Novel Small Molecule ROCK2 Inhibitor GNS-3595 Attenuates Pulmonary Fibrosis in Preclinical Studies.

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease that leads to respiratory decline due to scarring and thickening of lung tissues. Multiple pathways contribute to the fibrotic process in this disease, such as inflammation, epithelial to mesenchymal transition and oxidative stress. The RhoA/ROCK signaling pathway is a key regulator of profibrotic signaling, as it affects the organization of actin-myosin and the remodeling of the extracellular matrix. ROCK1/2, a downstream effector of RhoA, is overexpressed in IPF patients and is a promising target for IPF therapy. However, due to hypotensive side effects of ROCK1/2 inhibitors, selective ROCK2 compounds are being explored. In this study, we report the discovery of GNS-3595, a potent and selective ROCK2 inhibitor that has ~80-fold selectivity over ROCK1 at physiological concentrations of ATP. GNS-3595 effectively inhibited ROCK2-mediated phosphorylation of myosin light chain (p-MLC) and reduced the expression of fibrosis-related proteins, such as collagen, fibronectin, and alpha-smooth muscle actin (α-SMA) in various in vitro cellular models. GNS-3595 also prevented transforming growth factor beta (TGF-ß)-induced fibroblast-to-myofibroblast transition (FMT). Additionally, in a bleomycin-induced mouse model of pulmonary fibrosis, therapeutic exposure to GNS-3595, suppressed lung fibrosis, stabilized body weight loss, and prevented fibrosis-induced lung weight gain. Transcriptome and protein expression analysis from lung tissues showed that GNS-3595 can revert the fibrosis-related gene expression induced by bleomycin. These results indicate that GNS-3595 is a highly potent, selective, and orally active ROCK2 inhibitor with promising therapeutic efficacy against pulmonary fibrosis.

Treatment of a Delayed Type IIIb Endoleak 20 Years Post EVAR With Inverted Contralateral Limb Custom-Made Device: A Case Report.

PURPOSE: Type III endoleak can be difficult to distinguish from Type I endoleak. Depending on the stent graft anatomy, the use of standard bifurcated endografts may not be technically feasible, and patients may have to be subject to an aorto-uni-iliac repair with femoral-femoral bypass or open surgery. CASE REPORT: We report a case of an 86-year-old male who had a Type IIIb endoleak 20 years post EVAR which was characterized on angiography to be from a hole close to the bifurcation limb origin. The initial Talent (Medtronic, Santa Rosa, California) device had a 50 mm main body common trunk, which was not amenable to treatment with standard devices. He was successfully treated with a custom-made device with an inverted contralateral limb. CONCLUSIONS: Our case highlights the need for lifelong surveillance post EVAR as endoleak may present decades post initial EVAR. It also demonstrates that many Type III endoleak which were otherwise deemed unsuitable for treatment with standard devices may potentially be treatable with custom-made device (CMD). This solution preserves a percutaneous option in a now older person which avoids surgical bypass. Further studies are required to establish the durability of this treatment and survey for recurrence.

Are salvage techniques safe and effective in the treatment of peritoneal dialysis catheter-related exit-site and tunnel infections? A systematic review and description of the authors' preferred technique.

BACKGROUND: Peritoneal dialysis catheter (PDC)-related infections account for significant morbidity, PD disruptions and costs. Patients with refractory exit-site or tunnel track infections without peritonitis may need catheter removal and reinsertion which can be complicated by bleeding, organ injury, catheter failure or malposition. Some patients may need to switch to haemodialysis in such a setting. An alternative is a salvage procedure. The purpose of this systematic review is to evaluate the safety and efficacy of salvage techniques. METHODS: A comprehensive search of PubMed, Medline and Scopus databases was performed from inception to December 2021 in accordance with PRISMA guidelines. After a broad search, articles were stratified into two main categories for assessment: (1) cuff-shaving (CS) techniques and its variations of en-bloc resection (BR) and/or catheter diversion (CD) and (2) partial reimplantation with CD. RESULTS: A total of 409 patients (445 salvage procedures) from 20 studies were included in analysis. Of 409 patients, 234 patients (57.2%) underwent 251 (56.4%) CS procedures and its variations, 163 patients (39.9%) underwent 182 (40.9%) partial PDC reimplantations with CD and 12 patients (2.7%) underwent local curettage. Overall PDC salvage rate after intervention was 73.2%. Overall PDC removal rate attributable to infection was 26.8%. Overall complication rate attributable to the procedures was 2.7%, with the most common complication being dialysate leakage (n = 10) followed by PDC laceration (n = 1) and subcutaneous haematoma (n = 1). We also included a description of our technique of BR of infected tissue, CS and CD. In a series of six patients, the PDC salvage rate was 83.3% and median PDC survival after intervention was 10 months. CONCLUSION: PDC salvage techniques are relatively safe and provide reasonable catheter salvage rates in selected patients. Results of this review should lend weight to consideration of a salvage-first approach as an option in selected patients.

Endoleak Complicated by communicating psoas abscess and aorto-enteric fistula in an immunocompromised patient.

