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PDF file - 376K, Inhibition rates (IR) of tumor growth (A) and response rates at IR30 (chemosensitivity) (B). The IRs and IR30 of a single bevacizumab or cetuximab regimen were significantly less than those of the other four combination regimens (P � 0.001). IR, inhibition rate; FRB, FOLFIRI + bevacizumab; FXB, FOLFOX + bevacizumab; FRC, FOLFIRI + cetuximab; FXC, FOLFOX + cetuximab.

Purpose: Methods for predicting individual responsiveness to targeted chemotherapy are urgently needed, considering the frequent resistance and extremely high cost.Experimental Design: A chemosensitive single-nucleotide polymorphism (SNP) discovery schema is presented that utilizes (i) genome-wide SNP screening with a human SNP array and an in vitro chemosensitivity assay in 118 colorectal cancers, (ii) clinical association analysis in the other 98 patients who had received chemotherapy for metastatic cancer, and (iii) biological utility assessment using cell viability assays of transfected colorectal cancer (CRC) cells.Results: Nine SNPs related to bevacizumab and cetuximab regimen sensitivity were chosen during screening. Overall responses for bevacizumab regimens revealed that patients carrying the TT genotype at ANXA11 rs1049550 or at least one G allele at LINS1 rs11247226 seemed greater chemosensitive than those carrying at least one C allele or the AA genotype, respectively (P < 0.05). For cetuximab regimens, patients carrying the GG genotype at DFNB31 rs2274159 or LIFR rs3729740 seemed greater chemosensitive than those carrying at least one A allele (P = 0.025 and P = 0.07). Cytotoxicity analyses showed that all RKO and HCT116 CRC clones transfected with the G allele at LIFR rs3729740 and the C allele at ISX rs361863 were more sensitive to cetuximab regimens than those with the A and T allele, respectively (P ≤ 0.001–0.024).Conclusions: Chemosensitive SNP markers were identified using a novel three-step process. The candidate marker LIFR rs3729740 and possibly ISX rs361863 will hopefully predict responsive patients to cetuximab regimens, although further validation is needed in large cohorts. Clin Cancer Res; 17(5); 1200–9. ©2011 AACR.

PDF file - 2.6MB, Genome-wide association with in vitro chemosensitivity to targeted regimens: FRB (A), FXB (B), FRC (C), and FXC (D). Association of SNPs with the inhibition ratio was tested by linear regression analysis. P-values of < 0.001 are indicated by red dots. FRB, FOLFIRI + bevacizumab; FXB, FOLFOX + bevacizumab; FRC, FOLFIRI + cetuximab; FXC, FOLFOX + cetuximab.

PDF file - 1.4MB, Cell viability measured by MTT assay in transfected CRC clones (a. DFNB31 rs2274159; b. ANXA11 rs1049550; c. LINS1 rs11247226) treated with FRC (a), FRB (b), and FXB (c), respectively. Bold font, P < 0.05. FRC, FOLFIRI + cetuximab; FRB, FOLFIRI + bevacizumab; FXB, FOLFOX + bevacizumab.

Tumor size and growth are important parameters when evaluating bone and soft tissue neoplasms. There are no reports comparing the intra- and interobserver reliability among physicians in their evaluation of musculoskeletal (MSK) tumor imaging. This study investigates the accuracy and precision of measurements made by orthopedic and radiology physicians in different stages of training. Blinded magnetic resonance imaging (MRI) scans from six patients, three soft tissue, and three bone tumors were selected: each case included an "old" and "new" scan that was performed at least 3 months apart. Fourteen participants were selected, representing varying levels of education and experience, including two of each of the following: medical students, orthopedic and radiology residents, oncology and nononcologic orthopedic attendings, and MSK and non-MSK radiology attendings. Participants compared the old and new studies, recording tumor size in the transverse, cranial-caudal, and anterior-posterior dimensions, and determined if the tumor was stable or unstable. The MRI's official report served as the "gold standard." Average intraobserver variability (|Trial 1 - Trial 2|/[(Trial 1 + Trial 2)/2])) in size measurements was 11.08% (0.00%-68.62%). The lowest variability was recorded by the MSK radiologist 1 (6.16%), and the greatest variability by Orthopedic Surgery Resident 1 (16.70%). Participants correctly determined stability 82% of the time (71%-100%). Only MSK radiologists correctly determined stability in over 90% of cases. There is considerable variability and inaccuracy in MRI-based measurements of MSK tumors. These findings motivate opportunities for improving MSK imaging education of radiology and orthopedic residents. Physicians ordering MRI scans should evaluate them themselves, instead of relying on the radiology report alone, to inform clinical decision-making.

The Korean government has established “minor damage repair standards” that require repair without replacement when vehicle bumpers can be repaired to reduce plastic bumper waste. However, when blind spot detection and lane change assist systems, active safety systems, are installed, there is a controversy over whether the standards can be applied to restore the minor damage bumper covers because the short-range radar sensor for them is located inside each corner of the rear bumper. Therefore, it is necessary to identify the difference between original and repair conditions to confirm the repair methods that can meet the government’s standards while maintaining the safety performance of the systems. The experiments were designed two sectors, most vehicle bumper cover repair methods were produced as test specimens which are used for static tests to compare with the new vehicle state, and based on the results, specimens needed field confirmation were prepared and dynamic tests were conducted. The microscopic performance difference of the safety systems according to the refinishing was determined by analyzing the dynamic test results using null-hypothesis significance testing and analysis of variance methods. The results of the tests showed that applying a filler to form the bumper surface does not cause performance problems if the radar signal transmission area of 10 m2is avoided. In the case of paintwork on the radar signal area, two or three layers of paint did not show any difference from the manufacturer’s bumper, therefore paint layer scratches can be refinished up to twice. However, if metal-colored paint layers are three as a result of paintwork twice, the maximum detection angle performance is adversely affected. Through this study, new experimental methods were suggested for identifying the safety performance of advanced driver assistance systems when various repair methods are applied to the plastic bumper cover.

