Immunomodulation of susceptibility to pneumococcal pneumonia infection in mouse lungs exposed to carbon nanoparticles via dysregulation of innate and adaptive immune responses.

Carbon nanotubes (CNTs) are emerging pollutants of occupational and environmental health concern. While toxicological mechanisms of CNTs are emerging, there is paucity of information on their modulatory effects on susceptibility to infections. Here, we investigated cellular and molecular events underlying the effect of multi-walled CNT (MWCNT) exposure on susceptibility to Streptococcus pneumoniae infection in our 28-day sub-chronic exposure mouse model. Data indicated reduced phagocytic function in alveolar macrophages (AMs) from MWCNT-exposed lungs evidenced by lower pathogen uptake in 1-h infection assay. At 24-h post-infection, intracellular pathogen count in exposed AMs showed 2.5 times higher net increase (2-fold in vehicle- versus 5-fold in MWCNT-treated), indicating a greater rate of intracellular multiplication and/or survival due to MWCNT exposure. AMs from MWCNT-exposed lungs exhibited downregulation of pathogen-uptake receptors CD163, Phosphatidyl-serine receptor (Ptdsr), and Macrophage scavenger receptors class A type 1 (Msr1) and type 2 (MSr2). In whole lung, MWCNT exposure shifted the macrophage polarization state towards the immunosuppressive phenotype M2b and increased the CD11c+ dendritic cell population required to activate the adaptive immune response. Notably, the MWCNT pre-exposure dysregulated T-cell immunity, evidenced by diminished CD4 and Th17 response, and exacerbated Th1 and Treg responses (skewed Th17/Treg ratio), thereby favoring the pneumococcal infection. Overall, these findings indicated that MWCNT exposure compromises both innate and adaptive immunity leading to diminished host lung defense against pneumonia infection. To our knowledge, this is the first report on an immunomodulatory role of CNT pre-exposure on pneumococcal infection susceptibility due to dysregulation of both innate and adaptive immunity targets.

Tobacco Smoke Exposure and Sleep Duration among U.S. Adolescents.

OBJECTIVES: Tobacco smoke exposure (TSE) and poor sleep are public health problems with their own set of consequences. This study assessed whether TSE was associated with sleep duration among U.S. adolescents. METHOD: We conducted a secondary analysis of 2013-2018 National Health and Nutrition Examination Survey data including 914 nontobacco-using adolescents ages 16-19 years. TSE measures included cotinine and self-reported home TSE groups including no home TSE, thirdhand smoke (THS) exposure, and secondhand smoke (SHS)+THS exposure. Sleep duration was assessed in hours and categorically as insufficient sleep (recommended hours). Weighted multiple linear regression and multinomial regression models were conducted. RESULTS: Adolescents with higher log-cotinine levels had higher number of sleep hours (ß = 0.31, 95%CI = 0.02,0.60) and were at increased odds of reporting excess sleep (AOR = 1.41, 95%CI = 1.40,1.42), but were at reduced odds of reporting insufficient sleep (AOR = 0.88, 95%CI = 0.87,0.89). Compared to adolescents with no home TSE, adolescents with home THS exposure and home SHS+THS exposure were at increased odds of reporting insufficient sleep (AOR = 2.27, 95%CI = 2.26,2.29; AOR = 2.75, 95%CI = 2.72,2.77, respectively) and excess sleep (AOR = 1.89, 95%CI = 1.87,1.90; AOR = 5.29, 95%CI = 5.23,5.34, respectively). CONCLUSIONS: TSE may affect insufficient and excess sleep duration among adolescents. Eliminating TSE may promote adolescent respiratory and sleep health.

Carcinogenic and tobacco smoke-derived particulate matter biomarker uptake and associated healthcare patterns among children.

