Youth E-Cigarette Initiation After the Food and Drug Administration's Missed Deadline.

INTRODUCTION: The U.S. Food and Drug Administration was ordered to evaluate electronic nicotine delivery system (ENDS) products by September 9, 2021, but missed the court-ordered deadline. This study provides an estimate of electronic cigarette (E-cigarette) use initiation among youth and young adults after the U.S. Food and Drug Administration's missed deadline. METHODS: Data were obtained from the Truth Longitudinal Cohort, a probability-based longitudinal sample of youth and young adults aged between 15 and 24 years (N=1,393). Respondents were surveyed at baseline (July-October 2021) and at follow-up (January-June 2022). Individuals who had not previously used any E-cigarette products were included in analyses conducted in 2022. RESULTS: Results indicate that 6.9% of youth and young adults had initiated E-cigarette use, suggesting that about 900,000 youth aged 15-17 years and 320,000 young adults aged 18-20 years initiated E-cigarette use after the U.S. Food and Drug Administration's missed court-ordered deadline. CONCLUSIONS: Over a million youth and young adults initiated E-cigarette use after the U.S. Food and Drug Administration's missed court-ordered deadline. The U.S. Food and Drug Administration needs to continue evaluating premarket tobacco product applications, enforce decisions on premarket tobacco product applications, and remove E-cigarettes that are deemed harmful to public health to effectively address the E-cigarette epidemic among young people.

Biocatalytic conversion of ethylene to ethylene oxide using an engineered toluene monooxygenase.

Mutants of toluene o-xylene monooxygenase are demonstrated to oxidize ethylene to ethylene oxide in vivo at yields of >99%. The best mutant increases ethylene oxidation activity by >5500-fold relative to the native enzyme. This is the first report of a recombinant enzyme capable of carrying out this industrially significant chemical conversion.

Long-term response of rats to single intratracheal exposure of Libby amphibole or amosite.

In former mine workers and residents of Libby, Montana, exposure to amphibole-contaminated vermiculite has been associated with increased incidences of asbestosis and mesothelioma. In this study, long-term effects of Libby amphibole (LA) exposure were investigated relative to the well-characterized amosite asbestos in a rat model. Rat-respirable fractions of LA and amosite (aerodynamic diameter≤2.5 µm) were prepared by water elutriation. Male F344 rats were exposed to a single dose of either saline, amosite (0.65 mg/rat), or LA (0.65 or 6.5 mg/rat) by intratracheal (IT) instillation. One year after exposure, asbestos-exposed rats displayed chronic pulmonary inflammation and fibrosis. Two years postexposure, lung inflammation and fibrosis progressed in a time- and dose-dependent manner in LA-exposed rats, although the severity of inflammation and fibrosis was smaller in magnitude than in animals exposed to amosite. In contrast, gene expression of the fibrosis markers Col 1A2 and Col 3A1 was significantly greater in LA-exposed compared to amosite-exposed rats. There was no apparent evidence of preneoplastic changes in any of the asbestos-exposed groups. However, all asbestos-exposed rats demonstrated a significant increase in the expression of epidermal growth factor receptor (EGFR) 2 yr after instillation. In addition, only LA-exposed rats showed significant elevation in mesothelin (Msln) and Wilms' tumor gene (WT1) expression, suggesting possible induction of tumor pathways. These results demonstrate that a single IT exposure to LA is sufficient to induce significant fibrogenic, but not carcinogenic, effects up to 2 yr after exposure that differ both in quality and magnitude from those elicited by amosite administration at the same mass dose in F344 rats. Data showed that LA was on a mass basis less potent than amosite.

Ethical and legal aspects of global tobacco control.

On 28 February 2005, the Framework Convention on Tobacco Control came into force as a result of at least 40 countries becoming State Parties through ratification of this first ever health treaty sponsored by the World Health Organization. This article discusses the bioethical, trade, and legal aspects of global tobacco control. Special emphasis is given to globalisation of tobacco use and the challenges it poses to sovereign nations. It also advocates a bioethical basis in the pursuit of global solutions to expanding tobacco use.

Residential fire related deaths and injuries among children: fireplay, smoke alarms, and prevention.

