Search

Sang-Soo Kim,1,2 Manish Moghe,1 Antonina Rait,1 Kathryn Donaldson,1 Joe B Harford,2 Esther H Chang1 1Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA; 2SynerGene Therapeutics, Inc, Potomac, MD, USACorrespondence: Esther H Chang, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road N.W., Research Building E420, Washington, DC, 20057, USA, Email change@georgetown.eduPurpose: Atypical teratoid rhabdoid tumor (ATRT) is a deadly, fast-growing form of pediatric brain cancer with poor prognosis. Most ATRTs are associated with inactivation of SMARCB1, a subunit of the chromatin remodeling complex, which is involved in developmental processes. The recent identification of SMARCB1 as a tumor suppressor gene suggests that restoration of SMARCB1 could be an effective therapeutic approach.Methods: We tested SMARCB1 gene therapy in SMARCB1-deficient rhabdoid tumor cells using a novel tumor-targeted nanomedicine (termed scL-SMARCB1) to deliver wild-type SMARCB1. Our nanomedicine is a systemically administered immuno-lipid nanoparticle that can actively cross the blood-brain barrier via transferrin receptor-mediated transcytosis and selectively target tumor cells via transferrin receptor-mediated endocytosis. We studied the antitumor activity of the scL-SMARCB1 nanocomplex either as a single agent or in combination with traditional treatment modalities in preclinical models of SMARCB1-deficient ATRT.Results: Restoration of SMARCB1 expression by the scL-SMARCB1 nanocomplex blocked proliferation, and induced senescence and apoptosis in ATRT cells. Systemic administration of the scL-SMARCB1 nanocomplex demonstrated antitumor efficacy as monotherapy in mice bearing ATRT xenografts, where the expression of exogenous SMARCB1 modulates MYC-target genes. scL-SMARCB1 demonstrated even greater antitumor efficacy when combined with either cisplatin-based chemotherapy or radiation therapy, resulting in significantly improved survival of ATRT-bearing mice.Conclusion: Collectively, our data suggest that restoring SMARCB1 function via the scL-SMARCB1 nanocomplex may lead to therapeutic benefits in ATRT patients when combined with traditional chemoradiation therapies. Keywords: lipid nanoparticle, nanodelivery, SMARCB1, gene therapy, atypical teratoid rhabdoid tumor

Kathleen F Pirollo,1 Manish Moghe,1 Miaoyin Guan,1 Antonina S Rait,1 Aibing Wang,1 Sang-Soo Kim,1,2 Esther H Chang,1 Joe B Harford2 1Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, 20057, USA; 2SynerGene Therapeutics, Inc., Potomac, MD, 20854, USACorrespondence: Esther H Chang, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road N.W., Research Building E420, Washington, DC, 20057, USA, Tel +1 202 687 8418, Email change@georgetown.eduIntroduction: Organophosphates are among the deadliest of known chemicals based on their ability to inactivate acetylcholinesterase in neuromuscular junctions and synapses of the central and peripheral nervous systems. The consequent accumulation of acetylcholine can produce severe acute toxicities and death. Oxime antidotes act by reactivating acetylcholinesterase with the only such reactivator approved for use in the United States being 2-pyridine aldoxime methyl chloride (a.k.a., pralidoxime or 2-PAM). However, this compound does not cross the blood–brain barrier readily and so is limited in its ability to reactivate acetylcholinesterase in the brain.Methods: We have developed a novel formulation of 2-PAM by encapsulating it within a nanocomplex designed to cross the blood–brain barrier via transferrin receptor-mediated transcytosis. This nanocomplex (termed scL-2PAM) has been subjected to head-to-head comparisons with unencapsulated 2-PAM in mice exposed to paraoxon, an organophosphate with anticholinesterase activity.Results and Discussion: In mice exposed to a sublethal dose of paraoxon, scL-2PAM reduced the extent and duration of cholinergic symptoms more effectively than did unencapsulated 2-PAM. The scL-2PAM formulation was also more effective than unencapsulated 2-PAM in rescuing mice from death after exposure to otherwise-lethal levels of paraoxon. Improved survival rates in paraoxon-exposed mice were accompanied by a higher degree of reactivation of brain acetylcholinesterase.Conclusion: Our data indicate that scL-2PAM is superior to the currently used form of 2-PAM in terms of both mitigating paraoxon toxicity in mice and reactivating acetylcholinesterase in their brains.Keywords: lipid nanoparticle, nanodelivery, organophosphate, paraoxon, blood–brain barrier, transcytosis

