Efficacy, Immunogenicity, and Safety of a 9-Valent Human Papillomavirus Vaccine: Subgroup Analysis of Participants From Asian Countries.

Background: A 9-valent human papillomavirus-6/11/16/18/31/33/45/52/58 (9vHPV) vaccine extends coverage to 5 next most common oncogenic types (31/33/45/52/58) in cervical cancer versus quadrivalent HPV (qHPV) vaccine. We describe efficacy, immunogenicity, and safety in Asian participants (India, Hong Kong, South Korea, Japan, Taiwan, and Thailand) from 2 international studies: a randomized, double-blinded, qHPV vaccine-controlled efficacy study (young women aged 16-26 years; NCT00543543; Study 001); and an immunogenicity study (girls and boys aged 9-15 years; NCT00943722; Study 002). Methods: Participants (N = 2519) were vaccinated at day 1 and months 2 and 6. Gynecological samples (Study 001 only) and serum were collected for HPV DNA and antibody assessments, respectively. Injection-site and systemic adverse events (AEs) were monitored. Data were analyzed by country and vaccination group. Results: 9vHPV vaccine prevented HPV-31/33/45/52/58-related persistent infection with 90.4%-100% efficacy across included countries. At month 7, ≥97.9% of participants seroconverted for each HPV type. Injection-site AEs occurred in 77.7%-83.1% and 81.9%-87.5% of qHPV and 9vHPV vaccine recipients in Study 001, respectively, and 62.4%-85.7% of girls/boys in Study 002; most were mild to moderate. Conclusions: The 9vHPV vaccine is efficacious, immunogenic, and well tolerated in Asian participants. Data support 9vHPV vaccination programs in Asia. Clinical Trials Registration: NCT00543543; NCT00943722.

Clinical and economic impact of school-based nonavalent human papillomavirus vaccine on women in Singapore: a transmission dynamic mathematical model analysis.

OBJECTIVE: To examine the epidemiological and economic impact of a nine-valent (nonavalent) human papillomavirus (HPV) 6/11/16/18/31/33/45/52/58 vaccine programme for young teenagers in Singapore. DESIGN: Mathematical modelling. SETTING: Pharmaco-economic simulation projection. POPULATION: Singapore demography. METHODS: Clinical, epidemiological and financial data from Singapore were used in a validated HPV transmission dynamic mathematical model to analyse the impact of nonavalent HPV vaccination over quadrivalent and bivalent vaccines in a school-based 2-dose vaccination for 11- to 12-year-old girls in the country. The model assumed routine cytology screening in the current rate (50%) and vaccine coverage rate of 80%. MAIN OUTCOME MEASURES: Changes over a 100-year time period in the incidence and mortality rates of cervical cancer, case load of genital warts, and incremental cost-effectiveness ratio (ICER). RESULTS: Compared with bivalent and quadrivalent HPV vaccination programmes, nonavalent HPV universal vaccination resulted in an additional reduction of HPV31/33/45/52/58 related CIN1 of 40.5%, CIN 2/3 of 35.4%, cervical cancer of 23.5%, and cervical cancer mortality of 20.2%. Compared with bivalent HPV vaccination, there was an additional reduction in HPV-6/11 related CIN1 of 75.7%, and genital warts of 78.9% in women and 73.4% in men. Over the 100 years, after applying a discount of 3%, disease management cost will be reduced by 32.5% (versus bivalent) and 7.5% (versus quadrivalent). The incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year gained was SGD 929 compared with bivalent vaccination and SGD 9864 compared with quadrivalent vaccination. CONCLUSION: Universal two-dose nonavalent HPV vaccination for 11- to 12-year-old adolescent women is very cost-effective in Singapore. TWEETABLE ABSTRACT: Nonavalent HPV vaccination of 11- to 12-year-old girls is cost-effective in Singapore.

No effect of femoral offset on bone implant micromotion in an experimental model.