BACKGROUND: The objective was to assess the associations of child tobacco smoke exposure (TSE) biomarkers (urinary cotinine, NNAL, and nicotelline N-oxides) and parent-reported smoking and child TSE patterns with total hospital visits, pediatric emergency department (PED) visits, urgent care (UC), revisits, and hospital admissions among 0-9-year-olds. METHODS: A convenience sample of PED/UC patients (N = 242) who presented to a large, US children's hospital who had baseline urine samples assayed for the TSE biomarkers of interest were included. Biomarker levels were log-transformed, and linear and Poisson regression models were built. RESULTS: The geometric means of child cotinine, creatinine-adjusted NNAL, and N-oxide levels were 11.2 ng/ml, 30.9 pg/mg creatinine, and 24.1 pg/ml, respectively. The mean (SD) number of daily cigarettes smoked by parents was 10.2 (6.1) cigarettes. Each one-unit increase in log-NNAL levels was associated with an increase in total UC visits (aRR = 1.68, 95% CI = 1.18-2.39) among 0-9-year-olds, while controlling for the covariates. Each one-unit increase in child log-NNAL/cotinine ratio (×103) values was associated with an increase in total hospital visits (aRR = 1.39, 95% CI = 1.10-1.75) and UC visits (aRR = 1.56, 95% CI = 1.14-2.13) over 6 months. CONCLUSION: Systematic screening for child TSE should be conducted during all hospital visits. The comprehensive assessment of TSE biomarkers should be considered to objectively measure young children's exposure. IMPACT: Higher levels of cotinine, a widely used tobacco smoke exposure biomarker, have been associated with higher healthcare utilization patterns among children. Less is known on the associations of carcinogenic and tobacco smoke-derived particulate matter biomarker uptake with child healthcare utilization patterns. This study assessed the associations of several biomarkers with healthcare utilization patterns among pediatric emergency department patients ages 0-9 years who lived with tobacco smokers. Higher urinary NNAL biomarker levels, in individual and ratio form with cotinine, increased children's risk for urgent care visits over 6 months. Higher parent-reported cumulative child tobacco smoke exposure increased children's risk for hospital admissions.

Distinguishing Exposure to Secondhand and Thirdhand Tobacco Smoke among U.S. Children Using Machine Learning: NHANES 2013-2016.

While the thirdhand smoke (THS) residue from tobacco smoke has been recognized as a distinct public health hazard, there are currently no gold standard biomarkers to differentiate THS from secondhand smoke (SHS) exposure. This study used machine learning algorithms to assess which combinations of biomarkers and reported tobacco smoke exposure measures best differentiate children into three groups: no/minimal tobacco smoke exposure (NEG); predominant THS exposure (TEG); and mixed SHS and THS exposure (MEG). Participants were 4485 nonsmoking 3-17-year-olds from the National Health and Nutrition Examination Survey 2013-2016. We fitted and tested random forest models, and the majority (76%) of children were classified in NEG, 16% were classified in TEG, and 8% were classified in MEG. The final classification model based on reported exposure, biomarker, and biomarker ratio variables had a prediction accuracy of 95%. This final model had prediction accuracies of 100% for NEG, 88% for TEG, followed by 71% for MEG. The most important predictors were the reported number of household smokers, serum cotinine, serum hydroxycotinine, and urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). In the absence of validated biomarkers specific to THS, comprehensive biomarker and questionnaire data for tobacco smoke exposure can distinguish children exposed to SHS and THS with high accuracy.

Sources of Tobacco Smoke Exposure and Their Associations With Serum Cotinine Levels Among US Children and Adolescents.

INTRODUCTION: We assessed tobacco smoke exposure (TSE) levels based on private and public locations of TSE according to race and ethnicity among US school-aged children ages 6-11 years and adolescents ages 12-17 years. AIMS AND METHODS: Data were from 5296 children and adolescents who participated in the National Health and Nutrition Examination Survey (NHANES) 2013-2018. Racial and ethnic groups were non-Hispanic white, black, other or multiracial, and Hispanic. NHANES assessed serum cotinine and the following TSE locations: homes and whether smokers did not smoke indoors (home thirdhand smoke [THS] exposure proxy) or smoked indoors (secondhand [SHS] and THS exposure proxy), cars, in other homes, restaurants, or any other indoor area. We used stratified weighted linear regression models by racial and ethnic groups and assessed the variance in cotinine levels explained by each location within each age group. RESULTS: Among 6-11-year-olds, exposure to home THS only and home SHS + THS predicted higher log-cotinine among all racial and ethnic groups. Non-Hispanic white children exposed to car TSE had higher log-cotinine (ß = 1.64, 95% confidence interval [CI] = 0.91% to 2.37%) compared to those unexposed. Non-Hispanic other/multiracial children exposed to restaurant TSE had higher log-cotinine (ß = 1.13, 95% CI = 0.23% to 2.03%) compared to those unexposed. Among 12-17-year-olds, home SHS + THS exposure predicted higher log-cotinine among all racial and ethnic groups, except for non-Hispanic black adolescents. Car TSE predicted higher log-cotinine among all racial and ethnic groups. Non-Hispanic black adolescents with TSE in another indoor area had higher log-cotinine (ß = 2.84, 95% CI = 0.85% to 4.83%) compared to those unexposed. CONCLUSIONS: TSE location was uniquely associated with cotinine levels by race and ethnicity. Smoke-free home and car legislation are needed to reduce TSE among children and adolescents of all racial and ethnic backgrounds. IMPLICATIONS: Racial and ethnic disparities in TSE trends have remained stable among US children and adolescents over time. This study's results indicate that TSE locations differentially contribute to biochemically measured TSE within racial and ethnic groups. Home TSE significantly contributed to cotinine levels among school-aged children 6-11 years old, and car TSE significantly contributed to cotinine levels among adolescents 12-17 years old. Racial and ethnic differences in locations of TSE were observed among each age group. Study findings provide unique insight into TSE sources, and indicate that home and car smoke-free legislation have great potential to reduce TSE among youth of all racial and ethnic backgrounds.

