A pragmatic, phase III, multisite, double-blind, placebo-controlled, parallel-arm, dose increment randomised trial of regular, low-dose extended-release morphine for chronic breathlessness: Breathlessness, Exertion And Morphine Sulfate (BEAMS) study protocol.

INTRODUCTION: Chronic breathlessness is highly prevalent and distressing to patients and families. No medication is registered for its symptomatic reduction. The strongest evidence is for regular, low-dose, extended- release (ER) oral morphine. A recent large phase III study suggests the subgroup most likely to benefit have chronic obstructive pulmonary disease (COPD) and modified Medical Research Council breathlessness scores of 3 or 4. This protocol is for an adequately powered, parallel-arm, placebo-controlled, multisite, factorial, block-randomised study evaluating regular ER morphine for chronic breathlessness in people with COPD. METHODS AND ANALYSIS: The primary question is what effect regular ER morphine has on worst breathlessness, measured daily on a 0-10 numerical rating scale. Uniquely, the coprimary outcome will use a FitBit to measure habitual physical activity. Secondary questions include safety and, whether upward titration after initial benefit delivers greater net symptom reduction. Substudies include longitudinal driving simulation, sleep, caregiver, health economic and pharmacogenetic studies. Seventeen centres will recruit 171 participants from respiratory and palliative care. The study has five phases including three randomisation phases to increasing doses of ER morphine. All participants will receive placebo or active laxatives as appropriate. Appropriate statistical analysis of primary and secondary outcomes will be used. ETHICS AND DISSEMINATION: Ethics approval has been obtained. Results of the study will be submitted for publication in peer-reviewed journals, findings presented at relevant conferences and potentially used to inform registration of ER morphine for chronic breathlessness. TRIAL REGISTRATION NUMBER: NCT02720822; Pre-results.

Alterations in the growth plate associated with growth modulation by sustained compression or distraction.

Sustained mechanical load is known to modulate endochondral growth in the immature skeleton, but it is not known what causes this mechanical sensitivity. This study aimed to quantify alterations in parameters of growth plate performance associated with mechanically altered growth rate. Vertebral and proximal tibial growth plates of immature rats and cattle, and rabbit (proximal tibia only) were subjected to different magnitudes of sustained loading, which altered growth rates by up to 53%. The numbers of proliferative chondrocytes, their rate of proliferation, and the amount of chondrocytic enlargement occurring in the hypertrophic zone were quantified. It was found that reduced growth rate with compression and increased growth rate with distraction were associated with corresponding changes in the number of proliferative chondrocytes per unit width of growth plate, and in the final (maximum) chondrocytic height in the hypertrophic zone (overall correlation coefficients 0.38 and 0.56 respectively). According to multiple linear regression coefficients for these two variables (0.72 and 1.39 respectively), chondrocytic enlargement made a greater contribution to altered growth rates.

Intervertebral disc adaptation to wedging deformation.

UNLABELLED: Although scoliosis includes wedge deformities of both vertebrae and discs, little is known about the causes of the discal changes, and whether they result from mechanical influences on growth and/or remodelling. METHODS AND MATERIALS: An external apparatus attached to transvertebral pins applied compression and 15 degrees of angulation to each of two adjacent young rat caudal intervertebral discs for 5 weeks (four animals), or for 10 weeks (four animals). Each week, micro-CT scanning documented the in vivo discal wedging. After euthanasia, tail segments (three vertebrae and the 2 angulated discs) were excised and their flexibility was measured over a range of lateral bending. The angle of maximum flexibility was recorded. Then discs were fixed in situ (with the external apparatus in place) and sectioned for polarized light microscopy. RESULTS: The disc-wedging deformity averaged 15 degrees initially, it averaged 20 degrees after 5 weeks, and then reduced to 10 degrees (in 10 week animals). The lateral bending flexibility showed a distinct maximum at an average of 1.1 degrees from the in vivo position in the 5-week animals, indicating structural remodeling of the discs almost to the deformed geometry. The 10-week animals had maximum flexibility at 1.4 degrees from the in vivo position (no significant difference between 5 and 10-week animals.) Collagen crimp angles [Cassidy et al., Conn Tiss Res 1989, 23:75-88] were not significantly different between convex and concave sides, again suggesting that remodeling had occurred. CONCLUSIONS: In a mechanically induced scoliosis deformity in skeletally immature rats, the intervertebral discs underwent remodeling within 5 weeks. This indicates that this animal model is suitable for studying adaptive wedging changes in human scoliosis.