Immunomodulatory effects of intraoperative dexmedetomidine on T helper 1, T helper 2, T helper 17 and regulatory T cells cytokine levels and their balance: a prospective, randomised, double-blind, dose-response clinical study.

BACKGROUND: The ratio of T helper 1 (Th1) to T helper 2 (Th2) as well as T helper 17 (Th17) to regulatory T cells (Treg) represents the state and direction of immune response. Recent studies demonstrated that dexmedetomidine reduced the secretion of inflammatory cytokines. We performed this study to investigate the effect of different doses of intraoperative dexmedetomidine on the expression of Th1, Th2, T17 and Treg cytokines and their ratios. METHODS: Seventy-five patients undergoing laparoscopic cholecystectomy were randomly separated into one of three groups: the full dose group (n = 25), in which dexmedetomidine was infused with a 1.0 µg/kg loading followed by an infusion of 0.5 µg/kg/min after anaesthetic induction, or the half dose group (n = 26), in which the dose was half of that of full dose group, or the saline group (n = 24) which was control. T cell cytokines were quantified by sandwich enzyme-linked immunoassay for blood samples taken after anaesthetic induction (T0), at the end of surgery (T1), and 60 min after surgery (T2). IFN-gamma/IL-4 and IL-17/IL-10, which represent the ratio of Th1/Th2 and Th17/Treg cytokines, respectively, were calculated as indices of immune cell levels based upon serum cytokines levels in place of direct measurements. C-reactive protein (CRP) concentrations were measured on the next day following surgery. RESULTS: The full dose group was associated with higher ratios of IFN-gamma/IL-4 than those of half dose group and control [10.1 vs. 1.9 at T1 (P = 0.041) compared with half dose group, and 10.1 vs. 0.2 at T1 (P = 0.031), 7.4 vs. 0.1 at T2 (P = 0.025) compared with control]. IL-17/IL-10 ratios were higher in the full dose group than those in control [4.2 vs. 0.6 at T1 (P = 0.013), 3.0 vs. 0.3 at T2 (P = 0.011)]. The CRP levels were lower in the dexmedetomidine-treated groups in a dose-dependent manner. CONCLUSIONS: Dexmedetomidine exhibits immunomodulatory effects, shifting the Th1/Th2 and T17/Treg cytokine balance toward Th1 and T17, respectively, in a dose-dependent pattern in patients with surgical and anaesthetic stress. TRIAL REGISTRATION: Clinical Research Information Service, Republic of Korea (CRIS); KCT0000503 ; Registration date: Aug 13, 2012.

Highly compacted biodegradable DNA nanoparticles capable of overcoming the mucus barrier for inhaled lung gene therapy.

Gene therapy has emerged as an alternative for the treatment of diseases refractory to conventional therapeutics. Synthetic nanoparticle-based gene delivery systems offer highly tunable platforms for the delivery of therapeutic genes. However, the inability to achieve sustained, high-level transgene expression in vivo presents a significant hurdle. The respiratory system, although readily accessible, remains a challenging target, as effective gene therapy mandates colloidal stability in physiological fluids and the ability to overcome biological barriers found in the lung. We formulated highly stable DNA nanoparticles based on state-of-the-art biodegradable polymers, poly(ß-amino esters) (PBAEs), possessing a dense corona of polyethylene glycol. We found that these nanoparticles efficiently penetrated the nanoporous and highly adhesive human mucus gel layer that constitutes a primary barrier to reaching the underlying epithelium. We also discovered that these PBAE-based mucus-penetrating DNA nanoparticles (PBAE-MPPs) provided uniform and high-level transgene expression throughout the mouse lungs, superior to several gold standard gene delivery systems. PBAE-MPPs achieved robust transgene expression over at least 4 mo following a single administration, and their transfection efficiency was not attenuated by repeated administrations, underscoring their clinical relevance. Importantly, PBAE-MPPs demonstrated a favorable safety profile with no signs of toxicity following intratracheal administration.

Prediction of postoperative final degree and recurrence of pectus excavatum using machine learning algorithms.

