Effects of hypobaric hypoxia during a simulated ultra-long-haul flight on inflammation and regeneration after muscle trauma and muscle trauma-hemorrhagic shock.

INTRODUCTION/AIMS: Because wounded warfighters or trauma victims may receive en route care to the closest medical facility via airplane transport, we investigated the effects of extended mild hypobaric hypoxia (HB), the environmental milieu of most airplanes, on inflammation and regeneration after muscle trauma or monotrauma (MT) and muscle trauma-hemorrhagic shock or polytrauma (PT). METHODS: Male C57BL/6N mice were assigned to one of six groups pertaining to injury (control/uninjured, MT, and PT) and atmospheric pressure exposure (HB and normobaric normoxia, NB). Body mass, blood and muscle leukocyte number by flow cytometry, immunohistochemistry, or both, and the muscle relative mRNA level of selected genes involved in inflammation and muscle regeneration were examined at ~1.7, 4, 8, and 14 days post trauma (dpt). At 14 dpt, the proportion of smaller- and larger-sized myofibers at the regenerating site of MT mice was determined. RESULTS: Greater body mass loss, an increased number of blood and muscle leukocytes, and differential muscle relative mRNA levels were observed in MT and PT groups compared to controls. The MT+HB or PT+HB mice demonstrated more body mass loss and altered relative mRNA level than the corresponding NB mice. Additionally, a subgroup of MT+HB mice demonstrated a greater proportion of smaller myofibers (250 to 500 µm2 ) than MT+NB mice at 14 dpt. DISCUSSION: HB exposure after muscle trauma alone may prolong regeneration. Following HB exposure, therapies that promote oxygenation may be needed during this muscle recovery.

LncRNA PAINT is associated with aggressive prostate cancer and dysregulation of cancer hallmark genes.

Long noncoding RNAs (lncRNAs) play regulatory role in cellular processes and their aberrant expression may drive cancer progression. Here we report the function of a lncRNA PAINT (prostate cancer associated intergenic noncoding transcript) in promoting prostate cancer (PCa) progression. Upregulation of PAINT was noted in advanced stage and metastatic PCa. Inhibition of PAINT decreased cell proliferation, S-phase progression, increased expression of apoptotic markers, and improved sensitivity to docetaxel and Aurora kinase inhibitor VX-680. Inhibition of PAINT decreased cell migration and reduced expression of Slug and Vimentin. Ectopic expression of PAINT suppressed E-cadherin, increased S-phase progression and cell migration. PAINT expression in PCa cells induced larger colony formation, increased tumor growth and higher expression of mesenchymal markers. Transcriptome analysis followed by qRT-PCR validation showed differentially expressed genes involved in epithelial mesenchymal transition (EMT), apoptosis and drug resistance in PAINT-expressing cells. Our study establishes an oncogenic function of PAINT in PCa.

Unassisted Quitting and Smoking Cessation Methods Used in the United States: Analyses of 2010-2011 Tobacco Use Supplement to the Current Population Survey Data.

INTRODUCTION: The study estimated the prevalence of unassisted quitting (ie, quitting without pharmacological aids or other interventions) among former smokers and identified the most common smoking cessation methods used by U.S. adult smokers who quit smoking between 2007 and 2011. Among long-term quitters, smoking-related behaviors and factors associated with using pharmacological methods and quitting unassisted were examined. METHODS: The analytic sample consisted solely of former smokers, including 3,583 "long-term quitters" (those who quit 1 to 3 years prior to the survey) and 2,205 "recent quitters" (those who quit within a year prior to the survey), who responded to the 2010-2011 Tobacco Use Supplement to the Current Population Survey. RESULTS: About 72% of former smokers quit unassisted, 26% used at least one pharmacological method, and 7% used at least one nonpharmacological method. The most common pharmacological methods were the nicotine patch (12%), Chantix/Varenicline (11%), and a nicotine gum/lozenge (8%). For long-term quitters, cutting back on cigarettes gradually and relying on social support were more commonly associated with pharmacological methods. Among long-term quitters, younger adults (18 to 44 years old), Non-Hispanic Blacks, Hispanics, those who were less nicotine dependent prior to quitting and those who did not visit a doctor in the past 12 months before quitting had higher odds of reporting unassisted quitting than quitting with pharmacological methods. CONCLUSIONS: Unassisted quitting remains the predominant means of recent and long-term smoking cessation in the United States. Attempters may try different ways of quitting during the same quit attempt. IMPLICATIONS: Unassisted quitting remains a much more common method for recent and long-term smoking cessation than use of pharmacological or nonpharmacological methods. Smokers may try different ways of quitting during the same quit attempt. Thus, population-based studies that investigate the use of particular methods while ignoring other ways of quitting may overestimate the benefits of certain methods for smoking cessation.

