Fractional exhaled nitric oxide in the assessment of exercise-induced bronchoconstriction: A multicenter retrospective analysis of UK-based athletes.

INTRODUCTION: Exercise-induced bronchoconstriction (EIB) is not only highly prevalent in people with asthma, but can also occur independently, particularly in athletes. Fractional exhaled nitric oxide (FeNO) is an indirect biomarker of type 2 airway inflammation that has an established role in the assessment and management of asthma. The aim was to evaluate the value of FeNO in the assessment of EIB in athletes. METHOD: Multicenter retrospective analysis. In total, 488 athletes (male: 76%) performed baseline FeNO, and spirometry pre- and post-indirect bronchial provocation via eucapnic voluntary hyperpnea (EVH). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for established FeNO thresholds-that is, intermediate (≥25 ppb) and high FeNO (≥40 ppb and ≥ 50 ppb)-and were evaluated against objective evidence of EIB (≥10% fall in FEV1 ). The diagnostic accuracy of FeNO was calculated using receiver operating characteristics area under the curve (ROC-AUC). RESULTS: Thirty-nine percent of the athletes had a post-EVH fall in FEV1 consistent with EIB. FeNO values ≥25 ppb, ≥40 ppb, and ≥ 50 ppb were observed in 42%, 23%, and 17% of the cohort, respectively. The sensitivity of FeNO ≥25 ppb was 55%, which decreased to 37% and 27% at ≥40 ppb and ≥ 50 ppb, respectively. The specificity of FeNO ≥25 ppb, ≥40 ppb, and ≥ 50 ppb was 66%, 86%, and 89%, respectively. The ROC-AUC for FeNO was 0.656. CONCLUSIONS: FeNO ≥40 ppb provides good specificity, that is, the ability to rule-in a diagnosis of EIB. However, due to the poor sensitivity and predictive values, FeNO should not be employed as a replacement for indirect bronchial provocation in athletes.

Associations Between Anxiety and Home Learning Difficulties in Children and Adolescents with ADHD During the COVID-19 Pandemic.

The COVID-19 pandemic has markedly impacted functioning for children and adolescents including those with attention-deficit/hyperactivity disorder (ADHD). We explored home learning difficulties (HLD) during COVID-19 restrictions in Australian children (aged 5-17) with ADHD, aiming to: (1) describe home learning experiences, and (2) examine associations between child anxiety (i.e., concurrent anxiety symptoms and pre-existing anxiety disorder status) and HLD. Baseline data from the longitudinal ADHD COVID-19 Survey were used (n = 122). Parents reported on school factors and HLD; pre-existing anxiety and co-occurring difficulties; anxiety, ADHD, and oppositional symptoms; demographics; and medications. Parents retrospectively reported more children often looked forward to school pre-pandemic, than during the pandemic. Anxiety symptoms, but not pre-existing anxiety disorder status, were associated with HLD after accounting for covariates. ADHD inattention symptoms were also associated with HLD. Results support recommendations to continue pre-pandemic supports to assist with ADHD symptoms during home learning, and strategies/supports for families are discussed.

Digital Health Interventions for Delivery of Mental Health Care: Systematic and Comprehensive Meta-Review.

BACKGROUND: The COVID-19 pandemic has shifted mental health care delivery to digital platforms, videoconferencing, and other mobile communications. However, existing reviews of digital health interventions are narrow in scope and focus on a limited number of mental health conditions. OBJECTIVE: To address this gap, we conducted a comprehensive systematic meta-review of the literature to assess the state of digital health interventions for the treatment of mental health conditions. METHODS: We searched MEDLINE for secondary literature published between 2010 and 2021 on the use, efficacy, and appropriateness of digital health interventions for the delivery of mental health care. RESULTS: Of the 3022 records identified, 466 proceeded to full-text review and 304 met the criteria for inclusion in this study. A majority (52%) of research involved the treatment of substance use disorders, 29% focused on mood, anxiety, and traumatic stress disorders, and >5% for each remaining mental health conditions. Synchronous and asynchronous communication, computerized therapy, and cognitive training appear to be effective but require further examination in understudied mental health conditions. Similarly, virtual reality, mobile apps, social media platforms, and web-based forums are novel technologies that have the potential to improve mental health but require higher quality evidence. CONCLUSIONS: Digital health interventions offer promise in the treatment of mental health conditions. In the context of the COVID-19 pandemic, digital health interventions provide a safer alternative to face-to-face treatment. However, further research on the applications of digital interventions in understudied mental health conditions is needed. Additionally, evidence is needed on the effectiveness and appropriateness of digital health tools for patients who are marginalized and may lack access to digital health interventions.

