Thoracic Endovascular Aortic Repair in the Setting of Compromised Distal Landing Zones.

BACKGROUND: The short-term and intermediate-term outcomes of two distinct approaches to thoracic endovascular aortic repair (TEVAR) for descending aortic aneurysms in patients with compromised distal landing zones are reported. METHODS: Fifty-one patients (38 female, average age 72 ± 9 years) underwent 55 TEVARs (2008 to 2018) for aneurysmal disease. Inclusion criteria consisted of TEVAR in a compromised distal landing zone, defined as follows: diameter 3.5 cm or greater; cross-sectional thrombus 50% or greater; or 25% or greater circumferential mural calcification in the 2 cm supraceliac aorta; or tortuosity index of 1.1 or more over the 10 cm supraceliac aorta. Treatment cohorts were (1) TEVAR alone (n = 29), and (2) TEVAR with adjunct consisting of visceral snorkel graft with distal stent extension (n = 20) or EndoAnchors (Medtronic, Minneapolis, MN [n = 6]). RESULTS: Perioperative complication rate was 20%. Thirty-day mortality was 5% including one access-site related intraoperative death and one postoperative death from embolic mesenteric ischemia. Median clinical follow-up was 2.2 years. Intermediate-term outcomes include type 1B endoleaks, 35%; 0.5 cm or more per year maximal aortic diameter growth, 9%; reintervention, 15%; and all-cause mortality, 25%. The distal landing zone diameter increased by 0.3 cm per year in the TEVAR alone cohort; however, it decreased by 0.1 cm per year in the adjunct cohort ( P = .04). CONCLUSIONS: Thoracic endovascular aortic repair is a viable alternative for the treatment of thoracoabdominal aortic aneurysms in patients with compromised distal landing zones, although these patients may benefit significantly from the development of branched thoracoabdominal devices. In the interim, the use of TEVAR adjuncts may limit progressive degeneration of the distal landing zone in this patient population.

Discovery of Orally Bioavailable and Liver-Targeted Hypoxia-Inducible Factor Prolyl Hydroxylase (HIF-PHD) Inhibitors for the Treatment of Anemia.

We report herein the design and synthesis of a series of orally active, liver-targeted hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitors for the treatment of anemia. In order to mitigate the concerns for potential systemic side effects, we pursued liver-targeted HIF-PHD inhibitors relying on uptake via organic anion transporting polypeptides (OATPs). Starting from a systemic HIF-PHD inhibitor (1), medicinal chemistry efforts directed toward reducing permeability and, at the same time, maintaining oral absorption led to the synthesis of an array of structurally diverse hydroxypyridone analogues. Compound 28a was chosen for further profiling, because of its excellent in vitro profile and liver selectivity. This compound significantly increased hemoglobin levels in rats, following chronic QD oral administration, and displayed selectivity over systemic effects.

Design of Potent and Orally Active GPR119 Agonists for the Treatment of Type II Diabetes.

We report herein the design and synthesis of a series of potent and selective GPR119 agonists. Our objective was to develop a GPR119 agonist with properties that were suitable for fixed-dose combination with a DPP4 inhibitor. Starting from a phenoxy analogue (1), medicinal chemistry efforts directed toward reducing half-life and increasing solubility led to the synthesis of a series of benzyloxy analogues. Compound 28 was chosen for further profiling because of its favorable physicochemical properties and excellent GPR119 potency across species. This compound exhibited a clean off-target profile in counterscreens and good in vivo efficacy in mouse oGTT.

Hematoma volume as the major determinant of outcomes after intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is a leading cause of morbidity and mortality, greatly linked to hematoma volume. Understanding the characteristics and size of hematoma is integral to evaluating severity and prognosis after ICH. Examination of the literature suggests that markers for hematoma size vary, but the key range between 20-30 mL is most widely used as the cut-off for classification of hematoma volume. The role of hematoma volume in episodes of hematoma expansion and re-bleeding further impact outcomes, with increased growth associated with larger hematoma volume. Additionally, many commonly used predictors of ICH outcomes are directly related to hematoma volume, implicating it as an important variable when determining outcomes. In conclusion, hematoma volume is likely the most significant determinant of outcomes in intracerebral hemorrhage.