This executive summary of the guideline update provides evidence-based recommendations for patient selection and surgical indications for managing tympanostomy tubes in children. The summary and guideline are intended for any clinician involved in managing children aged 6 months to 12 years with tympanostomy tubes or children being considered for tympanostomy tubes in any care setting as an intervention for otitis media of any type. The target audience includes specialists, primary care clinicians, and allied health professionals.The purpose of this executive summary is to provide a succinct overview for clinicians of the key action statements (recommendations), summary tables, and patient decision aids from the update of the American Academy of Otolaryngology-Head and Neck Surgery Foundation's "Clinical Practice Guideline: Tympanostomy Tubes in Children (Update)." The new guideline updates recommendations in the prior guideline from 2013 and provides clinicians with trustworthy, evidence-based recommendations on patient selection and surgical indications for managing tympanostomy tubes in children. This summary is not intended to substitute for the full guideline, and clinicians are encouraged to read the full guideline before implementing the recommended actions.The guideline on which this summary is based was developed using methods outlined in the American Academy of Otolaryngology-Head and Neck Surgery Foundation's "Clinical Practice Guideline Development Manual, Third Edition: A Quality-Driven Approach for Translating Evidence Into Action," which were followed explicitly. The guideline update group represented the disciplines of otolaryngology-head and neck surgery, otology, pediatrics, audiology, anesthesiology, family medicine, advanced practice nursing, speech-language pathology, and consumer advocacy.

Insertion of tympanostomy tubes is the most common ambulatory surgery performed on children in the United States. Tympanostomy tubes are most often inserted because of persistent middle ear fluid, frequent ear infections, or ear infections that persist after antibiotic therapy. All these conditions are encompassed by the termThe purpose of this clinical practice guideline update is to reassess and update recommendations in the prior guideline from 2013 and to provide clinicians with trustworthy, evidence-based recommendations on patient selection and surgical indications for managing tympanostomy tubes in children. In planning the content of the updated guideline, the guideline update group (GUG) affirmed and included all the original key action statements (KASs), based on external review and GUG assessment of the original recommendations. The guideline update was supplemented with new research evidence and expanded profiles that addressed quality improvement and implementation issues. The group also discussed and prioritized the need for new recommendations based on gaps in the initial guideline or new evidence that would warrant and support KASs. The GUG further sought to bring greater coherence to the guideline recommendations by displaying relationships in a new flowchart to facilitate clinical decision making. Last, knowledge gaps were identified to guide future research.In developing this update, the methods outlined in the American Academy of Otolaryngology-Head and Neck Surgery Foundation's "Clinical Practice Guideline Development Manual, Third Edition: A Quality-Driven Approach for Translating Evidence Into Action" were followed explicitly. The GUG was convened with representation from the disciplines of otolaryngology-head and neck surgery, otology, pediatrics, audiology, anesthesiology, family medicine, advanced practice nursing, speech-language pathology, and consumer advocacy.The GUG made

Subcutaneous implantable cardioverter-defibrillator (S-ICD) placement may cause significant postoperative pain. Limited research exists on regional anesthesia for pediatric S-ICD placement. This case series examined transversus thoracic plane blocks (TTPBs), pectointercostal fascial plane blocks (PIFBs), pectoralis nerve I and II blocks, paravertebral, serratus anterior plane, and erector spinae plane blocks (ESPBs) in 10 children receiving S-ICDs. Parasternal nerve blocks consisting of TTPB or PIFB and left ESPB appeared to provide adequate pain control. These children had reduced opioid consumption, lower mean pain scores, longer delay in first postoperative analgesic, and no complications. Regional anesthesia may reduce pain after pediatric S-ICD implantation.