Evidence of telescoping in regular smoking onset age.

INTRODUCTION: We examined the evidence of telescoping bias in self-reports of regular smoking onset age. Since the exact year of the onset was not available, the discrepancy (termed shift) in self-reports was explored. The study was targeted at establishing the relationships between the prevalence and the magnitude of shifting and respondent and survey characteristics and identifying the key factors contributing to forward and backward shifting. METHODS: The 2002-2003 Tobacco Use Supplement to the Current Population Survey was administered using phone and in-person interviews to the same respondents in 2002 and 2003. The regular smoking onset age, reported by current and former smokers during both years, was used. All statistical analyses incorporated replicate weights to adjust for the complex survey design. RESULTS: In our sample, about 31.6% (31.8%) of respondents forwardly (backwardly) shifted the smoking onset age, with the mean magnitude of discrepancy about 2.7 years (both directions). The elapsed time since the onset was shown to be the most important considered predictor of prevalence of shifting. The prevalence of forward (backward) shifting tends to increase (decrease) as elapsed time increases. Furthermore, the discrepancy in forwardly shifted responses tends to increase, on average, with elapsed time. CONCLUSIONS: The findings indicate that both forward and backward shifting may be prevalent in reports on smoking onset age. The extent of shifting depends on elapsed time since the onset (and therefore, the respondent's age) and other respondent and survey characteristics. The findings are consistent with presence of both forward and backward telescoping biases.

Large sample tests for simultaneous comparison to multiple controls in terms of binomial proportions.

A problem of illustrating simultaneous superiority of a certain treatment over three (or more) controls in terms of binomial proportions is considered. Applications of nine large sample intersection-union tests are discussed. The tests include the Min tests based on Wald, pooled, and Falk and Koch ( 1998 ) tests for the differences between two proportions, and their adjustments via Berger and Boos ( 1994 ) and Röhmel and Mansmann ( 1999 ) methods. Results of a large simulation study conducted to compare the proposed tests in terms of their Type I error rate and power and investigate proximity of the proposed approximate power and alternative approaches to estimate the minimum required sample size for balanced designs are discussed.

Applications of asymptotic confidence intervals with continuity corrections for asymmetric comparisons in noninferiority trials.

A large-sample problem of illustrating noninferiority of an experimental treatment over a referent treatment for binary outcomes is considered. The methods of illustrating noninferiority involve constructing the lower two-sided confidence bound for the difference between binomial proportions corresponding to the experimental and referent treatments and comparing it with the negative value of the noninferiority margin. The three considered methods, Anbar, Falk-Koch, and Reduced Falk-Koch, handle the comparison in an asymmetric way, that is, only the referent proportion out of the two, experimental and referent, is directly involved in the expression for the variance of the difference between two sample proportions. Five continuity corrections (including zero) are considered with respect to each approach. The key properties of the corresponding methods are evaluated via simulations. First, the uncorrected two-sided confidence intervals can, potentially, have smaller coverage probability than the nominal level even for moderately large sample sizes, for example, 150 per group. Next, the 15 testing methods are discussed in terms of their Type I error rate and power. In the settings with a relatively small referent proportion (about 0.4 or smaller), the Anbar approach with Yates' continuity correction is recommended for balanced designs and the Falk-Koch method with Yates' correction is recommended for unbalanced designs. For relatively moderate (about 0.6) and large (about 0.8 or greater) referent proportion, the uncorrected Reduced Falk-Koch method is recommended, although in this case, all methods tend to be over-conservative. These results are expected to be used in the design stage of a noninferiority study when asymmetric comparisons are envisioned.

