Rhodium-Catalyzed Synthesis of 2-Methylindoles via C-N Bond Cleavage of N-Allylbenzimidazole.

A rhodium-catalyzed oxidative C-H/N-H dehydrogenative [3 + 2] annulation strategy has been reported between anilines and N-allylbenzimidazole for the synthesis of 2-methylindole scaffolds. An N-allylbenzimidazole has been used as a 2C synthon for the synthesis of indole, and more importantly, this transformation involves the cleavage of the thermodynamically stable C-N bond of allylamine. Detailed mechanistic studies have been performed and a key intermediate was detected in HRMS. This transformation proceeds through a cascade of C(sp2)-H allylation followed by intramolecular cyclization.

Annulation of Indole-2-Carboxamides with Bicycloalkenes Catalyzed by Ru(II) at Room Temperature: An Easy Access to ß-Carboline-1-one Derivatives under Mild Conditions.

Herein, we report the annulation of indole-2-carboxamides with bicycloalkenes, to synthesize ß-carboline-1-one derivatives under mild conditions. The commercially available ruthenium catalyst was used for the reaction. This reaction tolerates a wide range of functional groups and affords a good yield of ß-carboline-1-one derivatives. A reversible cyclometalation pathway was found to be operative in the mechanistic study.

Pyridone Directed Ru-Catalyzed Olefination of sp2(C-H) Bond Using Michael Acceptors: Creation of Drug Analogues.

Herein, the ruthenium-catalyzed regioselective sp2(C-H) monoalkenylation of N-arylpyridones has been demonstrated, where the pyridone was utilized as a weakly coordinating directing group. Importantly, the current methodology has been effectively applied to the synthesis of many drug analogues such as pirfenidone, naproxen, ibuprofen, geraniol, umbelliferone, pregnenolone, and estrone. This methodology tolerates a wide range of functional groups and yields up to 93% yield. A six-membered ruthenium complex was also detected by HRMS.

Descriptive Study on Vascular Anatomy of the Upper Lip.

INTRODUCTION: The superior labial artery (SLA) is a facial artery (FA) that drains into the peri-oral region (dangerous area of face). Owing to the recent rise in the demand for reconstructive procedures and filler injections in this region, it is important to understand its arterial topography. This paper aims to study the embranchment pattern of the labial arteries in the eastern Indian population. METHOD: An observational study using conventional dissection and dry dye injection methods was conducted to visualize the facial and superior labial arteries in 56 hemifaces. The origin, morphometry (length and diameter), branching pattern, and termination of the arteries were recorded and compared with the existing data. RESULTS: Two hemifaces were excluded from analysis (vessels damaged in dissection); in the remaining 54, a single SLA was present in all samples originating at a mean distance of 1.29 ± 0.32 cm from oral commissure (68.51% originating above). Lee type II (independent SLA giving off alar branch) was the predominant pattern (56.2%), followed by type I (independent SLA and alar branches, 33%) and type III (FA terminating as SLA, 10.8%). The average length of SLA was 4.75 ± 1.28 cm and 4.56 ± 0.78 cm on the right and left sides, respectively. CONCLUSION: The SLA is highly variable in occurrence, course, and depth, sometimes even occurring unilaterally; therefore, any intervention in this region should be done with caution. Since the SLA was not found subcutaneously at the vermillion border, the intradermal and the subcutaneous injections used here are relatively safer. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Cobalt(III)-Catalyzed C-6 Alkenylation of 2-Pyridones by Using Terminal Alkyne with High Regioselectivity.

Co(III)-catalyzed alkenylation of 2-pyridones by using terminal alkyne as a reaction partner with high regioselectivity has been demonstrated for the first time. The reaction conditions are mild and compatible with a wide range of substrate combinations. It also shows good functional group tolerance. It proceeds through cyclometalation followed by alkyne insertion and protodemetalation steps. The formation of five- and seven-membered cobaltacycle intermediates was also detected through high-resolution mass spectrometry.

Ruthenium-Catalyzed Cross Dehydrogenative Annulation of N-(7-Azaindole)benzamides with Maleimides: One-Step Access to Highly Functionalized Pyrroloisoquinoline.

A ruthenium(II)-catalyzed cross dehydrogenative annulation of N-(7-azaindole)benzamides with maleimides has been demonstrated. Herein, we have explored the use of N-amino-7-azaindole as a new bidentate directing group for dehydrogenative [4 + 2] annulation. This method works efficiently, affording a variety of pharmacologically useful 7-azaindole-based isoquinolones and showing a wide functional group tolerance.