This update of a 2011 guideline developed by the American Academy of Otolaryngology-Head and Neck Surgery Foundation provides evidence-based recommendations on the pre-, intra-, and postoperative care and management of children 1 to 18 years of age under consideration for tonsillectomy. Tonsillectomy is defined as a surgical procedure performed with or without adenoidectomy that completely removes the tonsil, including its capsule, by dissecting the peritonsillar space between the tonsil capsule and the muscular wall. Tonsillectomy is one of the most common surgical procedures in the United States, with 289,000 ambulatory procedures performed annually in children15 years of age, based on the most recent published data. This guideline is intended for all clinicians in any setting who interact with children who may be candidates for tonsillectomy.The purpose of this multidisciplinary guideline is to identify quality improvement opportunities in managing children under consideration for tonsillectomy and to create explicit and actionable recommendations to implement these opportunities in clinical practice. Specifically, the goals are to educate clinicians, patients, and/or caregivers regarding the indications for tonsillectomy and the natural history of recurrent throat infections. Additional goals include the following: optimizing the perioperative management of children undergoing tonsillectomy, emphasizing the need for evaluation and intervention in special populations, improving the counseling and education of families who are considering tonsillectomy for their children, highlighting the management options for patients with modifying factors, and reducing inappropriate or unnecessary variations in care. Children aged 1 to 18 years under consideration for tonsillectomy are the target patient for the guideline. For this guideline update, the American Academy of Otolaryngology-Head and Neck Surgery Foundation selected a panel representing the fields of nursing, anesthesiology, consumers, family medicine, infectious disease, otolaryngology-head and neck surgery, pediatrics, and sleep medicine.The guideline update group made strong recommendations for the following key action statements (KASs): (1) Clinicians should recommend watchful waiting for recurrent throat infection if there have been7 episodes in the past year,5 episodes per year in the past 2 years, or3 episodes per year in the past 3 years. (2) Clinicians should administer a single intraoperative dose of intravenous dexamethasone to children undergoing tonsillectomy. (3) Clinicians should recommend ibuprofen, acetaminophen, or both for pain control after tonsillectomy. The guideline update group made recommendations for the following KASs: (1) Clinicians should assess the child with recurrent throat infection who does not meet criteria in KAS 2 for modifying factors that may nonetheless favor tonsillectomy, which may include but are not limited to multiple antibiotic allergies/intolerance, PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and adenitis), or history of1 peritonsillar abscess. (2) Clinicians should ask caregivers of children with obstructive sleep-disordered breathing and tonsillar hypertrophy about comorbid conditions that may improve after tonsillectomy, including growth retardation, poor school performance, enuresis, asthma, and behavioral problems. (3) Before performing tonsillectomy, the clinician should refer children with obstructive sleep-disordered breathing for polysomnography if they are2 years of age or if they exhibit any of the following: obesity, Down syndrome, craniofacial abnormalities, neuromuscular disorders, sickle cell disease, or mucopolysaccharidoses. (4) The clinician should advocate for polysomnography prior to tonsillectomy for obstructive sleep-disordered breathing in children without any of the comorbidities listed in KAS 5 for whom the need for tonsillectomy is uncertain or when there is discordance between the physical examination and the reported severity of obstructive sleep-disordered breathing. (5) Clinicians should recommend tonsillectomy for children with obstructive sleep apnea documented by overnight polysomnography. (6) Clinicians should counsel patients and caregivers and explain that obstructive sleep-disordered breathing may persist or recur after tonsillectomy and may require further management. (7) The clinician should counsel patients and caregivers regarding the importance of managing posttonsillectomy pain as part of the perioperative education process and should reinforce this counseling at the time of surgery with reminders about the need to anticipate, reassess, and adequately treat pain after surgery. (8) Clinicians should arrange for overnight, inpatient monitoring of children after tonsillectomy if they are3 years old or have severe obstructive sleep apnea (apnea-hypopnea index ≥10 obstructive events/hour, oxygen saturation nadir80%, or both). (9) Clinicians should follow up with patients and/or caregivers after tonsillectomy and document in the medical record the presence or absence of bleeding within 24 hours of surgery (primary bleeding) and bleeding occurring later than 24 hours after surgery (secondary bleeding). (10) Clinicians should determine their rate of primary and secondary posttonsillectomy bleeding at least annually. The guideline update group made a strong recommendation against 2 actions: (1) Clinicians should not administer or prescribe perioperative antibiotics to children undergoing tonsillectomy. (2) Clinicians must not administer or prescribe codeine, or any medication containing codeine, after tonsillectomy in children younger than 12 years. The policy level for the recommendation about documenting recurrent throat infection was an option: (1) Clinicians may recommend tonsillectomy for recurrent throat infection with a frequency of at least 7 episodes in the past year, at least 5 episodes per year for 2 years, or at least 3 episodes per year for 3 years with documentation in the medical record for each episode of sore throat and ≥1 of the following: temperature38.3°C (101°F), cervical adenopathy, tonsillar exudate, or positive test for group A beta-hemolytic streptococcus.Incorporating new evidence profiles to include the role of patient preferences, confidence in the evidence, differences of opinion, quality improvement opportunities, and any exclusion to which the action statement does not apply. There were 1 new clinical practice guideline, 26 new systematic reviews, and 13 new randomized controlled trials included in the current guideline update. Inclusion of 2 consumer advocates on the guideline update group. Changes to 5 KASs from the original guideline: KAS 1 (Watchful waiting for recurrent throat infection), KAS 3 (Tonsillectomy for recurrent infection with modifying factors), KAS 4 (Tonsillectomy for obstructive sleep-disordered breathing), KAS 9 (Perioperative pain counseling), and KAS 10 (Perioperative antibiotics). Seven new KASs: KAS 5 (Indications for polysomnography), KAS 6 (Additional recommendations for polysomnography), KAS 7 (Tonsillectomy for obstructive sleep apnea), KAS 12 (Inpatient monitoring for children after tonsillectomy), KAS 13 (Postoperative ibuprofen and acetaminophen), KAS 14 (Postoperative codeine), and KAS 15a (Outcome assessment for bleeding). Addition of an algorithm outlining KASs. Enhanced emphasis on patient and/or caregiver education and shared decision making.

Subcutaneous implantable cardioverter-defibrillator (S-ICD) placement may cause significant postoperative pain. Limited research exists on regional anesthesia for pediatric S-ICD placement. This case series examined transversus thoracic plane blocks (TTPBs), pectointercostal fascial plane blocks (PIFBs), pectoralis nerve I and II blocks, paravertebral, serratus anterior plane, and erector spinae plane blocks (ESPBs) in 10 children receiving S-ICDs. Parasternal nerve blocks consisting of TTPB or PIFB and left ESPB appeared to provide adequate pain control. These children had reduced opioid consumption, lower mean pain scores, longer delay in first postoperative analgesic, and no complications. Regional anesthesia may reduce pain after pediatric S-ICD implantation.

EDITOR’S PERSPECTIVE What We Already Know about This Topic Dantrolene effectively treats malignant hyperthermia, but there are discrepant recommendations for dantrolene availability in facilities that stock succinylcholine for airway rescue but do not use volatile anesthetics. What This Article Tells Us That Is New The authors performed an analysis of data from three databases and a systematic literature review. Providers frequently use succinylcholine, including during difficult mask ventilation. Succinylcholine given without volatile anesthetics triggered 24 malignant hyperthermia events, 13 of which were treated with dantrolene. Fourteen patients experienced substantial complications, and one died. Delayed dantrolene treatment worsened patient outcomes. Background Although dantrolene effectively treats malignant hyperthermia (MH), discrepant recommendations exist concerning dantrolene availability. Whereas Malignant Hyperthermia Association of the United States guidelines state dantrolene must be available within 10 min of the decision to treat MH wherever volatile anesthetics or succinylcholine are administered, a Society for Ambulatory Anesthesia protocol permits Class B ambulatory facilities to stock succinylcholine for airway rescue without dantrolene. The authors investigated (1) succinylcholine use rates, including for airway rescue, in anesthetizing/sedating locations; (2) whether succinylcholine without volatile anesthetics triggers MH warranting dantrolene; and (3) the relationship between dantrolene administration and MH morbidity/mortality. Methods The authors performed focused analyses of the Multicenter Perioperative Outcomes Group (2005 through 2016), North American MH Registry (2013 through 2016), and Anesthesia Closed Claims Project (1970 through 2014) databases, as well as a systematic literature review (1987 through 2017). The authors used difficult mask ventilation (grades III and IV) as a surrogate for airway rescue. MH experts judged dantrolene treatment. For MH morbidity/mortality analyses, the authors included U.S. and Canadian cases that were fulminant or scored 20 or higher on the clinical grading scale and in which volatile anesthetics or succinylcholine were given. Results Among 6,368,356 queried outcomes cases, 246,904 (3.9%) received succinylcholine without volatile agents. Succinylcholine was used in 46% (n = 710) of grade IV mask ventilation cases (median dose, 100 mg, 1.2 mg/kg). Succinylcholine without volatile anesthetics triggered 24 MH cases, 13 requiring dantrolene. Among 310 anesthetic-triggered MH cases, morbidity was 20 to 37%. Treatment delay increased complications every 10 min, reaching 100% with a 50-min delay. Overall mortality was 1 to 10%; 15 U.S. patients died, including 4 after anesthetics in freestanding facilities. Conclusions Providers use succinylcholine commonly, including during difficult mask ventilation. Succinylcholine administered without volatile anesthetics may trigger MH events requiring dantrolene. Delayed dantrolene treatment increases the likelihood of MH complications. The data reported herein support stocking dantrolene wherever succinylcholine or volatile anesthetics may be used.

