European survey on national training activities in clinical research.

BACKGROUND: Investigator-initiated clinical studies (IITs) are crucial to generate reliable evidence that answers questions of day-to-day clinical practice. Many challenges make IITs a complex endeavour, for example, IITs often need to be multinational in order to recruit a sufficient number of patients. Recent studies highlighted that well-trained study personnel are a major factor to conduct such complex IITs successfully. As of today, however, no overview of the European training activities, requirements and career options for clinical study personnel exists. METHODS: To fill this knowledge gap, a survey was performed in all 11 member and observer countries of the European Clinical Research Infrastructure Network (ECRIN), using a standardised questionnaire. Three rounds of data collection were performed to maximize completeness and comparability of the received answers. The survey aimed to describe the landscape of academic training opportunities, to facilitate the exchange of expertise and experience among countries and to identify new fields of action. RESULTS: The survey found that training for Good Clinical Practice (GCP) and investigator training is offered in all but one country. A specific training for study nurses or study coordinators is also either provided or planned in ten out of eleven countries. A majority of countries train in monitoring and clinical pharmacovigilance and offer specific training for principal investigators but only few countries also train operators of clinical research organisations (CRO) or provide training for methodology and quality management systems (QMS). Minimal requirements for study-specific functions cover GCP in ten countries. Only three countries issued no requirements or recommendations regarding the continuous training of study personnel. Yet, only four countries developed a national strategy for training in clinical research and the career options for clinical researchers are still limited in the majority of countries. CONCLUSIONS: There is a substantial and impressive investment in training and education of clinical research in the individual ECRIN countries. But so far, a systematic approach for (top-down) strategic and overarching considerations and cross-network exchange is missing. Exchange of available curricula and sets of core competencies between countries could be a starting point for improving the situation.

Psychosocial stress and major cardiovascular events in patients with stable coronary heart disease.

OBJECTIVES: Assess the risk of ischaemic events associated with psychosocial stress in patients with stable coronary heart disease (CHD). METHODS: Psychosocial stress was assessed by a questionnaire in 14 577 patients (median age 65.0, IQR 59, 71; 81.6% males) with stable CHD on optimal secondary preventive therapy in the prospective randomized STABILITY clinical trial. Adjusted Cox regression models were used to assess associations between individual stressors, baseline cardiovascular risk factors and outcomes. RESULTS: After 3.7 years of follow-up, depressive symptoms, loss of interest and financial stress were associated with increased risk (hazard ratio, 95% confidence interval) of CV death (1.21, 1.09-1.34; 1.15, 1.05-1.27; and 1.19, 1.08-1.30, respectively) and the primary composite end-point of CV death, nonfatal MI or nonfatal stroke (1.21, 1.13-1.30; 1.19, 1.11-1.27; and 1.17, 1.10-1.24, respectively). Living alone was related to higher risk of CV death (1.68, 1.38-2.05) and the primary composite end-point (1.28, 1.11-1.48), whereas being married as compared with being widowed, was associated with lower risk of CV death (0.64, 0.49-0.82) and the primary composite end-point (0.81, 0.67-0.97). CONCLUSIONS: Psychosocial stress, such as depressive symptoms, loss of interest, living alone and financial stress, were associated with increased CV mortality in patients with stable CHD despite optimal medical secondary prevention treatment. Secondary prevention of CHD should therefore focus also on psychosocial issues both in clinical management and in future clinical trials.

Seroprevalence of human Toxocara infections in the Roma and non-Roma populations of Eastern Slovakia: a cross-sectional study.

Socioeconomic conditions and health of the Roma population, the most numerous minority in Europe, are worse than that of the non-Roma population. Information about the occurrence of human toxocarosis and other parasitic diseases in the Roma population is scarce or completely missing. The aim of this study was to map the seroprevalence of toxocarosis in the population living in segregated Roma settlements and to compare the data with the occurrence of antibodies in the non-Roma population of Eastern Slovakia. The seropositivity to Toxocara in 429 examined Roma inhabitants of segregated settlements reached 22·1%, while only 4/394 samples of the non-Roma population were found to be positive (odds ratio 27·7, P < 0·0001). Headache, muscle pain, influenza-like symptoms and diarrhoea occurred significantly more often in seropositive persons than in seronegative individuals. In the Roma population positivity was not influenced by gender, level of education and poverty, but age, lack of sanitary facilities and heating with wood significantly increased the risk of infection. It can be assumed that besides the high prevalence of toxocarosis, other parasitic diseases and communicable diseases will also be more prevalent in the Roma population living in segregated settlements.

[Statin myopathy--rarity or reality?]. / Statínová myopatia--rarita, alebo realita?