Background: Chest wall re-depression after bar removal (BR) in pectus excavatum (PE) is insufficiently investigated. However, it is not easy to investigate chest wall re-depression due to its multifactorial characteristics. Herein, we investigated chest wall re-depression after BR using machine learning algorithms. To the best of my knowledge, this is the first study of chest wall re-depression after BR using machine learning algorithms. Methods: We retrospectively reviewed 199 consecutive subjects who underwent both minimally invasive repair of pectus excavatum (MIRPE) and BR at a single hospital from March 2012 to June 2020. We investigated attributes of chest wall re-depression and risk factors for recurrence after BR, predicted final degree and recurrence of PE after BR, and suggested the optimal age at the time of MIRPE based on recurrence. Data for the chest wall re-depression were analyzed to discover differences according to age group [<10 years (early repair group; EG) vs. ≥10 years (late repair group; LG)]. Results: We observed no significant difference between the Haller index and radiographical pectus index (RPI) (P=0.431) and a significant correlation between Haller index and RPI (P<0.001). RPI significantly increased for the first 6 months after BR in both age groups (both P<0.001) and was maintained at 1 year after BR. RPI value of the LG were significantly higher than those of the EG for the entire period after MIRPE (P=0.041). Recurrence of PE in the LG was significantly more frequent than in the EG (P<0.001). RPI values before and after MIRPE and age group were identified as independent risk factors for recurrence after BR (P<0.001, P=0.007, and P=0.001, respectively). The linear regression model outperformed for final RPI with performance scores of mean squared error 0.198, root mean squared error 0.445, mean absolute error 0.336, and R2 0.415. In addition, the logistic regression model outperformed for predicting recurrence with performance scores of 0.865 the area under the curve, 0.884 accuracy, 0.859 F1, 0.865 precision, and 0.884 recall. Conclusions: The present study shows that machine learning algorithms can provide good estimates for postoperative results in PE. An approach integrating machine learning models and readily available clinical data can be used to create other models in the thoracic surgery field.

Repair of pectus excavatum in a patient with an Eloesser thoracostomy window: sequential extrapleural Nuss procedure and modified Ravitch procedure.

A 28-year-old man with a history of tuberculous empyema and pectus excavatum visited our hospital for progressive dyspnea and leg edema. The patient had undergone an Eloesser window operation for repetitive pleuro-cutaneous fistula due to chronic tuberculous empyema in the left thorax one year prior. Chest computed tomography demonstrated severe compression of the right ventricle and inferior vena cava and chronic empyema with the Eloesser window in the left thorax. Because conservative treatment had failed, the patient underwent a total extrapleural Nuss procedure, resulting in marked relief of compression and complete resolution of leg edema and congestive hepatopathy. However, he required ventilation support due to carbon dioxide retention. Therefore, the patient underwent a modified Ravitch procedure and was weaned off ventilation support. Herein, we represent the first report of a sequential extrapleural Nuss procedure and a modified Ravitch procedure in a patient with chronic tuberculous empyema with an Eloesser window.

Chest CT Has Higher Yield for Infection than CT Sinus in Febrile Neutropenic Patients.

OBJECTIVE: Chest and sinus CT imaging among cancer patients undergoing chemotherapy and bone marrow transplant in the setting of neutropenic fever is not uncommon, yet the utility of routine imaging surveillance remains unclear. We aim to compare the rates of acute infection detected on CT chest and CT sinus exams performed in this clinical setting. METHODS: Reports of 1059 consecutive CT chest and sinus examinations for the clinical indication of neutropenic fever on 262 patients performed between January through June 2017 were retrospectively reviewed. Infection as reported was characterized as acute or worsening, improving, stable, indeterminate or negative. Results were tabulated and Pearson's chi-square test was used for comparison analysis. RESULTS: Absence of infection on CT sinus was significantly higher than CT chest (86.1% vs. 58.5%; P<0.001). Conversely, CT chest had significantly higher incidence of acute or worsening infection than CT sinus (28.7% vs. 11.6%; P<0.001). CT chest also showed significantly higher incidence of improving infection compared to CT sinus (6.2% vs. 1.1%; P<0.001). There was no significant difference between incidence of stable infection on CT chest and CT sinus (1.1% vs. 0.2%; P=0.059). Infection was indeterminate in 5.5% of CT chest vs. 1% on CT sinus (P<0.001). CONCLUSIONS: CT chest showed significantly higher diagnostic yield for acute infection than CT sinus, suggesting that sinusitis is less likely to be the source of fever than chest infections in febrile neutropenic patients. The majority of CT studies showed absence of infection, raising the question of the overall utility of routine surveillance CT imaging among this subset of patients.