Redox-Neutral Cobalt(III)-Catalyzed C-H Activation/Annulation of α,ß-Unsaturated Oxime Ether with Alkyne: One-Step Access to Multisubstituted Pyridine.

A redox neutral Co(III)-catalyzed annulation of α,ß-unsaturated oxime ether with alkyne has been reported. Multisubstituted pyridines were synthesized in good yields without the use of any heavy metal oxidants. The developed methodology tolerates a variety of functional groups. Notably, this transformation has been applied to the late-stage modification of the bioactive molecule dehydropregnenolone.

Rhodium-Catalyzed One-Pot Access to N-Polycyclic Aromatic Hydrocarbons from Aryl Ketones through Triple C-H Bond Activations.

A Rh-catalyzed pot and step economic synthesis of aza-polycyclic aromatic hydrocarbons (N-PAHs) from readily available aryl ketones and alkynes has been disclosed. Additionally, a novel synthetic application of the well-known aminating reagent hydroxylamine-O-sulfonic acid (HOSA) has been explored as an in situ redox-neutral directing group for the formation of N-PAHs via isoquinoline. Multiple bond formation in a single operation through a cascade of triple C-H bond activations is the beauty of this protocol. The challenging annulations of two different alkynes in a regioselective fashion have been demonstrated effectively. Mechanistic studies reveal that 3,4-diphenyl-1-methylisoquinoline is an active intermediate for this one-pot transformation.

Management of Hepatitis C: A Practical Primer for Nurses.

Nurses have been at the forefront of the care of patients with hepatitis C since hepatitis C virus was identified in 1989. Treatments of patients with hepatitis C have evolved over the time to the present moment, where there are numerous options available for patients that are efficacious, simple, and well-tolerated. However, many patients with hepatitis C do not know they are infected or have never been treated. Nurses can continue to influence patients' engagement in their care, direct patients toward testing, and support them through their treatment and follow-up. This article discusses the role of the nurse in the management of hepatitis C and offers the most up-to-date information regarding the current standards of care for patients, from identifying patients for testing to managing patients through treatment and follow-up.

Real-World Study on Sofosbuvir-based Therapies in Asian Americans With Chronic Hepatitis C.

BACKGROUND: Limited data exist with regard to treatment outcomes in Asian Americans with chronic hepatitis C (CHC). We evaluated sofosbuvir (SOF)-based regimens in a national cohort of Asian Americans. METHODS: Eligible Asian Americans patients with CHC who had posttreatment follow-up of 24 weeks for SOF -based therapies from December 2013 to June 2017 were enrolled from 11 sites across the United States. The primary endpoint was sustained virologic response (SVR) rates at posttreatment weeks 12 and 24. Secondary endpoints were to evaluate safety by tolerability and adverse events (AEs). RESULTS: Among 231 patients screened, 186 were enrolled. At baseline, 31% (57/186) patients were cirrhotic, 34% (63/186) were treatment experienced. Most of the subjects (42%, 79/186) received ledispavir/SOF therapy. The overall SVR12 was 95%, ranging from 86% in genotype (GT) 1b on SOF+ribavirin to 100% in GT 1b patients on ledipasvir/SOF at subgroup analyses. SVR12 was significantly lower in cirrhotic than in noncirrhotic patients [88% (50/57) vs. 98% (126/129), P<0.01]. Stratified by GT, SVR12 were: 96% (43/45) in GT 1a; 93% (67/72) in GT 1b; 100% (23/23) in GT 2; 90% (19/21) in GT 3; 100% (1/1) in GT 4; 83% (5/6) in GT 5; and 100% (16/16) in GT 6. Cirrhotic patients with treatment failure were primarily GT 1, (GT 1a, n=2; GT 1b, n=4) with 1 GT 5 (n=1). Patients tolerated the treatment without serious AEs. Late relapse occurred in 1 patient after achieving SVR12. CONCLUSIONS: In Asian Americans with CHC, SOF-based regimens were well tolerated without serious AEs and could achieve high SVR12 regardless of hepatitis C viral infection GT.

Real-world study of hepatitis C treatment with direct-acting antivirals in patients with drug abuse and opioid agonist therapy.