BACKGROUND: In total hip replacement (THR), the femoral offset (FO) is assessed preoperatively, and the surgeon must determine whether to restore, increase, or decrease the FO based on experience and the patient's clinical history. The FO is known to influence the abductor muscle strength, range of motion (ROM), gait, and hip pain after THR; however, the true effect of FO on bone implant micromotion is unclear. Therefore, we investigated to assess: (1) the muscle loading response during gait, (2) whether FO affects bone implant micromotion during gait. HYPOTHESIS: A variation of ±10mm from the anatomical FO affects the muscle loading forces. MATERIALS AND METHODS: We modified a personalized musculoskeletal model of the lower extremity to determine the 3-dimensional contact forces at the hip joint in the presence of a stem with varying offsets during a gait cycle. A detailed finite element (FE) model was then constructed for increased, restored, and decreased FOs. The maximum load obtained during normal walking gait from the musculoskeletal model was applied to the respective FE models, and the resultant stem-bone micromotion and stress distribution were computed. RESULTS: Increasing the FO to +10mm decreased the peak force generated by the abductor muscles during the cycle by 15.0% and decreasing the FO to -10mm increased the von Mises stress distribution at the distal bone by 77.5% (P<0.05). A variation of the offset within 10mm of the anatomical offset showed no significant differences in micromotion (P>0.05) and peak stresses (P>0.05). DISCUSSION: Coupling the musculoskeletal model of the gait cycle with FE analysis provides a realistic model to understand how FO affects bone implant micromotion. We found that there was no effect of FO on bone implant micromotion; thus, a surgeon does not need to evaluate the implications of FO on micromotion and can determine a FO that best decreases the work load of abductor muscles, increases ROM, and reduces hip pain. LEVEL OF EVIDENCE: IV, biomechanical study.

Intraoperative fluid and pharmacologic management and the anesthesiologist's supervisory role for nontraditional technologies during liver transplantation: a survey of US academic centers.

BACKGROUND: Volume resuscitation and use of vasoactive medications during liver transplantation has not been systematically assessed. Furthermore, the anesthesiologist's role for intraoperative oversight of technologies such as renal replacement therapy and procedures such as venovenous bypass is poorly defined, and it is unclear if the center's annual transplant frequency affects these practices. METHODS: We conducted a database analysis of the Liver Transplant Anesthesia Consortium survey 202 that addresses these questions. Data from US academic liver transplant anesthesia programs meeting inclusion criteria were included. Results were categorized by their annual transplant volume. RESULTS: A representative sample of 66% of all eligible centers contributed to the results. Normal saline among crystalloids and albumin among colloids were the most frequently chosen maintenance and non-blood product volume expansion fluids, with little variation by center size. A large variety of vasoactive agents is routinely utilized across programs, with vasopressors as a cornerstone of hemodynamic support. Large programs seem to use less of these agents compared with lower volume centers. CONCLUSION: Anesthesiologists are increasingly involved in oversight and management of intraoperative renal replacement therapies, venovenous bypass and cell saver devices with rising transplant frequency. This new insight may be indicative of skill sets needed by members of liver transplantation anesthesia teams and should be considered in curriculum design for hepatobiliary transplant anesthesia fellowships.

Liver transplantation outcome in patients with angiographically proven coronary artery disease: a multi-institutional study.

Over the last decade the age of liver transplant (LT) recipients and the likelihood of coronary artery disease (CAD) in this population have increased. There are no multicenter studies that have examined the impact of CAD on LT outcomes. In this historical cohort study, we identified adult LT recipients who underwent angiography prior to transplantation at seven institutions over a 12-year period. For each patient we recorded demographic data, recipient and donor risk factors, duration of follow-up, the presence of angiographically proven obstructive CAD (≥50% stenosis) and post-LT survival. Obstructive CAD was present in 151 of 630 patients, the CAD(+) group. Nonobstructive CAD was found in 479 patients, the CAD(-) group. Patient survival was similar for the CAD(+) group (adjusted HR 1.13, CI = [0.79, 1.62], p = 0.493) compared to the CAD(-) group. The CAD(+) patients were further stratified into severe (CADsev, >70% stenosis, n = 96), and moderate CAD (CADmod, 50-70% stenosis, n = 55) groups. Survival for the CADsev (adjusted HR = 1.26, CI = [0.83, 1.91], p = 0.277) and CADmod (adjusted HR = 0.93, CI = [0.52, 1.66], p = 0.797) groups were similar to the CAD(-) group. We conclude that when current CAD treatment strategies are employed prior to transplant, post-LT survival is not significantly different between patients with and without obstructive CAD.