Assessment of indoor bioaerosol exposure using direct-reading versus traditional methods-potential application to home health care.

Home healthcare workers (HHCWs) can be occupationally exposed to bioaerosols in their clients' homes. However, choosing the appropriate method to measure bioaerosol exposures remains a challenge. Therefore, a systematic comparison of existing measurement approaches is essential. Bioaerosol measurements with a real-time, fluorescence-based Wideband Integrated Bioaerosol Sensor (WIBS) were compared to measurements with four traditional off-line methods (TOLMs). The TOLMS included optical microscopic counting of spore trap samples, microbial cultivation of impactor samples, qPCR, and next-generation sequencing (NGS) of filter samples. Measurements were conducted in an occupied apartment simulating the environments that HHCWs could encounter in their patients' homes. Descriptive statistics and Spearman's correlation test were computed to compare the real-time measurement with those of each TOLM. The results showed that the geometric mean number concentrations of the total fluorescent aerosol particles (TFAPs) detected with the WIBS were several orders of magnitude higher than those of total fungi or bacteria measured with the TOLMs. Among the TOLMs, concentrations obtained with qPCR and NGS were the closest to the WIBS detections. Correlations between the results obtained with the WIBS and TOLMs were not consistent. No correlation was found between the concentrations of fungi detected using microscopic counting and any of the WIBS fluorescent aerosol particle (FAP) types, either indoors or outdoors. In contrast, the total concentrations detected with microbial cultivation correlated with the WIBS TFAP results, both indoors and outdoors. Outdoors, the total concentration of culturable bacteria correlated with FAP-type AC. In addition, fungal and bacterial concentrations obtained with qPCR correlated with FAP types AB and AC. For a continuous, high-time resolution but broad scope, the real-time WIBS could be considered, whereas a TOLM would be the best choice for specific and more accurate microbial characterization. HHCWs' activities tend to re-aerosolize bioaerosols causing wide temporal variation in bioparticle concentrations. Thus, the advantage of using the real-time instrument is to capture those variations. This study lays a foundation for future exposure assessment studies targeting HHCWs.

Residential bacteria and fungi identified by high-throughput sequencing and childhood respiratory health.

The objective of this study was to examine and compare environmental microbiota from dust and children's respiratory health outcomes at ages seven and twelve. At age seven, in-home visits were conducted for children enrolled in the Cincinnati Childhood Allergy and Air Pollution Study (CCAAPS). Floor dust was collected and analyzed for bacterial (16 S rRNA gene) and fungal (internal transcribed spacer region) microbiota. Respiratory outcomes, including physician-diagnosed asthma, wheeze, rhinitis, and aeroallergen sensitivity were assessed by physical examination and caregiver-report at ages seven and twelve. The associations between dust microbiota and respiratory outcomes were evaluated using Permanova, DESeq, and weighted quantile sum (WQS) regression models. Four types of WQS regression models were run to identify mixtures of fungi or bacteria that were associated with the absence or presence of health outcomes. For alpha or beta diversity of fungi and bacteria, no significant associations were found with respiratory health outcomes. DESeq identified specific bacterial and fungal indicator taxa that were higher or lower with the presence of different health outcomes. Most individual indicator fungal species were lower with asthma and wheeze and higher with aeroallergen positivity and rhinitis, whereas bacterial data was less consistent. WQS regression models demonstrated that a combination of species might influence health outcomes. Several heavily weighted species had a strong influence on the models, and therefore, created a microbial community that was associated with the absence or presence of asthma, wheeze, rhinitis, and aeroallergen+. Weights for specific species within WQS regression models supported indicator taxa findings. Health outcomes might be more influenced by the composition of a complex mixture of bacterial and fungal species in the indoor environment than by the absence or presence of individual species. This study demonstrates that WQS is a useful tool in evaluating mixtures in relation to potential health effects.

COVID-19 case fatality rate and tuberculosis in a metropolitan setting.