Background: Limited data exist evaluating the treatment outcomes with direct-acting antivirals (DAAs) in patients with drug use in the community setting. We aim to assess the treatment response of DAAs in this subset of patients with or without the opioid agonist therapy (OAT). Methods: All the hepatitis C virus (HCV) infected patients treated with DAAs were retrospectively analyzed. Patients were stratified into two groups by the presence or absence of abusing alcohol, cocaine and heroin. All the patients who were assigned to the abuser group had positive urine toxicology with one of the drugs during the DAA treatment. The primary assessment was the sustained virologic response (SVR12) at 12 weeks post-treatment (SVR12). Results: Among the 314 patients, 152, 128 and 58 were patients with drug use, non-drug use and receiving OAT. Among the patients with injectable or non-injectable drug use treatment, completion rate was 99% (151/152) and SVR12 was 93.4%. Among the patients with no drug use treatment, completion rate was 95% (122/128) and SVR12 was 88.3%. Among patients receiving OAT alone, SVR12 was 100%, and in patients with OAT + other drug use, SVR12 was 96.5%. None of the patients included in this study discontinued the treatment due to adverse events associated with treatment medications. Conclusions: In this community-based study, DAAs are safe, effective with high overall SVR12 in patients with active drug use (injectable and non-injectable) and OAT enrolled patients. These results support the removal of drug use as a barrier to DAA therapy.

Diagnosis and Management of Hepatitis C Infection in Primary Care Settings.

Hepatitis C virus (HCV) infection is a significant health problem worldwide, and is the leading cause of cirrhosis, hepatocellular carcinoma, and liver transplantation in the United States. The management of HCV has changed significantly over the last 5 years, as treatments have become simpler and more efficacious. Medication efficacy is now greater than 90%, with a high barrier to resistance and few side effects. This review is a collaboration between primary care and hepatology providers to explore all aspects of HCV management: acute versus chronic HCV infection, transmission and testing, and diagnosis and treatment. Specific medications for the treatment of HCV infection are considered, and patient and medication factors including genotype, liver disease status, and comorbidities affecting medication choice are discussed. This is a new era for the management of HCV infection, and interested primary care physicians, family doctors, and general internists can be at the forefront of diagnosis, management, and treatment of HCV.

Risk Factor Analysis Between Newly Screened and Established Hepatitis C in GI and Hepatology Clinics.

BACKGROUND: Several studies show inconsistencies in the rate of hepatitis C virus (HCV) detection among baby boomers (born 1945-1965). We conducted a cross-sectional HCV screening followed by a case-controlled comparison of the newly screened population with established HCV subjects. METHOD: Enrollment was offered to subjects aged 40-75 at our gastroenterology and hepatology clinics. Demographic data and potential risk factors were obtained, and HCV antibody test was offered to those who had never been screened and compared with a group with established HCV. Logistic regression analysis and Fisher's exact test were performed. RESULTS: Six hundred and seventy-five patients were offered participation, of whom 128 declined while 50 consented to participate but did not perform the HCV antibody test. Of 497 enrolled subjects, 252 patients had HCV, while 245 subjects (188 patients among "baby boomer") underwent screening for HCV. There were more females (62.4 vs. 41.7%) and immigrants (34.7 vs. 22.2%) among the newly screened group. Among the screened population, five patients had HCV antibody (2.04%), and two of them had positive viral load (0.82%) of whom only one fell in the baby boomer category (0.53%). Compared to HCV group, screened group had significantly lower-risk factors, such as IV drug use (1.22 vs. 43.3%), intranasal cocaine use (14.3 vs. 49.6%), and blood transfusion (18.8 vs. 32.5%). CONCLUSION: We found a slightly lower but similar prevalence of HCV antibody when screening based on birth cohort as compared to larger baby boomer studies. Future studies evaluating addition of other screening strategies or possibly universal screening may be needed.

Predictive value of ALT levels for non-alcoholic steatohepatitis (NASH) and advanced fibrosis in non-alcoholic fatty liver disease (NAFLD).

