Adverse events and deterioration reported by participants in the PACE trial of therapies for chronic fatigue syndrome

Objective

Adverse events (AEs) are health related events, reported by participants in clinical trials. We describe AEs in the PACE trial of treatments for chronic fatigue syndrome (CFS) and baseline characteristics associated with them.

Methods

AEs were recorded on three occasions over one year in 641 participants. We compared the numbers and nature of AEs between treatment arms of specialist medical care (SMC) alone, or SMC supplemented by adaptive pacing therapy (APT), cognitive behaviour therapy (CBT) or graded exercise therapy (GET). We examined associations with baseline measures by binary logistic regression analyses, and compared the proportions of participants who deteriorated by clinically important amounts.

Results

Serious adverse events and reactions were infrequent. Non-serious adverse events were common; the median (quartiles) number was 4 (2, 8) per participant, with no significant differences between treatments (P = .47). A greater number of NSAEs were associated with recruitment centre, and baseline physical symptom count, body mass index, and depressive disorder. Physical function deteriorated in 39 (25%) participants after APT, 15 (9%) after CBT, 18 (11%) after GET, and 28 (18%) after SMC (P < .001), with no significant differences in worsening fatigue.

Conclusions

The numbers of adverse events did not differ significantly between trial treatments, but physical deterioration occurred most often after APT. The reporting of non-serious adverse events may reflect the nature of the illness rather than the effect of treatments. Differences between centres suggest that both standardisation of ascertainment methods and training are important when collecting adverse event data.     

The Relationships Between Obsessive–Compulsive Symptom Dimensions and Cognitions in Obsessive–Compulsive Disorder

Several studies have linked obsessive–compulsive symptoms to specific obsessive–compulsive cognitions, however methodologies have varied, and no study has determined obsessive–compulsive symptoms using the most widely used clinician rating scale, the Yale–Brown Obsessive–Compulsive Scale (Y-BOCS). Considering that almost all studies that used factor analysis to ascertain OCD symptom dimensions were based on the Y-BOCS and that self-report instruments assessing obsessive–compulsive symptoms correlate poorly with the Y-BOCS, there is a need to use the Y-BOCS to examine the relationship between obsessive–compulsive cognitions and obsessive–compulsive symptom dimensions. This study examined the relationship between five Y-BOCS-derived obsessive–compulsive symptom dimensions and the three obsessive–compulsive cognitive domains identified by the obsessive-beliefs questionnaire (OBQ). The symmetry/ordering symptom dimension was associated with increased perfectionism/intolerance of uncertainty, the unacceptable/taboo thoughts symptom dimension was associated with increased importance/control of thoughts and the doubt/checking symptom dimension was associated with increased responsibility/threat estimation. There was no statistical evidence of an association between any OBQ belief sub-scale and the hoarding symptom dimension nor the contamination/cleaning symptom dimension. The findings encourage symptom-based approaches to cognitive-behavioural therapy for some OCD symptoms and call for further research on cognitions associated with contamination/cleaning symptoms and hoarding.     

Urocortin is a novel regulator of osteoclast differentiation and function through inhibition of a canonical transient receptor potential 1-like cation channel

This study investigated the role of urocortin (UCN), a member of the corticotrophin-releasing factor (CRF) family of peptides, in osteoclast maturation and function. We found that 10(-7)?M UCN significantly (P<0.05) suppressed osteoclast differentiation from bone marrow precursor cells in culture and reduced the expression of several osteoclastic markers. Furthermore, UCN potently suppressed osteoclast bone resorption, by significantly inhibiting both the plan area of bone resorbed by osteoclasts and actin ring formation within osteoclasts at 10(-9)?M (P<0.05), with complete inhibition at 10(-7)?M (P<0.001). UCN also inhibited osteoclast motility (10(-7)?M) but had no effect on osteoclast survival. Osteoclasts expressed mRNA encoding both UCN and the CRF receptor 2β subtype. Pre-osteoclasts however, expressed CRF receptor 2β alone. Unstimulated osteoclasts contained constitutively active cation channel currents with a unitary conductance of 3-4?pS, which were inhibited by over 70% with UCN (10(-7)?M). Compounds that regulate calcium signalling and energy status of the cell, both crucial for osteoclast activity were investigated. The non-selective cation channel blockers, lanthanum (La(3)(+)) and gadolinium (Gd(3)(+)), inhibited actin ring formation in osteoclasts, whereas modulators of voltage-dependent Ca(2)(+) channels and K(ATP) channels had no effect. These findings show for the first time that UCN is a novel anti-resorptive molecule that acts through a direct effect on osteoclasts and their precursor cells.     

Opposing roles of membrane and soluble forms of the receptor for advanced glycation end products in primary respiratory syncytial virus infection

Respiratory syncytial virus (RSV), a common respiratory pathogen in infants and the older population, causes pulmonary inflammation and airway occlusion that leads to impairment of lung function. Here, we have established a role for receptor for advanced glycation end products (RAGE) in RSV infection. RAGE-deficient (ager(-/-)) mice were protected from RSV-induced weight loss and inflammation. This protection correlated with an early increase in type I interferons, later decreases in proinflammatory cytokines, and a reduction in viral load. To assess the contribution of soluble RAGE (sRAGE) to RSV-induced disease, wild-type and ager(-/-) mice were given doses of sRAGE following RSV infection. Of interest, sRAGE treatment prevented RSV-induced weight loss and neutrophilic inflammation to a degree similar to that observed in ager(-/-) mice. Our work further elucidates the roles of RAGE in the pathogenesis of respiratory infections and highlights the opposing roles of membrane and sRAGE in modulating the host response to RSV infection.