Intensive care nurses' perceptions of various ethics concerns affecting clinical research.

BACKGROUND: Intensive-care unit (ICU) nurses have an important role in the recruitment of patients for scientific research and in the performance of clinical research. AIM: A study was conducted to examine ICU nurses' perceptions of ethics-related aspects of ICU-based research. The study focused on nurse attitudes and knowledge related to clinical research, with special emphasis on perceptions of the informed-consent process in ICU research. METHOD: The study applied a descriptive qualitative approach, involving semi-structured group interviews and theme-based inductive content analysis. Subjects were ICU nurses (n = 28) at a university hospital ICU who had experience with research protocols applied in that unit. FINDINGS: The nurses had mainly positive perceptions of clinical studies. They found research beneficial for future patients and for society. The nurses considered the information given to them about the studies inadequate. They were concerned about the fact that the consent for research is almost always obtained at the beginning of the ICU care, when patients and relatives are still in the crisis period. This limits the possibility of understanding and assimilating the information provided on the study. CONCLUSIONS: The role of ICU nurses in clinical studies should be more prominent and taken into account in the planning of ICU studies.

A liquid chromatography-tandem mass spectrometry analysis of nine cytochrome P450 probe drugs and their corresponding metabolites in human serum and urine.

Cocktail phenotyping using specific probe drugs for cytochrome P450 (CYP) enzymes provides information on the real-time activity of multiple CYPs. We investigated different sample preparation techniques and validated a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with simple protein precipitation for the analysis of nine CYP probe drugs and their metabolites in human serum and urine. Specific CYP probe drugs (melatonin, CYP1A2; nicotine, CYP2A6; bupropion, CYP2B6; repaglinide, CYP2C8; losartan, CYP2C9; omeprazole, CYP2C19 and CYP3A4; dextromethorphan, CYP2D6; chlorzoxazone, CYP2E; midazolam, CYP3A4) and their main metabolites, with the exception of 3'-hydroxyrepaglinide, were quantified in human serum and urine using the developed LC-MS/MS method. The analytical method was fully validated showing high selectivity, linearity, acceptable accuracy (85-115 %) and precision (2-19 %) and applied to a pharmacokinetic study in four healthy volunteers after oral administration of drugs given as a cocktail. All probe drugs and their metabolites (totally 19 analytes) were detected and quantified from human serum and urine over the time range of 1 to 6 h after oral administration. Therefore, the proposed method is applicable for drug interaction and CYP phenotyping studies utilizing a cocktail approach. Graphical Abstract Workflow overwiew of cocktail CYP-phenotyping study.

Co-morbidity and clinically significant interactions between antiepileptic drugs and other drugs in elderly patients with newly diagnosed epilepsy.

PURPOSE: A study was conducted to investigate the frequency of potential pharmacokinetic drug-to-drug interactions in elderly patients with newly diagnosed epilepsy. We also investigated co-morbid conditions associated with epilepsy. METHOD: From the register of Kuopio University Hospital (KUH) we identified community-dwelling patients aged 65 or above with newly diagnosed epilepsy and in whom use of the first individual antiepileptic drug (AED) began in 2000-2013 (n=529). Furthermore, register data of the Social Insurance Institution of Finland were used for assessing potential interactions in a nationwide cohort of elderly subjects with newly diagnosed epilepsy. We extracted all patients aged 65 or above who had received special reimbursement for the cost of AEDs prescribed on account of epilepsy in 2012 where their first AED was recorded in 2011-2012 as monotherapy (n=1081). Clinically relevant drug interactions (of class C or D) at the time of starting of the first AED, as assessed via the SFINX-PHARAO database, were analysed. RESULTS: Hypertension (67%), dyslipidemia (45%), and ischaemic stroke (32%) were the most common co-morbid conditions in the hospital cohort of patients. In these patients, excessive polypharmacy (more than 10 concomitant drugs) was identified in 27% of cases. Of the patients started on carbamazepine, 52 subjects (32%) had one class-C or class-D drug interaction and 51 (31%) had two or more C- or D-class interactions. Only 2% of the subjects started on valproate exhibited a class-C interaction. None of the subjects using oxcarbazepine displayed class-C or class-D interactions. Patients with 3-5 (OR 4.22; p=0.05) or over six (OR 8.86; p=0.003) other drugs were more likely to have C- or D-class interaction. The most common drugs with potential interactions with carbamazepine were dihydropyridine calcium-blockers, statins, warfarin, and psychotropic drugs. CONCLUSIONS: Elderly patients with newly diagnosed epilepsy are at high risk of clinically relevant pharmacokinetic interactions with other drugs, especially if exposed to carbamazepine, but these interactions can be controlled via rational drug choices and with prediction of the possible drug-to-drug interactions. Patients on dihydropyridine calcium-channel blockers, statins, warfarin, and risperidone face the highest risk of interactions.

