Assessment of digital perfusion as a surrogate outcome in Raynaud's phenomenon clinical trials.

OBJECTIVES: Measurement of digital perfusion, sometimes coupled with a cold challenge, has been widely used as an objective outcome in trials evaluating drug therapies in Raynaud's Phenomenon (RP), in addition to patient-reported outcomes or to establish the proof-of-concept in preliminary studies. However, whether digital perfusion is a valid surrogate for clinical outcomes in RP trials has never been explored. The principal aim of this study was to evaluate the potential surrogacy of digital perfusion, by combining individual-level and trial-level data. METHODS: We used individual data from a series of n-of-1 trials, and trial data from a network meta-analysis. We estimated individual-level surrogacy through coefficients of determination between digital perfusion and clinical outcomes (R2ind). We further calculated the coefficients of determination between treatment effect on the clinical outcomes and on digital perfusion, at the individual level (R2TEInd) and at the trial level (R2trial), using non-weighted linear regression, with their 95% CI calculated through bootstrapping. RESULTS: Results from 33 patients and 24 trials were included in the final analysis. At the individual level, there was no correlation between digital perfusion and clinical outcomes at rest and in response to various cooling tests (the highest R2ind was 0.03 [-0.07; 0.09]), and R2TEinf was also very low 0.07 [0; 0.29]. At the trial level, the highest value of R2trial was 0.1 [0; 0.477]. CONCLUSIONS: Digital perfusion, at rest or in response to a cold challenge, and whatever the method used, does not fulfill the criteria of a valid surrogate for existing patient-reported outcomes in RP trials.

Anatomical variations in distal portion of the thoracic duct-A systematic review.

The objective of this study was to identify and analyze the anatomical variations in the termination of the thoracic duct (TD) in cadavers or patients by anatomical dissections and surgical or radiological procedures for better knowledge of the interindividual variations through a systematic review. The search strategy included PubMed and reference tracking. Studies were identified by searching the electronic Medline databases. The search terms included "TD," "Jugular Vein," "Subclavian Vein," or "Cervical," and the protocol used is reported herein. These search results yielded 20 qualitative review articles out of the 275 articles consulted. We collected all the important data from these 20 articles with 1,352 TD analyzed by varying sources in our search. Regarding the characteristics of the studies and the anatomy of the TD, the results were heterogeneous. The TD most commonly terminates in the internal jugular vein in 54.05% of cases (95% confidence interval [CI]: 54.03; 54.07), in the jugular-venous angle in 25.79% (95% CI: 25.77; 25.81), and in the subclavian vein in 8.16% of cases (95% CI: 8.14;8.18). Other terminations were found in 12% of cases. This systematic review provided an overview of the variations in the distal portion of the TD. This study can be helpful for surgeons in selecting the most appropriate methods to achieve successful surgical results and avoid complications, such as chylothorax; it also offers detailed information on the cervical termination of the TD in new diagnostic and therapeutic methods involving the TD. Clin. Anat. 32:99-107, 2019. © 2019 Wiley Periodicals, Inc.

Impact of Bariatric Surgery on Medication Efficacy: an Analysis of World Health Organization Pharmacovigilance Data.

Bariatric surgery is the most effective treatment of severe obesity. However, this surgery can have an impact on the bioavailability and metabolism of oral drugs as it modifies absorption, intestinal, and hepatic metabolism, and efflux transporter activity. The clinical impact of such modifications often remains unknown. To investigate, we extracted and summarized all reports of changes in drug efficacy associated with bariatric surgery registered in the WHO pharmacovigilance database. We identified 165 drug reports affecting 128 patients. The majority involved gastric bypass surgery (77.3%). Most reports concerned drug ineffectiveness (74.7%). The most frequent modifications concerned psychotropic drugs with a reduction in efficacy. This study underlines the urgent need for more research to better characterize the impact of bariatric surgery on drug pharmacokinetics and clinical efficacy.

Treprostinil Hydrogel Iontophoresis in Systemic Sclerosis-Related Digital Skin Ulcers: A Safety Study.

Digital skin ulcers are a severe complication of systemic sclerosis. The first-line treatment is intravenous iloprost, but it induces dose-limiting adverse effects. Local administration of treprostinil through skin iontophoresis may be a safe alternative. We conducted a 2-stage, randomized, placebo-controlled single-ascending-dose study in healthy volunteers and patients with systemic sclerosis-related digital ulcer. We further explored the effect of the procedure on skin blood flux. In a first group of healthy subjects, treprostinil and placebo iontophoresis were performed at 3 locations (ie, 6 skin sites): the sole of the foot, the leg, and the fingers. We used a 1-mg/mL hydrogel of treprostinil. We then randomly treated systemic sclerosis-related digital ulcers in a 3:1 ratio of treprostinil or placebo. We used concentrations from 0.1 to 1 mg/mL. All adverse events were recorded and rated according to the Common Terminology Criteria for Adverse Events (CTCAE), whereas skin microvascular blood flux was recorded with laser speckle contrast imaging. Among the 12 healthy volunteers, we observed 60 local adverse effects: burns, skin pain, erythema, and pruritus, graded 1 or 2 on the 5-point CTCAE scale. Treprostinil iontophoresis significantly increased skin blood flux on the leg (AUC0-4 h at 88 460% ± 6436% versus 12 730% ± 3397% baseline flux.min respectively; P < .001) and on the sole of the foot (AUC0-3 h at 20 124% ± 6119% versus 3142% ± 3036% baseline flux.min, respectively; P = .018) with a trend on the finger. Among 5 patients with systemic sclerosis-related digital ulcer, 2 resolutive local adverse effects were reported. Iontophoresis of treprostinil hydrogel was safe in systemic sclerosis patients with digital ulcer.

French translation and linguistic validation of the Raynaud's condition score.

The Raynaud's condition score is a 11-point scale severity score used in Raynaud's phenomenon clinical trials since 1998. The Raynaud's condition score diary has been recommended for use in clinical trials assessing efficacy of interventions on scleroderma related Raynaud's phenomenon. However, this score has never been formally validated in French. We thus performed a translation and a linguistic validation of the Raynaud's condition score through a forward/backward translations process followed by an expert review and cognitive patient interviews. The translations led to a French version of the Raynaud's condition score that was linguistically valid, and conceptually equivalent to the original English version. This "Score de Raynaud" will be usable to perform and harmonize clinical trials in French-speaking patients with secondary Raynaud's phenomenon.