Real-World Experience With Apremilast in the Treatment of Adults With Moderate to Severe Plaque Psoriasis in Québec: A Claims-Based Analysis of Drug Utilization and Healthcare Resource Utilization.

BACKGROUND: In Québec, targeted biologic therapies for moderate to severe plaque psoriasis are restricted to patients who have not responded to phototherapy or conventional systemic treatment, primarily due to high drug costs. Apremilast, an oral treatment for plaque psoriasis, was added to the Québec provincial health insurance plan (Régie de l'assurance maladie du Québec; RAMQ) formulary in 2015, making this the only province in Canada with public drug plan reimbursement for apremilast. OBJECTIVES: The aim of this study is to describe patients' characteristics, treatment patterns, healthcare resource utilization (HCRU), and associated costs and to measure real-world budget impact of using apremilast before biologics in plaque psoriasis. METHODS: This study was performed using RAMQ drug claims and medical services data. Patients diagnosed with psoriasis between January 2015 and December 2017 were identified. Medical services and prescription claims were categorized as all-cause and psoriasis-related. Using RAMQ database estimates, a 3-year budget impact analysis was developed comparing treatment cost with and without the addition of apremilast to the formulary. RESULTS: In all, 540 patients were identified (apremilast: n = 92; biologics: n = 448). Comorbidity burden and treatment persistence and adherence were comparable between apremilast and biologic users. The year following the index date, all-cause HCRU was lower for apremilast versus biologic users (CAN$19 763 vs CAN$28 025; P < .01), mainly driven by drug cost. Using apremilast before biologics resulted in an estimated RAMQ net savings of CAN$49 290 (2015), CAN$746 856 (2016), and CAN$1 216 512 (2017), and a total savings of CAN$2 012 658 since apremilast's addition to the formulary. CONCLUSION: Adding apremilast to the drug formulary of other Canadian provinces could result in significant healthcare savings.

Early diaphragm pacing in patients with amyotrophic lateral sclerosis (RespiStimALS): a randomised controlled triple-blind trial.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder associated with respiratory muscle weakness and respiratory failure. Non-invasive ventilation alleviates respiratory symptoms and prolongs life, but is a palliative intervention. Slowing the deterioration of diaphragm function before respiratory failure would be desirable. We aimed to assess whether early diaphragm pacing could slow down diaphragm deterioration and would therefore delay the need for non-invasive ventilation. METHODS: We did a multicentre, randomised, controlled, triple-blind trial in patients with probable or definite ALS in 12 ALS centres in France. The main inclusion criterion was moderate respiratory involvement (forced vital capacity 60-80% predicted). Other key eligibility criteria were age older than 18 years and bilateral responses of the diaphragm to diagnostic phrenic stimulation. All patients were operated laparoscopically and received phrenic stimulators. Clinicians randomly assigned patients (1:1) to receive either active or sham stimulation with a central web-based randomisation system (computer-generated list). Investigators, patients, and an external outcome allocation committee were masked to treatment. The primary outcome was non-invasive ventilation-free survival, analysed in the intention-to-treat population. Safety outcomes were also assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01583088. FINDINGS: Between Sept 27, 2012, and July 8, 2015, 74 participants were randomly assigned to receive either active (n=37) or sham (n=37) stimulation. On July 16, 2015, an unplanned masked analysis was done after another trial showed excess mortality with diaphragm pacing in patients with hypoventilation (DiPALS, ISRCTN 53817913). In view of this finding, we analysed mortality in our study and found excess mortality (death from any cause) in our active stimulation group. We therefore terminated the study on July, 16, 2015. Median non-invasive ventilation-free survival was 6·0 months (95% CI 3·6-8·7) in the active stimulation group versus 8·8 months (4·2-not reached) in the control (sham stimulation) group (hazard ratio 1·96 [95% CI 1·08-3·56], p=0·02). Serious adverse events (mainly capnothorax or pneumothorax, acute respiratory failure, venous thromboembolism, and gastrostomy) were frequent (24 [65%] patients in the active stimulation group vs 22 [59%] patients in the control group). No treatment-related death was reported. INTERPRETATION: Early diaphragm pacing in patients with ALS and incipient respiratory involvement did not delay non-invasive ventilation and was associated with decreased survival. Diaphragm pacing is not indicated at the early stage of the ALS-related respiratory involvement. FUNDING: Hospital Program for Clinical Research, French Ministry of Health; French Patients' Association for ALS Research (Association pour la Recherche sur la Sclérose Latérale Amyotrophique); and Thierry de Latran Foundation.