Statins are the most effective drugs for reducing LDL-cholesterol and have strong evidence based medicine documented by significant reduction of cardiovascular events in wide variety of patients. Despite this fact, they are still underused in common clinical practice. Many physicians have expressed concern about potential adverse effects, particularly severe muscle toxicity, which is an impediment to appropriate statin use. The clinical symptoms of statin myopathy include myalgia or muscle weakness, tiredness, cramps and/or creatinkinase activity increases (CK). Because hypercholesterolaemia is usually asymptomatic, any unwanted effect of drug used for its management can undermine adherence. Therefore it is very important to evaluate myopathy magnitude, prompt and rational individual management, and if applicable, restart of lipid-lowering therapy as soon as possible with regard to its type, dose and concomitant treatment.

n-3 PUFAs-From dietary supplements to medicines.

Although there has been a great progress in the prevention of cardiovascular diseases, the mortality of patients with acute myocardial infarction (AMI) still remains high. One of the most important underlying causes explaining this phenomenon is the sudden cardiac death. Nearly half of all cardiovascular deaths in the USA each year is attributed to this unpredictable and unexpected complication of AMI. Hence, there is an urgent medical need for a targeted therapy to reduce the incidence of sudden cardiac death. Since 1980 there have been several epidemiological and other studies concerning the benefits of n-3 polyunsaturated fatty acids (n-3 PUFAs) in cardiovascular health and prevention. Results from one of the largest studies, GISSI Prevenzione Trial show that adding the n-3 PUFAs to standard therapy of patients who survived AMI reduces sudden cardiac death (44% risk reduction, p=0.0006). In addition, significant decline in all-cause cardiovascular mortality (21% risk reduction, p=0.0064) further emphasizes the role of n-3 PUFA in cardiovascular prevention. To date, beneficial effects of n-3 PUFA are attributed to their antiarrhythmic, lipid lowering, antithrombotic and anti-inflammatory properties. To conclude, EPA and DHA improve the prognosis of cardiovascular patients in the secondary prevention of sudden cardiac death without any documented side effects.

[Dynamic changes in the QT interval during the head-up tilt test in patients with vasovagal syncope]. / Dynamické zmeny QT intervalu pocas head-up tilt testu u pacientov s vazovagálnou synkopou.

Dynamic changes of the QT and QTc interval as well as QT dispersion and QTc dispersion during the head-up tilt test were investigated in 15 patients (8 men, mean age 32 years) with vasovagal syncope (VVS) and a positive head-up tilt test and in a control group of 15 patients with syncope in the case-history and a negative head-up tilt test (9 men, mean age 33 years). The value at rest of the QT interval did not differ in patients with VVS and controls. In controls at the beginning of HUT shortening of QT occurred (0.447 sec. vs. 0.419 sec. p = 0.0002), subsequently the QT did not change significantly. In patients with VVS during the beginning of the test only an insignificant shortening of QT occurred, while during the development of the syncope QT was prolonged (0.394 sec. vs. 0.420 sec. p < 0.0001). QT corrected for the pulse rate (QTc) did not change significantly during HUT. QTc dispersion was in patients with VVS significantly lower 3 minutes before the development of the syncope (0.067 sec. vs. 0.085 sec. p = 0.03), which may indicate the decline of the sympathetic and increase of the parasympathetic tonus which subsequently leads to the development of vasovagal syncope. QTc dispersion before the test was higher in patients with VVS as compared with controls (0.087 sec. vs. 0.063 sec., p = 0.03), which suggests an increase in the baseline sympathetic tonus in patients with VVS.

New insights into circadian aspects of health and disease.

Early awakening and early to bed as well as good conduct, thought, diet, interpersonal dealings and physical activity have been suggested for healthy life in Ayurveda. Circadian rhythms, coordinated in part by the parietal hypothalamic-pituitary and adrenal mechanisms, have been reported in almost all variables examined thus far, including the circulation. It is possible that all metabolic functions undergo circadian rhythms. It remains to be explored whether these rhythms may be optimized by Ayurvedic practices. The onsets of myocardial ischemia, unstable angina, acute myocardial infarction, sudden cardiac death, and strokes have been reported to exhibit a circadian variation, with increased frequency in the second quarter of the day. An increased physical and mental load caused by an attempt to prepare for the day may be important in triggering acute cardiovascular events. Depending on their timing, meditation (Ayurvedic practice), n-3 fatty acids, coenzyme Q10, beta-blockers and estrogens may have beneficial effects, whereas progestins and mental load may have adverse effects on heart rate and blood pressure variability, which may be expressed by different circadian patterns. Around the clock serial recordings of blood pressure and heart rate during usual activities and lifestyles may be recorded and may be analyzed by computer-implemented curve fitting to assess the about 24-hour (circadian) variation, among other rhythmic, chaotic, and trend components of the time structure (chronome) of these variables. The new disease risk syndrome circadian hyper-amplitude-tension (CHAT), a condition characterized by an excessive circadian amplitude of blood pressure, cannot be ascertained on the basis of single casual blood pressure measurements. The International Chronome Ecological Study of Heart Rate (and blood pressure) Variability in various ethnic groups aims at collecting further evidence regarding the role of blood pressure and heart rate variability in the pathogenesis of cardiovascular events, while also examining any role played by ethnicity and lifestyle-associated factors.