The chapter highlights current challenges in the perianesthetic care of children presenting for liver transplantation. Pediatric liver transplantation is a lifesaving intervention for children with various congenital or acquired acute and chronic liver diseases. The relatively low number of liver transplantations in the pediatric population nationwide presents a challenge to developing and maintaining sufficient knowledge and skills that are mandatory for the successful anesthetic care of these most critically ill patients. The essential information presented can be utilized to facilitate standardization of practice in any institution performing liver transplantation. The details of perianesthetic management include patient evaluation, comorbidities, monitoring requirements, therapeutic interventions, and postoperative care. The intraoperative period consisting of the preanhepatic, anhepatic, and neohepatic stages are each distinct in their anesthetic management. The clinical challenges encountered in liver transplantation demands an in-depth understanding of the unique physiology in order to avoid and appropriately treat any abnormalities that occur during a successful liver transplant.

To the Editor Ultrasound guided nerve blocks present unique challenges to anesthesiologists. These include altered spatial orientation and usage of a monitor requiring the provider’s gaze to be away from the working field.[1][1] A monitor by itself can decrease performance relative to native

Limited data are available on the efficacy of anti-IGF-1R agents in KRAS mutant colorectal cancer (CRC). We analysed outcome of 69 chemorefractory, KRAS exon 2 mutant CRC patients who were enrolled in a double-blind, randomised, phase II/III study of irinotecan and cetuximab plus dalotuzumab 10 mg/kg once weekly (arm A), dalotuzumab 7.5 mg/kg every second week (arm B) or placebo (arm C). Objective response rate (5.6% vs. 3.1% vs. 4.8%), median progression-free survival (2.7 vs. 2.6 vs. 1.4 months) and overall survival (7.8 vs. 10.3 vs. 7.8 months) were not statistically significantly different between treatment groups. Most common grade ≥3 treatment-related toxicities included neutropenia, diarrhoea, hyperglycaemia, fatigue and dermatitis acneiform. Expression of IGF-1R, IGF-1, IGF-2 and EREG by quantitative real-time polymerase chain reaction was assessed in 351 patients from the same study with available data on KRAS exon 2 mutational status. Median cycle threshold values for all biomarkers were significantly lower (i.e., higher expression, p

Although dantrolene effectively treats malignant hyperthermia (MH), discrepant recommendations exist concerning dantrolene availability. Whereas Malignant Hyperthermia Association of the United States guidelines state dantrolene must be available within 10 min of the decision to treat MH wherever volatile anesthetics or succinylcholine are administered, a Society for Ambulatory Anesthesia protocol permits Class B ambulatory facilities to stock succinylcholine for airway rescue without dantrolene. The authors investigated (1) succinylcholine use rates, including for airway rescue, in anesthetizing/sedating locations; (2) whether succinylcholine without volatile anesthetics triggers MH warranting dantrolene; and (3) the relationship between dantrolene administration and MH morbidity/mortality.The authors performed focused analyses of the Multicenter Perioperative Outcomes Group (2005 through 2016), North American MH Registry (2013 through 2016), and Anesthesia Closed Claims Project (1970 through 2014) databases, as well as a systematic literature review (1987 through 2017). The authors used difficult mask ventilation (grades III and IV) as a surrogate for airway rescue. MH experts judged dantrolene treatment. For MH morbidity/mortality analyses, the authors included U.S. and Canadian cases that were fulminant or scored 20 or higher on the clinical grading scale and in which volatile anesthetics or succinylcholine were given.Among 6,368,356 queried outcomes cases, 246,904 (3.9%) received succinylcholine without volatile agents. Succinylcholine was used in 46% (n = 710) of grade IV mask ventilation cases (median dose, 100 mg, 1.2 mg/kg). Succinylcholine without volatile anesthetics triggered 24 MH cases, 13 requiring dantrolene. Among 310 anesthetic-triggered MH cases, morbidity was 20 to 37%. Treatment delay increased complications every 10 min, reaching 100% with a 50-min delay. Overall mortality was 1 to 10%; 15 U.S. patients died, including 4 after anesthetics in freestanding facilities.Providers use succinylcholine commonly, including during difficult mask ventilation. Succinylcholine administered without volatile anesthetics may trigger MH events requiring dantrolene. Delayed dantrolene treatment increases the likelihood of MH complications. The data reported herein support stocking dantrolene wherever succinylcholine or volatile anesthetics may be used.

SummaryBackground Malignant Hyperthermia (MH) is a potentially fatal metabolic disorder. Due to its rarity, limited evidence exists about risk factors, morbidity, and mortality especially in children. Methods Using the Nationwide Inpatient Sample and the Kid's Inpatient Database (KID), admissions with the ICD-9 code for MH (995.86) were extracted for patients 0–17 years of age. Demographic characteristics were analyzed. Logistic regression was performed to identify patient and hospital characteristics associated with mortality. A subset of patients with a surgical ICD-9 code in the KID was studied to calculate the prevalence of MH in the dataset. Results A total of 310 pediatric admissions were seen in 13 nonoverlapping years of data. Patients had a mortality of 2.9%. Male sex was predominant (64.8%), and 40.5% of the admissions were treated at centers not identified as children's hospitals. The most common associated diagnosis was rhabdomyolysis, which was present in 26 cases. Regression with the outcome of mortality did not yield significant differences between demographic factors, age, sex race, or hospital type, pediatric vs nonpediatric. Within a surgical subset of 530 449 admissions, MH was coded in 55, giving a rate of 1.04 cases per 10 000 cases. Conclusions This study is the first to combine two large databases to study MH in the pediatric population. The analysis provides an insight into the risk factors, comorbidities, mortality, and prevalence of MH in the United States population. Until more methodologically rigorous, large-scale studies are done, the use of databases will continue to be the optimal method to study rare diseases.

