Context The b-carboline alkaloid harmane is widely distributed in common foods, beverages and hallucinogenic plants. Harmane exerts potential in therapies for Alzheimer's and depression diseases. However, little information on its dynamic metabolic profiles and pharmacokinetics in vivo is currently available. Objective This study investigates the dynamic metabolic profiles and pharmacokinetic properties of harmane and its metabolites in rats in vivo. Materials and methods A highly selective, sensitive and rapid ultra-performance liquid chromatography combined with electrospray ionization tandem mass spectrometry (UPLC-ESI-MS/MS) method was developed and well-validated for simultaneous quantitative determination of harmane and its uncertain endogenous metabolite harmine, as well as for semiquantitative determination of 10 harmane metabolites in rats after intravenous injection and oral administration of harmane at 1.0 and 30.0 mg/kg, respectively. Results The calibration curves of harmane and harmine showed excellent linearity within the concentration range of 1-2000 ng/mL with acceptable accuracy, precision, selectivity, recovery, matrix effect and stability. Ten metabolites, including harmane but not harmine, were detected and identified after intravenous and oral administration of harmane. The absolute bioavailability of harmane following an oral dose was 19.41 ± 3.97%. According to the AUC 0-t values of all the metabolites, the metabolic levels of phase II metabolites were higher than those of phase I metabolites, and the sulphation pathways were the dominant metabolic routes for harmane in both routes of administration. Discussion and conclusion The pharmacokinetic properties of harmane and its 10 metabolites in rats were determined. Sulphate conjugation was the predominant metabolic process of harmane in rats.

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Ear amputations are common in emergency departments as the auricle's protrusion from the lateral aspect of the head makes it particularly susceptible to trauma. Of the numerous approaches for auricle injuries, the classic methods include microsurgical replantation, primary reattachment, composite graft, retroauricular pocket principle, 1 secondary reconstruction with rib cartilage, and methods using postauricular flap. The success of the operation depends largely on choosing the appropriate surgical procedure since many factors can influence surgical outcome. There is no 1 gold standard technique to treat the variety of auricle injuries. Inappropriate choice of surgical approach can be detrimental to subsequent reconstructive surgery. Therefore, the initial choice of optimal surgical approach is particularly important. In this article, a rare report of left subtotal ear laceration with inferior lobule pedicle by nonmicrosurgical primary reattachment was presented. The operation obtained an ideal cosmetic effect.

Background Persistent left superior vena cava (PLSVC) is a rare congenital vascular anomaly. Permanent pacemaker implantation (PPI) in patients with PLSVC can be challenging because of the venous anomalies. We reported a case series of patients with PLSVC who underwent PPI with double active fixation leads. Methods From January 2012 to July 2016, 9 patients (three male and six females, mean age 68 ± 11 years) with PLSVC who received a dual-chamber pacemaker with double active fixation leads were enrolled retrospectively in this observational study. The indications for pacemaker implantation were symptomatic third-degree atrioventricular block in one and sick sinus syndrome in eight patients. Results PPI were implanted successfully in all 9 patients. Successful positioning of the ventricular leads at the right ventricular outflow tract (RVOT) septum with a “C” shaped stylet was achieved in 7 patients (77.8%). In the remaining two cases, the ventricular leads were placed in the right ventricular apex and the inferior free wall of the sub-tricuspid annulus. The atrial leads were placed at the lateral wall of the right atrium in all patients. Procedure time and fluoroscopy time were 85.3 ± 11.3 min and 4.5 ± 1.1 min respectively. During a mean follow-up of 4 years, no complications were observed and pacing parameters did not change significantly. Conclusion PPI through PLSVC may be technically feasible, safe, and effective. Double active fixation leads may be standard for patients with PLSVC and most of the ventricular leads could be placed at the RVOT septum.

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Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have improved the prognosis of mutant lung cancer; however, the clinical application value of TKIs for nonclassical EGFR mutation is unclear, especially for patients with rare uncommon mutations. Methods: A retrospective study based on electronic medical records was conducted to collect data on the effectiveness of afatinib in patients with stage IIIB/IV lung adenocarcinoma (LUAD) bearing uncommon mutations between January 2017 and January 2021. Results: Forty-two patients with uncommon mutations treated with afatinib were enrolled. The objective response rate (ORR) was 50.0% (10 of 20 patients). The median time to treatment failure (TTF) was 11.7 months (95% confidence interval = 8.5-18.3 months). Of the 42 patients, the median TTF was 15.0, 11.7, and 16.6 months in patients with Gly719Xaa (G719X), Ser768Ile (S768I), and Leu861Gln (L861Q) mutations, respectively. In patients with the rare uncommon mutation, the median TTF was 10.0 months, and the ORR was 50.0%. Afatinib demonstrated clinical activity across a set type of specific rare uncommon mutations, including EGFR L747P, A767_V769dup, and L833V/H835L, with a case having a TTF of more than 1 year. Molecular profiling reports of 16 afatinib-resistant biopsy samples were available, and the secondary T790M mutation was detected in one patient with L833V/ H835L mutation and one harboring S768I/L858R mutation. Conclusions: Our findings suggested that afatinib is effective in patients with uncommon mutations. Mechanisms of afatinib resistance vary and need further investigation.

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