Experimental design of the Effects of Dehydroepiandrosterone in Pulmonary Hypertension (EDIPHY) trial.

Pulmonary arterial hypertension (PAH) remains life-limiting despite numerous approved vasodilator therapies. Right ventricular (RV) function determines outcome in PAH but no treatments directly target RV adaptation. PAH is more common in women, yet women have better RV function and survival as compared to men with PAH. Lower levels of the adrenal steroid dehydroepiandrosterone (DHEA) and its sulfate ester are associated with more severe pulmonary vascular disease, worse RV function, and mortality independent of other sex hormones in men and women with PAH. DHEA has direct effects on nitric oxide (NO) and endothelin-1 (ET-1) synthesis and signaling, direct antihypertrophic effects on cardiomyocytes, and mitigates oxidative stress. Effects of Dehydroepiandrosterone in Pulmonary Hypertension (EDIPHY) is an on-going randomized double-blind placebo-controlled crossover trial of DHEA in men (n = 13) and pre- and post-menopausal women (n = 13) with Group 1 PAH funded by the National Heart, Lung and Blood Institute. We will determine whether orally administered DHEA 50 mg daily for 18 weeks affects RV longitudinal strain measured by cardiac magnetic resonance imaging, markers of RV remodeling and oxidative stress, NO and ET-1 signaling, sex hormone levels, other PAH intermediate end points, side effects, and safety. The crossover design will elucidate sex-based phenotypes in PAH and whether active treatment with DHEA impacts NO and ET-1 biosynthesis. EDIPHY is the first clinical trial of an endogenous sex hormone in PAH. Herein we present the study's rationale and experimental design.

Mechanical embolectomy for acute ischemic stroke beyond six hours from symptom onset using MRI based perfusion imaging.

INTRODUCTION: There is very limited data on the use of MRI based perfusion imaging to select patients with acute ischemic stroke and large vessel occlusion (LVO) for intraarterial therapy beyond 6h from onset. Our aim is to report the outcome of patients with acute ischemic stroke and large artery occlusion who presented beyond 6h from onset, had favorable MRI imaging profile, and underwent mechanical embolectomy. METHODS: This is a single institution (Rhode Island Hospital) retrospective study between December 1st, 2015, and July 30th, 2016 that included patients with acute ischemic stroke and proximal LVO with CT ASPECTS of 6 or more and 6-24h from symptom onset who were assessed for mechanical embolectomy using MRI based perfusion imaging. Favorable imaging profile was defined based on prior studies as 1) DWI lesion volume (as defined as apparent diffusion coefficient<620×10-6mm2/s) of 70ml or less; 2) Penumbra volume (as defined by volume of tissue with Tmax>6s) of 15ml or greater; 3) A mismatch ratio of 1.8 or more; and 4) Volume of tissue with perfusion lesion with Tmax>10s is <100ml. Good outcome was defined as a 90-day mRS≤2. RESULTS: 41 patients met the inclusion criteria; 22 (53.7%) had favorable imaging profile and underwent mechanical embolectomy. The rate of good outcomes in this series was similar to that in a patient level pooled meta-analysis of the recent endovascular trials (63.6% vs. 46%, p=0.13). None of the patients in our cohort had symptomatic intracereberal hemorrhage. CONCLUSIONS: MRI perfusion based imaging may help select patients with acute ischemic stroke and proximal emergent LVO for embolectomy beyond the treatment window used in most endovascular trials. This provides compelling evidence for stroke centers to participate in ongoing trials using advanced imaging to study endovascular treatment in this patient population.

The effect of medial and lateral calcaneal osteotomies on the tarsal tunnel.

BACKGROUND: As an entrapment phenomenon, tarsal tunnel syndrome has been described after calcaneal osteotomy, and since the tibial nerve has also been shown to be very sensitive to ankle position, position of the calcaneus after osteotomy and displacement was thought to likely influence the environment of the tibial nerve within the tarsal canal. The respective volume of the tarsal canal was therefore hypothesized to decrease with medial or lateral displacement osteotomies of the calcaneus. METHODS: Anterior and posterior calcaneal osteotomies were made in cadaveric matched pairs and brought through sequential medial and lateral displacements. Magnetic resonance imaging was used to estimate the comparative resultant volume of the tarsal canal after each of these new positions were assumed, as compared with baseline. The proximity of the osteotomy cut to the nerve's location was also measured. RESULTS: The tarsal tunnel volume was calculated for all 5 displacement states and were as follows: far-lateral (9506 mm(3)), near-lateral (10 073 mm(3)), normal (11 839 mm(3)), near-medial (11 489 mm(3)), and far-medial (11 760 mm(3)). No significant difference in tarsal tunnel volume was identified between the normal, nondisplaced specimens in the anterior or posterior groups (11 954 mm(3) vs 11 809 mm(3)). No difference in tarsal tunnel volume was identified between the anterior and posterior osteotomies at any of the 4 displacements. The distance from tibial nerve to the medial exit site of the osteotomy was found to be significantly less in the anterior group compared to the posterior group (4 mm vs 14.2 mm, P < .0001). CONCLUSION: Lateral, but not medial, osteotomy fragment displacement results in significant reduction of tarsal tunnel volume. The location of the cut does not seem to affect any substantive change in volume. Anteriorly placed osteotomies appear to jeopardize the neurovascular structures more than posteriorly placed osteotomies. CLINICAL RELEVANCE: These findings provide surgeons with clinical evidence in support of performing a prophylactic tarsal tunnel release for patients undergoing lateralizing calcaneal osteotomies.