Evidence of immunometabolic dysregulation and airway dysbiosis in athletes susceptible to respiratory illness.

BACKGROUND: Respiratory tract infection (RTI) is a leading cause of training and in-competition time-loss in athlete health. The immune factors associated with RTI susceptibility remain unclear. In this study, we prospectively characterise host immune factors in elite athletes exhibiting RTI susceptibility. METHODS: Peripheral blood lymphocyte flow cytometry phenotyping and 16S rRNA microbial sequencing of oropharyngeal swabs was performed in a prospective elite athlete cohort study (n = 121). Mass cytometry, peripheral blood mononuclear cell (PBMC) stimulation and plasma metabolic profiling was performed in age-matched highly-susceptible (HS) athletes (≥4RTI in last 18 months) (n = 22) compared to non-susceptible (NS) (≤1RTI in last 18 months) (n = 23) athletes. Findings were compared to non-athletic healthy controls (HC) (n = 19). FINDINGS: Athletes (n = 121) had a reduced peripheral blood memory T regulatory cell compartment compared to HC (p = 0.02 (95%CI:0.1,1.0)) and reduced upper airway bacterial biomass compared to HC (p = 0.032, effect size r = 0.19). HS athletes (n = 22) had lower circulating memory T regulatory cells compared to NS (n = 23) athletes (p = 0.005 (95%CI:-1.5,-0.15)) and HC (p = 0.002 (95%CI:-1.9,-0.3) with PBMC microbial stimulation assays revealing a T-helper 2 skewed immune response compared to HC. Plasma metabolomic profiling showed differences in sphingolipid pathway metabolites (a class of lipids important in infection and inflammation regulation) in HS compared to NS athletes and HC, with sphingomyelin predictive of RTI infection susceptibility (p = 0.005). INTERPRETATION: Athletes susceptible to RTI have reduced circulating memory T regulatory cells, metabolic dysregulation of the sphingolipid pathway and evidence of upper airway bacterial dysbiosis. FUNDING: This study was funded by the English Institute of Sport (UK).

A preliminary examination of key strategies, challenges, and benefits of remote learning expressed by parents during the COVID-19 pandemic.

Among the many impacts of the Coronavirus disease (COVID-19) pandemic, one of the most dramatic was the immediate closure of in-person schooling in March/April 2020 when parents were faced with much greater responsibility in supporting their children's learning. Despite this, few studies have examined parents' own perspectives of this experience. The aims of this preliminary study were to (a) identify challenges, benefits, and useful strategies related to remote learning and (b) examine differences in findings across two countries, between parents of youth with and without attention-deficit/hyperactivity disorder (ADHD), and between parents of children and adolescents. To address these aims, parent responses to open-ended questions on the Home Adjustment to COVID-19 Scale (HACS; Becker, Breaux, et al., 2020) were examined across three studies conducted in the United States and Australia (N = 606, children: 68.5% male, ages 6-17 years). The challenges most frequently expressed by parents included the child's difficulty staying on task (23.8% of parents), lack of motivation (18.3%), remote learning factors (17.8%), and lack of social interaction (14.4%). The most frequently expressed strategy related to using routines and schedules (58.2%) and the biggest benefit was more family time (20.3%). Findings were largely consistent across countries, ADHD status, and age, with a few notable group differences. Given that the most common challenges involved child- (e.g., difficulties with staying on task and motivation), parent- (e.g., balancing remote learning with work responsibilities), and school- (e.g., remote instruction difficulties) related factors, there is a need for improved support across these systems going forward. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Physical Health, Media Use, and Mental Health in Children and Adolescents With ADHD During the COVID-19 Pandemic in Australia.

