Reaching for equitable care: High levels of disability-related knowledge and cultural competence only get us so far.

BACKGROUND: Achieving equitable medical care for people with disabilities is a complex challenge with emphasis often placed on the need for improved physician knowledge and cultural competence. Physical medicine and rehabilitation (PM&R) is a specialty dedicated to maximizing patient function, where a focus on working with and learning from patients with complex disabilities informs physician training and patient care. OBJECTIVE: The purpose of this study was to assess barriers to equitable care in PM&R clinics through a structural checklist and semi-structured interviews with clinic staff and physicians. METHODS: We used qualitative analysis with a grounded theory approach to develop a unified explanation of how existing clinic processes and provider attitudes affect equitable access to medical care. RESULTS: We found physicians comfortable with and respectful of patient differences who described leveraging unpaid time and creativity to navigate structural, resource, and awareness barriers. Staff and physicians described current barriers as negatively affecting quality of care, clinic efficiency, and, in some cases, patient and staff safety. CONCLUSION: Our results suggest that high levels of physician disability-related knowledge and cultural competence may be insufficient to the challenge of achieving equitable care.

Cardiac Safety of Rupatadine in a Single-Ascending-Dose and Multiple-Ascending-Dose Study in Healthy Japanese Subjects, Using Intensive Electrocardiogram Assessments-Comparison With the Previous White Caucasian Thorough QT Study.

A thorough QT/QTc study in healthy white Caucasian subjects demonstrated that rupatadine has no proarrhythmic potential and raised no cardiac safety concerns. The present phase 1 study aimed to confirm the cardiac safety of rupatadine in healthy Japanese subjects. In this randomized, double-blind, placebo-controlled study, 27 healthy Japanese subjects were administered single and multiple escalating rupatadine doses of 10, 20, and 40 mg or placebo. Triplicate electrocardiogram (ECG) recordings were performed on days -1, 1, and 5 at several points, and time-matched pharmacokinetic samples were also collected. Concentration-effect analysis based on the change in the QT interval corrected using Fridericia's formula (QTcF) from average baseline was performed. Data from the formal TQT study in white Caucasian subjects was used for a comparison analysis. The ECG data for rupatadine at doses up to 40 mg did not show an effect on the QTc interval of regulatory concern. The sensitivity of this study to detect small changes in the QTc interval was confirmed by demonstrating a significant shortening of QTcF on days 1 and 5 four hours after a standardized meal. The data from this study exhibited no statistically significant differences in the QTc effect between Japanese and white Caucasian subjects.

Results from the IQ-CSRC prospective study support replacement of the thorough QT study by QT assessment in the early clinical phase.

The QT effects of five "QT-positive" and one negative drug were tested to evaluate whether exposure-response analysis can detect QT effects in a small study with healthy subjects. Each drug was given to nine subjects (six for placebo) in two dose levels; positive drugs were chosen to cause 10 to 12 ms and 15 to 20 ms QTcF prolongation. The slope of the concentration/ΔQTc effect was significantly positive for ondansetron, quinine, dolasetron, moxifloxacin, and dofetilide. For the lower dose, an effect above 10 ms could not be excluded, i.e., the upper bound of the confidence interval for the predicted mean ΔΔQTcF effect was above 10 ms. For the negative drug, levocetirizine, a ΔΔQTcF effect above 10 ms was excluded at 6-fold the therapeutic dose. The study provides evidence that robust QT assessment in early-phase clinical studies can replace the thorough QT study.

Biomarkers and proof of concept.

Starting with an overview over the early human phase of drug development, the Pearson index, a normalized measure for the financial net present value of a drug development project, is introduced and it is shown how the value of obtaining critical information early can be quantified. Biomarkers used in this phase can be a means to obtain such information. Biomarkers can be classified as mechanistic, empirical or model based. Proof of concept trials are used to obtain the information. These trials can be proof of mechanism if they use a biomarker to investigate their mode of action, proof of viability if they investigate tolerability of putatively therapeutic doses or proof of efficacy if they use a clinical endpoint in a selected, homogenous population. If these trials are to decide on further development of a candidate drug, traditional statistical methods are not adequate. In the framework of decision analysis. Bayesian statistics offer an alternative. The basic techniques of this concept are introduced. The role of clinical electrophysiology is discussed in this framework.