Current Use of Cigarettes in the United States: The Joint Role of Race/Ethnicity and Health Insurance Coverage.

The goal of this study was to assess the joint role of race/ethnicity and a health insurance coverage type (private, Medicare, Medicaid) in current cigarette use among adults in the U.S. Data from the 2019 Tobacco Use Supplement and the 2019 Annual Social and Economic Supplement of the Current Population Survey were merged (n = 39,882). Bivariate associations between each coverage type and smoking prevalence were examined within each of six racial/ethnic groups. A multiple logistic regression model (for the odds of current cigarette use) was estimated to explore the interactions between race/ethnicity and an indicator of each type of coverage among Hispanic, non-Hispanic (NH) Black/African American, and NH White adults. All analyses included survey weights. Results of bivariate analyses indicated that private and Medicare coverage were associated with significantly lower smoking prevalence (compared to no such coverage), while Medicaid coverage was associated with significantly higher smoking prevalence (all p ≤ 0.05). Some of these associations were significant among NH Black/African American and NH White adults (all p ≤ 0.05). The model indicated that the interaction between race/ethnicity and the indicator of private coverage was significant (p = 0.044): private coverage was significantly associated with lower prevalence among NH White adults only (AOR = 0.59, 98.3%, CI = 0.46:0.76). In addition, Medicaid coverage was significantly associated with higher smoking prevalence (overall). The study points to possible racial/ethnic disparities in the quality of smoking-related health care that people with the same type of coverage receive and possible underutilization of health care services even among adults with health insurance coverage, especially among communities of color and Medicaid enrollees.

Negative impact of chronic pandemic-specific financial stress on food security among college students.

Since the pandemic started, food insecurity has become a more serious issue for U.S. college students. The study goals were to evaluate whether pandemic-specific stress contributes to current food insecurity (as of February-March of 2022) and to determine which student characteristics are associated with food insecurity. We used the 2022 Spring American College Health Association-National College Health Assessment data (n = 620) collected at a public university. We estimated two multiple logistic regression models. The odds of having very low food security (OR = 8.65, 95% CI = 4.84:15.43) and low food security (OR = 2.87, 95% CI = 1.66:4.96) were significantly higher among students whose financial situation had become a lot more stressful as a result of the pandemic (relative to the other students). Sexual and gender minority, relationship, and current tobacco use statuses were associated with very low food security. There is a need for continued efforts to decrease the negative impact of the pandemic on students' food security.

Financial stress caused by the pandemic was significantly associated with food insecurityVery low food security (VLFS) was more common among sexual and gender minority (SGM) relative to non-SGM studentsVLFS was more common among current users of tobacco relative to non-usersAbout 50% of students could not afford balanced meals occasionally or often in the last 30 days (L30D)Almost a quarter of students ever were hungry but didn't eat in the L30D because there wasn't enough money.

Correlates of COVID-19 vaccine uptake among U.S. College students.

Hesitance toward COVID-19 vaccination has greatly decreased over the course of the pandemic in the U.S. However, some populations have lower vaccination rates than the general population. This study was conducted to identify correlates of being fully vaccinated (i.e., having received all doses required to be fully vaccinated) among college students using students' responses to the 2022 Spring American College Health Association-National College Health Assessment. The surveys were administered in March of 2022. The sample (n = 617) included 18-to-30-year-old students. Firth logistic regression models were performed that controlled for age, sex assigned at birth, and food security (at a 5% significance level). The model-assisted results indicated that being a member of sexual and gender minority communities, being a graduate student, and being concerned about someone close getting COVID-19 were positively associated with being fully vaccinated, while current use of any tobacco product and current use of e-cigarettes were negatively associated with being fully vaccinated (all p-values < 0.05). In addition, the percentage of fully vaccinated students was higher among transgender/gender non-binary students (95%) than among cisgender men and women (85-87%), and among sexual minority groups (93-97%) than among heterosexual/straight students (82%). Among the racial/ethnic groups considered, the percentage of fully vaccinated students was lowest among non-Hispanic Black/African American students (77%), but the racial/ethnic differences were not statistically significant (at 5% level). The study points to a critical need for development and implementation of tailored vaccination campaigns to help students from diverse communities, including tobacco users, make informed decisions and become fully vaccinated.