Sung-Soo Kim,1,* Sojung Won,2,* Ha Eun Lee,2 Seung Hyun Ryu,2 Dong Joon Choi,2 Sung Ig Cho,2 Byoung Joo Gwag,2 Hwa-Young Youn,3 Jin Hwan Lee2 1VIP Animal Medical Center KR, Seoul, 02830, Republic of Korea; 2GNT Pharma, Yongin, Gyeonggi, 17096, Republic of Korea; 3Laboratory of Veterinary Internal Medicine, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea*These authors contributed equally to this workCorrespondence: Jin Hwan Lee, GNT Animal Health Business Unit, Yongin, Gyeonggi, 17096, Republic of Korea, Tel +82 10 8878 0456, Fax +82 31 8005 9931, Email jhlee@gntpharma.comPurpose: Nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase (COX)-2 selective inhibitors are the most widely used drugs to treat pain. Conventional NSAIDs and COX-2 selective inhibitors, however, cause several side effects such as gastric damage, kidney damage, and cardiovascular problems. Our previous study showed that 2-acetoxy-5-(2-4-(trifluoromethyl)-phenethylamino)-benzoic acid ie, flusalazine (also known as ND-07), which exerts dual actions by serving both as an anti-inflammatory agent and a free radical scavenger, is an effective and safe treatment for severe inflammatory diseases in mice. The goal of the present study was to examine the potential analgesic action and safety of flusalazine in mice models of pain.Methods and Results: Flusalazine showed a significant analgesic effect in an acetic acid-induced abdominal constriction model. Likewise, total paw licking was reduced significantly in neurogenic (early stage) and inflammatory (late stage) pain induced by formalin in flusalazine-treated mice. In the tail immersion test, flusalazine significantly increased tail withdrawal time at 2 h after its administration. Also, the formation of paw edema in the flusalazine-treated group was significantly inhibited in a carrageenan-induced inflammatory pain model. Gastric damage was not induced by flusalazine even up to 1000 mg/kg, while aspirin and indomethacin caused critical gastric bleeding.Conclusion: These findings suggest that flusalazine’s safety profile and analgesic effects have high translational potential for the clinical treatment of patients experiencing pain.Keywords: analgesic effect, aspirin, flusalazine, indomethacin, NSAIDs

Anuranjan Ghimire,1 Gregory S Maves,1,2 Stephani S Kim,1,2 Vidya T Raman,1,2 Joseph D Tobias1,2 1Department of Anesthesiology & Pain Medicine, Nationwide Children’s Hospital, Columbus, OH, USA; 2Department of Anesthesiology & Pain Medicine, the Ohio State University College of Medicine, Columbus, OH, USACorrespondence: Anuranjan Ghimire, Department of Anesthesiology & Pain Medicine, Nationwide Children’s Hospital, 700 Children’s Dr, Columbus, OH, 43235, USA, Tel +1 614-722-4200, Fax: +1 614-722-4203, Email Anuranjan.Ghimire@nationwidechildrens.orgIntroduction: Cancellation of surgery or delay on the day of service is a huge burden for the patient, family, and healthcare system. Preventable delays impact efficiency and workflow, which may increase costs due to overtime and idle rooms during peak hours. Non-compliance to nil per os (NPO) guidelines remains one of the most common preventable causes for surgical cancellations. The current study sought to investigate and understand patient factors that may be associated with non-compliance to NPO guidelines.Methods: After IRB approval, a retrospective review of completed and cancelled pediatric procedures requiring the use of anesthesia over a 5-year period was performed. Emergency procedures and inpatient surgeries were excluded. Data regarding patient demographics and surgical service were extracted from the electronic medical records for comparison. A logistic regression model was used to identify factors associated with cancellations due to NPO non-compliance.Results: There were 825 cancellations due to NPO non-compliance of 144,049 cases for an incidence of 0.57% over the 5-year period. Patients in the 6– 12 year old age range and those who self-identified as non-White or non-English speaking had a higher incidence of cancelling due to NPO non-compliance. Compared to ear, nose, and throat (ENT) procedures, cancellations due to NPO non-compliance were more likely in radiology, dental, and urology procedures.Discussion: Many factors may impact a family’s compliance with NPO guidelines. Patient-related factors included those who self-identified as non-White or non-English speaking. Patients having ENT surgery were less likely to have NPO non-compliance than those having radiologic procedures, dental surgery, or urologic surgery. Future interventions focused on these groups may be most effective in limiting day of surgery cancellations.Keywords: nil per os, pediatric anesthesia, cancellation

Jinhwa Jang,1 Myung-Jae Hwang,1 Yoo-Yeon Kim,1 Shin Young Park,1 Myeongsu Yoo,1 Seong-Sun Kim,1 Sangwon Lee,2 Donghyok Kwon1 1Division of Public Health Emergency Response Research, Korea Disease Control and Prevention Agency, Cheongju-si, Chungcheongbuk-do, Republic of Korea; 2Director General for Public Health Emergency Preparedness, Korea Disease Control and Prevention Agency, Cheongju-si, Chungcheongbuk-do, Republic of KoreaCorrespondence: Donghyok Kwon, Division of Public Health Emergency Response Research, Korea Disease Control and Prevention Agency, 187, OsongSaengmyeong 2-ro, Osong-eup, Heungdeok-gu, Cheongju-si, Chungcheongbuk-do, 28159, Republic of Korea, Tel +82-43-719-7730, Fax +82-43-719-7749, Email vethyok@korea.krBackground: In South Korea, the epidemiological characteristics of children and adolescents infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) have not been reported to date. The purpose of this study was to identify major epidemiological characteristics and transmission patterns of coronavirus disease 2019 (COVID-19) in children and adolescents.Methods: This study was conducted through a system integrated in an epidemiological investigation by the Korea Disease Control and Prevention Agency from January 20, 2020, to June 5, 2021. We analyzed the epidemiological characteristics of 14,967 children and adolescents with COVID-19 according to the age groups and transmission age patterns of 3721 infector-infectee pairs in South Korea.Results: Among the total confirmed COVID-19 cases, 14,967 patients were aged 0– 18 years. The most affected age group among children and adolescents were those aged 16– 18 years (3589, 24.0%). For all age groups, the infection route through friends and family members (31.9%) was the highest. For the contact age pattern analysis, infection from infectors aged 30– 49 years to infectees aged 0– 12 years showed a statistically significant relation (p < 0.001) compared to that in other age groups. On the other hand, among the infectees aged 13– 15 years and 16– 18 years were significantly related with adolescents aged 10– 19 years (p < 0.05).Conclusion: These results suggest that adolescents aged 13– 18 years were more infected with COVID-19 than those aged 0– 12 years. Furthermore, they are particularly more likely to be infected by friends and family members. Besides, in patients aged 13– 18 years, transmission of SARS-CoV-2 was more common from adolescents to adolescents than from adults to adolescents. This research will provide scientific evidence for school policies and vaccine strategies for COVID-19 prevention in children and adolescents.Keywords: coronavirus disease-2019, severe acute respiratory syndrome coronavirus-2, incidence rate, mortality

