A Comparison of the Assay Sensitivity of Average and Worst Pain Intensity in Pharmacologic Trials: An ACTTION Systematic Review and Meta-Analysis

Identifying methods to improve assay sensitivity in randomized clinical trials (RCTs) may facilitate the discovery of efficacious pain treatments. RCTs evaluating pain treatments typically use average pain intensity (API) or worst pain intensity (WPI) as the primary efficacy outcome. However, little evidence is available comparing the assay sensitivity of these 2 measures. In this systematic review and meta-analysis, we comprehensively reviewed all low back pain, osteoarthritis pain, fibromyalgia, diabetic peripheral neuropathy pain, and postherpetic neuralgia RCTs that used a parallel group design. Eligibility required: 1) primary RCT report published between 1980 and 2016, 2) comparing 1 or more active, efficacious pharmacologic pain treatment(s) with placebo, and 3) providing data on the standardized effect size (SES) for API as well as WPI for all treatment arms. Twenty-seven active versus placebo comparisons were identified in 23 eligible articles. Using a random-effects meta-analysis, API SES and WPI SES did not differ significantly (difference?=??.021, 95% confidence interval = ?.047 to .004, P?=?.12). The findings indicate that, depending on the objectives of the study, either API or WPI could be used as a primary outcome measure in clinical trials for the chronic pain conditions included in this analysis.

Rapid Response Events in Hospitalized Patients: Patient Symptoms and Clinician Communication

Context

Patients triggering rapid response team (RRT) intervention are at high risk for adverse outcomes. Data on symptom burden of these patients do not currently exist, and current symptom management and communication practices of RRT clinicians are unknown.

Production of reflex cough by brainstem respiratory networks

Delineation of neural mechanisms involved in reflex cough is essential for understanding its many physiological and clinical complexities, and the development of more desirable antitussive agents. Brainstem networks that generate and modulate the breathing pattern are also involved in producing the motor patterns during reflex cough. Neurones of the ventrolateral medulla respiratory pattern generator mutually interact with neural networks in the pons, medulla and cerebellum to form a larger dynamic network. This paper discusses evidence from our laboratory and others supporting the involvement of the nucleus tractus solitarii, midline raphe nuclei and lateral tegmental field in the medulla, and the pontine respiratory group and cerebellum in the production of reflex cough. Gaps in our knowledge are identified to stimulate further research on this complicated issue.     

Identification of somatic JAK1 mutations in patients with acute myeloid leukemia

Somatic mutations in JAK2 are frequently found in myeloproliferative diseases, and gain-of-function JAK3 alleles have been identified in M7 acute myeloid leukemia (AML), but a role for JAK1 in AML has not been described. We screened the entire coding region of JAK1 by total exonic resequencing of bone marrow DNA samples from 94 patients with de novo AML. We identified 2 novel somatic mutations in highly conserved residues of the JAK1 gene (T478S, V623A), in 2 separate patients and confirmed these by resequencing germ line DNA samples from the same patients. Overexpression of mutant JAK1 did not transform primary murine cells in standard assays, but compared with wild-type JAK1, JAK1^T478S, and JAK1^V623A expression was associated with increased STAT1 activation in response to type I interferon and activation of multiple downstream signaling pathways. This is the first report to demonstrate somatic JAK1 mutations in AML and suggests that JAK1 mutations may function as disease-modifying mutations in AML pathogenesis.