Lack of Analgesic Effect Induced by Ropivacaine Wound Infiltration in Thyroid Surgery: A Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Surgical site infiltration with local anesthetic reduces analgesic requests in various types of surgeries. Because thyroid surgery may induce severe postoperative pain, we tested the hypothesis that ropivacaine surgical site infiltration would significantly decrease postoperative administration of morphine in patients undergoing thyroid surgery. METHODS: We performed a double-blind, placebo-controlled superiority trial to assess the efficacy of surgical site analgesia with ropivacaine (10 mL, 75 mg) performed at the end of thyroid surgery in adult patients. The primary end point was the proportion of patients not requiring IV morphine in the postanesthesia care unit. RESULTS: One hundred sixty-three patients completed the study, 85 in the placebo group and 88 in the ropivacaine group. The proportion of patients requiring morphine administration in the postanesthesia care unit (55% vs 53%, P = 0.80), the dose of IV morphine administered (5.6 ± 6.1 vs 5.5 ± 6.0 mg, P = 0.90), the total dose of opioids administered (expressed as oral morphine equivalent dose: 64 ± 27 vs 69 ± 29 mg, P = 0.20), and the visual analog pain scale over the first 24 hours were not significantly different between groups. The incidence of adverse events (36% vs 39%, P = 0.88), morphine-related adverse events (19% vs 17%, P = 0.84), serious adverse events (0% vs 2%, P = 0.50), and the patient satisfaction scores (9 ± 1 vs 9 ± 1, P = 0.70) was not significantly different between the 2 groups. CONCLUSIONS: Surgical site analgesia with ropivacaine at the end of thyroid surgery is not associated with any significant analgesic benefit.

Randomized controlled trial of alfacalcidol supplementation for the reduction of hypocalcemia after total thyroidectomy.

BACKGROUND: The aim of this study was to evaluate the effect of perioperative alfacalcidol on postoperative hypocalcemia after total thyroidectomy. METHODS: A total of 219 patients scheduled for total thyroidectomy were randomized into groups not receiving (group A) or receiving (group B) perioperative alfacalcidol. Postoperative hypocalcemia was compared between groups on postoperative day (POD) 1 and POD2. Patients with hypocalcemia (<2.00 mmol/L) received oral calcium supplementation. Calcium and vitamin D levels were measured at 5-week and 6-month follow-ups. RESULTS: The incidence of symptomatic hypocalcemia was significantly lower in group A (P = .02), whereas similarly low levels of calcemia were observed in both groups on POD1 (37% and 30%, respectively; P = not significant) and persisted on POD2 (14% and 6%, respectively; P = not significant). Patients with severe hypocalcemia (<1.90 mmol/L) showed faster recovery in group A compared with group B (6% vs 1%, P = .04). At 5 weeks, calcium and vitamin D levels were similar between the groups. Six months after surgery, 4% (group A) versus 0% (group B) of subjects exhibited permanent hypoparathyroidism (P = .04). CONCLUSIONS: Although the treatment did not correct vitamin D deficiency, perioperative alfacalcidol uptake resulted in decreased transient hypocalcemia and related symptoms in patients undergoing total thyroidectomy.

Investigating transcriptional regulation by fluorescence spectroscopy, from traditional methods to state-of-the-art single-molecule approaches.

Gene expression regulation, in particular at the level of transcription, has been demonstrated to play a key role in the development of human diseases, including cancer, and in bacteria it is crucial for proliferation as well as for pathogenicity. Transcriptional regulation is based on complex networks of interactions, including those of the regulatory proteins with the operator DNAs, which are further modulated by ligands. Thus, understanding transcriptional regulation mechanisms requires a thorough analysis of the physical parameters underlying the interactions involved. Among the panoply of methods available, fluorescence spectroscopy-based approaches have been widely used for the assessment of the thermodynamics and structural dynamics of biomolecular interactions. Here we will discuss the application of three fluorescence spectroscopy methods--fluorescence anisotropy and fluorescence correlation and cross-correlation spectroscopy--for the investigation of protein-DNA, protein-protein, and protein-ligand interactions. The weaknesses and the strengths of each method will be highlighted on the basis of our experience in the analysis of the interactions of bacterial repressors implicated in transcriptional regulation in bacilli.

Time-resolved fluorescence anisotropy studies show domain-specific interactions of calmodulin with IQ target sequences of myosin V.

Single cysteine mutants of calmodulin, Cam(S38C) and Cam(N111C), have been specifically labelled with Alexa488 maleimide to study the effects of calcium on the structural dynamics of calmodulin complexed with IQ3, IQ4 and IQ34 target peptide motifs of mouse unconventional myosin-V. Using phase fluorometry, the time-resolved anisotropy shows well-separated global and segmental correlation times. The calcium-sensitive global motion of either calmodulin domain can be independently monitored in domain-specific interactions of either apo- or Ca(4).calmodulin with IQ3 or IQ4 peptides. C-domain interactions predominate, and apo-N-domain interactions are unexpectedly weak. The 1:1 complex of Ca(4).calmodulin with IQ34 behaves as a compact globular species. The results demonstrate novel dynamic aspects of calmodulin-IQ interactions relating to the calcium regulation of motility of unconventional myosin.