[German-Latvian cooperation in the pathology specialty]. / Deutsch-Lettische Beziehungen im Fachgebiet der Pathologie.

In the field of pathology there have been very close connections since the beginning of this century and a regular exchange of ideas between the pathologists of Latvia and Germany. Pathologists of Latvia were members of the German Association of Pathology. The stages of political changes in Europe very much influenced the exchanges of ideas. The following presentation will outline the activities and personalities in the sector of pathology in the time period until 1918--time of the Russian Czar Empire--, during the National State of Latvia and the Second World War (1918-1940), then during the Russian occupation of Latvia (1944-1991) and also the new time period after the political changes. Evaluated in this presentation the yearly support of the Baltic/German Symposiums, assisted by the IAP, which in addition to the activities in pathology also promote and encourage many personal contacts and friendships.

[Use of automatic, computer-assisted EEG analysis in clinical practice]. / Der Einsatz einer automatischen, rechnergstützten EEG-Analyse in der klinischen Praxis.

Digital EEG-recorders are being increasingly accepted for clinical routine application, thereby offering the possibility for an automated computerised EEG evaluation. This paper presents the results of a corresponding computer programme developed in our group. Based on 313 clinical routine-EEG we compared the computer reports to the visual EEG-interpretations and obtained the following result: Background activity is reliably detected with a rate comparable to a human interpreter. Similar results were observed with focussed pathological activity. Intermittent activity (Parenrhythmia, dysrhythmia) however lacks a sufficiently high score of correct evaluation and requires further development. Epileptiform potentials, especially spikes, are detected with high sensitivity, however, at the cost of low specificity, and are therefore still in need of further improvement.

Effect of morphine on the electroencephalogram and other physiological and other physiological and behavioral parameters.

A double-blind, crossover, placebo-controlled study was carried out in 10 healthy male volunteers to investigate the effects of subcutaneously administered single doses of 4 and 8 mg morphine and 2.5 and 5 mg of a new centrally acting analgesic with a benzomorphane structure. After an adaptation session, each subject received all five treatments in a random sequence at intervals of 1 week. Quantified EEG, cardiovascular and behavioral parameters, quantitative respiratory measurements, body temperature, symptom reports, pain threshold estimates, and blood drug assays were used to assess the effects of the drugs. The measurement battery was completed before injection and after 30, 60, 120, 240 and 360 min. In addition, EEG, blood samples and respiratory signals were also taken during/after the first 5, 10, 15, 20 and 25 min. As the new compound did not show any obvious advantages over morphine, only the results with the latter substance are reported here. As the main effects of morphine on the EEG a dose-dependent slowing and monorhythmization of alpha and an increase of the average frequency of fast beta activity were observed. Slow EEG waves tended to decrease. Heart rate and body temperature decreased, whereas there was no discernible effect on blood pressure. Subjects reported feelings of drowsiness, muzziness, lethargy and mental slowness. The pain threshold increased. All these effects had a maximum between min 120 and 240, although the highest blood levels of the parent drug were measured 10-25 min after drug administration. An explanation for this delay might be that the pharmacological effects are due not to free morphine but to one of its metabolites.

Quantitative pharmaco-electroencephalographic differentiation between the CNS effects of bromocriptine and imipramine, drugs with qualitatively different antidepressant properties.

Two double-blind, placebo-controlled studies were carried out at two different centers using the same protocol. Eight young healthy male volunteers were recruited for each of the studies, which were both undertaken to investigate the effect of single doses of 0.6, 1.25 and 2.5 mg bromocriptine (Parlodel) in comparison with 25 and 50 mg imipramine (Tofranil) on the electroencephalogram (EEG), subjective mental and emotional states, blood pressure, heart rate, and plasma prolactin levels. Side effects were also noted. The changes in the resting EEG power spectrum after imipramine were an increase in slow wave and fast beta activity and a decrease in alpha activity. At the same time imipramine depressed subjective mental and emotional states. Bromocriptine slowed the alpha activity of the resting EEG power spectrum, depressed subjective mental and emotional states, lowered blood pressure, and reduced prolactin secretion.

Investigation of the effect of fluperlapine on the EEG in schizophrenic patients.