Reliability of adult self-reported smoking history: data from the tobacco use supplement to the current population survey 2002-2003 cohort.

INTRODUCTION: This study examined the reliability of self-reported smoking history measures. The key measures of interest were time since completely quitting smoking among former smokers; age at which fairly regular smoking was initiated among former and current smokers; the number of cigarettes smoked per day and the number of years of daily smoking among former smokers; and never smoking. Another goal was to examine sociodemographic factors and interview method as potential predictors of the odds of strict agreement in responses. METHODS: Data from the 2002-2003 Tobacco Use Supplement to the Current Population Survey were examined. Descriptive analysis was performed to detect discrepant data patterns, and intraclass and Pearson correlations and kappa coefficients were used to assess reporting consistency over the 12-month interval. Multiple logistic regression models with replicate weights were built and fitted to identify factors influencing the logit of agreement for each measure of interest. RESULTS: All measures revealed at least moderate levels of overall agreement. However, upon closer examination, a few measures also showed some considerable differences in absolute value. The highest percentage of these differences was observed for former smokers' reports of the number of years smoking every day. CONCLUSIONS: Overall, the data suggest that self-reported smoking history characteristics are reliable. The logit of agreement over a 12-month period is shown to depend on a few sociodemographic characteristics as well as their interactions with each other and with interview method.

Simultaneous confidence bands for comparisons to placebo, with application to detecting the minimum effective dose.

In this article we consider a max-min approach to construct two-sided and one-sided simultaneous confidence bands in a dose-response study for the contrast in mean responses of each ascending dose versus placebo. The method utilizes the assumption of monotone non-decreasing dose-response curve. Also discussed is a step-down testing procedure that utilizes the lower bands to estimate the minimum effective dose (MED). The performance of our proposed step-down procedure is assessed by simulations and is shown to be superior to competitors when the MED is the lowest dose in a dose-response study.

Expected loss functions as additional measures to assess performance of multiple testing procedures for combination drug dose finding.

There are several measures that are commonly used to assess performance of a multiple testing procedure (MTP). These measures include power, overall error rate (family-wise error rate), and lack of power. In settings where the MTP is used to estimate a parameter, for example, the minimum effective dose, bias is of interest. In some studies, the parameter has a set-like structure, and thus, bias is not well defined. Nevertheless, the accuracy of estimation is one of the essential features of an MTP in such a context. In this paper, we propose several measures based on the expected values of loss functions that resemble bias. These measures are constructed to be useful in combination drug dose response studies when the target is to identify all minimum efficacious drug combinations. One of the proposed measures allows for assigning different penalties for incorrectly overestimating and underestimating a true minimum efficacious combination. Several simple examples are considered to illustrate the proposed loss functions. Then, the expected values of these loss functions are used in a simulation study to identify the best procedure among several methods used to select the minimum efficacious combinations, where the measures take into account the investigator's preferences about possibly overestimating and/or underestimating a true minimum efficacious combination. The ideas presented in this paper can be generalized to construct measures that resemble bias in other settings. These measures can serve as an essential tool to assess performance of several methods for identifying set-like parameters in terms of accuracy of estimation.

Mild hypobaric hypoxia influences splenic proliferation during the later phase of stress erythropoiesis.