Anna Gibbs,1 Stephani S Kim,2 Grant Heydinger,2,3 Giorgio Veneziano,2,3 Joseph Tobias2,3 1The Ohio State University College of Medicine, Columbus, OH, USA; 2Department of Anesthesiology & Pain Medicine, Nationwide Children’s Hospital, Columbus, OH, USA; 3Department of Anesthesiology & Pain Medicine, The Ohio State University College of Medicine, Columbus, OH, USACorrespondence: Giorgio VenezianoNationwide Children’s Hospital, Columbus, OH 43205, USATel +1 (614) 722-4209Fax +1 (614) 722-4203Email Giorgio.Veneziano@nationwidechildrens.orgIntroduction: In neonates and infants, epidural analgesia has gained popularity as a means of providing postoperative analgesia, limiting opioid-related adverse effects and improving the postoperative course. In addition to a local anesthetic agent, adjunctive agents may be added to further augment analgesia. Clonidine is an α2-adrenergic agonist that is frequently added to single-shot caudal analgesia, but there are limited data regarding its use in a continuous epidural infusion, especially in patients ≤ 12 months of age.Methods: We retrospectively reviewed the hospital records of neonates and infants who received postoperative epidural infusions with 2-chloroprocaine, and clonidine was identified over a 4-year period.Results: The study cohort included 52 neonates and infants ranging in age from 0 to 12 months and in weight from 2.1 to 10.1 kilograms. The catheters were dosed with either 1.5% 2-chloroprocaine (n=47) or 3% 2-chloroprocaine (n=5) with clonidine (median concentration 0.2 μg/mL) infused at a median rate of 0.72 mL/kg/hour. Pain scores were uniformly ≤ 3 at all evaluation points during the first 72 postoperative hours with a limited need for supplemental systemic opioids. No serious adverse effects were noted.Conclusion: With the recognized limitations of a retrospective study, these preliminary data demonstrate the safety of adding clonidine to an epidural infusion of 2-chloroprocaine in neonates and infants less than 12 months of age. Future studies are needed to determine its analgesic efficacy compared to 2-chloroprocaine alone and the optimal clonidine concentration for postoperative epidural infusions.Keywords: chloroprocaine, epidural analgesia, clonidine, neonatal anesthesia

Mohammed Hakim,1 Jason Bryant,1,2 Renata Miketic,1,2 Kent Williams,3 Steven H Erdman,3 Shabana Z Shafy,1 Stephani S Kim,1 Joseph D Tobias1,2 1Department of Anesthesiology & Pain Medicine, Nationwide Children’s Hospital, Columbus, OH, USA; 2Department of Anesthesiology & Pain Medicine, The Ohio State University, Columbus, OH, USA; 3Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Nationwide Children’s Hospital and the Ohio State University, Columbus, OH, USACorrespondence: Jason BryantDepartment of Anesthesiology & Pain Medicine, Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205, USATel +614 722-4200Fax +614 722-0487Email Jason.Bryant@nationwidechildrens.orgIntroduction: During esophagogastroduodenoscopy (EGD), general anesthesia (GA) may be provided using a laryngeal mask airway (LMA) with the endoscope inserted behind the cuff of the LMA into the esophagus. Passage of the endoscope may increase the intracuff of the LMA. We evaluated a newly designed LMA (LMA® Gastro™ Airway) which has an internal channel exiting from its distal end to facilitate EGD. The current study compared the change of LMA cuff pressure between this new LMA and a standard clinical LMA (Ambu® AuraOnce™) during EGD.Methods: Patients less than 21 years of age and weighing more than 30 kg were randomized to receive airway management with one of the two LMAs during EGD. After anesthetic induction and successful LMA placement, the intracuff pressure of the LMAs was continuously monitored during the procedure. The primary outcome was the change of intracuff pressure of the LMAs.Results: The study cohort included 200 patients (mean age 13.6 years and weight 56.6 kg) who were randomized to the LMA® Gastro™ Airway (n=100) or the Ambu® AuraOnce™ LMA (n=100). Average intracuff pressures during the study period (before and after endoscope insertion) were not different between the two LMAs. Ease of the procedure was slightly improved with the LMA® Gastro™ Airway (p< 0.001).Discussion: The LMA® Gastro™ Airway blunted, but did not prevent an increase in intracuff pressure during EGD when compared to the Ambu® AuraOnce™ LMA. Throat soreness was generally low, and complications were infrequent in both groups. The ease of the procedure was slightly improved with the LMA® Gastro™ Airway compared to the Ambu® AuraOnce™ LMA.Keywords: intracuff pressure, endoscope, pediatric anesthesia, general anesthesia, laryngeal mask airway, LMA® Gastro™ Airway

