased risk of 30-day cardiovascular mortality (calibrated HR 2·19 [95% CI 1·22-3·95]), chest pain or angina (1·15 [1·05-1·26]), and heart failure (1·22 [1·02-1·45]). INTERPRETATION: Hydroxychloroquine treatment appears to have no increased risk in the short term among patients with rheumatoid arthritis, but in the long term it appears to be associated with excess cardiovascular mortality. The addition of azithromycin increases the risk of heart failure and cardiovascular mortality even in the short term. We call for careful consideration of the benefit-risk trade-off when counselling those on hydroxychloroquine treatment. FUNDING: National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, NIHR Senior Research Fellowship programme, US National Institutes of Health, US Department of Veterans Affairs, Janssen Research and Development, IQVIA, Korea Health Industry Development Institute through the Ministry of Health and Welfare Republic of Korea, Versus Arthritis, UK Medical Research Council Doctoral Training Partnership, Foundation Alfonso Martin Escudero, Innovation Fund Denmark, Novo Nordisk Foundation, Singapore Ministry of Health's National Medical Research Council Open Fund Large Collaborative Grant, VINCI, Innovative Medicines Initiative 2 Joint Undertaking, EU's Horizon 2020 research and innovation programme, and European Federation of Pharmaceutical Industries and Associations.

Single nucleotide polymorphisms and health behaviours related to obesity - trawling the evidence in the prospect of personalised prevention.

Efforts aimed at primary and secondary prevention of cardiovascular diseases, the major killer of contemporary adult populations, largely rely on modification of risk behaviours related to smoking, physical activity, dietary intake, and alcohol consumption, and also control of obesity and hypertension, the interim risk states between health and disease. We propose that the extent to which the gene x 'obesogenic' environment interaction depends on associations between particular single nucleotide polymorphisms (SNPs) and behavioural risk factors for overweight or obesity determines opportunities for novel, personalised preventive interventions. We systematically searched for SNPs that might be of interest for this postulate, and we present various SNPs that have been shown to be associated with overweight or obesity and behavioural risk factors for developing these traits, and thus hold promise for future design of personalised preventive interventions.

The prevalence of overweight, obesity and central obesity in six regions of Croatia: results from the Croatian Adult Health Survey.

Our aim was to estimate the prevalence of overweight, obesity and increased waist circumference in the adult population of Croatia and investigate regional differences in six regions of Croatia. Using the data from the 2003 Croatian Adult Health Survey we estimated the overall prevalence of overweight, obesity and increased waist circumference for the entire population of Croatia at 38.11%, 20.34% and 43.52%, respectively. For men, this was 43.2%, 20.1% and 34.98% and for women 33.6%, 20.6% and 51.13%, respectively for the three indicators of increased body weight. We found conflicting evidence as to whether the Mediterranean part of the country, compared with the continental part, bears a lesser degree of cardiovascular risk. Planners should pay particular attention to the Northern region, where the burden of increased body weight was the highest.

Health behavior factors associated with obesity in the adult population in Croatia.

The aim of this study was to examine the association of obesity and selected health behaviors, based on the data from Croatian Adult Health Survey 2003. Cross-sectional study on representative random sample of 9070 Croatian adults showed that in both men and women, mean BMI varied significantly with age (p < 0.001). It tended to increased with age until 55-64 years, and then decreased slightly in men, but remained unchanged in women. The prevalence of obesity (BMI > or = 30.0 kg m(-2)) demonstrated almost the same prevalence in men and women, 20.1% and 20.6% respectively. The likelihood of being obese, either in men or women, was more likely in the middle-aged groups, among respondents from rural areas and those from the Continental region of Croatia, with drinking lifestyle pattern, and non-smokers. Women who mostly used animal fat for food preparations were more likely to be obese. Overweight and obesity are major public health problem in the adult population in Croatia, and health promotion strategies based on behavioral correlates are needed to prevent excess weight gain in the Croatian population.

Primary and secondary prevention of cardiovascular diseases embedded in the visiting nurse services: description of the intervention model.

