Patient and caregiver involvement in the formulation of guideline questions: findings from the European Academy of Neurology guideline on palliative care of people with severe multiple sclerosis.

BACKGROUND AND PURPOSE: Patient and public involvement in clinical practice guideline development is recommended to increase guideline trustworthiness and relevance. The aim was to engage multiple sclerosis (MS) patients and caregivers in the definition of the key questions to be answered in the European Academy of Neurology guideline on palliative care of people with severe MS. METHODS: A mixed methods approach was used: an international online survey launched by the national MS societies of eight countries, after pilot testing/debriefing on 20 MS patients and 18 caregivers, focus group meetings of Italian and German MS patients and caregivers. RESULTS: Of 1199 participants, 951 (79%) completed the whole online survey and 934 from seven countries were analysed: 751 (80%) were MS patients (74% women, mean age 46.1) and 183 (20%) were caregivers (36% spouses/partners, 72% women, mean age 47.4). Participants agreed/strongly agreed on inclusion of the nine pre-specified topics (from 89% for 'advance care planning' to 98% for 'multidisciplinary rehabilitation'), and <5% replied 'I prefer not to answer' to any topic. There were 569 free comments: 182 (32%) on the pre-specified topics, 227 (40%) on additional topics (16 guideline-pertinent) and 160 (28%) on outcomes. Five focus group meetings (three of MS patients, two of caregivers, and overall 35 participants) corroborated the survey findings. In addition, they allowed an explanation of the guideline production process and the exploration of patient-important outcomes and of taxing issues. CONCLUSIONS: Multiple sclerosis patient and caregiver involvement was resource and time intensive, but rewarding. It was the key for the formulation of the 10 guideline questions and for the identification of patient-important outcomes.

The spiroindolone drug candidate NITD609 potently inhibits gametocytogenesis and blocks Plasmodium falciparum transmission to anopheles mosquito vector.

The global malaria agenda has undergone a reorientation from control of clinical cases to entirely eradicating malaria. For that purpose, a key objective is blocking transmission of malaria parasites from humans to mosquito vectors. The new antimalarial drug candidate NITD609 was evaluated for its transmission-reducing potential and compared to a few established antimalarials (lumefantrine, artemether, primaquine), using a suite of in vitro assays. By the use of a microscopic readout, NITD609 was found to inhibit the early and late development of Plasmodium falciparum gametocytes in vitro in a dose-dependent fashion over a range of 5 to 500 nM. In addition, using the standard membrane feeding assay, NITD609 was also found to be a very effective drug in reducing transmission to the Anopheles stephensi mosquito vector. Collectively, our data suggest a strong transmission-reducing effect of NITD609 acting against different P. falciparum transmission stages.

Technical aspects and clinical results of an esophageal pick-up for better recording of posteriorly generated heart sounds.

A miniature esophageal microphone has been constructed. It has a cylindrical shape with 5-mm outer diameter and 25-mm length. It is a type of accelerometer that detects vibration from the esophageal wall. It has a resonance frequency of 2.1 kHz and an acceleration charge sensitivity of 2.8 pCm-1s2. The upper limit of the useful frequency range is about 1 kHz. It has directional sensitivity which reaches a maximum perpendicular to the plane of the crystal. With the esophageal microphone cardiovascular sound is recorded simultaneously with other tracings: external phonocardiogram, E.C.G., carotid pulse and M-mode echocardiogram. The great advantage of the application of the esophageal microphone is that it can be positioned in the esophagus close to the mitral valve and the left atrium by use of fluoroscopy, so that sounds and murmurs originating from that part of the heart are recorded in detail. In a case of a shunt between aorta and pulmonary artery the microphone was used at different levels in the esophagus, showing different amplitudes of a continuous murmur. In all other cases the probe was situated in the esophagus just above the level of the mitral valve behind the left atrium. In 2 cases the advantage of the esophageal microphone (revealing signs of slight mitral incompetence) over the body surface microphone is shown. In 3 patients with artificial valves in the aortic and mitral orifices (where left heart catheterisation and left ventricular angiography is a considerable risk), the esophageal microphone also improved the postoperative evaluation and diagnosis of mitral valve regurgitation considerably.

Continuous measurement of left ventricular volume in animals and humans by conductance catheter.

An eight-electrode conductance catheter previously developed by us and used to determine stroke volume in dogs was applied in human beings and dogs to measure absolute left ventricular volume quantitatively. For calibration we developed the formula V(t) = (1/alpha)(L2/sigma b)G(t) - Vc, where V(t) is time-varying left ventricular volume, alpha is a dimensionless constant, L is the electrode separation, sigma b is the conductivity of blood obtained by a sampling cuvette, and G(t) is the measured conductance within the left ventricular cavity. Vc is a correction term caused by the parallel conductance of structures surrounding the cavity and is measured in two ways. The first method, applicable in the anesthetized animal, consists of temporary reduction of volume to zero by suction. The second method uses a transient change in sigma b by injection of a small bolus of hypertonic saline (dogs) or 10 ml of cold glucose (humans) into the pulmonary artery. The validity of the formula was previously established for the isolated postmortem canine heart. The predicted linearity, slope constant alpha, and accuracy of Vc for the left ventricle in vivo were investigated by comparing the conductance volume data with results from independent methods: electromagnetic blood flow measurement for stroke volume and indicator dilution technique for ejection fraction (dogs), thermal dilution for cardiac output (12 patients), and single-plane cineventriculography for V(t) (five patients). In all comparisons, linear regression showed high correlation (from r = .82 [n = 46] to r = .988 [n = 20]) while alpha, with one exception, ranged from 0.75 to 1.07 and the error in Vc ranged from 0.5% to 16.5% (mean 7%). After positioning of the catheter, no arrhythmias were observed. It is concluded that the conductance catheter provides a reliable and simple method to measure left ventricular volume, giving an on-line, time-varying signal that is easily calibrated. Together with left ventricular pressure obtained through the catheter lumen, the instrument may be used for instantaneous display of pressure-volume loops to facilitate assessment of left ventricular pump performance.

Continuous stroke volume and cardiac output from intra-ventricular dimensions obtained with impedance catheter.

To improve assessment of ventricular function during cardiac catheterisation there should be available a continuous registration of stroke volume and cardiac output in addition to ventricular pressure. To obtain the desired volumetric quantities a catheter has been developed which measures changes in intraventricular dimensions by electrical impedance. For this purpose, the catheter is equipped with eight electrodes spaced over a distance equal to the long axis of the left ventricle into which it is introduced. A constant current is imposed between the outermost electrodes while the inner six are used to measure resistance of volume segments of the blood contained within the ventricular cavity. The difference in resistance at the beginning and end of ejection is proportional to the contribution of each segment to stroke volume, which follows from addition to the segmental terms. Calibration is obtained by measuring electrical conductivity of a blood sample. The catheter was tested over a tenfold range of cardiac output, both in vitro, using an artificial heart model, while performance in vivo was evaluated in 12 dogs. In the animals study, stroke volume and cardiac output from the catheter were compared with flows obtained with an electromagnetic flowmeter. In both studies, linear regression analysis showed excellent correlation of cardiac output (r = 0.99, n = 10 in vitro, r = 0.95, n = 126 in vivo) while the regression equations were close to those of identity. Very good correlation (r = 0.98, n = 28) was also obtained for stroke volumes on a beat to beat basis during arrhythmia. It is concluded that the catheter, which has great potential for application in man, fulfills its primary aim of continuously recording stroke volume and cardiac output.