Hope for better treatment in participating clinical drug trials.

An informed consent is a prerequisite for participating in medical trials, whereby the person asked to take part in the trial shall understand what he is committing himself to, and that the consent is given voluntarily. Voluntariness can be undermined by so-called therapeutic optimism, i.e. belief in personal benefit brought about by the trial, as well as the difficulty of understanding how conventional treatment and the trial differ from each other, i.e. the so-called therapeutic misconception. The investigator, especially if he is also the attending physician, may influence the development of therapeutic misconception, because the participant may assume that the physician works as an investigator for the best benefit of the patients. It is important to recognize unrealistic optimism and therapeutic misconception of the trial, because for the participant they may result in disappointment and loss of confidence during the trial.

Therapeutic misconception correlates with willingness to participate in clinical drug trials among patients with epilepsy; need for better counseling.

OBJECTIVES: To ensure the development of new effective treatments in medicine, clinical trials (CTs) need to be conducted. The study was aimed at assessing knowledge of and attitudes toward clinical drug trials among patients with epilepsy, along with factors that motivate them to participate in CTs. Use of this information could improve recruitment for future trials and enhance their quality. METHODS: A 45-item questionnaire on the views of patients with epilepsy about CTs was developed. It included statements that the respondents assessed on a Likert scale from 1 ('strongly disagree') to 5 ('strongly agree'). The questionnaire was mailed to a random sample (n=1875) of members of the Finnish Epilepsy Association aged at least 18 years. In all, 342 questionnaires were returned, and 325 were accepted after exclusion. RESULTS: The analysis indicates that the general attitudes of patients with epilepsy toward CTs are positive. Most of the patients with epilepsy saw participation in clinical trials as indispensable to new treatments becoming available. Retired respondents and persons who had developed epilepsy when young had inadequate knowledge of general issues related to CTs. Level of education and number of antiepileptic medications (AEDs) were significant predictors for failure to understand the nature and purpose of clinical research - i.e., for therapeutic misconception (TM). Additionally, strong correlation was found between TM and respondents' willingness to participate in clinical trials. CONCLUSIONS: The new treatments are often studied in patients with a high risk of TM and impaired comprehension of general procedures associated with CTs. Clinically, it may be worthwhile for the investigators to be able to recognize vulnerable individuals and pay special attention to the information provided on the purposes and methods of the trial, to contribute to high-quality AED studies.

Placebo-controlled clinical trials: how trial documents justify the use of randomisation and placebo.

BACKGROUND: Randomised clinical trials (RCTs) involve procedures such as randomisation, blinding, and placebo use, which are not part of standard medical care. Patients asked to participate in RCTs often experience difficulties in understanding the meaning of these and their justification. METHODS: We reviewed RCT protocols, statements of the principal investigator (PI), and participant-information materials, as submitted for opinion to a research ethics committee. We evaluated how the justification for the use of placebo was described in these documents and how the participants had been informed about randomisation, placebo use, and the possible risks of receiving placebo. RESULTS: In total, 52 RCTs were identified. Eighteen of the study protocols (35%) provided some rationale for the use of placebo. In 15 (29%) of the statements, the PI had provided justification for its use. Possible risks related to placebo use were described in nine (17%) of the statements. An explanation as to why placebo was necessary featured in only 12 (23%) of the sets of participant-information materials, and only six (12%) of the documents discussed the possible risks associated with placebo. CONCLUSIONS: The justification of placebo control was inadequately described in the RCT study protocols, by principal or national co-ordinating investigators, and in participant-information documents. Furthermore, possible health-related risks associated with the use of placebo were poorly explained in the participant-information documents. Ethics committes and study participants need to be better informed of the rationale for the use of placebo, along with the associated risks.