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) patients with elevated serum alanine aminotransferase (ALT) generally undergo a liver biopsy to evaluate for possible non-alcoholic steatohepatitis (NASH) or advanced fibrosis. However, patients with normal ALT could also have advanced stages of NAFLD. AIM: To determine ALT value that will accurately predict NASH and advanced fibrosis using area under the receiver operating characteristics curve (AUROC) analysis. METHODS: Demographic, clinical and laboratory data of an ethnically diverse cohort of biopsy proven NAFLD patients were retrospectively analysed under univariate and multivariate analyses. Liver biopsies were scored using NASH clinical research network (NASH CRN) system. AUROC were performed for NAFLD Activity Score ≥5 (NASH) and fibrosis score ≥2 (advanced fibrosis). RESULTS: Two hundred and twenty-two patients were analysed. Fifty six (23%) had normal ALT. There was no difference in the rate of advanced fibrosis between normal and elevated ALT (26.8% vs. 18.1%, P = 0.19). However, significantly lower percentage of normal ALT group had NASH compared with elevated ALT group (10.7% vs. 28.9%, P < 0.01). Overall, 37.5% of normal ALT group had NASH or advanced fibrosis, whereas 53% of elevated ALT had no NASH or advanced fibrosis. Higher ALT values correlated with higher specificity, but lower sensitivity for both NASH and advanced fibrosis. AUROC for ALT level correlating NASH and advanced fibrosis were 0.62 and 0.46 respectively. CONCLUSION: There is no optimal ALT level to predict NASH and advanced fibrosis. Metabolic risk factors should be evaluated to select patients for a liver biopsy to confirm NASH and advanced fibrosis.

Use of extracorporeal membrane oxygenation and cerebral oximetry in a stage 1 norwood repair for hypoplastic left heart syndrome.

The role of extracorporeal membrane oxygenation (ECMO) and its indications in stage I Norwood palliation are controversial. The decision to initiate ECMO and its timing remains difficult with no definitive cut-off points or evidence-based guidelines. It varies on a case-to-case basis. We report a case where the use of ECMO was beneficial after stage I Norwood palliation with severe ventricular dysfunction. The systemic-to-pulmonary artery shunt was kept open to balance the systemic and pulmonary circulations. Cerebral oximetry can be useful as an additional monitoring modality to guide management, monitor cerebral perfusion, and help detect cerebral steal.

Use of immune function test in monitoring immunosuppression in liver transplant recipients.

Immune function test (Immuknow™) is a measure of cell-mediated immunity based on peripheral CD4+ T cell adenosine triphosphate activity (desired range, 225-525 ng/mL). We evaluated the role of immune function test (IFT) in monitoring and adjustment of immunosuppression in orthotopic liver transplant (OLT) recipients. A total of 289 IFTs were obtained from 171 patients from March 2007 to June 2008. Graft/patient status was classified as stable, serious infection, or malignancy. IFT levels were analyzed with duration of follow-up after OLT, graft/patient status, and the presence of hepatitis C (HCV) infection. The mean age was 54±14 yr, with 62% men. The median follow-up was 65 (2-249) months. Mean IFT levels were significantly lower in patients who were <24 months than in those≥24 months post-OLT (220±19.5 vs. 257±11.3 ng/mL, p=0.03). Clinically stable patients had higher IFT levels than those with serious infection or malignancy (254±11.1 vs. 162.5±23.9, p<0.001). HCV-infected patients had lower IFT levels than uninfected patients (206.7±15.7 vs. 273±12.0 ng/mL, p<0.001). Immunosuppression was reduced in 58 patients with IFT levels<225 ng/mL, and 90% maintained stable graft function after a median follow-up of 22 (1-39) months. IFT may be a useful tool in monitoring and lowering of immunosuppression in long-term OLT recipients.

Overcoming the Challenges toward Selective C(6)-H Functionalization of 2-Pyridone with Maleimide through Mn(I)-Catalyst: Easy Access to All-Carbon Quaternary Center.

An earth-abundant and inexpensive Mn(I)-catalyzed alkylation of 2-pyridone with maleimide has been reported for the first time, in contrast to previously reported Diels-Alder products. Notably, an unexpected rearrangement has been discovered in the presence of acetic acid, which also provides a unique class of compounds bearing three different N-heterocycles with an all-carbon quaternary center. Furthermore, single crystal X-ray and HRMS revealed a five-membered manganacycle intermediate. This methodology tolerates a wide variety of functional groups delivering the alkylated products in moderate to excellent yields.

N-Allylbenzimidazole as a strategic surrogate in Rh-catalyzed stereoselective trans-propenylation of aryl C(sp2)-H bond.

A Rh-catalyzed C(sp2)-H propenylation has been reported by taking N-allyl benzimidazole as an allylamine congener. This transformation has been observed for the first time, where a tandem process of C-H allylation followed by alkene isomerization delivers a highly stereoselective trans-propenylated product. Detailed mechanistic studies including the characterization of rhodacycle-intermediates have been conducted to understand the mechanism.