Salmonella Typhimurium ghost vaccines containing antigens of enterotoxigenic Escherichia coli (ETEC) were obtained by a strain harboring pMMP184, which carries a ghost cassette. The immune responses of BALB/c mice orally vaccinated with these ghost vaccines were determined in this study. Total IgG against S. Typhimurium were highly detected by the oral immunization route in BALB/c mice. IgGs against ETEC antigens in the ghost cells carrying F41 and intimin were detected at 4 weeks after vaccination. However, FedF elicited a delayed induction of IgGs, whereas FedA immune response failed to or barely induced IgGs after vaccination. Proliferations of CD3e/CD4-T cells were observed in splenocytes of BALB/c mice immunized with S. Typhimurium ghost cells carrying FedF. However, CD45R-B220/CD23-B cells were proliferated by ghost cells carrying FedA, F41, and intimin. The immunized BALB/c mice showed 25~50% protection against challenge with wild type S. Typhimurium, when compared to control mice. Therefore, it is assumed that oral vaccination of S. Typhimurium ghost cells has the potential to protect mice against pathogenic E. coli., Salmonella Typhimurium rekombinantna cjepiva što sadrže antigene enterotoksigenih sojeva Escherichia coli (ETEC) proizvedena su od soja koji posjeduje pMMP184 i nosi rekombinantnu kasetu. Istražen je imunosni odgovor BALB/c miševa oralno cijepljenih tim rekombinantnim cjepivima. Ustanovljena je visoka razina ukupnih IgG za S. Typhimurium nakon oralne imunizacije miševa BALB/c. Imunoglobulini IgG za antigene ETEC u rekombinantnom cjepivu koje sadrži F41 i intimin bili su dokazani četiri tjedna nakon cijepljenja. Ipak, FedF je potaknuo kasnu tvorbu imunoglobulina IgG, dok FedA nije potaknuo ili je potaknuo slab imunosni odgovor nakon cijepljenja. Proliferacija CD3e/CD4-T stanica bila je dokazana u splenocitima miševa BALB/c imuniziranih rekombinantnim cjepivom S. Typhimurium s ugrađenim FedF. Međutim, stanice CD45R-B220/CD23-B proliferirale su nakon cijepljenja rekombinantom FedA, F41 i intimin. Imunizirani miševi BALB/c pokazivali su 25~50% zaštitu nakon izazivačke infekcije serovarom S. Typhimurium u usporedbi s necijepljenim kontrolnim miševima. Stoga se pretpostavlja da oralno cijepljenje s rekombinantnim stanicama serovara S. Typhimurium ima potencijal da zaštiti miševe od infekcije patogenim sojevima E. coli.

Limited data are available on the efficacy of anti-IGF-1R agents in KRAS mutant colorectal cancer (CRC). We analysed the outcome of 69 chemorefractory, KRAS exon 2 mutant CRC patients who were enrolled in a double-blind, randomised, phase II/III study of irinotecan and cetuximab plus dalotuzumab 10 mg/kg once weekly (arm A), dalotuzumab 7.5 mg/kg every second week (arm B) or placebo (arm C). Objective response rate (5.6% vs. 3.1% vs. 4.8%), median progression-free survival (2.7 vs. 2.6 vs. 1.4 months) and overall survival (7.8 vs. 10.3 vs. 7.8 months) were not statistically significantly different between treatment groups. Most common grade ≥3 treatment-related toxicities included neutropenia, diarrhoea, hyperglycaemia, fatigue and dermatitis acneiform. Expression of IGF-1R, IGF-1, IGF-2 and EREG by quantitative real-time polymerase chain reaction was assessed in 351 patients from the same study with available data on KRAS exon 2 mutational status. Median cycle threshold values for all biomarkers were significantly lower (i.e., higher expression, p 0.05) among patients with KRAS wild-type compared to those with KRAS exon 2 mutant tumours. No significant changes were found according to location of the primary tumour with only a trend towards lower expression of IGF-1 in colon compared to rectal cancers (p = 0.06). Albeit limited by the small sample size, this study does not appear to support a potential role for anti-IGF-1R agents in KRAS exon 2 mutant CRC. Data on IGF-1R, IGF-1 and IGF-2 expression here reported may be useful for patient stratification in future trials with inhibitors of the IGF pathway.

Preparation of anaesthesia machines for use by malignant hyperthermia susceptible patients requires purging the machines of halogenated anaesthetic agents. The endpoint of this process is to reach a gas concentration of 5 ppm or less, which has been arbitrarily chosen as the safe limit of exposure to avoid triggering a malignant hyperthermia event. We examined the washout characteristics of sevoflurane and desflurane from the Datex-Ohmeda Aestiva® Anaesthesia System and Aisys® Anaesthesia Carestation®anaesthetic machines. The machines were contaminated for two hours using either sevoflurane 2 vol% or desflurane 6 vol%. At the end of the priming period, the patient breathing circuit and reservoir bag, carbon dioxide absorbent, sampling line and test lung were replaced with uncontaminated components. During the test period, machines were purged using oxygen flows of 10 l/minute. The average time to reach 5 ppm with the Aestiva machines was 51 minutes with sevoflurane and 71 minutes with desflurane. The average time to reach 5 ppm for the Aisys machines was 55 minutes with sevoflurane and 69 minutes with desflurane. All configurations of machines and anaesthetic gases demonstrated a rebound effect in agent concentration above 5 ppm when the fresh gas flow was subsequently reduced from 10 to 2 l/minute. Aestiva and Aisys anaesthetic machines require a prolonged period to adequately purge them of halogenated volatile anaesthetic agent. The rebound effect poses a serious concern, suggesting that after the purging period, fresh gas flows of 10 l/minute should be maintained for the duration of anaesthesia care of the malignant hyperthermia susceptible patient.

Patients with malignant hyperthermia experience an exaggerated metabolic response when exposed to volatile anesthetic gases and succinylcholine. The minimum concentration of anesthetic gas needed to trigger a malignant hyperthermia crisis in humans is unknown and may remain so because of the inherent risks associated with studying the complex nature of this rare and lethal genetic disorder. The Malignant Hyperthermia Association of the United States provides specific instructions on purging anesthesia machines of volatile agents to reduce the risk of exposure. However, these recommendations were developed from studies of older generation machines. Modern anesthesia workstations are more complex and contain more gas absorbing materials. A review of the literature found the current guidelines inadequate to prepare newer generation workstations, which require more time for purging anesthetic gases, autoclaving or replacement of parts, and modifications to the gas delivery system. Protocols must be developed to prepare newer generation anesthesia machines.