Emily D Geyer,1 Rebecca Miller,1 Stephani S Kim,1 Joseph D Tobias,1,2 Olubukola O Nafiu,1 Dmitry Tumin3 1Department of Anesthesiology and Pain Medicine, Nationwide Children’s Hospital, Columbus, OH, USA; 2Department of Anesthesiology & Pain Medicine, The Ohio State University, Columbus, OH, USA; 3Department of Pediatrics, East Carolina University, Greenville, NC, USACorrespondence: Stephani S Kim KimDepartment of Anesthesiology and Pain Medicine, Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205, USATel +1 614 722-2675Fax +1 614 722-4203Email Stephani.Kim@nationwidechildrens.orgAbstract: New technology has facilitated survey research of anesthesia professional society members. We evaluated prevailing metrics of quality and impact of published research studies based on surveys of anesthesiologists. We hypothesized that adherence to recommended practices (such as use of reminders) would be associated with increased survey response rates, and that higher response rates would be associated with higher article impact. Using the MEDLINE database, we identified 45 English-language research articles published in 2010– 2017 reporting original data from surveys of anesthesiologists. The median response rate was 37% (IQR: 25– 46%). Recommended survey practices, including the use of reminders (p = 0.861) and validated questionnaires (p = 0.719), were not correlated with response rates. In turn, survey response rates were not associated with measures of article impact (p = 0.528). The impact of published research based on surveys of anesthesiologists, as measured by citation scores (p = 0.493) and Altmetrics (p = 0.826), may be driven primarily by the novel data or questions raised using survey methodology, but does not appear to be associated with response rates. Improving reporting of survey methodology and understanding possible sources of non-response bias are important for future studies in this area.Keywords: survey methodology, anesthesiologist, response rate, survey research, systematic review

Yoshikazu Yamaguchi,1– 3 Tetsuya Miyashita,1 Yuko Matsuda,1 Makoto Sasaki,1 Shunsuke Takaki,1 Stephani S Kim,2 Joseph D Tobias,2,3 Takahisa Goto1 1Department of Anesthesiology and Critical Care, Yokohama City University, Kanagawa, Japan; 2Department of Anesthesiology and Pain Medicine, Nationwide Children’s Hospital, Columbus, OH, USA; 3Department of Anesthesiology and Pain Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USACorrespondence: Yoshikazu YamaguchiDepartment of Anesthesiology and Pain Medicine, Nationwide Children’s Hospital, Columbus, OH 43205, USATel +1 (614) 722-4200Fax +1 (614) 722-4203Email yoshikaz@rd6.so-net.ne.jpBackground: Precise control of tidal volume is one of the keys in limiting ventilator-induced lung injury and ensuring adequate ventilation in mechanically ventilated neonates. The aim of the study was to compare the tidal volume (mVT) measured from the expiratory limb of the ventilator with the actual tidal volume (aVT) that would be delivered to the patient using a lung model to simulate a neonate.Methods: This study was conducted using the ASL5000 lung simulator. Three combinations of parameters were set: resistance (cmH2O/L/sec) and compliance (mL/cmH2O) of 50 and 2 (Group 1), 100 and 1 (Group 2), and 150 and 0.5 (Group 3), respectively. The ASL5000 was connected to each of the ventilators including one anesthesia machine ventilator (Drager Fabius GS) and two ICU ventilators (Servo-i Universal and Evita Infinity V500). Each ventilator was evaluated with a set tidal volume of 30 mL (sVT) and a respiratory rate of 25 breathes/minute in both the volume-controlled ventilation (VCV) and dual-controlled ventilation (DCV) modes.Results: The discrepancies between sVT, mVT and aVT were highest with the Fabius anesthesia machine ventilator and increased in the simulated lung injury groups. When comparing the ICU ventilators, the difference was greater the Servo-i and increased when using the DCV mode and with simulated lung injury.Conclusion: Accurate tidal volumes were achieved only with the Infinity ICU ventilator. This was true regardless of mode of ventilation and even during simulated lung injury.Keywords: mechanical ventilation, pediatric anesthesia, tidal volume, flow sensor, lung protective ventilation, volutrauma

Seok Kyu Yoon,1 Kyun-Seop Bae,1 Dong Hyun Hong,2 Seong Su Kim,2 Young Kweon Choi,2 Hyeong-Seok Lim1 1Department of Clinical Pharmacology and Therapeutics, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, Republic of Korea; 2Department of Pharmaceutical Research, iCure Pharmaceutical Incorporated, Seoul, Republic of KoreaCorrespondence: Hyeong-Seok LimDepartment of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Songpa-Gu, Seoul Tel +82-2-3010-4623Fax +82-2-3010-4622Email mdlhs@amc.seoul.krIntroduction: This study characterized the pharmacokinetics (PKs) of a donepezil patch formulation currently under development, using mixed effect modeling analysis, and explored optimal patch dosing regimens in comparison with the donepezil oral formulation.Methods: PK data used in this analysis were from 60 healthy Korean male subjects participating in two Phase I studies, where subjects received single or multiple doses of donepezil of 43.75, 87.5, and 175 mg via patches, and 12 of them received a single oral dose of 10 mg of donepezil, followed by a single dose of donepezil via a patch. Donepezil PKs were analyzed by nonlinear mixed effect modeling using NONMEM software.Results: A well-stirred model with two-compartment distribution and delayed absorption was chosen as the best model for the oral formulation. The PKs of donepezil after the patch applications were best described by a two-compartment linear model with zero-order absorption (D2) and absorption delay. The relative bioavailability (BA) of donepezil after the patch application compared with oral dosing was described to be affected by the duration of patch application.Conclusion: PK simulations based on the chosen PK models suggested that, overall, donepezil exposure in plasma is similar whether with 10 mg of oral donepezil every 24 h or a 175 mg patch every 72 h, and likewise with 5 mg of oral donepezil every 24 h or an 87.5 mg patch every 72 h.Keywords: clinical trial(s), clinical trial simulation(s), pharmacokinetics, pharmacometrics, analysis