The investigations of the EEG during an open study with the antipsychotic drug fluperlapine in acute schizophrenic patients are reported. Due to ethical and practical considerations some of the common pharmaco-electroencephalographic procedures as well as placebo controlled study designs could not be applied in these patients. To overcome at least partly these limitations, intraindividual as well as interindividual correlations were used. They were computed between plasma concentrations of unchanged fluperlapine as well as its metabolite N-oxide fluperlapine, on one hand, and EEG variables, on the other. The intraindividual correlations can be computed either on the first day of the active treatment over various time points of that day (acute effects) or across several appointed treatment days always taking values at the same time during these days (chronic effects). The intraindividual correlations of a set of subjects were submitted to a sign test to obtain an overall result for the relation between the EEG and blood plasma levels of the drug. In this way an acute and a chronic effect of fluperlapine on the EEG could be shown consisting mainly of an increase in slow waves, a decrease in the alpha-activity and a tendency of beta-activity to decrease. A comparison of the correlations between the plasma levels of fluperlapine and the EEG variables with the correlations between the plasma levels of N-oxide fluperlapine and the EEG gives rise to the hypothesis that unchanged fluperlapine has a stronger effect on the EEG than its metabolite.

Treatment of some nonstationarities in the EEG.

In many situations, EEG recordings cannot be assumed to be second-order stationary. The definition of stationarity is reviewed and the implications of the nonstationarity of the EEG are investigated. Some methods to overcome the problem caused by the nonstationarity are discussed. They include measures of variability, condensed time series and segmentation. The discussion is restricted to FFT spectral estimators and broad-band parameters derived thereof.

[Automatic detection of grouped patterns in EEG]. / Automatische Erkennung gruppierter Muster im EEG.

The detection and classification of grouped (so called paroxysmal) activity and of artefacts of similar appearance is a necessary part of the automated description of clinical EEGs. An algorithm for this task is presented. It is based on short-time spectra and on parameters extracted from them. The rate of agreement with the visual assessment is nearly the same as that between well trained EEGers. This is true for the classification and to nearly the same degree for the detection. Nevertheless these patterns must be grouped and validated if the method is to be used in practice. A modification useful for a fast analysis combined with the quantitative description of the background activity is discussed.

Electroencephalographic and psychometric assessment of the CNS effects of single doses of guanfacine hydrochloride (Estulic) and clonidine (Catapres).

A double-blind, placebo-controlled study was carried out in 10 young healthy volunteers to investigate the effects of single doses of 1 and 2 mg guanfacine hydrochloride (Estulic) and 0.15 and 0.3 mg clonidine (Catapres) on the electroencephalogram (EEG), subjective mental and emotional state, blood pressure and heart rate. These doses are considered to be equipotent with regard to their antihypertensive effects, as shown in long-term therapeutic trials. Each subject received all five treatments in random sequence at intervals of 1 week. The EEG tracings were evaluated quantitatively by spectral analysis. Procedures were carried out before and at 1, 2, 4, 6 and 8 h after drug administration. After clonidine the EEG showed increased slow-wave activity and decreased alpha activity, these effects being dose-dependent. They were of the sedative type and did not clearly indicate specific psychotropic properties. The subjective mental and emotional state questionnaire indicated a decrease of alertness, extroversion, concentration and mood (in that order), changes which paralleled the EEG changes. The changes observed after guanfacine were qualitatively similar to those after clonidine, but were of considerably lower intensity. Our data suggest that guanfacine has less central nervous system-depressant activity than clonidine.

[Detection of EMG artifacts for use in automatic routine analysis of clinical EEG's]. / EMG-Artefakt-Erkennung für die Verwendung bei der automatischen Routine-Analyse des klinischen EEG.

Automatic computerized EEG-evaluation in several stages requires information about whether or not EMG-artifacts are present. Furthermore, algorithms for recognition of EMG-artifacts may be helpful while reproducing low pass filtered EEG-signals. Depending on the kind of application three algorithms for the recognition of EMG-artifacts are proposed, taking into account the different kind of results required as well as the different nature of input data. The algorithms have been constructed under the guideline of numerical simplicity to match the requirements of routine EEG-evaluation. They have shown to be a sufficient tool for any EMG-recognition task arising from computerized analysis of clinical EEG-signals.