OBJECTIVE: To examine the impact of COVID-19 restrictions among children with attention-deficit/hyperactivity disorder (ADHD). METHODS: Parents of 213 Australian children (5-17 years) with ADHD completed a survey in May 2020 when COVID-19 restrictions were in place (i.e., requiring citizens to stay at home except for essential reasons). RESULTS: Compared to pre-pandemic, children had less exercise (Odds Ratio (OR) = 0.4; 95% CI 0.3-0.6), less outdoor time (OR = 0.4; 95% 0.3-0.6), and less enjoyment in activities (OR = 6.5; 95% CI 4.0-10.4), while television (OR = 4.0; 95% CI 2.5-6.5), social media (OR = 2.4; 95% CI 1.3-4.5), gaming (OR = 2.0; 95% CI 1.3-3.0), sad/depressed mood (OR = 1.8; 95% CI 1.2-2.8), and loneliness (OR = 3.6; 95% CI 2.3-5.5) were increased. Child stress about COVID-19 restrictions was associated with poorer functioning across most domains. Most parents (64%) reported positive changes for their child including more family time. CONCLUSIONS: COVID-19 restrictions were associated with both negative and positive impacts among children with ADHD.

Correlated Population Genetic Structure in a Three-Tiered Host-Parasite System: The Potential for Coevolution and Adaptive Divergence.

Three subspecies of Northern Bahamian Rock Iguanas, Cyclura cychlura, are currently recognized: C. c. cychlura, restricted to Andros Island, and C. c. figginsi and C. c. inornata, native to the Exuma Island chain. Populations on Andros are genetically distinct from Exuma Island populations, yet genetic divergence among populations in the Exumas is inconsistent with the 2 currently recognized subspecies from those islands. The potential consequences of this discrepancy might include the recognition of a single subspecies throughout the Exumas rather than 2. That inference also ignores evidence that populations of C. cychlura are potentially adaptively divergent. We compared patterns of population relatedness in a three-tiered host-parasite system: C. cychlura iguanas, their ticks (genus Amblyomma, preferentially parasitizing these reptiles), and Rickettsia spp. endosymbionts (within tick ectoparasites). Our results indicate that while C. c. cychlura on Andros is consistently supported as a separate clade, patterns of relatedness among populations of C. c. figginsi and C. c. inornata within the Exuma Island chain are more complex. The distribution of the hosts, different tick species, and Rickettsia spp., supports the evolutionary independence of C. c. inornata. Further, these patterns are also consistent with two independent evolutionarily significant units within C. c. figginsi. Our findings suggest coevolutionary relationships between the reptile hosts, their ectoparasites, and rickettsial organisms, suggesting local adaptation. This work also speaks to the limitations of using neutral molecular markers from a single focal taxon as the sole currency for recognizing evolutionary novelty in populations of endangered species.

Screening Identifies Suboptimal Vaccination Protection in Illness-Susceptible Elite Athletes.

OBJECTIVE: Some groups of elite athletes have an apparent increased susceptibility to respiratory tract infection (RTI) with implications for their health and athletic performance. In this study, we aim to systemically evaluate vaccine response patterns as a potentially efficacious intervention strategy in elite athletes preparing for Olympic competition. DESIGN: Cross-sectional observational study. SETTING: A UK Sport-funded Olympic training program. PATIENTS: One hundred twenty elite athletes and 10 matched healthy controls were studied. A subset of athletes were classified as RTI highly susceptible (n = 22), RTI nonsusceptible (n = 23), and asthmatic (n = 33), with matched controls also recruited (n = 10, 27 ± 3 years). INTERVENTIONS/OUTCOME MEASURE: Serum samples were analysed from participants analysing enzyme-linked immunosorbent assay for Immunoglobulin G (IgG) responses against measles, mumps, rubella, and pneumococcus vaccines. RESULTS: Although a majority of athletes (>90%) had detectable IgG levels against measles and rubella, only 76% had detectable mumps responses, with similar findings apparent in controls. Of those RTI-susceptible and asthmatic athletes, 22% had suboptimal antipneumococcal responses below 30 mg/L. CONCLUSION: A significant proportion of elite athletes preparing for Olympic competition seem to be at risk of mumps infection. In addition, RTI-susceptible and asthmatic athletes exhibit suboptimal pneumococcal antibody responses, highlighting a need for prospective immune screening in athletes to ensure vaccination strategies are effectively delivered.

Diagnosis and Treatment of Pericardial Effusions.

A pericardial effusion is an atypical accumulation of fluid in the pericardial space. It has many potential causes, including cardiac or renal failure, trauma, surgical complications, and myocardial infarctions. Medical imaging aids in diagnosing and determining the cause of pericardial effusions. Echocardiography is the first imaging choice when pericardial effusions are suspected, but cross-sectional computed tomography (CT) and cardiac magnetic resonance (MR) imaging also have important roles. This article discusses the causes and types of pericarditis as well as the advantages of echocardiography, CT, and cardiac MR imaging for diagnosing pericardial effusions. Treatment options and complications also are discussed.