Beneficial effects of Rhizopus oligosporus fermentation on reduction of glucosinolates, fibre and phytic acid in rapeseed (Brassica napus) meal.

Solid state fermentation was employed using Rhizopus oligosporus to develop a fermented product from rapeseed meal (RSM). The contents of glucosinolates, thiooxazolidones, phytic acid and crude fibre declined by 43.1%, 34%, 42.4% and 25.5%, respectively, following inoculation with R. oligosporus. Fermentation also increased nitrogen and protein contents of the meal. This study may open a new prospective for a simple and cost effective technique for reduction of toxicants in RSM.

Clamp for coronary artery operations.

Aortocoronary bypass grafting is an accepted procedure for ischemic heart disease. Proper visualization of the coronary artery is mandatory for good surgical anastomosis. This is essential when a coronary operation is performed without cardioplegia or in surgical procedures without bypass support. For better visualization of a coronary artery, we are presenting a coronary artery clamp. We have used this clamp in minimally invasive coronary artery operations to achieve a bloodless field.

Pathology of fatal perioperative myocardial infarction: implications regarding pathophysiology and prevention.

The aim of this study was to determine the pathology of fatal postoperative myocardial infarction (MI) and compare it with that of non-operative myocardial infarction. Histopathological analyses of coronary arteries and myocardium were performed on autopsy heart specimens (n = 67), and clinical attributes were studied. Findings of perioperative MI (n = 42) were compared to those of non-perioperative MI (n = 25). Significant atherosclerotic obstruction (> 50% cross-sectional narrowing) was observed in the majority of patients (93%). Left main (> 50% cross-sectional narrowing) and/or three-vessel coronary artery disease were especially common (44%) in this group. Evidence of unstable plaques with disruption was noted in 55% of perioperative MI patients (n = 23); plaque hemorrhage was found in 45% (n = 19). Predicting the site of infarction based on severity of underlying stenosis would have been unsuccessful in more than half the patients in both perioperative and nonoperative MI groups. Clinical profiles of the patients in the two groups were similar in terms of prior cardiac history, gender and age. Fatal perioperative MI occurs predominantly in patients with multivessel coronary disease, especially left main and three-vessel disease. The severity of preexisting underlying stenosis did not predict the resulting infarct territory. Evidence of acute plaque disruption in the infarct-related artery is common. Perioperative MIs have similar coronary artery pathology to non-operative MIs with regard to coronary plaque hemorrhage, rupture, and thrombus formation and probably occur by a similar mechanism.

Improved gas chromatography/mass spectrometry analysis of barbiturates in urine using centrifuge-based solid-phase extraction, methylation, with d5-pentobarbital as internal standard.

Effective solid-phase extraction, derivatization, and GC/MS procedures are developed for the simultaneous determinations of butalbital, amobarbital, pentobarbital, and secobarbital, using a deuterated pentobarbital (d5-pentobarbital) as the internal standard. Buffered (pH 7) urine samples were extracted with Bond Elute Certify II cartridge. Iodomethane/tetramethylammonium hydroxide in dimethylsulfoxide was used for methylation, while a HP 5970 MSD equipped with a 13 m J & W DB-5 column (5% phenyl polysiloxane phase) and the Thru-Put Target software package were used for GC/MS analysis and data processing. This protocol was found to be superior, in both chromatographic performance characteristics and quantitation results, over a liquid-liquid extraction procedure without derivatization using hexobarbital as the internal standard. Extraction recoveries observed from control samples containing four barbiturates range from 80% to 90%. Good one-point calibration data are obtained for all four barbiturates in the 50 to 3200 ng/mL range. Interestingly, the one-point calibration data for pentobarbital are inferior to the other three barbiturates--due to interference from the internal standard (d5-pentobarbital). The calibration data of pentobarbital are best described by a hyperbolic curve regression model. Precision data (% CV) for GC/MS analysis, over-all procedure, and day-to-day performance are approximately 2.0%, 6.0%, and 8.0%, respectively. With the use of a 2 mL sample size, the attainable detection limit is approximately 20 ng/mL.

