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Practical Considerations for Building Priors for Confirmatory Studies
Published in Mani Lakshminarayanan, Fanni Natanegara, Bayesian Applications in Pharmaceutical Development, 2019
Guochen Song, John Zhong, Stacy Lindborg, Baoguang Han
The PNCR study observed SMA Type I patients with characteristics like those in Studies CS3A and CS3B in terms of genetic confirmation of SMN1 deletion or homozygous mutation and known SMN2 copy number. Moreover, the observational study and clinical trials used the same definition of SMA Type I (i.e., symptom onset within 6 months of age). Unlike the clinical trials, the PNCR study had no age limit at enrollment for its SMA Type I population, as expected given the goal of the PNCR registry. PNCR SMA Type I patient natural history study data included demographic information (age, sex, and ethnicity), SMA history (age at symptom onset, age at clinical diagnosis, and history of motor developmental milestones gained and/or lost), other relevant medical and surgical history, medication/supplements taken, physical examination findings, motor function test results (CHOP INTEND), ulnar nerve compound muscle action potential (CMAP) and motor unit number estimation (MUNE), ventilation information, and details on death.
Immunology In Anxiety and Depression
Published in Siegfried Kasper, Johan A. den Boer, J. M. Ad Sitsen, Handbook of Depression and Anxiety, 2003
Ströhle Andreas, Holsboer Florian
Cytokines activate CNS cells in different ways. First, several cytokines such as IL-1 [20], IL-2 [21], and TNF-α[22], can be transported from the blood into the CNS by active transport mechanisms, as shown in in vitro studies. Second, glia cells secrete cytokines after activation by an antigenic challenge. Finally, it was recently reported that cytokine secretion in the CNS can be stimulated by neurotransmitters [22a]. Noradrenaline stimulates the release of IL-6 from astrocytes in vitro in a dose-dependent manner, an effect that can be antagonized by blocking the adrenergic receptors. Since IL-6 is closely linked to the function of other cytokines (e.g., IL-1, IL-2, and TNF-α), this finding indicates that neurotransmitters can activate the cascade of cytokines [23]. This represents possibly a relevant psychoneuroimmunological regulative mechanism affecting (auto-)im- mune disorders, susceptibility to infections, and psychiatric disorders. Noradrenaline, released during stress [24], may act as a cytokine-activating stimulus, which in turn activates immune phenomena mediated by the cytokine cascade.
Diaphragm Ultrasound in Patients with Neuromuscular Disorders
Published in Massimo Zambon, Ultrasound of the Diaphragm and the Respiratory Muscles, 2022
ALS is a degenerative neuromuscular disorder with a worse prognosis. The disease affects upper motor neurons and lower motor neurons. Clinical findings include pseudo bulbar derangement, hyperreflexia, and spasticity. Physical examination may find muscle atrophy, weakness, and fasciculations. Diagnosis relies on clinic and electromyography (17). Respiratory insufficiency occurs during the course of the disease and is the main cause of death. Monitoring respiratory function is essential in this disease. Tests used to follow ALS patients include measurements of forced VC, Motor Unit Number Estimation (MUNE), and ALS Functional Rating Scale (ALSFRS) (18). Diaphragm function is affected in ALS and diaphragm US can be used to monitor patients with ALS (17). In ALS, diaphragm thickness at rest and at inspiration are reduced compared to healthy persons (19). Yoshioka et al. (20) reported cases series of clinical application of ultrasound to evaluate diaphragm weakness, diaphragm paralysis and diaphragm atrophy in ALS (20). In fact, a significant association between the diaphragm end inspiratory thickness measured with US and the peak-to-peak amplitude of the diaphragmatic motor response to phrenic nerve stimulation in patients with ALS (21). Hiwatani et al. (22) reported a significant association between VC and diaphragm end inspiratory thickness, diaphragm end expiratory thickness and diaphragm thickening ratio. Diaphragm ultrasound parameters were reduced in ALS patients with a pulmonary VC < 80% (22). Sartucci et al. (19) found in ALS patients a significant correlation between diaphragm ultrasound and respiratory function parameters (forced VC and FEV) as well as a significant correlation between diaphragm ultrasound and clinical scores. In conclusion, ALS, diaphragm ultrasound can be used to assess patients with dyspnea, screen patients at risk of respiratory insufficiency, and monitor patients (17).
Reducing sample size requirements for future ALS clinical trials with a dedicated electrical impedance myography system
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2018
Jeremy M. Shefner, Seward B. Rutkove, James B. Caress, Michael Benatar, William S. David, Michael S. Cartwright, Eric A. Macklin, Jose L. Bohorquez
How such a single-muscle measure would be used in a clinical trial is yet to be determined. There are two straightforward possibilities. In one, a muscle would be selected a priori in each individual prior to initiation of therapy. This muscle would be one that would be expected to have the steepest slope of EIM decline in that patient in the coming months (e.g. in a limb where weakness is just becoming evident at study initiation); such an approach could also include a short lead-in phase. In point of fact, this is similar to how most motor unit number estimation (MUNE) or motor unit number index (MUNIX) techniques are applied to a clinical trial since generally only one muscle is studied with the results thought to represent the true rate of progression of the disease in that individual. The second approach would be to perform the analysis post hoc, as we have essentially done here. Since the study would be presumably blinded, there would be no reason why such an approach should bias the results.
Current and emerging ALS biomarkers: utility and potential in clinical trials
Published in Expert Review of Neurotherapeutics, 2018
Arens Taga, Nicholas J. Maragakis
Motor unit number estimation (MUNE) offers an indirect estimation of the number of neurons innervating a muscle. This is achieved first by calculating the average amplitude of the single motor unit potentials (SMUPs) that contribute to the supramaximal CMAP, and then dividing this into the CMAP [111]. For MUNIX, the surface interference pattern is measured at various voluntary contraction levels and divided into the CMAP [110].