[Update on Current Care Guideline: epilepsies (adult]. / Epilepsiat (aikuiset).

First epileptic seizure is an indication for an urgent referral to a neurology care unit. Diagnosis of epilepsy is based on medical history and clinical examination, supplemented with MRI, EEG and laboratory tests. Exact diagnosis of the epilepsy type and etiology are the basis of the treatment. Patient education improves outcomes. The goal is complete long-term seizure control without significant adverse effects. Antiepileptic medication is usually initiated after the second epileptic seizure. If the patient does not respond to two appropriate drug schedules, patient should be evaluated for surgical treatment options.

The Catechol O-Methyltransferase Inhibitor Entacapone in the Treatment of Parkinson's Disease: Personal Reflections on a First-in-Class Drug Development Programme 40 Years On.

In the 1980s, Orion Pharma, then a mid-ranking Nordic area pharmaceutical company, established a drug development programme on the inhibition of catechol O-methyltransferase (COMT). This enzyme, which plays an important role in the inactivation of catecholamine neurotransmitters and drugs with a catechol structure, thus came under consideration as a target in the innovative translational and clinical programme we describe in this historical review. The starting point was the conjecture that a peripherally acting COMT inhibitor might improve entry of levodopa into the brain. This had potentially significant implications for the medical treatment of Parkinson's disease (PD). The rationale was that more efficient delivery of levodopa to the brain might allow the high therapeutic doses of levodopa to be reduced and the dose interval to be extended. Elucidation of structure-activity relations paved the way for the discovery and development of entacapone, a 5-nitrocatechol that was a potent and highly specific inhibitor of COMT. Experience in phase III clinical trials established that entacapone, used as an adjunct to regular or controlled-release levodopa preparations (also including a peripherally acting dopa-decarboxylase inhibitor), increased ON-time and reduced OFF-time and improved clinical condition in patients with PD experiencing wearing-off, often with a reduced daily levodopa dose. Several of these studies also identified that entacapone improved patients' quality of life and was cost-effective. Subsequently, entacapone has been amalgamated into a triple-combination preparation (Stalevo®) with levodopa and carbidopa to create a flexible and convenient drug therapy for patients with PD who have end-of-dose motor fluctuations not stabilised on levodopa/dopa-decarboxylase inhibitor treatment. This review offers a historical perspective on a successful programme of drug development by researchers who played central roles in the progress from exploratory hypothesis to registered pharmaceutical product.

Education of research ethics for clinical investigators with Moodle tool.

BACKGROUND: In clinical research scientific, legal as well as ethical aspects are important. It is well known that clinical investigators at university hospitals have to undertake their PhD-studies alongside their daily work and reconciling work and study can be challenging. The aim of this project was to create a web based course in clinical research bioethics (5 credits) and to examine whether the method is suitable for teaching bioethics. The course comprised of six modules: an initial examination (to assess knowledge in bioethics), information on research legislation, obtaining permissions from authorities, writing an essay on research ethics, preparing one's own study protocol, and a final exam. All assignments were designed with an idea of supporting students to reflect on their learning with their own research. METHODS: 57 PhD-students (medical, nursing and dental sciences) enrolled and 46 completed the course. Course evaluation was done using a questionnaire. The response rate was 78%. Data were analyzed using quantitative methods and qualitative content analysis. RESULTS: The course was viewed as useful and technically easy to perform. Students were pleased with the guidance offered. Personal feedback from teachers about students' own performance was seen advantageous and helped them to appreciate how these aspects could be applied their own studies. The course was also considered valuable for future research projects. CONCLUSIONS: Ethical issues and legislation of clinical research can be understood more easily when students can reflect the principles upon their own research project. Web based teaching environment is a feasible learning method for clinical investigators.