BACKGROUND: The aim of the study was to describe the epidemiology of residential fire related deaths and injuries among children, and identify risk factors for these injuries through a linked dataset for the city of Dallas, Texas. METHODS: Data for all residential fires were linked with fire related injury data, using fire department records, ambulance transports, hospital admissions, and medical examiner records, for children 0-19 years of age. Causes of fires, including fireplay (children playing with fire or combustibles), arson and other causes, were determined by fire department investigation. RESULTS: From 1991-98, 76 children were injured in residential fires (39 deaths, 37 non-fatal). The highest rates occurred in the youngest children (<5 years) and in census tracts with lowest income. Fireplay accounted for 42% (32/76) of all injuries, 62% (15/24) of deaths in children 0-4 years, and 94% (13/14) of deaths from apartment and mobile home fires. Most of the fireplay related injuries (27/32, 84%) were from children playing with matches or lighters. Most started in a bedroom. Smoke alarms showed no protective efficacy in preventing deaths or injuries in fires started by fireplay or arson, but there was significant protective efficacy for a functional smoke alarm in fires started from all other causes (p<0.01). CONCLUSIONS: Residential fire related injuries among children in Dallas occurred predominantly in the youngest ages (<5 years) and in poor neighborhoods. Most of the deaths, especially those in apartments and mobile homes, resulted from fireplay. Smoke alarms appeared to offer no protection against death or injury in fireplay associated fires, possibly from the nature of the child's behavior in these fires, or from the placement of the smoke alarm. Prevention of childhood residential fire related deaths may require interventions to prevent fireplay in order to be successful.

A double-blind placebo-controlled randomized phase III trial of 5-fluorouracil and leucovorin, plus or minus trimetrexate, in previously untreated patients with advanced colorectal cancer.

BACKGROUND: Trimetrexate (TMTX) biochemically modulates 5-fluorouracil (5-FU) and leucovorin (LCV). Two phase II trials demonstrated promising activity for TMTX/5-FU/LCV in patients with untreated advanced colorectal cancer (ACC). This trial was designed to demonstrate the safety and efficacy of TMTX/5-FU/LCV as first-line treatment in ACC. PATIENTS AND METHODS: Eligible patients with ACC were randomized in double-blind fashion to receive placebo or TMTX (110 mg/m2) intravenously (i.v.) followed 24 h later by i.v. LCV 200 mg/m2, and 5-FU 500 mg/m2 plus oral LCV rescue. Both schedules were given weekly for 6 weeks every 8 weeks. Patients were evaluated for progression-free survival (PFS), overall survival (OS), tumor response, quality of life (QoL) and toxicity. RESULTS: A total of 382 eligible patients were randomized. Significant toxicities were noted more frequently with TMTX/5-FU/LCV. Diarrhea was the most common grade 3 or 4 side-effect (41% and 28% on the TMTX and placebo arms, respectively). QoL scores and response rates did not differ between treatment arms. PFS was 5.3 months and 4.4 months in the TMTX and placebo arms, respectively (P = 0.77; Wilcoxon). OS was 15.8 months and 16.8 months, respectively (P = 0.73; Wilcoxon). CONCLUSIONS: The addition of TMTX to a weekly regimen of 5-FU/LCV worsened grade 3 or 4 diarrhea. The inclusion of TMTX did not yield any significant improvements in response rate, PFS or OS.

Multicenter US study of hospital resource utilization associated with cytomegalovirus-related readmission of renal and heart transplant patients.

Incidence of cytomegalovirus (CMV)-related rehospitalization and associated resource use were captured by the Transplant Infection Cost Analysis (TICA) program, which examined patient records and hospital billing data in multiple solid organ transplant centers in the US. The experiences of two adult heart and three adult renal transplant centers were each pooled for analysis. Financial data were standardized to 1998 US dollars using the Medical Care component of the US Consumer Price Index. CMV-related readmissions among renal transplant patients averaged 10.5 days (range 1-56) with average charges of $22,598. Heart transplant patients readmitted for CMV incurred an average charge of $42,111 and average hospital stay of 10.9 days (range 2-95). CMV-related hospital resource use represented a significant portion of the average cost of the original transplant and associated length of stay.

ROC surface: a generalization of ROC curve analysis.

Receiver operating characteristic (ROC) curve analysis is widely used in biomedical research to assess the performance of diagnostic tests. Much of the work has been directed at developing accurate indices to describe ROC curves and appropriate statistics to test differences between them. The analysis, however, is largely built on the assumption that the test results are dichotomous. We generalize the ROC curve analysis to allow for tests to have more than two outcomes. The generalized ROC curve constitutes a surface. We propose to use the volume under the surface to measure the accuracy of a diagnostic test.