The paper describes a visiting nurse led intervention model for the primary and secondary prevention of cardiovascular diseases (CVD) and specificities of its application. Although CVD burden is high in Croatia, the visiting nurse services have not been specifically focused on CVD prevention in the population until now. The intervention model described here is being implemented alongside the second cycle of the Croatian Adult Health Survey (2008 CAHS). The model includes an objective evaluation of respondents' CVD risk factors through quantitative and qualitative analyses, as well as respondents' self-evaluation of risk factors and motivation to change. At the same time, respondents are educated and intervention is evaluated. A 'health booklet' was specifically designed for documentation during one year's follow-up, where both the user and the visiting nurse keep copies of the negotiated targets and strategies set to achieve them. This intervention model has the potential to mobilize the service towards permanent incorporation of primary and secondary CVD prevention into routine care and, due to work specificities of the visiting nurse services, to cover the entire population in an organized CVD prevention.

Regional pattern of cardiovascular risk burden in Croatia.

The objective of this study was to investigate regional gradient of a synthetic cardiovascular burden (CVRB) in Croatia. Analysis was based on a multistage stratified sample representative of general adult population in six regions of Croatia (Croatian Adult Health Survey). Synthetic CVRB was defined by incidents (heart attack, stroke), blood pressure, overweight/obesity (BMI, waist circumference), and risky behaviours (smoking, physical inactivity, high alcohol consumption, inadequate nutrition). Total CVRB in Croatia was 44.7% for men and 50.3% for women. Combining both high and moderate CVRB, men were found to be under more risk than women (72.8% vs. 61.7%, respectively). The result showed an east-north-west gradient in continental Croatia, with high CVRB in Eastern (40.2%) and Central region (44.3%), City of Zagreb (45.7%) and Northern region (53.1%). Mountainous region had the lowest prevalence of respondents with high CVRB (39.2%). Coastal region with the prevalence of 46.3% of high CVRB was nearly the same as the City of Zagreb. The results suggest the presence of substantial regional differences in the cardiovascular risk burden.

Using Simulation Modeling to Inform Policy Makers for Planning Physician Workforce in Healthcare System in Croatia.

The objective of this paper is to show how a simple but powerful simulation model can be build up using standard spreadsheet program and used to simulate future, needs and supply of physicians in order to inform policy makers at national level when deciding on enrollment to medical schools and immigration quotas for physicians. The Republic of Croatia is facing a serious shortage of physicians in the healthcare system and simulation results have shown that the gap between needs and supply will even increase if current enrollment qoutas to medical schools would persist. Increasing enrollment quotas, adjusting immigration policy, re-directing physicians from other professions to the healthcare system, task shift and skill mix options are just some of the measures needed to be taken promptly in order to prevent a huge deficit of physicians in the future. Simulation modeling is certainly a method for predicting changes within healthcare systems with a possibility to examine multiple different scenarios and suggest interventions.

Biomedical Informatics Workforce in Croatia: Qualitative Analysis of Teachers' Opinions on Needs and Employment Opportunities.

We report a qualitative analysis of higher education biomedical informatics (BMI) teachers' opinions on the needs for BMI workforce and employment opportunities in the Croatian health care system. Needs were perceived as considerable; however this was not coupled with adequate employment opportunities. Barriers were identified to correcting this imbalance, including the failure of the health care system planners to recognise BMI experts as an important part of the workforce and lack of adequate educational opportunities.

Educational Landscape of Biomedical Informatics in Croatia: Who Are the Teachers and What Are Their Attitudes.

Lack of experts with complementary competences in the field of information technology as well as medicine and health care has been recognised as an important obstacle to successful computerisation of the health care system. Using a questionnaire survey, we aimed to describe the current educational landscape of biomedical informatics in Croatia, focussing on teachers' profiles and attitudes about existing educational opportunities in the field. Our findings show that Croatian institutions of higher education should better recognise the need for education in biomedical informatics. Dedicated programs need to be established and teacher force strengthened. Joint efforts of existing teachers-institutionalised through a working group focussing on education within the Croatian Society for Medical Informatics, for which strong support exists-might contribute to recognition of the field and improvement of educational opportunities.