Medication reminder service for mobile phones: an open feasibility study in patients with Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder in which drug dosing regimens become increasingly complicated with the progression of the disease. This poses a significant risk of nonadherence to drug dosing and a failure in treatment response. We hypothesized that a medication reminder delivered by short message service (SMS) could be one way to ameliorate the problem of medication errors. We conducted an open feasibility study in 50 patients with advanced PD. The subjects set up the process to receive reminders by a Web tool, after which they started to receive automatically transmitted text messages as a medication reminder for 4 weeks. In total, 35 of 50 subjects (70.0%) were able to set up the reminder system without any help. The majority (69%) of the subjects rated the set-up process as "very easy" or "easy." Almost all (41 subjects, 91%) felt that SMS reminders worked well for them, and only 4 subjects (9%) felt that SMS texts were totally valueless. Almost half of the subjects (22 of 45, 49%) considered that there were clear benefits, and an additional 17 subjects (38%) enjoyed some benefits in using the medication reminder system. Our results indicate that an SMS medication reminder system is a feasible method, even in subjects with advanced PD.

[Under study or treatment?]. / Tutkimuksessa vai hoidossa?

Persons taking part in a clinical study are patients in the need of treatment. Although the values of the study and the treatment are largely consistent with each other, their goals, methods and ethics differ. Randomized studies in particular involve features that are strange to conventional treatments, such as blinding and placebo medication. Anyone participating in a study should understand that instead of obtaining a health benefit for an individual participant, its primary goal is generalizable knowledge. Any misunderstanding of the therapeutic meaning of the study may lead to disappointment of the participant.

Problems Experienced by Health Care Professionals with Do not Attempt Resuscitation (DNAR) Orders - A Qualitative Study.

A 'Do Not Attempt Resuscitation' (DNAR) order is one of the most important yet difficult medical decisions. Despite the recent European guidelines, health care professionals (HCPs) in general perceive challenges in making a DNAR order. We aimed to evaluate the types of problems related to DNAR order making. A link to a web-based multiple-choice questionnaire including open-ended questions was sent by e-mail to all physicians and nurses working in the Tampere University Hospital special responsibility area covering a catchment area of 900,000 Finns. The questionnaire covered issues on DNAR order making, its meaning and documentation. Here we report the analysis of the open-ended questions, examined based on the Ottawa Decision Support Framework with expanded individual decisional needs categories. Qualitative data describing respondents' opinions (N=648) regarding problems related to DNAR order decision making were analysed using Atlas.ti 23.12 software. In total, 599 statements (phrases) dealing with inadequate advice, information, emotional support, and instrumental help were identified. Our results show that HCPs experience lack of support in DNAR decision making on multiple levels. Digital decision-making support integrated into electronic patient records (EPR) to assure timely and clearly visible DNAR orders could be beneficial.

Feasibility and patient acceptability of a commercially available wearable and a smart phone application in identification of motor states in parkinson's disease.