PURPOSE: While endovascular repair of aortic aneurysm (EVAR) has become the mainstay treatment for abdominal aortic aneurysm (AAA), it is not without its disadvantages. Feared complications include graft infections, fistulation and endoleak, the outcomes of which may be life limiting. CASE REPORT: We present a case of a 57 year-old patient with human immunodeficiency virus (HIV) previously treated with EVAR for AAA complicated by endoleak post treatment. He developed an aorto-psoas abscess 2 years later which harboured Mycobacterium avium complex, and medical therapy was unsuccessful. He eventually underwent an extra-anatomical bypass and graft explant, for which an aortoenteric fistula was also discovered and repaired. CONCLUSION: Infection of endografts post EVAR is relatively rare, and there are presently no guidelines concerning its management. The concomittance of aorto-psoas abscess and aortoenteric fistula is even more uncommon, and necessitated surgical explant for source control purposes in our patient. Lifelong surveillance is required for complications of the aortic stump and bypass patency.

Rare case of gallbladder mucocele causing gastric outlet obstruction treated with cholecystectomy.

INTRODUCTION: Gallstone(s) impacted at the distal small bowel causing intestinal obstruction as a result of cholecystoenteric fistula is a well-known, albeit uncommon surgical condition. The rare Bouveret's Syndrome, which refers to the proximal impaction of gallstone(s) in the duodenum or pylorus resulting in the gastric outlet obstruction (GOO), has also been described in the literature. However, gallbladder mucocele with extrinsic compression of the duodenum and/or pylorus causing GOO is a separate entity that is extremely rare. PRESENTATION OF CASE: A patient who presented with loss of appetite and weight, with intermittent vomiting over a course of eight months was found to have GOO secondary to extrinsic duodenal compression from a large gallbladder mucocele. Surgical intervention in the form of cholecystectomy was performed, and the patient's symptoms resolved post-operatively. DISCUSSION: We describe an extremely rare case of GOO, which can be easily corrected with cholecystectomy. Removal of the gallbladder removes the root cause of the issue, and should be first line therapy unless the patient is unfit for surgery. CONCLUSION: This extremely rare cause of GOO should be recognized, and treated promptly with surgery if possible.

Endovascular Aneurysm Repair (EVAR) of an Infrarenal Abdominal Aortic Aneurysm (AAA) in a Young Patient with Systemic Lupus Erythematosus (SLE).

INTRODUCTION: While hypertension, pericardial, myocardial, and coronary artery disease are common cardiovascular manifestations of systemic lupus erythematosus (SLE), aortic aneurysms (AA) are rare but increasingly diagnosed, with the true incidence unknown. CASE REPORT: A 40 year old female suffering from SLE with a 5.3 cm saccular eccentric infrarenal abdominal aortic aneurysm (AAA) was treated successfully with endovascular aneurysm repair (EVAR) using the Medtronic Endurant II bifurcated stent graft and followed up 2 years post-operatively. Pre-operatively, open and EVAR options were offered and the latter was chosen by the patient. DISCUSSION: Proposed mechanisms for AA formation in SLE including accelerated atherosclerosis brought about by chronic steroid use and SLE associated vasculitis and cystic medial degeneration (CMD) have been discussed in other case reports and series. To the authors' knowledge, the use of EVAR for AAA in SLE patients has not been reported in available literature. The need for earlier repair, screening, and detection as well as the long-term suitability, durability, and surveillance of EVAR remain unknown. The benefit of using the Ovation device in minimising late neck dilatation is also discussed. CONCLUSION: EVAR was demonstrated to be a suitable form of repair in a young female patient with SLE and AAA, followed up 2 years post-surgery. The ideal repair and the natural history of these aneurysms remains to be studied.

Risk of intracerebral hemorrhage in patients with cerebral microbleeds undergoing endovascular intervention.

BACKGROUND AND PURPOSE: Cerebral microbleeds (CMBs) on MRI gradient echo images are hemosiderin deposits, which may predict intracerebral hemorrhage (ICH). The risk of ICH in patients with CMBs could be exacerbated by the use of antithrombotics. The purpose of our study is to prospectively evaluate the risk of ICH in patients with ischemic stroke who receive dual antiplatelet therapy for endovascular intervention. METHODS: We analyzed MRI of 133 patients admitted consecutively for intra- and extracranial stenting for symptomatic large artery atherosclerosis who received aspirin and clopidogrel. Quantity and location of CMBs were recorded by neuroradiologists independent from the angioplasty team. The primary end point was symptomatic ICH as evident in CT of the brain within 12 weeks of procedure. RESULTS: CMBs were identified in 23 patients. Mean number of CMBs was 2.3 ± 1.6. Four patients had >5 CMBs. Forty-seven patients had intracranial stents, 84 patients had extracranial stents, and 2 patients had both intracranial and extracranial stents. There was no difference in risk of symptomatic ICH between those with (4.3%) and without CMBs (5.5%) patient with CMBs (P=1.000). CONCLUSIONS: The presence of a small number of CMBs does not cause a large increase in the short-term risk of symptomatic ICH in patients with ischemic stroke who undergo endovascular intervention with dual antiplatelet therapy. The risk of ICH in patients with ≥ 5 CMBs, however, remains unclear. Further studies with a larger sample size of patients with multiple CMBs are needed.