Fatal intracardiac and pulmonary arterial thromboembolic damage following ABO-incompatible living donor liver transplantation for autoimmune hepatitis: A case report.

RATIONALE: We present the case of a patient with autoimmune hepatitis who suffered fatal intracardiac and pulmonary arterial thromboembolic complications after ABO-incompatible living donor liver transplantation (ABOi LDLT) with splenectomy. PATIENT CONCERNS: A 46-year-old female (blood type B+) with autoimmune hepatitis and hepatitis B carrier status underwent elective ABOi LDLT. The donor liver was from a 51-year-old male living donor (blood type A+). A splenectomy was performed without bleeding complications. Intraoperatively, the patients hemodynamic condition was acceptable, with no evidence of thromboembolism on transesophageal echocardiography (TEE). DIAGNOSIS: Postoperatively, her platelet count increased from 15.0 to 263.0 (× 109/L) and thromboelastographic parameters indicated hypercoagulable state. She suffered acute circulatory collapse, respiratory distress and, eventually, a decline in mental status. The attending physicians in the intensive care unit (ICU) immediately performed resuscitation. INTERVENTIONS: The patient underwent emergency exploratory surgery. Intraoperatively, hypotension, bradycardia and arrhythmia developed, together with high central venous pressure. Assessment of cardiac structure and function using rescue TEE incidentally identified multiple, huge thromboembolic clots in the cardiac chambers; therefore, the patient underwent cardiac thromboembolectomy, including cardiopulmonary bypass with hypothermia therapy. OUTCOMES: Due to severe cardiac and respiratory distress, the patient required venoarterial extracorporeal membrane oxygenation (VAECMO) in the operating room and ICU. Despite continuous resuscitation in the ICU and maintenance of VAECMO, she suffered severe hypotension and massive bleeding that eventually led to death. LESSONS: In patients with autoimmune hepatitis, risk factors for thromboembolism should be rigorously controlled during the peak period of reactive thrombocytosis after ABOi LDLT with splenectomy.

Reaching across the aisle: Cross-disciplinary collaboration in otolaryngology research.

OBJECTIVES: Collaboration and diversity of expertise are increasingly emphasized in the production of successful research. However, the degree of cross-disciplinary collaboration in otolaryngology research is unknown. In this study, we quantify cross-disciplinary collaboration in otolaryngology publications. METHODS: We retrospectively analyzed authorship and study characteristics for all original articles published from January 2014 to December 2016 in three key peer-reviewed otolaryngology journals: Laryngoscope, Otolaryngology-Head & Neck Surgery, and JAMA Otolaryngology-Head & Neck Surgery. Author affiliations and online searches were used to determine author's primary discipline. Subspecialty topic of article, study design, and funding sources were also recorded. Fisher exact test was used to compare characteristics of articles with and without cross-disciplinary authorship. RESULTS: A total of 2,378 articles were reviewed, of which 1,312 (55%) articles had one or more cross-disciplinary collaborators. Among articles with cross-disciplinary collaboration, the greatest representation of disciplines was from other medical specialties (1,109, 50.9%), epidemiology/biostatistics (266, 12.2%), pathology/histology (175, 8.0%), biologic sciences (168, 7.7%), and radiology/imaging (144, 6.6%). Cross-disciplinary studies had a significantly greater proportion of articles on the topic of head and neck compared to studies without collaboration (P < 0.0001). The proportion of funded studies was significantly greater among articles with collaboration compared to articles without collaboration (P < 0.0001). CONCLUSION: The majority of articles published during a 3-year period in three influential otolaryngology journals had cross-disciplinary collaboration. There is potential opportunity for further leveraging expertise, funding opportunities, and dissemination of key findings through collaborative research. LEVEL OF EVIDENCE: NA Laryngoscope, 129:1800-1805, 2019.