The benefits of a systematic assessment of respiratory health in illness-susceptible athletes.

Respiratory tract illness is a leading cause of training and in-competition time loss in elite athletes. Asthma is known to be prevalent in athletes, but the coexistence of other respiratory problems in those deemed to be susceptible to respiratory tract illness is unknown. The aim of this study was to apply a comprehensive prospective approach to identify respiratory problems and explore relationships in athletes with heightened respiratory illness susceptibility.UK World Class Performance Programme athletes prospectively completed a systematic review of respiratory health with validated questionnaires and respiratory-focused investigations, including studies of nasal flow, exhaled nitric oxide, spirometry, bronchoprovocation testing and allergy testing.Systematic respiratory health assessment was completed by 122 athletes (55 females, mean±sd age 24±4 years). At least one respiratory health issue, requiring intervention, was identified in 97 (80%) athletes and at least two abnormalities were found in 73 (60%). Sinonasal problems were the most commonly identified problem (49%) and 22% of athletes had a positive indirect bronchoprovocation test. Analysis revealed two respiratory health clusters: 1) asthma, sinus problems and allergy; and 2) laryngeal and breathing pattern dysfunction. Respiratory illness susceptible athletes had 3.6±2.5 episodes in the year prior to assessment and were more likely to have allergy (OR 2.6, 95% CI 1.0-6.5), sinonasal problems (2.6, 1.1-6.0) and symptoms of laryngeal (5.4, 1.8-16.8) and breathing pattern dysfunction (3.9, 1.1-14.0) than nonsusceptible athletes (all p<0.05).A systematic approach to respiratory assessment identifies a high prevalence and coexistence of multiple respiratory problems in illness-susceptible athletes.

The impact of a heat and moisture exchange mask on respiratory symptoms and airway response to exercise in asthma.

Respiratory symptoms, including cough, are prevalent in individuals with asthma when exercising. This study investigates whether a heat and moisture exchanger (HME) face mask is effective in modulating exercise-induced bronchoconstriction (EIB) and post-exercise cough in a cold, dry environment in individuals with asthma. Twenty-six participants diagnosed with asthma (20 males, 6 females) completed three cycling exercise challenges at 8°C and 24% relative humidity in a randomised order. Participants wore either an HME mask (MASK), sham mask (SHAM), or no mask (CONT). Following a 3-min warm-up, participants completed 6-min cycling at 80% peak power output. Before and after exercise, maximal flow-volume loops were recorded. Post-exercise cough was monitored with a Leicester Cough Monitor (LCM) for 24 h. Results were analysed using repeated-measures ANOVA and Friedman's tests and data were presented as the mean±sd or median (interquartile range (IQR)). Eleven participants failed to demonstrate EIB (i.e. >10% fall in forced expiratory volume in 1 s after exercise) and were removed from analysis. The percentage fall in forced expiratory volume in 1 s following exercise in CONT was greater than MASK (MASK: -6% (7%), SHAM: -11% (11%), CONT: -13% (9%); p<0.01). No difference was found between exercise in cough count per hour over the 24-h monitoring period or the number of coughs in the first hour after exercise. HME masks can attenuate EIB when exercising in cold, dry environments. The SHAM mask may not have been entirely inert, demonstrating the challenges of running randomised control trials utilising control and sham conditions.

Food Insecurity Among College Students with and without Medical Disorders at a University in Appalachia.

Objective: This study compared severity of food insecurity, characteristics, and behaviors of college students with and without diagnosed medical disorders. Design: Data were collected using a cross-sectional online questionnaire. Variables measured were food security status, disorders, coping strategies, and perceived barriers to food access. Descriptive and inferential statistics examined associations and compared groups. Statistical significance was p≤0.05. Setting: Data were collected at Appalachian State University in North Carolina. Participants: The sample was 247 food insecure students, of whom 60% were females, 50% 3rd- and 4th-year students, and 75% whites. Results: Medical disorders were reported by 67.2% of food insecure students, and a greater proportion of students with than without disorders experienced very low food security (63.3% vs. 43.2%, p=0.003). The most common disorder categories were psychiatric (40.5%) and gastrointestinal (31.6%). Characteristics of food insecure students with disorders included female gender, suboptimal academic performance, employed, off-campus residence. Coping strategies used by students with and without disorders, respectively, to improve food access, included brought food back to school after visiting family, friends, significant others (90.9% vs. 63.0%) and ate less healthy food so you could eat more (77.7% vs. 49.4%). Perceived barriers among students with disorders included feel overwhelmed making food choices (12.7%) and meal plan runs out (10.2%). Food insecure students with disorders made greater use of coping strategies and identified more perceived barriers. Conclusions: Food insecure students with disorders experienced more severe food deprivation and require multidimensional food assistance programs beyond those generally available on college campuses.