In this study, we aimed to assess the relationship between tuberculosis case rate and COVID-19 case fatality rate (CFR) among districts within a tuberculosis-endemic metropolitan area. We analyzed data from 43 districts in Lima, Peru. We used districts as the units of observation. Linear regressions were used to investigate the relationship between COVID-19 CFRs and tuberculosis case rates. The mean COVID-19 CFR in each district for reporting Weeks 5-32 was used as the dependent variable. Independent variable was the mean rate of confirmed pulmonary tuberculosis cases for 2017-2019 period. Analyses were adjusted by population density, socioeconomic status, crowded housing, health facility density, and case rates of hypertension, diabetes mellitus, and HIV infection. The mean COVID-19 CFR in Lima was 4.0% ± 1.1%. The mean tuberculosis rate was 16.0 cases per 10,000 inhabitants. In multivariate analysis, tuberculosis case rate was associated with COVID-19 CFR (ß = 1.26; 95% confidence interval: 0.24-2.28; p = .02), after adjusting for potential confounders. We found that Lima districts with a higher burden of tuberculosis exhibited higher COVID-19 CFRs, independent of socioeconomic, and morbidity variables.

See One, Do One, Forget One: Early Skill Decay After Paracentesis Training.

INTRODUCTION: Internal medicine residents perform paracentesis, but programs lack standard methods for assessing competence or maintenance of competence and instead rely on number of procedures completed. This study describes differences in resident competence in paracentesis over time. METHODS: From 2016 to 2017, internal medicine residents (n = 118) underwent paracentesis simulation training. Competence was assessed using the Paracentesis Competency Assessment Tool (PCAT), which combines a checklist, global scale, and entrustment score. The PCAT also delineates two categorical cut-point scores: the Minimum Passing Standard (MPS) and the Unsupervised Practice Standard (UPS). Residents were randomized to return to the simulation lab at 3 and 6 months (group A, n = 60) or only 6 months (group B, n = 58). At each session, faculty raters assessed resident performance. Data were analyzed to compare resident performance at each session compared with initial training scores, and performance between groups at 6 months. RESULTS: After initial training, all residents met the MPS. The number achieving UPS did not differ between groups: group A = 24 (40%), group B = 20 (34.5%), p = 0.67. When group A was retested at 3 months, performance on each PCAT component significantly declined, as did the proportion of residents meeting the MPS and UPS. At the 6-month test, residents in group A performed significantly better than residents in group B, with 52 (89.7%) and 20 (34.5%) achieving the MPS and UPS, respectively, in group A compared with 25 (46.3%) and 2 (3.70%) in group B (p < .001 for both comparison). DISCUSSION: Skill in paracentesis declines as early as 3 months after training. However, retraining may help interrupt skill decay. Only a small proportion of residents met the UPS 6 months after training. This suggests using the PCAT to objectively measure competence would reclassify residents from being permitted to perform paracentesis independently to needing further supervision.

Tobacco smoke exposure and fractional exhaled nitric oxide levels among U.S. adolescents.

BACKGROUND: Fractional exhaled nitric oxide (FeNO) can objectively guide clinical practice in the assessment, diagnosis, and treatment of eosinophilic airway inflammation. FeNO values may be affected by current smoking, but the role of tobacco smoke exposure (TSE) is understudied. OBJECTIVE: This study investigated the associations between biochemically validated and self-reported TSE and FeNO levels among U.S. nonsmoking adolescents without asthma. METHODS: National Health and Nutrition Examination Survey 2007-2012 data were used. TSE was assessed via serum cotinine and self-reported measures. We assessed FeNO continuously and using cutpoints of >35 ppb and >50 ppb to indicate likely eosinophilic inflammation in children and adults, respectively. We conducted linear and logistic regression adjusting for potential covariates. RESULTS: Overall, 34.0% of adolescents had low cotinine (0.05-2.99 ng/ml), 6.2% had high cotinine (≥3.00 ng/ml), and 11.9% had home TSE. Compared to adolescents with no/minimal cotinine, adolescents with high cotinine were at reduced odds to have FeNO >35 ppb (adjusted odds ratio [aOR] = 0.54, 95%CI = 0.43,0.69). Adolescents with low cotinine had lower FeNO values (ß = -2.05, 95%CI = -3.61,-0.49), and were also at decreased odds to have FeNO >35 ppb (aOR = 0.74, 95%CI = 0.66,0.83) and FeNO >50 ppb (aOR = 0.62, 95%CI = 0.53,0.72). Adolescents with home TSE were at reduced odds to have FeNO >50 ppb (aOR = 0.72, 95%CI = 0.57,0.91) than adolescents without home TSE. Adolescents with a higher number of cigarettes/day smoked inside their home were at reduced odds to have FeNO >35 ppb (OR = 0.98, 95%CI = 0.97,0.99) and FeNO >50 ppb (OR = 0.98, 95%CI = 0.96,0.99). CONCLUSIONS: TSE was associated with decreased FeNO levels. The addition of TSE may be clinically important when interpreting thresholds for FeNO.