MVP™ Micro Vascular Plug Systems for the Treatment of Pulmonary Arteriovenous Malformations.

PURPOSE: To describe our institutional experience with MVP™ micro vascular plug systems for the treatment of pulmonary arteriovenous malformations (PAVMs). MATERIALS AND METHODS: We performed a retrospective medical record review of 52 patients with 119 PAVMs treated exclusively with MVP™ systems (69 procedures/153 MVP™ systems) between July 2014 and July 2018. All patients had PAVMs with feeding artery diameters ≥ 2 mm. MVP™ systems were deployed according to physician preference. We collected patient demographic information; procedural data (including size of feeding artery, size and number of embolics used per PAVM, fluoroscopy time, contrast administration), technical success rates, complications, and persistence. Persistence was assessed using computed tomography angiography (CTA) performed 1-3 months and 3-5 years after embolization per clinical protocol. RESULTS: All procedures were technically successful without major complications. Mean feeding artery diameter was 3.3 ± 1.2 mm. Mean fluoroscopy time per procedure and contrast volume administered per procedure were 35 ± 16 min and 217 ± 101 mL, respectively. A mean of 1.3 ± 0.8 MVP™ systems was used per PAVM. There were no instances of persistence during a mean follow-up time of 328 ± 258 days (range 26 to 914 days). CONCLUSIONS: For PAVMs with feeding artery diameters of 2 to 7.9 mm (mean 3.3 ± 1.2 mm), MVP™ systems are safe and effective given their high technical success rates and lack of persistence. Further prospective work will be required to elucidate the advantages and disadvantages of these MVP™ systems for PAVM embolization. LEVEL OF EVIDENCE: Level III.

Diffuse alveolar hemorrhage following sugammadex and remifentanil administration: A case report.

RATIONALE: Diffuse alveolar hemorrhage (DAH) is a rare life-threatening condition that accompanies general anesthesia. Negative-pressure pulmonary edema (NPPE) is a rare cause of DAH. PATIENT CONCERNS: A 25-year-old male patient developed hemoptysis following remifentanil administration by bolus injection with sugammadex at the emergence from general anesthesia. DIAGNOSIS: Chest x-ray and computed tomography showed DAH. INTERVENTIONS: Conservative care was provided with 4L of oxygen via nasal prong, 20 mg of Lasix and 2500 mg of tranexamic acid. OUTCOMES: The patient was discharged uneventfully. LESSONS: Muscle rigidity by remifentanil and the dissociated reversal of neuromuscular blockade by sugammadex was suspected as the cause of NPPE-related DAH. Therefore, the possibility NPPE-related DAH should be considered when using a bolus of remifentanil and sugammadex during emergence from general anesthesia.

MR-Guided Sclerotherapy for the Treatment of Low-Flow Vascular Malformations.

Low-flow vascular malformations are congenital lesions that can occur throughout the body. Treatment of these lesions is indicated to ameliorate pain, cosmetic disfigurement, and functional impairment. The first-line treatment of low-flow vascular malformations is percutaneous sclerotherapy. Traditionally, sclerotherapy is performed with a combination of ultrasound and fluoroscopy. However, malformations that are deep in the abdomen and pelvis or are obscured by overlying fascia or scar may be difficult to be visualized with ultrasound and fluoroscopy. MR-guided sclerotherapy has emerged as an alternative modality that can be used to needle guidance and sclerosant monitoring. In this review, we discuss the historical and current use of MR-guided sclerotherapy for the treatment of low-flow vascular malformations.

Non-cirrhotic portal hypertension in an ankylosing spondylitis patient.