Selection of an appropriate initial test cutoff concentration for workplace drug urinalysis--Cannabis example.

Apparent analyte concentration (equivalent of 11-nor-delta 9-tetrahydrocannabinol-9-carboxylic acid [9-THC-COOH]) obtained by radioimmunoassay (RIA) for cannabinoids using reagents manufactured at four different periods (from the same manufacturer) and specific 9-THC-COOH concentration as determined by GC/MS are examined for the significance of their correlation. The resulting regression equations are then used to estimate the apparent RIA analyte concentrations of reagents manufactured at different time periods that are equivalent to a specific 9-THC-COOH concentration. Correlation coefficients of the regression analysis improve from approximately 0.4 to 0.7 in parallel with the increasing reagent specificity. The apparent RIA analyte concentrations that correspond to 15 ng/mL 9-THC-COOH decrease from about 110 to 50 ng/mL again in parallel with the increasing reagent specificity. These findings empirically demonstrate that reagent specificity is the determining factor of the resulting apparent RIA analyte concentration when testing samples that contain 9-THC-COOH and other metabolites (derived from marijuana exposure). Thus, if the 9-THC-COOH concentration as determined by GC/MS is of primary concern, the initial test cutoff concentration should be adjusted in accordance with the specificity of the reagent used.

Mirage formation in the thermal region.

Formation of a mirage in the 8-12-µm band has been observed with a high-resolution thermal camera designed and developed by us. Thermal imagery recorded under actual field conditions is presented to illustrate the mirage phenomenon. Further analysis is in progress to estimate the effect of mirages in this waveband for civil and military applications.

Evaluation of enzyme immunoassay performance characteristics--phencyclidine example.

Four reagent formulations (three provided by a manufacturer; one prepared in-house by mixing equal volumes of two commercial reagents) are used for the assay of phencyclidine (PCP) in urine samples. Performance characteristics evaluated included assay precision and sensitivity at and near the assay cutoff concentration. Data resulting from the reagent prepared in-house are better than those using then commercially available formulations, and are comparable with those obtained using the recently available new commercial formulation.

Simultaneous analysis of amphetamine, methamphetamine, and 3, 4-methylenedioxymethamphetamine (MDMA) in urine samples by solid-phase extraction, derivatization, and gas chromatography/mass spectrometry.

A rapid and effective solid-phase extraction procedure using Bond Elute Certify bonded silica sorbent cartridges was adopted to extract amphetamine, methamphetamine, and 3,4-methylenedioxymethamphetamine (MDMA or Ecstasy) from urine samples. The extract was derivatized with trichloroacetic anhydride prior to gas chromatography/mass spectrometry (GC/MS) analysis with selected ion monitoring of the following ions: 190, 91, 188; 204, 91, 202; 162, 135, 202; 194, 123; and 211, 209 for the derivatized amphetamine, methamphetamine, MDMA, d5-amphetamine, and d9-methamphetamine, respectively. The first of the ions listed for each compound was used for quantitation. The compound d5-amphetamine was used as the internal standard for amphetamine, and d9-methamphetamine was used for methamphetamine and MDMA. Results showed a higher than 65% recovery and a reproducibility with less than a 5% coefficient of variation. When a sample size of 2 mL was used, the lowest detectable concentration was about 50 ng/mL, and a near-perfect fit can be obtained (within the 250 to 4000-ng/mL concentration range studied) using a second-order polynomial model.

Enzymatic digestion, solid-phase extraction, and gas chromatography/mass spectrometry of derivatized intact oxazepam in urine.

