Hepatitis C virus (HCV) infects millions of people worldwide, causing chronic liver disease that can lead to cirrhosis, hepatocellular carcinoma, and liver transplant. In the last several years, the advent of direct-acting antivirals, including NS3/4A protease inhibitors (PIs), has remarkably improved treatment outcomes of HCV-infected patients. However, selection of resistance-associated substitutions and polymorphisms among genotypes can lead to drug resistance and in some cases treatment failure. A proactive strategy to combat resistance is to constrain PIs within evolutionarily conserved regions in the protease active site. Designing PIs using the substrate envelope is a rational strategy to decrease the susceptibility to resistance by using the constraints of substrate recognition. We successfully designed two series of HCV NS3/4A PIs to leverage unexploited areas in the substrate envelope to improve potency, specifically against resistance-associated substitutions at D168. Our design strategy achieved better resistance profiles over both the FDA-approved NS3/4A PI grazoprevir and the parent compound against the clinically relevant D168A substitution. Crystallographic structural analysis and inhibition assays confirmed that optimally filling the substrate envelope is critical to improve inhibitor potency while avoiding resistance. Specifically, inhibitors that enhanced hydrophobic packing in the S4 pocket and avoided an energetically frustrated pocket performed the best. Thus, the HCV substrate envelope proved to be a powerful tool to design robust PIs, offering a strategy that can be translated to other targets for rational design of inhibitors with improved potency and resistance profiles. IMPORTANCE Despite significant progress, hepatitis C virus (HCV) continues to be a major health problem with millions of people infected worldwide and thousands dying annually due to resulting complications. Recent antiviral combinations can achieve >95% cure, but late diagnosis, low access to treatment, and treatment failure due to drug resistance continue to be roadblocks against eradication of the virus. We report the rational design of two series of HCV NS3/4A protease inhibitors with improved resistance profiles by exploiting evolutionarily constrained regions of the active site using the substrate envelope model. Optimally filling the S4 pocket is critical to avoid resistance and improve potency. Our results provide drug design strategies to avoid resistance that are applicable to other quickly evolving viral drug targets.

Carcinomatous pericarditis is a rare complication of locally aggressive breast cancer in which malignant cells directly extend into the pericardium causing inflammation and creating a pericardial effusion. A 40year-old woman with untreated metastatic breast cancer presented to an outpatient clinic in significant distress with symptoms of progressive shortness of breath and bilateral leg swelling. An urgent echocardiogram demonstrated a large pericardial effusion with echocardiographic evidence of cardiac tamponade. She underwent emergent pericardiocentesis of the effusion that was deemed to be malignant after cytologic evaluation. Subsequently, she opted for palliative treatment involving the surgical creation of a right pericardial window and placement of an indwelling pleural catheter. Internists should maintain a high index of suspicion for malignant cardiac tamponade in at-risk patients, especially those with locally aggressive and advanced malignancies.

Background: Hypersplenism, portal hypertension, and ascites have been seen after liver transplants. Patients are usually treated medically with refractory patients potentially undergoing splenectomy. Splenic artery embolism (SAE) is an alternative that can be performed to limit the surgical intervention that may have the benefit of improving portal hypertension. Few studies have studied the effect on main portal vein (MPV) velocities and hepatic artery resistive indices (HARIs) which may be beneficial as markers of portal hypertension. Purpose: This study aims to evaluate the efficacy and safety of interventional radiology (IR)-guided SAE for the management of portal hypertension in patients who have had liver transplants. Methods: A retrospective analysis was conducted on liver transplant patients who had undergone IR-guided SAE post-transplant at a single tertiary transplant center from 2012 to 2022. The primary outcome of intervention efficacy was quantified by peak HARIs and MPV velocities. Ultrasound with Doppler obtained before and after the intervention was reviewed for these parameters. Secondary outcomes included adverse events at the time of the procedure and within one year of the procedure, the need for splenectomy, and spleen size. Results: Twenty-eight patients met the criteria for inclusion. The mean age of patients was 52.5 years (21-71 years) and the time after transplant was 149.5 days (2-1588 days). About 96.4% of SAEs were technically successful (n=27). Twenty-one patients had MPV velocities available, and 24 had peak HARIs available. In these patients, HARIs decreased by an average of 0.063 (95% CI 0.014-0.112) after SAE. MPV velocity decreased by an average of 47.2 cm/s (95% CI 27.3-67.1) after SAE. About 10.4% of patients (n=3) developed a procedure-related complication, all of which were femoral access site aneurysms. No (0) patients suffered from bleeding, infections, or abscesses after the procedure. About 10.7% of patients (n=3) required splenectomy after SAE: one splenectomy was due to technical failure and two were due to refractory symptoms. Conclusion: We performed one of the first analyses on MPV and RI and showed that our patients saw an improvement post-embolization with a theoretical improvement in portal hypertension. The complication rate and risk of infection seem to be acceptable risks, making SAE a feasible option for management.

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contributed equally to this work. Author order was determined both alphabetically and in order of decreasing seniority.