Idiopathic non-cirrhotic portal hypertension (INCPH) is a disease with an uncertain etiology consisting of non-cirrhotic portal hypertension and portal pressure increase in the absence of liver cirrhosis. In INCPH, patients exhibit normal liver functions and structures. The factors associated with INCPH include the following: Umbilical/portal pyremia, bacterial diseases, prothrombic states, chronic exposure to arsenic, vinyl chloride monomers, genetic disorders, and autoimmune diseases. Approximately 70% of patients present a history of major variceal bleeding, and treatment relies on the prevention of complications related to portal hypertension. Autoimmune disorders associated with INCPH are mainly systemic sclerosis, systemic lupus erythematosus and rheumatoid arthritis. To the best of our knowledge, a case of ankylosing spondylitis (AS) associated with INCPH has not been reported thus far. Therfore, we report our experience of a patient with AS accompanied by INCPH, who showed perisplenic varices with patent spleno-portal axis and hepatic veins along with no evidence of cirrhosis on liver biopsy, and provide a brief literature review.

Biodegradable brain-penetrating DNA nanocomplexes and their use to treat malignant brain tumors.

The discovery of powerful genetic targets has spurred clinical development of gene therapy approaches to treat patients with malignant brain tumors. However, lack of success in the clinic has been attributed to the inability of conventional gene vectors to achieve gene transfer throughout highly disseminated primary brain tumors. Here, we demonstrate ex vivo that small nanocomplexes composed of DNA condensed by a blend of biodegradable polymer, poly(ß-amino ester) (PBAE), with PBAE conjugated with 5kDa polyethylene glycol (PEG) molecules (PBAE-PEG) rapidly penetrate healthy brain parenchyma and orthotopic brain tumor tissues in rats. Rapid diffusion of these DNA-loaded nanocomplexes observed in fresh tissues ex vivo demonstrated that they avoided adhesive trapping in the brain owing to their dense PEG coating, which was critical to achieving widespread transgene expression throughout orthotopic rat brain tumors in vivo following administration by convection enhanced delivery. Transgene expression with the PBAE/PBAE-PEG blended nanocomplexes (DNA-loaded brain-penetrating nanocomplexes, or DNA-BPN) was uniform throughout the tumor core compared to nanocomplexes composed of DNA with PBAE only (DNA-loaded conventional nanocomplexes, or DNA-CN), and transgene expression reached beyond the tumor edge, where infiltrative cancer cells are found, only for the DNA-BPN formulation. Finally, DNA-BPN loaded with anti-cancer plasmid DNA provided significantly enhanced survival compared to the same plasmid DNA loaded in DNA-CN in two aggressive orthotopic brain tumor models in rats. These findings underscore the importance of achieving widespread delivery of therapeutic nucleic acids within brain tumors and provide a promising new delivery platform for localized gene therapy in the brain.

Development of parenteral formulation for a novel angiogenesis inhibitor, CKD-732 through complexation with hydroxypropyl-beta-cyclodextrin.

The effect of hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) on the aqueous solubility and chemical stability of O-(4-Dimethylaminoethoxycinnamoyl)fumagillol (CKD-732), a new angiogenesis inhibitor, was investigated with an aim of preparing a stable and effective parenteral formulation. The CKD-732/HP-beta-CyD inclusion complex was obtained in solid state by freeze-drying and characterized in solution by proton nuclear magnetic resonance (1H NMR). Then, the pharmacokinetic profile in rats and the in vivo tumor growth inhibitory activity in mice following the parenteral administration of aqueous CKD-732/HP-beta-CyD complex were compared to those of CKD-732.hemioxalate solution having an equivalent concentration. The aqueous solubility of CKD-732 was markedly increased by the combination of pH adjustment and HP-beta-CyD complexation through a soluble 1:1 inclusion complex formation, which was supported by NMR spectroscopy. The hydrolysis of CKD-732 following pseudo first-order kinetics was decelerated moderately but significantly in acidic and basic solutions in the presence of HP-beta-CyD. The stability of lyophilized CKD-732/HP-beta-CyD complex was also drastically improved after storage in various conditions. The intravenous pharmacokinetic profile and the subcutaneous in vivo tumor growth inhibitory activity of aqueous CKD-732/HP-beta-CyD complex were not significantly different from those of CKD-732.hemioxalate solution with the favorable reduction of irritation. These results demonstrate that the CKD-732/HP-beta-CyD complex is an attractive formulation for use in the parenteral delivery of CKD-732.