Flexible multivariate joint model of longitudinal intensity and binary process for medical monitoring of frequently collected data.

A frequent problem in longitudinal studies is that data may be assessed at subject-selected, irregularly spaced time-points, resulting in highly unbalanced outcome data, inducing bias, especially if availability of data is directly related to outcome. Our aim was to develop a multivariate joint model in a mixed outcomes framework to minimize irregular sampling bias. We demonstrate using blood glucose monitoring throughout pregnancy and risk of preterm birth among women with type 1 diabetes mellitus. Blood glucose measurements were unequally spaced and intensity of sampling varied between and within individuals over time. Multivariate linear mixed effects submodel for the longitudinal outcome (blood glucose), Poisson model for the intensity of glucose sampling, and logistic regression model for binary process (preterm birth) were specified. Association between models is captured through shared random effects. Markov chain Monte Carlo methods were used to fit the model. The multivariate joint model provided better prediction, compared with a joint model with a multivariate linear mixed effects submodel (ignoring intensity of glucose sampling) and a two-stage model. Most association parameters were significant in the preterm birth outcome model, signifying improvement of predictive ability of the binary endpoint by sharing random effects between glucose monitoring and preterm birth. A simulation study is presented to illustrate the effectiveness of the multivariate joint modeling approach.

Combustible and electronic cigarette use and insufficient sleep among U.S. high school students.

The study aimed to investigate the relationships between current exclusive e-cigarette use, exclusive combustible cigarette smoking, and dual use of e-cigarettes and combustible cigarettes, and insufficient sleep among U.S. adolescents. We conducted a secondary data analysis of the 2017 Youth Risk Behavior Survey including 11,296 U.S. high school students. Current (past 30-day) tobacco use groups included exclusive e-cigarette users, exclusive combustible cigarette smokers, and dual-product users. We performed weighted unadjusted and adjusted logistic regression analyses. Insufficient sleep was defined as <8 h/night and < 7 h/night. Overall, 73.4% of adolescents reported insufficient sleep <8 h/night. Compared with non-tobacco users, exclusive e-cigarette users were more likely to report insufficient sleep <8 h/night (odds ratio [OR] = 1.55, 95%CI = 1.12-2.14; adjusted OR [aOR] = 1.57, 95%CI = 1.01-2.43) and < 7 h/night (OR = 1.55, 95%CI = 1.19-2.01; aOR = 1.61, 95%CI = 1.16-2.24). Dual-product users were at increased odds to report insufficient sleep <8 h/night (OR = 3.15, 95%CI = 1.87-5.32) and < 7 h/night (OR = 2.64, 95%CI = 1.87-3.72; aOR = 1.73, 95%CI = 1.14-2.62) than non-tobacco users. Exclusive combustible cigarette smokers were less likely to report insufficient sleep <8 h/night (aOR = 0.49, 95%CI = 0.29-0.84) than non-tobacco users, but no differences were found based on insufficient sleep <7 h/night. When comparing current use groups, exclusive e-cigarette users were at 3.20 increased odds (95%CI = 1.65-6.22) and dual-product users were at 3.26 increased odds (95%CI = 1.51-7.03) to report insufficient sleep <8 h/night when compared with exclusive combustible cigarette smokers after covariate adjustment. Dual-product users were 1.89 times more likely (95%CI = 1.01-3.51) to report insufficient sleep <7 h/night when compared with exclusive combustible cigarette smokers. School-based prevention efforts for tobacco use may promote sufficient sleep in youth.

Differential associations of hand nicotine and urinary cotinine with children's exposure to tobacco smoke and clinical outcomes.