Tissue trauma and hemorrhagic shock are common battlefield injuries that can induce hypoxia, inflammation, and/or anemia. Inflammation and hypoxia can initiate adaptive mechanisms, such as stress erythropoiesis in the spleen, to produce red blood cells and restore the oxygen supply. In a military context, mild hypobaric hypoxia-part of the environmental milieu during aeromedical evacuation or en route care-may influence adaptive mechanisms, such as stress erythropoiesis, and host defense. In the present study, healthy (control), muscle trauma, and polytrauma (muscle trauma and hemorrhagic shock) mice were exposed to normobaric normoxia or hypobaric hypoxia for ∼17.5 h to test the hypothesis that hypobaric hypoxia exposure influences splenic erythropoiesis and splenic inflammation after polytrauma. This hypothesis was partially supported. The polytrauma + hypobaric hypoxia group exhibited more splenic neutrophils, fewer total spleen cells, and fewer splenic proliferating cells than the polytrauma+normobaric normoxia group; however, no splenic erythroid cell differences were detected between the two polytrauma groups. We also compared splenic erythropoiesis and myeloid cell numbers among control, muscle trauma, and polytrauma groups. More reticulocytes at 1.7 days (40 h) post-trauma (dpt) and neutrophils at 4 dpt were produced in the muscle trauma mice than corresponding control mice. In contrast to muscle trauma, polytrauma led to a reduced red blood cell count and elevated serum erythropoietin levels at 1.7 dpt. There were more erythroid subsets and apoptotic reticulocytes in the polytrauma mice than muscle trauma mice at 4 and 8 dpt. At 14 dpt, the red blood cell count of the polytrauma + normobaric normoxia mice was 12% lower than that of the control + normobaric normoxia mice; however, no difference was observed between polytrauma + hypobaric hypoxia and control + hypobaric hypoxia mice. Our findings suggest muscle trauma alone induces stress erythropoiesis; in a polytrauma model, hypobaric hypoxia exposure may result in the dysregulation of splenic cells, requiring a treatment plan to ensure adequate immune functioning.

Comparison of gatekeeping and other testing methods for identifying superior drug combinations in bifactorial designs with isotonic parameters.

In this paper several multiple testing procedures are discussed with respect to the problem of detecting combination drug superiority for a bifactorial design with monotone gains. The testing methods include the generalized maximum test procedure (GMAXP) proposed by Soulakova (2009), and gatekeeping strategies: the general multistage gatekeeping method (GMGP) proposed by Dmitrienko et al. (2008a), and the serial Bonferroni gatekeeping method (TREE), proposed by Dmitrienko et al. (2007). The GMGP with the truncated Holm and Hochberg components is discussed. In addition, the truncated Sidak-Holm component is proposed, and shortcut alternatives to the GMGP are addressed. It is shown by simulations that the GMAXP achieves higher power if there are relatively many superior combinations, i.e., if the lower combinations are superior, while the gatekeeping methods perform better if there is a single or just a few superior combinations. While in some cases the GMGP with the truncated Sidak-Holm component outperforms the GMGP with the truncated Hochberg component, the observed power advantages are not substantial. Thus, the GMGP with the truncated Hochberg component is recommended as it can dominate the other methods when the Min test statistics are independent.

Three methods for constructing parallel gatekeeping procedures in clinical trials.

This paper gives a review of three classes of parallel gatekeeping procedures that can be used in clinical trials with multiple objectives grouped into two or more families. We begin with a high-level summary of three methods for building parallel gatekeeping procedures proposed in the literature and provide a detailed comparison of the three methods. The comparison is based on analytical arguments as well as simulation studies and helps us develop general recommendations on the use of these methods in clinical trial applications. The methods discussed in this paper are illustrated using clinical trial examples with two families of objectives.

Design-based single-mediator approach for complex survey data.

We discuss a two-step approach to test for a mediated effect using data gathered via complex sampling. The approach incorporates design-based multiple linear regressions and a generalized Sobel's method to test for significance of a mediated effect. We illustrate the applications to a study of nicotine dependence, race/ethnicity and cigarette purchase price among daily smokers in the U.S. The study goal was to assess significance of cigarette purchase price as a mediator in the association between race/ethnicity (non-Hispanic Black/African American, non-Hispanic White) and nicotine dependence measured in terms of the average number of cigarettes smoked per day. The single-mediator model incorporated 18 covariates as control factors. The results indicated a significant mediated effect of cigarette purchase price on the association. However, the relative effect size of 5% indicated low practical significance of the cigarette purchase price as a mediator in the association between race/ethnicity and nicotine dependence. The approach can be modified to studies where data are gathered via other types of complex sampling.