Brain-heart connection and the risk of heart attack.

Autonomic functions, such as increased sympathetic and parasympathetic activity and the brain's suprachiasmatic nucleus, higher nervous centres, depression, hostility and aggression appear to be important determinants of heart rate variability (HRV), which is, itself, an important risk factor of myocardial infarction, arrhythmias, sudden death, heart failure and atherosclerosis. The circadian rhythm of these complications with an increased occurrence in the second quarter of the day may be due to autonomic dysfunction as well as to the presence of excitatory brain and heart tissues. While increased sympathetic activity is associated with increased levels of cortisol, catecholamines, serotonin, renin, aldosterone, angiotensin and free radicals; increased parasympathetic activity may be associated with greater levels of acetylecholine, dopamine, nitric oxide, endorphins, coenzyme Q10, antioxidants and other protective factors. Recent studies indicate that hyperglycemia, diabetes, hyperlipidemia, ambient pollution, insulin resistance and mental stress can increase the risk of low HRV. These risk factors, which are known to favour cardiovascular disease, seem to act by decreasing HRV. There is evidence that regular fasting may modulate HRV and other risk factors of heart attack. While exercise is known to decrease HRV, exercise training may not have any adverse effect on HRV. In a recent study among 202 patients with acute myocardial infarction (AMI), the incidence of onset of chest pain was highest in the second quarter of the day (41.0%), mainly between 4.0-8.0 AM, followed by the fourth quarter, usually after large meals (28.2%). Emotion was the second most common trigger (43.5%). Cold weather was a predisposing factor in 29.2% and hot temperature (> 40 degrees celsius) was common in 24.7% of the patients. Dietary n-3 fatty acids and coenzyme Q10 have been found to prevent the increased circadian occurrence of cardiac events in our randomized controlled trials, possibly by increasing HRV. We have also found that n-3 fatty acids plus CoQ can decrease TNF-alpha and IL-6 in AMI which are pro-inflammatory agents. There is evidence that dietary n-3 fatty acids canenhance hippocampal acetylecholine levels, which may be protective. Similarly, the stimulation of the vagus nerve may inhibit TNF synthesis in the liver and acetylecholine, the principal vagal neurotransmitter, significantly attenuates the release of pro-inflammatory cytokines TNF-alpha, interleukin 1,6 and 18, but not the anti-inflammatory cytokine IL-10 in experiments. Therefore, any agent which can enhance brain acetylecholine levels, may be used as a therapeutic agent in protecting the suprachiasmatic nucleus, higher nervous centres, vagal activity and sympathetic nerve activity which are known to regulate the body clock and HRV and the risk of SCD and heart attack.

[Interferon in the treatment of Loeffler's endocarditis]. / Interferón v liecbe Löfflerovej endokarditídy.

The authors describe their own experience with the administration of recombinant alpha 2c interferon in the treatment of Loefller's endocarditis. Based on their analysis (as well as in keeping with the spares data in the literature-as a rare disease is involved), the authors consider this procedure as a qualitative advance of treatment. They consider their account as preliminary because of the short period of time, and therefore in future strict dispensary care of the patient is essential.

[Diagnostic sensitivity of 24-hour electrocardiographic Holter monitoring in indications for coronarography]. / Diagnostická citlivost' 24hodinového elektrokardiografického Holterovho monitorovania pre indikáciu na koronarografiu.

The authors evaluated 24-hour ECG monitoring (Holter monitoring) in 70 patients indicated for coronarography. They assessed the sensitivity, specificity, positive and negative predictive value of Holter monitoring. They compared the findings with data reported in the literature and with the sensitivity of the ergometric test for indication of patients for coronarographic examination. Although the sensitivity and specificity of Holter monitoring does not exceed generally reported values of sensitivity and specificity of bicycle ergometry, in the discussion the authors mention conditions where Holter monitoring is an asset for indication of patients for coronarographic examination.

[Transesophageal atrial stimulation in routine clinical practice]. / Transezofageálna stimulácia predsiení v beznej klinickej praxi.

The authors examined 90 patients by the method of transoesophageal atrial stimulation with different indications. They consider transoesophageal atrial stimulation a suitable method for basic examination of an impaired functional status of the sinoatrial node and atrioventricular conductivity. It is suitable for assessment of predisposition to supraventricular disorders of the rhythm and for testing the effectiveness of treatment of impaired supraventricular rhythm. The authors use it also for a modified loading test in patients with coronary heart disease. They evaluate transoesophagel al atrial stimulation as a simple, safe, non-invasive method, practically without contraindications, which extends our diagnostic and therapeutic possibilities, is not demanding from the technical and economic aspect and can be used in any hospital.