BACKGROUND: Children's overall tobacco smoke exposure (TSE) consists of both inhalation of secondhand smoke (SHS) and ingestion, dermal uptake, and inhalation of thirdhand smoke (THS) residue from dust and surfaces in their environments. OBJECTIVES: Our objective was to compare the different roles of urinary cotinine as a biomarker of recent overall TSE and hand nicotine as a marker of children's contact with nicotine pollution in their environments. We explored the differential associations of these markers with sociodemographics, parental smoking, child TSE, and clinical diagnoses. METHODS: Data were collected from 276 pediatric emergency department patients (Median age = 4.0 years) who lived with a cigarette smoker. Children's hand nicotine and urinary cotinine levels were determined using LC-MS/MS. Parents reported tobacco use and child TSE. Medical records were reviewed to assess discharge diagnoses. RESULTS: All children had detectable hand nicotine (GeoM = 89.7ng/wipe; 95 % CI = [78.9; 102.0]) and detectable urinary cotinine (GeoM = 10.4 ng/ml; 95%CI = [8.5; 12.6]). Although hand nicotine and urinary cotinine were highly correlated (r = 0.62, p < 0.001), urinary cotinine geometric means differed between racial groups and were higher for children with lower family income (p < 0.05), unlike hand nicotine. Independent of urinary cotinine, age, race, and ethnicity, children with higher hand nicotine levels were at increased risk to have discharge diagnoses of viral/other infectious illness (aOR = 7.49; 95%CI = [2.06; 27.24], p = 0.002), pulmonary illness (aOR = 6.56; 95%CI = [1.76; 24.43], p = 0.005), and bacterial infection (aOR = 5.45; 95%CI = [1.50; 19.85], p = 0.03). In contrast, urinary cotinine levels showed no associations with diagnosis independent of child hand nicotine levels and demographics. DISCUSSION: The distinct associations of hand nicotine and urinary cotinine suggest the two markers reflect different exposure profiles that contribute differentially to pediatric illness. Because THS in a child's environment directly contributes to hand nicotine, additional studies of children of smokers and nonsmokers are warranted to determine the role of hand nicotine as a marker of THS exposure and its potential role in the development of tobacco-related pediatric illnesses.

Phase 1 dose-finding study of metformin in combination with concurrent cisplatin and radiotherapy in patients with locally advanced head and neck squamous cell cancer.

BACKGROUND: The 5-year overall survival (OS) rate remains at 50% for patients with locally advanced head and neck squamous cell carcinoma (LAHNSCC), thereby underscoring the need for improved treatments. An antidiabetic agent, metformin, was found in retrospective studies to improve survival in patients with HNSCC. Therefore, the authors conducted a phase 1 dose escalation study combining metformin with chemoradiotherapy in patients with LAHNSCC. METHODS: Nondiabetic patients with LAHNSCC were enrolled in the current study to receive escalating doses of metformin and CRT based on the modified toxicity probability interval design. Metformin cohort doses included 2000 mg, 2550 mg, and 3000 mg daily in divided doses in addition to cisplatin (at a dose of 100 mg/m2 on days 1, 22, and 43) and standard radiotherapy (70 grays). Adverse events were categorized as per the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). RESULTS: Twenty patients were enrolled, 2 of whom withdrew consent. The median age of the patients was 56 years and the majority were male (83%), were white (88%), had p16-positive disease (72%), and were tobacco users (61%). The median length of metformin exposure was 28.5 days. The most common grade ≥3 toxicities were nausea (11%), vomiting (11%), mucositis (6%), acute kidney injury (17%), anemia (6%), and leukopenia (11%). Dose-limiting toxicities included diarrhea and acute kidney injury. After a median follow-up of 19 months, the 2-year overall survival and progression-free survival rates were 90% and 84%, respectively. No hypoglycemia events or lactic acidosis were observed. Cisplatin administration did not appear to affect metformin pharmacokinetics. The maximum tolerated dose for metformin could not be determined given the limited number of patients who tolerated metformin during chemoradiotherapy. CONCLUSIONS: To the authors' knowledge, the current study is the first phase 1 trial combining metformin with chemoradiotherapy. Rates of overall survival and progression-free survival were encouraging in this limited patient population, and warrant further investigation in a phase 2 trial.

Development and Establishment of Initial Validity Evidence for a Novel Tool for Assessing Trainee Admission Notes.

BACKGROUND: Documentation is a key component of practice, yet few curricula have been published to teach trainees proper note construction. Additionally, a gold standard for assessing note quality does not exist, and no documentation assessment tools integrate with established competency-based frameworks. OBJECTIVE: To develop and establish initial validity evidence for a novel tool that assesses key components of trainee admission notes and maps to the Accreditation Council for Graduate Medical Education (ACGME) milestone framework. DESIGN: Using an iterative, consensus building process we developed the Admission Note Assessment Tool (ANAT). Pilot testing was performed with both the supervising attending and study team raters not involved in care of the patients. The finalized tool was piloted with attendings from other institutions. PARTICIPANTS: Local experts participated in tool development and pilot testing. Additional attending physicians participated in pilot testing. MAIN MEASURES: Content, response process, and internal structure validity evidence was gathered using Messick's framework. Inter-rater reliability was assessed using percent agreement. KEY RESULTS: The final tool consists of 16 checklist items and two global assessment items. Pilot testing demonstrated rater agreement of 72% to 100% for checklist items and 63% to 70% for global assessment items. Note assessment required an average of 12.3 min (SD 3.7). The study generated validity evidence in the domains of content, response process, and internal structure for use of the tool in rating admission notes. CONCLUSIONS: The ANAT assesses individual components of a note, incorporates billing criteria, targets note "bloat," allows for narrative feedback, and provides global assessments mapped to the ACGME milestone framework. The ANAT can be used to assess admission notes by any attending and at any time after note completion with minimal rater training. The ANAT allows programs to implement routine note assessment for multiple functions with the use of a single tool.