This research was supported by a grant (04K1401-01710) from the Conter for Nanoscale Mechatronics & Manufacturing, one of the 21th Century Frontier Research Programs, which are supported by Ministry of Science and Technology, Korea. This work was also supported in part by the Micro Thermal System Research Conter of Seoul National University.

Modulus-tunable ultraviolet (UV) curing molds allow not only physical patterning of imprinting but also chemical patterning of microcontact printing. The mechanical properties of the mold can be tailored by the chain length of an acrylate modulator in the cross-linking reaction. This tunability can be utilized to obtain a proper balance that is needed for a given patterning technique between the rigidity requirement (tensile modulus = 320 MPa) of a mold for patterning a fine structure and the flexibility requirement (tensile modulus = 19.8 MPa) for a conformal contact. Successful low-pressure imprinting of sub-100-nm patterns and microcontact printing of submicrometer patterns verify the suitability of the mold for a wide spectrum of patterning techniques.

Summary Ingestion of foreign bodies is common in children. Here we present a unique case of a tracheoesophageal fistula from an ingested penny produced post 1982, highlighting the reaction of the zinc content of the penny with gastric acid to cause erosion of the esophagus. We also present the orderly foreign body removal through a tracheostomy as the penny's diameter was greater than the cricoid.

Background Insulin-like growth factor type 1 receptor (IGF-1R) mediates resistance to epidermal growth factor receptor (EGFR) inhibition and may represent a therapeutic target. We conducted a multicenter, randomized, double blind, phase II/III trial of dalotuzumab, an anti-IGF-1R monoclonal antibody, with standard therapy in chemo-refractory, KRAS wild-type metastatic colorectal cancer. Methods Eligible patients were randomly assigned to dalotuzumab 10mg/kg weekly (arm A), dalotuzumab 7.5mg/kg every alternate week (arm B), or placebo (arm C) in combination with cetuximab and irinotecan. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Secondary endpoints included exploratory biomarker analyses. All statistical tests were two-sided. Results The trial was prematurely discontinued for futility after 344 eligible KRAS wild-type patients were included in the primary efficacy population (arm A = 116, arm B = 117, arm C = 111). Median PFS was 3.9 months in arm A (hazard ratio [HR] = 1.33, 95% confidence interval [CI] = 0.98 to 1.83, P = .07) and 5.4 months in arm B (HR = 1.13, 95% CI = 0.83 to 1.55, P = .44) compared with 5.6 months in arm C. Median OS was 10.8 months in arm A (HR = 1.41, 95% CI = 0.99 to 2.00, P = .06) and 11.6 months in arm B (HR = 1.26, 95% CI = 0.89 to 1.79, P = .18) compared with 14.0 months in arm C. Grade 3 or higher asthenia and hyperglycaemia occurred more frequently with dalotuzumab compared with placebo. In exploratory biomarker analyses, patients with high IGF-1 mRNA tumors in arm A had numerically better PFS (5.6 vs 3.6 months, HR = 0.59, 95% CI = 0.28 to 1.23, P = .16) and OS (17.9 vs 9.4 months, HR = 0.67, 95% CI = 0.31 to 1.45, P = .31) compared with those with high IGF-1 mRNA tumors in arm C. In contrast, in arm C high IGF-1 mRNA expression predicted lower response rate (17.6% vs 37.3%, P = .04), shorter PFS (3.6 vs 6.6 months, HR = 2.15, 95% CI = 1.15 to 4.02, P = .02), and shorter OS (9.4 vs 15.5 months, HR = 2.42, 95% CI = 1.21 to 4.82, P = .01). Conclusions Adding dalotuzumab to irinotecan and cetuximab was feasible but did not improve survival outcome. IGF-1R ligands are promising biomarkers for differential response to anti-EGFR and anti-IGF-1R therapies.

Summary Background/Aim Malignant hyperthermia susceptible patients may experience a fatal reaction to volatile anesthetic gases. This study sought to determine the washout characteristics of desflurane, sevoflurane, and isoflurane from the Aisys®, Avance®, and Aestiva® anesthesia machines. (GE Healthcare, Madison, WI, USA). Methods All machines were inspected by a GE Healthcare engineer prior to testing. The machines were primed with desflurane 7 vol%, sevoflurane 2.5 vol%, and isoflurane 1.2 vol% on three separate occasions for 2 h each with each gas. The Aisys® and Avance® were tested with and without an Advanced Breathing System (ABS™, GE Healthcare, Madison, WI, USA). The Aestiva® was tested without modification to its breathing system. Additionally, the Aisys was evaluated with desflurane 1.2 vol% and the Avance with a preflushed fresh gas line was tested with an autoclaved ABS. After priming, disposable components of the patient breathing system were replaced. The fresh gas flow was increased to 15 lpm. Gas measurements were recorded until the concentration was 4 parts per million (p.p.m). Results The fastest median washout time was achieved by the Avance in 3 min or less without an ABS or with an autoclaved ABS. The longest median time was 35 min for the Aestiva®. Clearance of desflurane was the most time consuming for all machines. Conclusion This study demonstrates that saturated vapor pressure and priming concentration exert a greater effect on washout times than gas solubility. The Aisys utilizes an electronic vaporizer system that may expose the breathing system to retained saturated vapor. The breathing systems for all machines may hinder washout of gases.

The American Academy of Otolaryngology—Head and Neck Surgery Foundation (AAO-HNSF) has published a supplement to this issue featuring the new Clinical Practice Guideline: Tympanostomy Tubes in Children. To assist in implementing the guideline recommendations, this article summarizes the rationale, purpose, and key action statements. The 12 recommendations developed address patient selection, surgical indications for and management of tympanostomy tubes in children. The development group broadly discussed indications for tube placement, perioperative management, care of children with indwelling tubes, and outcomes of tympanostomy tube surgery. Given the lack of current published guidance on surgical indications, the group focused on situations in which tube insertion would be optional, recommended, or not recommended. Additional emphasis was placed on opportunities for quality improvement, particularly regarding shared decision making and care of children with existing tubes.