Use of Biosimilar Granulocyte Colony-Stimulating Factor for Mobilization in Autologous and Allogeneic Hematopoietic Stem Cell Transplantation.

The biologic medication filgrastim is approved by the Food and Drug Administration (FDA) to mobilize hematopoietic progenitor cells (HPCs) for collection by leukapheresis for autologous hematopoietic stem cell transplant (HSCT). The FDA-approved biologic tbo-filgrastim is currently used off-label for this indication in both autologous and allogeneic HSCT at the Tennessee Valley Healthcare System. The purpose of this review is to compare the efficacy of filgrastim and tbo-filgrastim for this indication. The primary outcomes were the proportion of autologous patients and allogeneic donors with a CD34+ count ≥15 × 103 cells/uL on day 4 of filgrastim or tbo-filgrastim mobilization. The secondary outcome was the use of plerixafor in the autologous population. A total of 469 subjects were identified for inclusion; 367 underwent mobilization for autologous HSCT and 102 for allogeneic HSCT donation. The primary outcome was achieved in 47.5% of patients who received filgrastim compared to 50.2% who received tbo-filgrastim in the autologous population (p = 0.67). Among donors for allogeneic HSCT, there was no difference between those eligible for collection on day 4 of filgrastim or tbo-filgrastim administration (97.6% vs. 100%, p = 0.41). No significant difference was identified in the number of patients requiring plerixafor use in the autologous HSCT population. The use of the biosimilar tbo-filgrastim for mobilization in either autologous HSCT patients or allogeneic HSCT donors has comparable outcomes to that of the biotherapeutic reference product filgrastim at a reduced cost to the healthcare system.

The complete mitochondrial genome of the critically endangered Lesser Antillean iguana (Iguana delicatissima; Squamata: Iguanidae).

The Lesser Antillean iguana, Iguana delicatissima Laurenti 1768, is one of the most endangered vertebrate taxa in the West Indies. This species faces significant threats, including introgressive hybridization with the introduced congener Iguana iguana. We deploy a combination of off-target sequence capture obtained from Illumina® reads and targeted Sanger reads to assemble the mitochondrial genome of I. delicatissima. The mitogenome is 16,616 bp in length and is comprised of 13 protein-coding genes, two ribosomal subunits (rRNAs), 22 transfer RNAs, and a control region. Gene order is identical to that of congener I. iguana and other closely related taxa, absent of any tandem repeat regions. We show the phylogenetic utility of the mitogenome with a maximum-likelihood analysis, which yields a topology concordant with previous studies of iguanine taxa. We are hopeful that this genomic resource will be useful in further informing applied conservation and management for this critically endangered species.

Impact of detecting and treating exercise-induced bronchoconstriction in elite footballers.

Our aim was to evaluate the prevalence of exercise-induced bronchoconstriction (EIB) in elite football players and assess subsequent impact of therapy on airway health and exercise performance. 97 male professional football players completed an airway health assessment with a eucapnic voluntary hyperpnoea (EVH) challenge to diagnose EIB. Players demonstrating a positive result (EVH+) were prescribed inhaler therapy depending on severity, including inhaled corticosteroids and inhaled short-acting ß2-agonists, and underwent repeat assessment after 9 weeks of treatment. Eight players (EVH+ n=3, EVH- n=5) completed a peak oxygen uptake (V'O2peak) test at initial and follow-up assessment. Out of the 97 players, 27 (28%) demonstrated a positive EVH result. Of these, 10 had no prior history (37%) of EIB or asthma. EVH outcome was not predictable by respiratory symptoms. Seven (24%) of the 27 EVH+ players attended follow-up and demonstrated improved post-challenge spirometry (forced expiratory volume in 1 s pre-test -22.9±15.4%, post-test -9.0±1.6%; p=0.018). At follow-up V'O2peak improved by 3.4±2.9 mL·kg-1·min-1 in EVH+ players compared to 0.1±2.3 mL·kg-1·min-1 in EVH- players. Magnitude of inference analysis indicated treatment was possibly beneficial (74%) for exercise capacity. Elite football players have a high EIB prevalence. Treatment with inhaler therapy reduces EIB severity.