In the quantification of symptoms of Parkinson's disease (PD), healthcare professional assessments, patient reported outcomes (PRO), and medical device grade wearables are currently used. Recently, also commercially available smartphones and wearable devices have been actively researched in the detection of PD symptoms. The continuous, longitudinal, and automated detection of motor and especially non-motor symptoms with these devices is still a challenge that requires more research. The data collected from everyday life can be noisy and frequently contains artefacts, and novel detection methods and algorithms are therefore needed. 42 PD patients and 23 control subjects were monitored with Garmin Vivosmart 4 wearable device and asked to fill a symptom and medication diary with a mobile application, at home, for about four weeks. Subsequent analyses are based on continuous accelerometer data from the device. Accelerometer data from the Levodopa Response Study (MJFFd) were reanalyzed, with symptoms quantified with linear spectral models trained on expert evaluations present in the data. Variational autoencoders (VAE) were trained on both our study accelerometer data and on MJFFd to detect movement states (e.g., walking, standing). A total of 7590 self-reported symptoms were recorded during the study. 88.9% (32/36) of PD patients, 80.0% (4/5) of DBS PD patients and 95.5% (21/22) of control subjects reported that using the wearable device was very easy or easy. Recording a symptom at the time of the event was assessed as very easy or easy by 70.1% (29/41) of subjects with PD. Aggregated spectrograms of the collected accelerometer data show relative attenuation of low (<5Hz) frequencies in patients. Similar spectral patterns also separate symptom periods from immediately adjacent non-symptomatic periods. Discriminative power of linear models to separate symptoms from adjacent periods is weak, but aggregates show partial separability of patients vs. controls. The analysis reveals differential symptom detectability across movement tasks, motivating the third part of the study. VAEs trained on either dataset produced embedding from which movement states in MJFFd could be predicted. A VAE model was able to detect the movement states. Thus, a pre-detection of these states with a VAE from accelerometer data with good S/N ratio, and subsequent quantification of PD symptoms is a feasible strategy. The usability of the data collection method is important to enable the collection of self-reported symptom data by PD patients. Finally, the usability of the data collection method is important to enable the collection of self-reported symptom data by PD patients.

Healthcare Professionals' Perceptions and Opinions on "Do not Attempt Resuscitation" (DNAR) Order and Documentation.

Insights on end-of-life care decisions, such as do not attempt resuscitation (DNAR), vary between institutions and individual health care professionals. At the era of electronic patient records (EPR), the information of DNAR order may still be recorded in multiple locations making it difficult to find and interpret. A link to a structured web-based questionnaire was sent to all physicians and nurses working in Tampere University Hospital special responsibility area covering a catchment area of 900 000 Finns. Perceptions on DNAR order and documentation was surveyed. In total 934 subjects responded, of which 727 (77%) were nurses and 219 (23%) physicians covering all specialties. We found substantial variation in DNAR order interpretation and documentation among all health care professionals possibly causing information breakdown and compromised end-of-life care.

Levels of IL-1beta and IL-1ra in cerebrospinal fluid of human patients after single and prolonged seizures.

BACKGROUND: Experimentally induced seizures are associated with increased production of inflammatory cytokines in the nervous system. Elevated cerebrospinal fluid levels of cytokine interleukin-6 (IL-6) have been found after a single generalized seizure in human patients. After prolonged seizures, levels of IL-6 have been shown to be even higher compared with single seizures. In the present study, we determined the levels of proconvulsive IL-1beta and anticonvulsive IL-1ra in cerebrospinal fluid after single tonic-clonic seizures as well as after prolonged seizures. METHODS: The levels of cytokines were measured using enzyme-linked immunosorbent assay. RESULTS: We found that after single seizures, a slight increase in anticonvulsive IL-1ra levels was found; however, after prolonged partial or recurrent tonic-clonic seizures, the levels of IL-1ra were significantly elevated, together with decreased IL-1beta levels. CONCLUSION: Our results indicate that after severe seizures, the balance between IL-1-type cytokines is changed towards a neuroprotective and anticonvulsive direction with an overproduction of IL-1ra with respect to potentially neurotoxic IL-1beta. This reaction may serve as a defense mechanism of the nervous system against excitotoxic neuronal damage.

Electroconvulsive therapy and biomarkers of neuronal injury and plasticity: Serum levels of neuron-specific enolase and S-100b protein.