Insertion of tympanostomy tubes is the most common ambulatory surgery performed on children in the United States. Tympanostomy tubes are most often inserted because of persistent middle ear fluid, frequent ear infections, or ear infections that persist after antibiotic therapy. Despite the frequency of tympanostomy tube insertion, there are currently no clinical practice guidelines in the United States that address specific indications for surgery. This guideline is intended for any clinician involved in managing children, aged 6 months to 12 years, with tympanostomy tubes or being considered for tympanostomy tubes in any care setting, as an intervention for otitis media of any type.The primary purpose of this clinical practice guideline is to provide clinicians with evidence-based recommendations on patient selection and surgical indications for and management of tympanostomy tubes in children. The development group broadly discussed indications for tube placement, perioperative management, care of children with indwelling tubes, and outcomes of tympanostomy tube surgery. Given the lack of current published guidance on surgical indications, the group focused on situations in which tube insertion would be optional, recommended, or not recommended. Additional emphasis was placed on opportunities for quality improvement, particularly regarding shared decision making and care of children with existing tubes. ACTION STATEMENTS: The development group made a strong recommendation that clinicians should prescribe topical antibiotic eardrops only, without oral antibiotics, for children with uncomplicated acute tympanostomy tube otorrhea. The panel made recommendations that (1) clinicians should not perform tympanostomy tube insertion in children with a single episode of otitis media with effusion (OME) of less than 3 months' duration; (2) clinicians should obtain an age-appropriate hearing test if OME persists for 3 months or longer (chronic OME) or prior to surgery when a child becomes a candidate for tympanostomy tube insertion; (3) clinicians should offer bilateral tympanostomy tube insertion to children with bilateral OME for 3 months or longer (chronic OME) and documented hearing difficulties; (4) clinicians should reevaluate, at 3- to 6-month intervals, children with chronic OME who did not receive tympanostomy tubes until the effusion is no longer present, significant hearing loss is detected, or structural abnormalities of the tympanic membrane or middle ear are suspected; (5) clinicians should not perform tympanostomy tube insertion in children with recurrent acute otitis media (AOM) who do not have middle ear effusion in either ear at the time of assessment for tube candidacy; (6) clinicians should offer bilateral tympanostomy tube insertion to children with recurrent AOM who have unilateral or bilateral middle ear effusion at the time of assessment for tube candidacy; (7) clinicians should determine if a child with recurrent AOM or with OME of any duration is at increased risk for speech, language, or learning problems from otitis media because of baseline sensory, physical, cognitive, or behavioral factors; (8) in the perioperative period, clinicians should educate caregivers of children with tympanostomy tubes regarding the expected duration of tube function, recommended follow-up schedule, and detection of complications; (9) clinicians should not encourage routine, prophylactic water precautions (use of earplugs, headbands; avoidance of swimming or water sports) for children with tympanostomy tubes. The development group provided the following options: (1) clinicians may perform tympanostomy tube insertion in children with unilateral or bilateral OME for 3 months or longer (chronic OME) and symptoms that are likely attributable to OME including, but not limited to, vestibular problems, poor school performance, behavioral problems, ear discomfort, or reduced quality of life and (2) clinicians may perform tympanostomy tube insertion in at-risk children with unilateral or bilateral OME that is unlikely to resolve quickly as reflected by a type B (flat) tympanogram or persistence of effusion for 3 months or longer (chronic OME).

This guideline provides otolaryngologists with evidence-based recommendations for using polysomnography in assessing children, aged 2 to 18 years, with sleep-disordered breathing and are candidates for tonsillectomy, with or without adenoidectomy. Polysomnography is the electrographic recording of simultaneous physiologic variables during sleep and is currently considered the gold standard for objectively assessing sleep disorders.There is no current consensus or guideline on when children 2 to 18 years of age, who are candidates for tonsillectomy, are recommended to have polysomnography. The primary purpose of this guideline is to improve referral patterns for polysomnography among these patients. In creating this guideline, the American Academy of Otolaryngology--Head and Neck Surgery Foundation selected a panel representing the fields of anesthesiology, pulmonology medicine, otolaryngology-head and neck surgery, pediatrics, and sleep medicine.The committee made the following recommendations: (1) before determining the need for tonsillectomy, the clinician should refer children with sleep-disordered breathing for polysomnography if they exhibit certain complex medical conditions such as obesity, Down syndrome, craniofacial abnormalities, neuromuscular disorders, sickle cell disease, or mucopolysaccharidoses. (2) The clinician should advocate for polysomnography prior to tonsillectomy for sleep-disordered breathing in children without any of the comorbidities listed in statement 1 for whom the need for surgery is uncertain or when there is discordance between tonsillar size on physical examination and the reported severity of sleep-disordered breathing. (3) Clinicians should communicate polysomnography results to the anesthesiologist prior to the induction of anesthesia for tonsillectomy in a child with sleep-disordered breathing. (4) Clinicians should admit children with obstructive sleep apnea documented on polysomnography for inpatient, overnight monitoring after tonsillectomy if they are younger than age 3 or have severe obstructive sleep apnea (apnea-hypopnea index of 10 or more obstructive events/hour, oxygen saturation nadir less than 80%, or both). (5) In children for whom polysomnography is indicated to assess sleep-disordered breathing prior to tonsillectomy, clinicians should obtain laboratory-based polysomnography, when available.

Patients with malignant hyperthermia experience an exaggerated metabolic response when exposed to volatile anesthetic gases and succinylcholine. The minimum concentration of anesthetic gas needed to trigger a malignant hyperthermia crisis in humans is unknown and may remain so because of the inherent risks associated with studying the complex nature of this rare and lethal genetic disorder. The Malignant Hyperthermia Association of the United States provides specific instructions on purging anesthesia machines of volatile agents to reduce the risk of exposure. However, these recommendations were developed from studies of older generation machines. Modern anesthesia workstations are more complex and contain more gas absorbing materials. A review of the literature found the current guidelines inadequate to prepare newer generation workstations, which require more time for purging anesthetic gases, autoclaving or replacement of parts, and modifications to the gas delivery system. Protocols must be developed to prepare newer generation anesthesia machines.