Seok Kyeong Oh, Byung Gun Lim, Young Sung Kim, Seong Shin Kim Department of Anesthesiology and Pain Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of KoreaCorrespondence: Byung Gun Lim Email bglim9205@korea.ac.krBackground: Anesthesia and surgery may deteriorate liver function in patients with elevated liver enzyme levels; therefore, in these patients, choosing anesthetics with less hepatotoxicity is important.Methods: This retrospective study investigated the effect of total intravenous anesthesia (TIVA) versus inhalation anesthesia (INHA) on the postoperative liver function in patients with preoperatively elevated liver enzyme levels (aspartate transaminase [AST] or alanine transaminase [ALT] > 40 U/L) who underwent non-hepatic surgery under general anesthesia. We compared the changes in enzyme levels within 24 hrs before and after surgery.Results: In 730 patients (TIVA: n=138; INHA: n=592), the baseline characteristics were comparable, except for higher comorbidity rates in the TIVA group. The median anesthesia and operation times were significantly longer in the TIVA group because approximately 50% of the TIVA group (vs 19.7% of the INHA group) underwent neurosurgery, which had a relatively longer operation time than other surgeries. Intraoperative hypotensive events and vasopressor use were more frequent in the TIVA group. After 1:4 propensity score matching (TIVA: n=94; INHA: n=376), the baseline characteristics and surgical variables were comparable, except for longer anesthesia time. Before matching, postoperative AST and ALT changes were significantly lower in the TIVA group than in the INHA group. After matching, only the ALT change was significantly lower after TIVA than after INHA [median (interquartile range), − 16.7 (− 32 to − 4) % vs − 12.0 (− 28.6– 6.5) %, P=0.025].Conclusion: TIVA may be safer for patients with preoperatively elevated liver transaminase levels.Keywords: alanine transaminase, aspartate transaminase, intravenous anesthetics, inhalation anesthetics, chemical and drug-induced liver injury

Sun S Kim,1 Sabreen Darwish,1 Sang A Lee,1 Courtenay Sprague,1–3 Rosanna F DeMarco1 1Department of Nursing, College of Nursing and Health Sciences, University of Massachusetts Boston, Boston, MA, USA; 2Department of Conflict Resolution, Global Governance and Human Security, John W. McCormack Graduate School of Policy and Global Studies, Boston, MA, USA; 3Wits Reproductive Health and HIV Institute, School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Background: People living with HIV smoke at a rate three times that of the general population. This randomized controlled pilot trial tested the feasibility and acceptability of a video-call smoking cessation intervention in women living with HIV and its preliminary efficacy compared with a voice-call smoking cessation intervention. The study focused on women due to a paucity of studies among this population, and women are less likely than men to quit smoking when provided with conventional treatment. Methods: Participants in both arms received an HIV-tailored smoking cessation intervention comprising eight 30-minute weekly counseling sessions in conjunction with active nicotine patches for 8 weeks. The only difference between the two arms was the delivery mode of the intervention: via either telephone-based video or voice call. Survival analysis and a Cox proportional hazard regression model were performed to identify factors predicting 6-month prolonged abstinence from smoking. Results: A video-call intervention was almost 30% less feasible than a voice-call intervention because women in their 50s and 60s or poorer women living in some southern states did not have access to video-call equipment. However, those who received the video-call intervention were more likely to complete the study than those who had the voice-call intervention. There was no difference in the acceptability of the two interventions. A survival analysis revealed that those in the video arm were significantly more likely to maintain smoking abstinence over the 6-month follow-up period than those in the voice arm (log rank χ2=4.02, P

Sun S Kim, Sabreen Darwish, Sang A Lee, Rosanna F DeMarco Department of Nursing, College of Nursing and Health Sciences, University of Massachusetts Boston, Boston, MA, USA Background: Prevalence of cigarette smoking is substantially higher among people living with human immunodeficiency virus (HIV) than the general population in the USA. Women living with HIV (WLHIV) who smoke are at higher risk of developing acquired immunodeficiency syndrome and have a higher mortality rate than nonsmoking WLHIV. Compared to men, women generally require more intensive counseling for smoking cessation. The primary aim of this study is to examine the acceptability and feasibility of a videoconferencing smoking cessation intervention that is tailored to the specific needs of WLHIV. Methods: A total of 50 WLHIV will be randomized at a ratio of 1:1 to either a videoconferencing or a telephone counseling arm. Both arms have the same cessation intervention, that is, eight weekly individualized counseling sessions of 30-minute cognitive behavioral therapy plus active nicotine patches for 8 weeks. The only difference between the two arms is the delivery mode of the counseling, that is, telephone video call vs. telephone voice call. Data collection is scheduled at baseline and three follow-up points: 1, 3, and 6 months from the target quit day. Data will be analyzed using STATA 14. The primary outcome is a 6-month prolonged abstinence. Home-based salivary cotinine test will be conducted to verify self-reported smoking abstinence using a NicAlert® test strip, while a research coordinator monitors the whole process by a telephone video call. Conclusion: The study is a two-arm parallel-group pilot clinical trial of a smoking cessation intervention. It attempts to examine whether videoconferencing smoking cessation intervention will be acceptable and feasible for WLHIV and will yield a better cessation outcome than telephone counseling intervention. Findings may have the potential to identify effective intervention strategies that will reduce and eliminate health disparities in tobacco control among WLHIV. Keywords: HIV, women, smoking cessation, videoconferencing, biochemical validation