Lumbar disc high-intensity zone: the value and significance of provocative discography in the determination of the discogenic pain source.

Disagreement still exists in the literature as to the significance of the high-intensity zone (HIZ) demonstrated on magnetic resonance imaging (MRI) as a potential pain indicator in patients with low back pain. A prospective blind study was therefore conducted to evaluate the lumbar disc high-intensity zone with the pain provocation response of lumbar discography. Consecutive patients with low back pain unresponsive to conservative treatment and being considered for spinal fusion were subjected to MRI followed by lumbar discography as a pre-operative assessment. The discographer was blinded to the results of the MRI scans. We used the chi-squared test to analyse our results. Ninety-two HIZs were identified in 73 patients, mainly occurring at L4/5 (48%) and L5/S1 (35%). Significant correlation was found between abnormal disc morphology and the HIZ (P < 0.001). In morphologically abnormal discs (grades 3, 4 and 5), there was a significant correlation between the HIZ and exact or similar pain reproduction (P < 0.001). The sensitivity, specificity and positive predictive value for pain reproduction were high, at 81%, 79% and 87% respectively. The nature of the HIZ remains unknown, but it may represent an area of secondary inflammation as a result of an annular tear. We conclude from our study that the lumbar disc HIZ observed on MRI in patients with low back pain is likely to represent painful internal disc disruption.

Planning impairments in frontal lobe dementia and frontal lobe lesion patients.

Patients with frontal lobe brain damage are reportedly impaired on tasks that require plan development and execution. In this study, we examined the performance of 15 patients diagnosed with frontal lobe dementia and 14 patients with focal frontal lobe lesions on the Tower of London planning task. Patients with frontal lobe dementia committed a significantly higher number of rule violations, made more moves, and demonstrated longer solution time latencies compared to their matched controls. Patients with frontal lobe lesions demonstrated significantly delayed solution times and also made more moves compared to their matched controls. Frontal lobe lesion patient performance suggests an impairment in execution-related processes, while frontal lobe dementia patients appear to be impaired in both plan development and execution. Despite these findings, the identification of a specific cognitive impairment that induces these planning problems remains elusive.

A direct comparison of the activities of two humanized respiratory syncytial virus monoclonal antibodies: MEDI-493 and RSHZl9.

Two humanized monoclonal antibodies, MEDI-493 and RSHZ19, were developed independently as potential improvements over RSV-IGIV for prevention of respiratory syncytial virus (RSV) infection. RSV-IGIV is a polyclonal human antibody preparation for intravenous infusion enriched for RSV neutralizing activity. A phase III clinical trial showed that MEDI-493 significantly reduced hospitalizations due to RSV infection. In a separate trial, RSHZ19 failed to show significant efficacy. In new studies, the in vitro and in vivo activities of MEDI-493 and RSHZ19 were compared to determine whether the different clinical results are related to differences in biologic activity. MEDI-493 was consistently 4- to 5-fold more potent than RSHZ19 in antigen binding, RSV neutralization, and fusion inhibition assays. Although both MEDI-493 and RSHZ19 were effective against A and B subtypes of RSV in the cotton rat model of RSV infection, 2- to 4-fold higher doses of RSHZ19 were required for similar protection. The enhanced activity of MEDI-493 compared with RSHZ19 may, in part, explain its better clinical effect.

Reduction of respiratory syncytial virus (RSV) in tracheal aspirates in intubated infants by use of humanized monoclonal antibody to RSV F protein.

Thirty-five children <2 years of age mechanically ventilated for respiratory syncytial virus (RSV) infection were randomized to receive an intravenous infusion of 15 mg/kg MEDI-493 or placebo. RSV concentration was measured in tracheal secretions by plaque assay before and at 24-h intervals after treatment. The reduction in tracheal RSV concentration from day 0 to day 1 (-1.7+/-0.28 vs. -0. 6+/-0.21 log10 pfu/mL; P=.004) and from day 0 to day 2 (-2.5+/-0.26 vs. -1.0+/-0.41 log10 pfu/mL; P=.012) was significantly greater in the MEDI-493 group than in the placebo group. RSV concentration in nasal aspirates did not differ significantly between the groups. No significant differences were observed in the tracheal aspirate white blood cell count, or myeloperoxidase or eosinophilic cationic protein concentration, or in measures of disease severity between the groups. Thus, treatment with 15 mg/kg MEDI-493 intravenously was well-tolerated and significantly reduced RSV concentration in tracheal aspirates of children with respiratory failure due to RSV.