Smokers' reports on receiving a doctor's advice to quit smoking; receiving the advice is more prevalent among smokers with Crohn's Disease relative to smokers with Ulcerative Colitis.

Receiving a doctor's advice to quit smoking is an important predictor for improving smokers' intentions to quit smoking and successful smoking cessation. We examined reports of smokers with Crohn's Disease (CD) and Ulcerative Colitis (UC) regarding receiving a doctor's advice to quit smoking in the past 12 months, and evaluated the differences in the rates of receiving the advice between the CD and UC patients. The data were retrospectively reported by CD and UC patients (n = 453) who self-identified as current smokers in online assessments conducted by IBD Partners in the period from 2011 to 2014 in the USA. Statistical methods included chi-square tests and a multiple logistic regression model for the logit of the probability of receiving the advice as a function of patient's characteristics and assessment year. Overall, about 77% of smokers reported receiving a doctor's advice to quit smoking. The percentage was significantly (p < 0.001) higher among smokers with CD (80%) than it was among smokers with UC (63%). While the specific differences by CD/UC depended on smoking initiation age, the overall effect of disease type on the odds of receiving the advice remained significant: the odds of receiving the advice were higher for smokers with CD relative to smokers with UC (OR = 3.6, p < 0.001). Although the majority of CD and UC patients report receiving a doctor's advice to quit smoking, the encountered difference associated with the disease type is concerning. Because long-term smoking increases cancer and mortality risks, doctors should address smoking cessation with all patients who smoke.

On identifying effective and superior drug combinations via Holm's procedure based on the min tests.

In this paper I consider a problem of identifying all effective and superior drug combinations. I formulate this problem in terms of a family of hypotheses and propose a two-stage method to solve it. The first stage uses individual p-values obtained via the Min tests, whereas Holm's approach is employed in the second stage to draw simultaneous inferences. This procedure is shown to control the family-wise error rate in a strong sense. The performance of the procedure is studied by simulation for different parameter settings. The conclusions of the simulation study are stated in terms of the power, family-wise error rate and lack of power.

Multimediation Method With Balanced Repeated Replications For Analysis Of Complex Surveys.

We propose a method suitable for analysis of cross-sectional studies with complex sampling and continuous variables. The method consists of R+4 steps, where R denotes the number of replications. In the first R+1 steps, the main and R replicate weights are used (one at a time) to estimate the product of coefficients for all mediation effects using a structural equation model. In step R+2, the standard errors of these estimates are computed via balanced repeated replications. In step R+3, the raw p-values corresponding to mediation effects are computed based on the generalized Sobel's tests. In the final step, R+4, the p-values are adjusted for multiplicity and statistical inferences regarding mediation effects are drawn. To illustrate the approach we examined significance of attitudes toward smoking bans as mediators in the association between smoking restrictions at work and nicotine dependence among male daily smokers.

Workplace smoking restrictions and support for smoking cessation in the USA: state, region, and overall trends from 2010-11 to 2014-15.

We discuss the most recent changes in smoking policies and support for smoking cessation offered to smokers at US workplaces. We used reports of employed adults (n = 112,008) regarding smoking restrictions and support for smoking cessation offered at their indoor workplaces from the 2010-11 and 2014-15 Tobacco Use Supplement-Current Population Survey. The percentage of adults who reported having workplace smoking restrictions was 94% in 2010-11 and 93% in 2014-15 (P = 0.001). There was a decrease in the Northeastern region (P < 0.001) and no significant changes in the other three US regions. The percentages decreased in Hawaii, New York, Oregon, Pennsylvania, and Tennessee and increased in Indiana, Nebraska, and Wyoming. The percentage of employees who reported having workplace support for smoking cessation increased from 24% to 29% (P < 0.001), which was uniform across all US regions but differed across the US states. The percentages decreased in Hawaii and increased in the majority of states. Analysis of smokers' reports (versus all reports) resulted in lower percentages of workplaces with smoking restrictions and support for smoking cessation. It is essential to further enhance support for smoking cessation offered to smokers at US workplaces.