Sun S Kim,1 Somporn Sitthisongkram,1 Kunsook Bernstein,2 Hua Fang,3 Won S Choi,4 Douglas Ziedonis5 1Department of Nursing, College of Nursing and Health Sciences, University of Massachusetts Boston, Boston, MA, 2Hunter-Bellevue School of Nursing, Hunter College, City University of New York, New York, NY, 3Department of Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, MA, 4Department of Preventive Medicine and Public Health, University of Kansas Medical Center, Kansas City, KS, 5Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA, USA Introduction: Korean women are reluctant to pursue in-person smoking cessation treatment due to stigma attached to women smokers and prefer treatment such as telephone and online smoking cessation programs that they can access secretively at home. However, there is some evidence that face-to-face interaction is the most helpful intervention component for them to quit smoking.Methods: This study is a pilot clinical trial that examined the acceptability and feasibility of a videoconferencing smoking cessation intervention for Korean American women and compared its preliminary efficacy with a telephone-based intervention. Women of Korean ethnicity were recruited nationwide in the United States and randomly assigned at a ratio of 1:1 to either a video arm or a telephone arm. Both arms received eight 30-minute weekly individualized counseling sessions of a deep cultural smoking cessation intervention and nicotine patches for 8 weeks. Participants were followed over 3 months from the quit day. Results: The videoconferencing intervention was acceptable and feasible for Korean women aged

Yo Han Kim,1 Hee Youn Choi,1 Hyeong-Seok Lim,1 Shi Hyang Lee,1 Hae Sun Jeon,1 Donghyun Hong,2 Seong Su Kim,2 Young Kweon Choi,2 Kyun-Seop Bae1 1Department of Clinical Pharmacology and Therapeutics, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, Republic of Korea; 2iCure Pharmaceutical lncorporated, Anseong, Gyeonggi-do, Republic of Korea Background: Donepezil is an acetylcholinesterase inhibitor indicated for Alzheimer’s disease. The aim of this randomized, single-blind, placebo-controlled, single-dose, dose-escalation study was to investigate the safety, tolerability, and pharmacokinetics of the donepezil patch in healthy male subjects. Methods: Each healthy male subject received a single transdermal donepezil patch (72 hours patch-on periods) of 43.75 mg/12.5 cm2, 87.5 mg/25 cm2, or 175 mg/50 cm2. Serial blood samples were collected up to 312 hours after patch application. The plasma concentrations of donepezil were determined by using a validated liquid chromatography–tandem mass spectrometry method. Pharmacokinetic parameters were obtained by noncompartmental analysis. Tolerability of the patches and performance of the patches (adhesion, skin irritation, residual donepezil content in the patch) were assessed throughout the study. Results: The study was completed by 36 healthy subjects. After patch application, the maximal plasma donepezil concentration (Cmax) and the area under the curve (AUC) increased in a dose-proportional manner. Median time to Cmax was ~74–76 hours (~2–4 hours after patch removal), and mean t1/2ß was ~63.77–93.07 hours. The average donepezil residue in the patch after 72 hours was ~73.9%–86.7% of the loading dose. There were neither serious adverse events nor adverse events that lead to discontinuation. Skin adhesion of the patch was good in 97.2% of the subjects. All skin irritations after patch removal were mild and were resolved during the study period. Conclusion: The donepezil patch appeared to be generally well tolerated and adhesive. Pharmacokinetic analysis of the donepezil patch demonstrated linear kinetics. Keywords: donepezil, transdermal patch, pharmacokinetics, healthy subjects

KR Jyothi,1 Jagadish Beloor,2 Ara Jo,1 Minh Nam Nguyen,1 Tae Gyu Choi,1 Jin-Hwan Kim,1 Salima Akter,1 Sang-Kyung Lee,2 Chi Hoon Maeng,3 Hyung Hwan Baik,1 Insug Kang,1 Joohun Ha,1 Sung Soo Kim1 1Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul, Republic of Korea; 2Department of Bioengineering and Institute for Bioengineering and Biopharmaceutical Research, Hanyang University, Seoul, Republic of Korea; 3Department of Medical Oncology and Hematology, Kyung Hee University Hospital, Seoul, Republic of Korea Abstract: Therapeutic options for hepatitis C virus (HCV) infection have been limited by drug resistance and adverse side effects. Targeting the host factor cyclophilin A (CypA), which is essential for HCV replication, offers a promising strategy for antiviral therapy. However, due to its immunosuppressive activity and severe side effects, clinical application of cyclosporine A (CsA) has been limited as an antiviral agent. To overcome these drawbacks, we have successfully developed a liver-specific, sustained drug delivery system by conjugating the liver-targeting peptide (LTP) to PEGylated CsA-encapsulated poly (lactic-co-glycolic) acid (PLGA) nanoparticles. Furthermore, our delivery system exhibited high specificity to liver, thus contributing to the reduced immunosuppressive effect and toxicity profile of CsA. Finally, targeted nanoparticles were able to effectively inhibit viral replication in vitro and in an HCV mouse model. As a proof of principle, we herein show that our delivery system is able to negate the adverse effects of CsA and produce therapeutic effects in an HCV mouse model.Keywords: HCV, liver-targeting peptide, targeted drug delivery