Novel alpha-glucosidase inhibitors, CKD-711 and CKD-711a produced by Streptomyces sp. CK-4416. III. Physico-chemical properties and structure elucidation.

We have isolated two novel a-glucosidase inhibitors, O-[4-deoxy-4-(2,3-epoxy-3-hydroxymethyl-4,5,6-trihydroxycyclohexane-1-yl-amino)-alpha-D-glucopyranosyl]-(1-->4)-O-alpha-D-glucopyranosyl-(1-->4)-alpha-D-glucopyranose (named CKD-711) and its hexameric analog CKD-711a, from the fermentation broth of Streptomyces sp. CK-4416. HRFAB-MS and NMR analyses reveal that molecular formulae of CKD-711 and CKD-711a are C25H43NO20 and C37H63NO30, respectively with the latter containing two more glucose moieties than the former. Detailed chemical structures of both compounds have been characterized by high-resolution two-dimensional NMR methods.

Absorption, distribution, metabolism, and excretion of CKD-732, a novel antiangiogenic fumagillin derivative, in rats, mice, and dogs.

The pharmacokinetics of CKD-732 (6-O-4-[dimethyl-aminoethoxy)cinnamoyl]-fumagillol x hemioxalate) was investigated in male SD rats and beagle dogs after bolus intravenous administration. The parent compound and metabolites obtained from in vitro and in vivo samples were determined by LC/MS. The main metabolite was isolated and identified as an N-oxide form of CKD-732 by NMR and LC/MS/MS. CKD-732 was metabolized into either M11 or others by rapid hydroxylation, demethylation, and hydrolysis. The blood level following the intravenous route declined in first-order kinetics with T(1/2)beta values of 0.72 to approximately 0.78 h for CKD-732 and 0.92 to approximately 1.09 h for M11 in rats at a dose of 7.5 to approximately 30 mg/kg. In dogs, T(1/2)beta values of CKD-732 and M11 were 1.54 and 1.79 h, respectively. Moreover, AUC values increased dose dependently for CKD-732 and M11 in rats and dogs. The CLtot and Vdss did not change significantly with increasing dose, indicating linear pharmacokinetic patterns. The excretion patterns through the urine, bile, and feces were also examined in the animals. The total amount excreted in urine, bile, and feces was 2.13% for CKD-732 and 1.29% for M11 in rats, and 1.58% for CKD-732 and 2.28% for M11 in dogs.

Two-port access versus four-port access laparoscopic ovarian cystectomy.

OBJECTIVE: This study was conducted to compare the surgical outcomes between two-port access and four-port access laparoscopic ovarian cystectomy. METHODS: Four hundred and eighty nine patients who had received two-port access laparoscopic ovarian cystectomy (n=175) and four-port access laparoscopic ovarian cystectomy (n=314) in Chungnam National University Hospital from January 2009 to August 2012 were analyzed retrospectively. The data were compared between the bilaterality of the cysts and cyst diameter of less than 6 cm and 6 cm or more. RESULTS: There were no significant differences in patient's age, parity, body weight, body mass index and history of previous surgery between the two-port and four-port access laparoscopy group. Bilaterality of ovarian cysts was more in fourport access laparoscopy group (13.7% vs. 32.5%, P=0.000). There were no significant differences in operation time, hemoglobin change, hospital stay, adhesiolysis, transfusion, and insertion of hemo-vac between the two-port and four-port access laparoscopy group for size matched compare. However additional analgesics were more in four-port access laparoscopy group for unilateral ovarian cystectomy. CONCLUSION: Two-port access laparoscopic surgery was feasible and safe for unilateral and bilateral ovarian cystectomy compare with four-port access laparoscopic surgery.