Safety, tolerance and pharmacokinetics of a humanized monoclonal antibody to respiratory syncytial virus in premature infants and infants with bronchopulmonary dysplasia. MEDI-493 Study Group.

BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants. MEDI-493 (palivizumab) is a humanized monoclonal antibody to the fusion protein of RSV and is active in animal models for prevention of pulmonary RSV replication. OBJECTIVE: To describe the safety, tolerance, immunogenicity and pharmacokinetics of repeat intravenous doses of MEDI-493 in premature infants or infants with bronchopulmonary dysplasia. DESIGN: Phase I/II multicenter, randomized, double blind, placebo-controlled, dose escalation trial. PATIENT POPULATION: Infants born prematurely (< or = 35 weeks of gestation) who were < or = 6 months of age and infants with bronchopulmonary dysplasia who were < or = 24 months of age were eligible for study participation. STUDY AGENTS: Participants received 3, 10 or 15 mg/kg MEDI-493 or 0.9% saline intravenously every 30 days for up to five doses. RESULTS: MEDI-493 was safe and well-tolerated and did not induce a specific anti-MEDI-493 response. The mean half-life of 20 days was comparable with that of other immunoglobulin G preparations. Mean trough serum concentrations 30 days after Infusion 1 were 6.8, 36.1 and 60.6 microg/ml for the 3-, 10- and 15-mg/kg dose groups, respectively. After Infusion 2 the trough concentrations were 11.9, 45.2 and 70.7 microg/ml. After subsequent doses the mean trough values ranged from 14 to 18 microg/ml in those given 3 mg/kg and were > 40 microg/ml for patients who received 10 or 15 mg/kg MEDI-493 (46 to 72 microg/ml and 88 to 96 microg/ml, respectively). CONCLUSIONS: MEDI-493 was safe and well-tolerated in this high risk pediatric population. Mean serum concentrations of MEDI-493 that have been shown to produce a 2-log reduction in pulmonary RSV titer in cotton rats were maintained when 10 or 15 mg/kg MEDI-493 was given every 30 days to pediatric patients at high risk for serious RSV disease. Monthly doses of 15 mg/kg maintained concentrations of > 40 microg/ml for the majority of patients.

CA15-3 serum levels in breast cancer and other malignancies--correlation with clinical course.

Serum levels of the breast cancer-associated tumor marker CA15-3 were evaluated in three patient groups: breast, colorectal and ovarian cancer and in healthy subjects. Of 51 blood samples obtained from 31 patients with metastatic breast cancer (Stage IV disease), 98% had marker levels greater than 30 u/ml and 86% had levels greater than 50 u/ml. In contrast, of 49 samples from 42 patients with Stage I-II disease, 45% had levels greater than 30 u/ml but only 6% had levels greater than 50 u/ml (mean 29.5 +/- 18 u/ml). The mean level of the CA15-3 antigen in patients with Stage IV breast cancer and responding to therapy was 79.8 +/- 27 u/ml, while the mean level in patients not responding to therapy was 134 +/- 66 u/ml (P less than 0.02). The mean serial changes in CA15-3 levels for those responding to therapy was -28.4% while the mean change for those not responding to therapy was +44%. The mean marker level for 26 patients with colorectal carcinoma was 29.8 +/- 29 u/ml; 23% of these patients had levels greater than 30 u/ml and 7% had levels greater than 50 u/ml. No substantial difference was seen in those with active compared with nonactive colorectal carcinoma. The mean marker level for 14 patients with active ovarian carcinoma was 83 +/- 62 u/ml. Of these patients, 78% had CA15-3 levels greater than 30 u/ml and 50% had levels greater than 50 u/ml. All healthy subjects (n = 22) had marker levels less than 30 u/ml. We compared CA15-3 and CEA blood levels in the same patient population; 86% of patients with metastatic breast cancer (Stage IV disease) had CA15-3 levels greater than 50 u/ml while only 72% of these patients had CEA levels greater than 5 ng/ml. These findings suggest that the CA15-3 assay reflects the clinical course of patients with advanced breast cancer and may be superior to CEA as a monitor of therapeutic efficacy.