Chul-Young Bae,1 Young Gon Kang,2 Young-Sung Suh,3 Jee Hye Han,4 Sung-Soo Kim,5 Kyung Won Shim61MediAge Research Center, Seoul, Korea; 2Chaum Power Aging Center, College of Medicine, CHA University, Seoul, Korea; 3Health Promotion Center, Keimyung University Dongsam Medical Center, Daegu, Korea; 4Department of Family Medicine, College of Medicine, Eulji University, Seoul, Korea; 5Department of Family Medicine, College of Medicine, Chungnam National University, Daejeon, Korea; 6Department of Family Medicine, Ewha Womans University Mokdong Hospital, Ewha Womans University, Seoul, KoreaBackground: To date, no studies have attempted to estimate body shape biological age using clinical parameters associated with body composition for the purposes of examining a person's body shape based on their age.Objective: We examined the relations between clinical parameters associated with body composition and chronological age, and proposed a model for estimating the body shape biological age.Methods: The study was conducted in 243,778 subjects aged between 20 and 90 years who received a general medical checkup at health promotion centers at university and community hospitals in Korea from 2004 to 2011.Results: In men, the clinical parameters with the highest correlation to age included the waist-to-hip ratio (r = 0.786, P < 0.001), hip circumference (r = −0.448, P < 0.001), and height (r = −0.377, P < 0.001). In women, the clinical parameters with the highest correlation to age include the waist-to-hip ratio (r = 0.859, P < 0.001), waist circumference (r = 0.580, P < 0.001), and hip circumference (r = 0.520, P < 0.001). To estimate the optimal body shape biological age based on clinical parameters associated with body composition, we performed a multiple regression analysis. In a model estimating the body shape biological age, the coefficient of determination (R2) was 0.71 in men and 0.76 in women.Conclusion: Our model for estimating body shape biological age might be a novel approach to variation in body shape that is due to aging. We assume that our estimation model would be used as an adjunctive measure in easily predicting differences in body shape with the use of clinical parameters that are commonly used to assess the status of obesity in a clinical setting.Keywords: chronological age, body shape, biological age

We present extended X-ray absorption fine structure (EXAFS) spectra and modeling of a series of structurally tunable quasi-one-dimensional mixed-valence platinum-halide linear chain materials, [Pt(en2)][Pt(en2)X2](ClO4)4 with X = Cl, Br, I. The materials exhibit a commensurate charge density wave with fractional charge states on alternating platinum ions in the chain, as well as a Peierls distortion with alternating platinum-halide bond lengths. The amplitude of the charge density wave and, correspondingly, the extent of the Peierls distortion are controlled by the identity of the bridging halide ion. We have carried out ab initio multiple scattering calculations using the FEFF9 code to relate the oriented Pt LIII EXAFS spectra to the tunable electronic and structural properties. The spectral modeling reveals distinct photoelectron threshold energy values for the two inequivalent platinum ions in each of the mixed-valence chains, with values that vary systematically with fractional valence state. The difference in the photoelectron threshold energies of the two inequivalent platinum ions within each material correlates directly with the amplitude of the charge density wave, reflecting the decrease in charge density wave strength through the halide series X = Cl, Br, and I. We use dynamical matrix modeling to relate the experimentally determined mean-square relative displacement parameters for the metal-halide bond distances to the chain-axis vibrational modes that modulate the charge density wave structure. In addition, we discuss the EXAFS fitting results for the Pt-I bond lengths in the [Pt(en2)][Pt(en2)I2](ClO4)4 complex in comparison to previous, mutually inconsistent structural determinations for this material.

Imaging hydraulically active fracture zones (HAFZ) is of paramount importance to subsurface resource extraction, geologic storage, and hazardous waste disposal. We have developed advanced 3D finite-element (FE) electrical imaging algorithms for HAFZ in the presence of a steel-cased well. The algorithms use tetrahedral FE meshes in the simulation domain and coarse rectangular finite-difference meshes in the imaging domain. This heterogeneous dual-mesh approach is well suited to modeling the multiscale earth model due to steel-cased wells. We find that the algorithms accurately and efficiently simulate surface electric field measurements over a 3D HAFZ at depth when one end point of a surface electric source is connected to a wellhead. For brevity, this configuration is called the top-casing electric source method. By replacing a hollow cased well with a solid prism, we improve our computational efficiency without affecting the solution accuracy. The sensitivity of the top-casing source method to HAFZ highly depends on the continuity of a steel-cased well because it makes currents preferentially flow to HAFZ. The sensitivity also depends on conductivity structures around the well because they control current leaking from the steel-cased well. We find that the method can image a localized HAFZ and detect changes in its width and height. The imaging results are improved when a volume of the imaging domain is constrained from geomechanical perspectives. A primary advantage of the method is the fact that the sources and receivers are placed on the surface, thus not interrupting the well operation.