Child tobacco smoke exposure and healthcare resource utilization patterns.

BACKGROUND: The objective was to examine the relationship between healthcare resource utilization patterns in tobacco smoke-exposed children (TSE group) compared with unexposed children (non-TSE group). METHODS: We matched 380 children in the TSE group with 1140 children in the non-TSE group based on child age, sex, race, and ethnicity using propensity scores. Healthcare resource utilization variables included respiratory-related procedures, diagnostic testing, disposition, and medications. Logistic and linear regression models were built. RESULTS: Child mean age was 4.9 (SD = 0.1) years, 50.5% were female, 55.5% black, and 73.2% had public insurance/self-pay. Compared to the non-TSE group, the TSE group was at increased odds to have the following performed/obtained: nasal bulb suctioning, infectious diagnostic tests, laboratory tests, and radiologic tests. The TSE group was more likely to be admitted to the hospital, and more likely to receive steroids and intravenous fluids during their visit. Among asthmatics, the TSE group was more likely to receive steroids, albuterol, or ipratropium alone, or a combination of all three medications during their visit, and be prescribed albuterol alone or steroids and albuterol. CONCLUSION: Tobacco smoke-exposed children are more likely to have higher resource utilization patterns, highlighting the importance of screening and providing TSE prevention and remediation interventions. IMPACT: Tobacco smoke exposure may affect the healthcare resource utilization patterns of children. Evidence is lacking concerning these associations among the highly vulnerable pediatric emergency department patient population. This study examined the association between tobacco smoke exposure and healthcare resource utilization patterns among pediatric emergency department patients. Tobacco smoke exposure increased the risk of pediatric patients having respiratory-related procedures, respiratory-related and non-respiratory-related testing, medications administered during the pediatric emergency department visit, and medications prescribed for home administration. Tobacco smoke-exposed patients were more likely to be admitted to the hospital compared to unexposed patients.

Clinical outcomes and survival following lung transplantation in patients with pulmonary Langerhans cell histiocytosis.

BACKGROUND AND OBJECTIVE: Disease-specific outcomes following lung transplantation (LT) in patients with pulmonary Langerhans cell histiocytosis (PLCH) are not well established. We queried the Organ Procurement and Transplantation Network database to identify adult PLCH patients who had undergone LT in the United States. METHODS: Overall survival data were analysed with Kaplan-Meier curves. Cox proportional hazard model was used to determine the effect of demographic, clinical and physiological variables on post-transplant survival. RESULTS: A total of 87 patients with PLCH underwent LT in the United States between October 1987 and June 2017, accounting for 0.25% of the total LT during this period. The mean age at LT for PLCH patients was 49 years (range: 19-67 years), with a near equal gender distribution. Bilateral sequential LT was performed in 71 patients (82%). Pulmonary hypertension was present in 85% of patients, with a mean pulmonary artery pressure of 38.5 ± 14.1 mm Hg. The mean pre-transplant forced expiratory volume in 1 s (FEV1 ) was 41 ± 21% predicted and the mean 6-min walk distance was 221 ± 111 m. Median post-LT survival for PLCH patients was comparable to patients with other lung diseases (5.1 vs 5.5 years, P = 0.76). The actuarial Kaplan-Meier post-LT survival for PLCH patients was 85%, 65%, 49% and 22% at 1, 3, 5 and 10 years, respectively. Female sex (hazard ratio (HR): 0.40, 95% CI: 0.22-0.72), pre-transplant serum bilirubin (HR: 1.66, 95% CI: 1.23-2.26) and serum creatinine (HR: 4.03, 95% CI: 1.01-14.76) were independently associated with post-LT mortality in our cohort. CONCLUSION: Post-LT survival in patients with PLCH is similar to patients with other lung diseases and is significantly affected by patient gender.

HEPA filtration improves asthma control in children exposed to traffic-related airborne particles.