Enzymatic digestion with beta-glucuronidase (EC 3.2.1.31) was used to release intact oxazepam from urine samples containing the d5-analog internal standard. The resulting specimens were extracted with Du Pont PREP Type W cartridge (processed by a PREP Automated Sample Processor), Bond Elut Certify, and J.T. Baker "spe" columns for comparison of the columns' extraction recovery and overall effectiveness. Methyl iodide/tetrahexylammonium hydrogen sulfate and N,O-bis(trimethylsilyl)trifluoroacetamide/trimethylchlorosilane (10 g/L) were used for the methylation and trimethylsilylation studies. We used a Hewlett-Packard HP 5790 mass-selective detector equipped with a 13-m J & W DB-5 column (5% phenyl polysiloxane phase) for gas chromatography/mass spectroscopy (GC/MS) analysis and the Thru-Put Target software package for data processing. After several exploratory experiments, we adopted the Du Pont PREP system methylation procedure because of its effective recovery, the superior stability of the derivatization product, the possibility of incorporating a clean-up step, and the potential for high throughput. The extraction recovery from a set of control samples was 87%. Coefficients of variation obtained for six replicates of GC/MS analysis and for the overall procedure were 1% and 3%, respectively. Excellent linearity was established in the 50-8000 micrograms/L concentration range studied. With the use of 3-mL samples, a 20-microL final reconstitution volume, oxazepam at 50 micrograms/L was easily detected under the adopted operation conditions.

Simultaneous gas chromatography/mass spectrometry assay of methadone and 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) in urine.

An efficient extraction and gas chromatography/mass spectrometry (GC/MS) procedure has been developed for the simultaneous determination of methadone and 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine in urine samples. The merits of this procedure include (1) effective high-volume sample processing; (2) excellent gas chromatography characteristics; (3) high precision for quantitative methadone determination--1.0% coefficient of variation (CV) for GC/MS injection replicates and 1.2% for extraction replicates; (4) excellent linearity within the range (0 to 1200 ng/mL) studied; and (5) adequate detection limits (50 ng/mL) for most practical purposes. The detection limit for methadone may be improved 40-fold by using a different internal standard.

Evaluation of immunoassay methods for the screening of cocaine metabolites in urine.

Immunoassay kits for urine cocaine (and metabolite) screening, obtained from two commercial sources, were examined for correlation of their results, expressed in terms of equivalent benzoylecgonine concentration, with the gas chromatography/mass spectrometry (GC/MS) concentration of benzoylecgonine. The correlation coefficients obtained, based on 62 (out of a total sample population of 3295) highly relevant samples, were 0.467 and 0.766 for Abuscreen (ARIA) and TDx (TDX), respectively. The preliminary screen cutoff values, which correspond to 150 ng/mL benzoylecgonine (as determined by GC/MS), were calculated based on the resulting regression equations and found to be 380 and 190 ng/mL for ARIA and TDX, respectively. With these cutoff values, ARIA generates 5 false negatives and 16 unconfirmed presumptive positives, while TDX results in 3 false negatives and 6 unconfirmed presumptive positives.

Correlations on radioimmunoassay, fluorescence polarization immunoassay, and enzyme immunoassay of cannabis metabolites with gas chromatography/mass spectrometry analysis of 11-nor-delta 9-tetrahydrocannabinol-9-carboxylic acid in urine specimens.

Results obtained from three commercial immunoassay kits, Abuscreen, TDx, and EMIT, commonly used for the initial test of urine cannabinoids (and metabolites) were correlated with the 11-nor-delta 9-tetrahydrocannabinol-9-carboxylic acid (9-THC-COOH) concentration as determined by GC/MS. Correlation coefficients obtained based on 26 (out of 1359 total sample population) highly relevant samples, are 0.601 and 0.438 for Abuscreen and TDx. Correlation coefficients obtained from a parallel study on a different set of 47 (out of 5070 total sample population) highly relevant specimens are 0.658 and 0.575 for Abuscreen and Emit. The immunoassay concentration levels, that correspond to the commonly used 15 ng/ml GC/MS cutoff value for 9-THC-COOH, as calculated from the regression equations are 82 ng/ml and 75 ng/ml for TDx and EMIT and 120 ng/ml and 72 ng/ml for Abuscreen manufactured at two different time periods. The difference of these calculated corresponding concentrations provides quantitative evidence of the reagent specificity differences.