Our primary aim was to evaluate the additive efficacy of histone deacetylase inhibitors (HDACIs) in established treatment regimens for colorectal cancer in concurrence with identifying the clinicopathological markers significantly associated with tumor responsiveness.The chemosensitivities of 125 colorectal carcinomas to established regimens [FLOX (5-FU + leucovorin + oxaliplatin) and FLIRI (5-FU + leucovorin + irinotecan)], two biologically targeted drugs (avastin and erbitux), and two hydroxamic acid derivatives (vorinostat, SAHA(R), and a novel candidate, CG2) were comparatively evaluated using an in vitro tumor response assay.The response rates of tumors (inhibition rateor =30%) were significantly greater for FLOX and combinations (55.2-68%) compared to FLIRI and combinations (44-63.2%) (p=0.001 to 0.048), except in the case of the CG2 combination. The additive effects of HDACIs on the respective established regimens were considerably greater for non-responsive tumors (64.3-80%) than responsive tumors (32.7-45%) (por =0.0001 to 0.008). A number of biological parameters, including less advanced tumors and p53 overexpression, were significantly associated with additive chemosensitivity to HDACIs in combination with FLOX and FLIRI in multivariate analyses (por =0.001 to 0.023). Expanding tumor growth, diffuse cytoplasmic carcinoembryonic antigen (CEA) expression and synchronous adenoma were associated with combination regimens with targeted drugs (p=0.013 to 0.032).Our findings show additive chemoresponsiveness of colorectal tumors to HDAC inhibitors in combination with established regimens. The significant parameters associated with combination regimens of targeted drugs and HDACIs may be applied as effective chemosensitive markers in future clinical trials.

The canonical molecular changes in colorectal tumorigenesis were assessed for correlation with response to chemotherapy, in order to identify candidate markers.In total, 156 patients received adjuvant postoperative fluoropyrimidine-based chemotherapy and 32 patients received oxaliplatin- or irinotecan-based chemotherapy following palliative surgery or for metastatic or recurrent colorectal tumors. Representative molecular changes in tumor tissues, including adenomatous polyposis coli (APC) gene, wingless-type MMTV integration site family (Wnt), mismatch repair (MMR), RAF, transforming growth factor (TGF)-beta, bone morphogenetic protein, and p53, had been previously determined, with an additional 42 patients included in this analysis.The disease-free survival period (mean+/-SEM) was significantly longer after fluoropyrimidine-based adjuvant chemotherapy in tumors with TGF-beta2 expression (42+/-1.4 vs. 21+/-4.7 months; p=0.005) and D18S46 loss of heterozygosity or microsatellite instability (45.7+/-1.5 vs. 40.5+/-1.4 months; p=0.048). In the metastatic settings, the high disease-control rate of oxaliplatin and irinotecan regimens correlated significantly with wild-type APC and intact MMR, respectively, relative to mutant APC and defective MMR (p=0.013, respectively). Interestingly, specific molecular steps of tumorigenensis were closely associated with particular toxicities.A subset of molecular changes occurring during colorectal tumorigenesis showed significant associations with therapeutic responses and toxicities to chemotherapy regimens, suggesting that these changes may be candidate predictors of chemoresponsiveness with further validation.

The supercritical gas turbine Brayton cycle has been adopted in the secondary loop of the Generation IV Nuclear Energy Systems, and also planned to be installed in power conversion cycles of the nuclear fusion reactors. Supercritical carbon dioxide (SCO2 ) is one of widely considered fluids for this application. The potential beneficiaries include the Secure Transportable Autonomous Reactor - Liquid Metal (STAR-LM), the Korea Advanced Liquid Metal Reactor (KALIMER), and the Battery Omnibus Reactor Integral System (BORIS) which is being developed at the Seoul National University. The reason for these welcomed applications is that the SCO2 Brayton cycle can possibly achieve higher energy conversion efficiency than the steam turbine Rankine cycle. Gas turbine design is crucial part in achieving this high efficiency. In this paper, a one-dimensional gas turbine analysis methodology is applied for optimal design of the component. Case study result shows that the entire turbine efficiency is increased as hub radius is increased for a same number of stage conditions. Comparing the efficiency which is applied the boundary condition, 4 stage turbines have optimal efficiency.Copyright © 2008 by ASME

Twenty-three of the 25 cysteine residues in apolipoprotein B-100 have been isolated directly from tryptic or peptic peptide mixtures. Sixteen cysteine residues exist in disulfide forms: Cys-1-Cys-3, Cys-2-Cys-4, Cys-5-Cys-6, Cys-7-Cys-8, Cys-9-Cys-10, Cys-11-Cys-12, Cys-13-Cys-14, and Cys-20-Cys-21. All of these except Cys-20-Cys-21 are recently discovered disulfide linkages. In addition to Cys-22 and Cys-24, which have been described as sulfhydryls on low density lipoprotein, Cys-15 to Cys-18 and Cys-23 are in the reduced form. Cys-19 and Cys-25 are not yet confirmed. Our results revealed that all identified disulfide linkages are located in the trypsin-releasable regions and that all except Cys-1-Cys-3 and Cys-2-Cys-4 are linked to the neighboring cysteine. We propose a linear model of apolipoprotein B-100 in low density lipoprotein that wraps around the low density lipoprotein molecule.

The complete amino acid sequence of chicken plasma apolipoprotein (apo) A-I was determined by sequencing overlapping peptide fragments produced by trypsin, S. aureus V8 protease, and cyanogen bromide cleavage respectively. All of the peptide fragments were purified on a Waters or on a Beckman HPLC system with a Vydac C18 column using 0.1% TFA in water as buffer A, and 0.08% TFA in 95% acetonitrile and 5% water as buffer B. Most of the peaks separated by these systems were pure. The partially purified fractions were subjected to rechromatography with a Hypersil ODS column using 0.005M sodium phosphate, pH 6.0, as buffer A, and 90% acetonitrile and 10% water as buffer B. The N-terminus of chicken apo A-I was determined to be aspartic acid by directly sequencing the intact protein up to 30 residues, while the C-terminus was identified as alanine by carboxypeptidase Y cleavage. There are 240 amino acid residues in mature chicken apo A-I. By direct analysis of cyanogen bromide peptide, we also determined the sequence of a 6 amino acid prosegment, which is present at approximately 10% of the molar amount of the mature protein in chicken plasma.