Traffic-related airborne particles are associated with asthma morbidity. The aim of this study was to assess the impact of a high-efficiency particulate air (HEPA) filtration on the concentrations of traffic particles and the resultant effect on children with asthma. Forty-three children with asthma were enrolled in this double-blind, placebo-controlled crossover design. A HEPA air cleaner or a placebo "dummy" was placed in participants' homes for four weeks, interrupted by a one-month washout period, before crossing over to the other treatment arm for four weeks. Air sampling and health outcomes, including asthma control (ACQ) and quality of life (AQLQ) measures, were completed prior to and at the end of each treatment arm. Indoor concentrations of traffic particles were significantly reduced with the HEPA treatment but not with the "dummy" treatment. In participants with poorly controlled asthma and lower quality of life at baseline, ACQ and AQLQ scores were significantly improved (1.3 to 0.9, P = .003 and 4.9 to 5.5, P = .02, respectively) following the HEPA treatment. In this study, HEPA filtration is associated with improved clinical outcomes and quality of life measures in children with uncontrolled asthma.

Blunt cerebrovascular injury in the geriatric population.

OBJECTIVE: Blunt cerebrovascular injury (BCVI) is associated with high rates of neurological morbidity and mortality. The detection and management of BCVI has improved with advances in imaging and sensitive screening protocols. Few studies have explored how these injuries specifically affect the geriatric population. The purpose of this retrospective analysis was to investigate the presentation and prognosis of BCVI in the elderly population and to assess its clinical implications in the management of these patients. METHODS: All patients presenting to the University of Cincinnati (UC) level I trauma center between February 2017 and December 2019 were screened for BCVI and entered into the prospectively maintained UC Neurotrauma Registry. Patients with BCVI confirmed by CT angiography underwent retrospective chart reviews to collect information regarding demographics, positive screening criteria, cause of injury, antithrombotic agent, injury location, Denver Grading Scale, hospital and ICU length of stay, and discharge disposition. Patients were divided into geriatric (age ≥ 65 years) and adult (age < 65 years) subgroups. Continuous variables were analyzed using the Student t-test and categorical variables with the Pearson chi-square test. RESULTS: Of 124 patients with BCVI, stratification by age yielded 23 geriatric and 101 adult patients. Injury in the geriatric group was associated with significantly higher mortality (p = 0.0194). The most common cause of injury in the elderly was falls (74%, 17/23; p < 0.0001), whereas motor vehicle accidents were most common in the adult group (38%, 38/100; p = 0.0642). With respect to the location of injury, carotid (p = 0.1171) and vertebral artery (p = 0.6981) injuries did not differ significantly for the geriatric group. The adult population presented more often with Denver grade I injuries (p < 0.0001), whereas the geriatric population presented with grade IV injuries (p = 0.0247). Elderly patients were more likely to be discharged to skilled nursing facilities (p = 0.0403) and adults to home or self-care (p = 0.0148). CONCLUSIONS: This study is the first to characterize BCVI to all cervical and intracranial vessels in the geriatric population. Older age at presentation is significantly associated with greater severity, morbidity, and mortality from injury, with no preference for the particular artery injured. These findings carry important clinical implications for adapting practice in an aging population.

Tobacco smoke exposure disparities persist in U.S. children: NHANES 1999-2014.

Tobacco smoke exposure (TSE) is a common modifiable hazard to children. The objective was to investigate how the prevalence of TSE varied from 1999 to 2014 among U.S. children and to calculate differences between sociodemographic characteristics and TSE by two-year increases. We also assessed associations between sociodemographics and TSE in 2013-2014. A secondary analysis of data from the National Health and Nutrition Examination Survey 1999-2014 was performed including 14,199 children 3-11 years old from nationwide. We conducted logistic regression analyses to assess TSE trends, and associations between sociodemographics and TSE in 2013-2014. TSE prevalence declined from 64.5% to 38.1% during 1999-2014 (a relative reduction of 44.4%). TSE declined among all sociodemographics. In 2013-2014, differences in TSE were found by race/ethnicity, family monthly poverty level [FPL], and house status. Non-Hispanic black children were 1.85 times more likely (95%CI[1.39-2.47]) to be exposed to tobacco smoke than non-Hispanic white children, whereas Non-Hispanic other (OR = 0.71, 95%CI[0.52-0.96]), Hispanic other (OR = 0.42, 95%CI[0.30-0.59]), and Hispanic Mexican (OR = 0.27, 95%CI[0.21-0.35]) children were at lower risk of exposure. Compared to those in the highest FPL category (>185%), children with FPL ≤130% were 3.37 times more likely (95%CI[2.73-4.15]) and children with FPL 131-185% were 1.80 times more likely (95%CI[1.31-2.49]) to be exposed. Children who lived in rented homes were 2.23 times more likely (95%CI[1.85-2.69]) to be exposed than children who lived in owned homes. Targeted tobacco control efforts are needed to reduce existing TSE disparities among children, especially those who are non-Hispanic black, low socioeconomic status, and live in rented homes.