Using three-dimensional nonlinear simulations of tokamak turbulence, we show that an edge transport barrier (ETB) forms naturally once input power exceeds a threshold value. Profiles, turbulence-driven flows, and neoclassical coefficients are evolved self-consistently. A slow power ramp-up simulation shows that ETB transition is triggered by the turbulence-driven flows via an intermediate phase which involves coherent oscillation of turbulence intensity and E × B flow shear. A novel observation of the evolution is that the turbulence collapses and the ETB transition begins when RT > 1 at t = tR (RT: normalized Reynolds power), while the conventional transition criterion (ω E × B > γ l i n where ω E × B denotes mean flow shear) is satisfied only after t = tC ( >tR), when the mean flow shear grows due to positive feedback.

An overview of the physics of intrinsic torque is presented, with special emphasis on the phenomenology of intrinsic toroidal rotation in tokamaks, its theoretical understanding, and the variety of momentum transport bifurcation dynamics. Ohmic reversals and electron cyclotron heating-driven counter torque are discussed in some detail. Symmetry breaking by lower single null versus upper single null asymmetry is related to the origin of intrinsic torque at the separatrix. © 2013 IAEA, Vienna.

We show that strong edge magnetic shear, which is generic to divertor plasmas, makes the E × B shearing of turbulence eddys in toroidal geometry more effective. From calculations of the E × B shearing rates for KSTAR edge parameters, we conclude that the enhanced magnetic shear at the diverted KSTAR plasma edge facilitates E × B shear suppression of turbulence and ensuing H-mode transition. © 2013 IAEA, Vienna.

This paper reports on the theoretical and simulation results of a gyro-Landau-fluid extension of the BOUT++ code, which contributes to increasing the physics understanding of edge-localized-modes (ELMs). Large ELMs with low-to-intermediate-n peeling-ballooning (P-B) modes are significantly suppressed due to finite Larmor radius (FLR) effects when the ion temperature increases. For type-I ELMs, it is found from linear simulations that retaining complete first order FLR corrections as resulting from the incomplete "gyroviscous cancellation" in Braginskii's two-fluid model is necessary to obtain good agreement with gyro-fluid results for high ion temperature cases (Ti3 keV) when the ion density has a strong radial variation, which goes beyond the simple local model of ion diamagnetic stabilization of ideal ballooning modes. The maximum growth rate is inversely proportional to Ti because the FLR effect is proportional to Ti. The FLR effect is also proportional to toroidal mode number n, so for high n cases, the P-B mode is stabilized by FLR effects. Nonlinear gyro-fluid simulations show results that are similar to those from the two-fluid model, namely that the P-B modes trigger magnetic reconnection, which drives the collapse of the pedestal pressure. Due to the additional FLR-corrected nonlinear E × B convection of the ion gyro-center density, for a ballooning-dominated equilibrium the gyro-fluid model further limits the radial spreading of ELMs. In six-field two fluid simulations, the parallel thermal diffusivity is found to prevent the ELM encroachment further into core plasmas and therefore leads to steady state L-mode profiles. The simulation results show that most energy is lost via ion channel during an ELM event, followed by particle loss and electron energy loss. Because edge plasmas have significant spatial inhomogeneities and complicated boundary conditions, we have developed a fast non-Fourier method for the computation of Landau-fluid closure terms based on an accurate and tunable approximation. The accuracy and the fast computational scaling of the method have been demonstrated. © 2013 AIP Publishing LLC.

We present a statistical analysis of heat transport in stationary enhanced confinement regimes obtained from flux-driven gyrofluid simulations. The probability density functions of heat flux in improved confinement regimes, characterized by the Nusselt number, show significant deviation from Gaussian, with a markedly fat tail, implying the existence of heat avalanches. Two types of avalanching transport are found to be relevant to stationary states, depending on the degree of turbulence suppression. In the weakly suppressed regime, heat avalanches occur in the form of quasi-periodic (QP) heat pulses. Collisional relaxation of zonal flow is likely to be the origin of these QP heat pulses. This phenomenon is similar to transient limit cycle oscillations observed prior to edge pedestal formation in recent experiments. On the other hand, a spectral analysis of heat flux in the strongly suppressed regime shows the emergence of a 1/f (f is the frequency) band, suggesting the presence of self-organized criticality (SOC)-like episodic heat avalanches. This episodic 1/f heat avalanches have a long temporal correlation and constitute the dominant transport process in this regime. © 2012 American Institute of Physics.

We study the interplay between intrinsic rotation and internal transport barrier (ITB) dynamics through the dynamic change of the parallel Reynolds stress. Global flux-driven gyrofluid simulations are used for this study. In particular, we investigate the role of parallel velocity gradient instability (PVGI) in the ITB formation and the back transition. It is found that the excitation of PVGI is followed by a change in the Reynolds stress which drives a momentum redistribution. This significantly influences E × B shear evolution and subsequent ITB dynamics. Nonlocal interactions among fluctuations are also observed during the PVGI excitation, resulting in turbulence suppression at the ITB. © 2012 American Institute of Physics.

We present an analytic study of the impact of external torque on the formation of ion internal transport barriers (ITBs). A simple analytic relation representing the effect of low external torque on transport bifurcations is derived based on a two field transport model of pressure and toroidal momentum density. It is found that the application of an external torque can either facilitate or hamper bifurcation in heat flux driven plasmas depending on its sign relative to the direction of intrinsic torque. The ratio between radially integrated momentum (i.e., external torque) density to power input is shown to be a key macroscopic control parameter governing the characteristics of bifurcation. © 2012 American Institute of Physics.