The renal outer medullary potassium (K ϩ ) channel, ROMK (Kir1.1), is a putative drug target for a novel class of loop diuretic that would lower blood volume and pressure without causing hypokalemia. However, the lack of selective ROMK inhibitors has hindered efforts to assess its therapeutic potential. In a high-throughput screen for small-molecule modulators of ROMK, we previously identified a potent and moderately selective ROMK antagonist, 7,13-bis(4-nitrobenzyl)-1,4,10-trioxa-7,13-diazacyclopentadecane (VU590), that also inhibits Kir7.1. Because ROMK and Kir7.1 are coexpressed in the nephron, VU590 is not a good probe of ROMK function in the kidney. Here we describe the development of the structurally related inhibitor 2,2Ј-oxybis(methylene)bis(5-nitro-1H-benzo-[d]imidazole) (VU591), which is as potent as VU590 but is selective for ROMK over Kir7.1 and more than 65 other potential off-targets. VU591 seems to block the intracellular pore of the channel. The development of VU591 may enable studies to explore the viability of ROMK as a diuretic target.

The inward rectifier family of potassium (Kir) channels is comprised of at least 16 family members exhibiting broad and often overlapping cellular, tissue, or organ distributions. The discovery of disease-causing mutations in humans and experiments on knockout mice has underscored the importance of Kir channels in physiology and in some cases raised questions about their potential as drug targets. However, the paucity of potent and selective small-molecule modulators targeting specific family members has with few exceptions mired efforts to understand their physiology and assess their therapeutic potential. A growing body of evidence suggests that G protein-coupled inward rectifier K (GIRK) channels of the Kir3.X subfamily may represent novel targets for the treatment of atrial fibrillation. In an effort to expand the molecular pharmacology of GIRK, we performed a thallium (Tl+) flux-based high-throughput screen of a Kir1.1 inhibitor library for modulators of GIRK. One compound, termed VU573, exhibited 10-fold selectivity for GIRK over Kir1.1 (IC50 = 1.9 and 19 μM, respectively) and was therefore selected for further study. In electrophysiological experiments performed on Xenopus laevis oocytes and mammalian cells, VU573 inhibited Kir3.1/3.2 (neuronal GIRK) and Kir3.1/3.4 (cardiac GIRK) channels with equal potency and preferentially inhibited GIRK, Kir2.3, and Kir7.1 over Kir1.1 and Kir2.1.Tl+ flux assays were established for Kir2.3 and the M125R pore mutant of Kir7.1 to support medicinal chemistry efforts to develop more potent and selective analogs for these channels. The structure–activity relationships of VU573 revealed few analogs with improved potency, however two compounds retained most of their activity toward GIRK and Kir2.3 and lost activity toward Kir7.1. We anticipate that the VU573 series will be useful for exploring the physiology and structure–function relationships of these Kir channels.

Orthopedic trauma patients demonstrated limited comprehension of their injuries, surgeries, and postoperative instructions. Patients with lower educational levels did significantly worse on the questionnaire than those with higher educational levels. The results of the study highlight a lack of comprehension within this patient population and suggest that an increased focus on patient communication by orthopedic providers may be necessary.

Background: Talus avascular necrosis (AVN) is a challenging entity to treat. Management options depend on disease severity and functional goals. Total talus replacement (TTR) is a treatment option that maintains joint range of motion. The literature on TTR is limited with variability in implant design and material. The purpose of this study was to evaluate outcomes following TTR with a custom 3D printed metal implant. Methods: Patients who underwent TTR were retrospectively reviewed over a 3-year period. Basic demographic data and comorbidities were collected. Medical records were reviewed to obtain postoperative and preoperative visual analog scale (VAS) scores, Foot and Ankle Outcome Scores (FAOSs), ankle range of motion, and postoperative complications. Statistical analysis was conducted to compare clinical and patient-reported outcomes pre- and postoperatively. Twenty-seven patients underwent TTR for talar AVN with a mean follow-up of 22.2 months. Results: Ankle range of motion remained unchanged postoperatively. VAS pain scores improved postoperatively from 7.1 to 3.9 ( P < .001). FAOSs improved postoperatively with regard to pain ( P < .001), symptoms ( P = .001), quality of life ( P < .001), and activities of daily living ( P < .001). There were 3 complications requiring reoperation in this cohort. Discussion: 3D printed TTRs represent a unique surgical option for patients with severe talar AVN. Patients in this cohort demonstrated significant improvements in pain scores and patient-reported outcomes. TTR allows for symptomatic improvement with the preservation of motion in individuals with talar collapse and AVN. Level of Evidence: Level IV, retrospective case series.