Electroconvulsive therapy (ECT) is considered an effective and safe treatment in major depressive disorders. However, the possibility that it may induce cognitive adverse effects observed in selected patients has raised a concern that ECT may induce neuronal damage. The biomarkers of brain damage, neuron-specific enolase (NSE) and S-100b protein (S-100b), were measured in serum before and after ECT to determine whether this treatment induces neuronal injury or glial activation. ECT was administered to 10 patients with major depressive disorder. The serum samples were analyzed before (baseline) and after ECT at 1 h, 2 h, 6 h, 24 h and 48 h. The severity of depression was scored with the Montgomery-Asberg Depression Rating Scale (MADRS) and Beck Depression Inventory (BDI) pre-to-post ECT. There were no statistically significant changes in the median concentrations of NSE or S-100b at various time points before or after ECT. However, there were substantial elevations in the levels of S-100b in four patients. High levels of S-100 at 2 and 6 h correlated with the response to the treatment. These results suggest that ECT does not produce neuronal injury. The transient increase in the levels of S-100b reflecting activation of glial cells may play a part in mediating the antidepressant effects of ECT.

[Update on current care guidelines. Parkinson's disease]. / Parkinsonin tauti.

Following the diagnosis of Parkinson's disease, treatment may be initiated with MAO-B-inhibitor, even prior to the development of any functional deficit. For patients with a functional deficit who are younger (usually under 75 years of age) and otherwise in good condition, treatment should be started with a dopamine agonist or MAO-B-inhibitor. In other patients, initial treatment with levodopa is recommended. In the case of difficult on-off-symptoms and dyskinesias in spite of optimal treatment, surgical procedures and duodenal levodopa infusion should be considered. Rehabilitation should be targeted at specific problems associated with functional skills.

Risk Assessment of Medical Study Procedures in the Documents Submitted to a Research Ethics Committee.

Several frameworks assist research ethics committees (RECs) in risk assessment of medical studies. However, little is known about how researchers describe risks of the procedures in study protocols and participant information sheets. We examined 349 study protocols and participant information sheets submitted to an REC and evaluated the risk assessments performed for 1,510 study procedures. Risks had been assessed for 399 (26%) procedures in study protocols and for 425 (28%) procedures in participant information sheets. Physical risks were assessed six times more frequently than psychological risks. Risks of medical procedures are not always detailed in study protocols or participant information sheets. Risk descriptions of procedures believed to be familiar to potential participants may be omitted.

A systematic evaluation of factors associated with nocturia--the population-based FINNO study.

In a case-control study with prevalence sampling, the authors explored the correlates for nocturia and their population-level impact. In 2003-2004, questionnaires were mailed to 6,000 subjects (aged 18-79 years) randomly identified from the Finnish Population Register (62.4% participated; 53.7% were female). Questionnaires contained items on medical conditions, medications, lifestyle, sociodemographic and reproductive factors, urinary symptoms, and snoring. Nocturia was defined as > or =2 voids/night. In age-adjusted analyses, factors associated with nocturia were entered into a multivariate model. Backward elimination was used to select variables for the final model, with adjustment for confounding. Although numerous correlates were identified, none affected > or =50% of nocturia cases of both sexes. The factors with the greatest impact at the population level were (urinary) urgency (attributable number/1,000 subjects (AN) = 24), benign prostatic hyperplasia (AN = 19), and snoring (AN = 16) for men and overweight and obesity (AN = 40), urgency (AN = 24), and snoring (AN = 17) for women. Moreover, correlates included prostate cancer and antidepressant use for men, coronary artery disease and diabetes for women, and restless legs syndrome and obesity for both sexes. Although several correlates were identified, none accounted for a substantial proportion of the population burden, highlighting the multifactorial etiology of nocturia.

[Mechanisms of action and clinical use of antiepileptic drugs]. / Epilepsialääkkeiden vaikutusmekanismit ja kliininen käyttö.

Treatment choices for epilepsy are made empirically, but drug responses and adverse effects can in part be predicted on the basis of the known mechanisms of action of the drugs. Antiepileptic drugs act by inhibiting voltage-gated sodium or calcium channels, opening potassium channels, enhancing gamma-aminobutyric acid (GABA)-mediated inhibition in the brain, inhibiting glutamate-mediated excitatory function or by altering intracellular signaling pathways. Knowledge of the mechanisms of action is essential when assessing the applicability of antiepileptic drugs in other indications such as in the management of pain and psychiatric symptoms.