Aripiprazole for Post-traumatic Stress Disorder: A Systematic Review.

OBJECTIVE: The aim of this study was to review the safety and efficacy of aripiprazole as monotherapy and adjunct therapy for the treatment of post-traumatic stress disorder (PTSD). METHODS: A search of both MEDLINE (1956 to May 2017) and EMBASE (1957 to May 2017) was conducted using the terms "aripiprazole" and "post-traumatic stress disorder," "posttraumatic stress disorder," or "PTSD." Studies evaluating the primary endpoint of PTSD in patients taking aripiprazole as monotherapy or adjunct therapy were analyzed for relevance. Those that met the objective of this study were included for evaluation: 1 placebo-controlled trial; 4 open-label trials; and 1 retrospective chart review. RESULTS: In patients with a history of PTSD, aripiprazole resulted in significant improvements in the primary outcome, including Clinician-Administered PTSD Symptom Scale or PTSD Checklist-Military scores, in all but 1 study analyzed. Study durations ranged from 10 to 16 weeks. Initial doses of aripiprazole ranged from 2 to 15 mg daily that could be titrated up or down in the range of 2 to 30 mg daily based on efficacy and tolerability. Overall, aripiprazole was well tolerated with the most common treatment-related study discontinuations attributed to the adverse events of anxiety, insomnia, akathisia, asthenia, restlessness, and somnolence. CONCLUSIONS: Based on the reviewed literature, aripiprazole is a reasonable therapy option as monotherapy or adjunct therapy in patients with PTSD. Larger randomized controlled trials are needed to better understand the role of this atypical antipsychotic in patients with PTSD.

MEDEX2015: Greater Sea-Level Fitness Is Associated with Lower Sense of Effort During Himalayan Trekking Without Worse Acute Mountain Sickness.

Rossetti, Gabriella M.K., Jamie H. Macdonald, Matthew Smith, Anna R. Jackson, Nigel Callender, Hannah K. Newcombe, Heather M. Storey, Sebastian Willis, Jojanneke van den Beukel, Jonathan Woodward, James Pollard, Benjamin Wood, Victoria Newton, Jana Virian, Owen Haswell, and Samuel J. Oliver. MEDEX2015: Greater sea-level fitness is associated with lower sense of effort during Himalayan trekking without worse acute mountain sickness. High Alt Med Biol. 18:152-162, 2017.-This study examined the complex relationships of fitness and hypoxic sensitivity with submaximal exercise responses and acute mountain sickness (AMS) at altitude. Determining these relationships is necessary before fitness or hypoxic sensitivity tests can be recommended to appraise individuals' readiness for altitude. Forty-four trekkers (26 men; 18 women; 20-67 years) completed a loaded walking test and a fitness questionnaire in normoxia to measure and estimate sea-level maximal aerobic capacity (maximum oxygen consumption [[Formula: see text]O2max]), respectively. Participants also completed a hypoxic exercise test to determine hypoxic sensitivity (cardiac, ventilatory, and arterial oxygen saturation responses to acute hypoxia, fraction of inspired oxygen [Fio2] = 0.112). One month later, all participants completed a 3-week trek to 5085 m with the same ascent profile. On ascent to 5085 m, ratings of perceived exertion (RPEascent), fatigue by Brunel Mood Scale, and AMS were recorded daily. At 5085 m, RPE during a fixed workload step test (RPEfixed) and step rate during perceptually regulated exercise (STEPRPE35) were recorded. Greater sea-level [Formula: see text]O2max was associated with, and predicted, lower sense of effort (RPEascent; r = -0.43; p < 0.001; RPEfixed; r = -0.69; p < 0.001) and higher step rate (STEPRPE35; r = 0.62; p < 0.01), but not worse AMS (r = 0.13; p = 0.4) or arterial oxygen desaturation (r = 0.07; p = 0.7). Lower RPEascent was also associated with better mood, including less fatigue (r = 0.57; p < 0.001). Hypoxic sensitivity was not associated with, and did not add to the prediction of submaximal exercise responses or AMS. In conclusion, participants with greater sea-level fitness reported less effort during simulated and actual trekking activities, had better mood (less fatigue), and chose a higher step rate during perceptually regulated exercise, but did not suffer from worse AMS or arterial oxygen desaturation. Simple sea-level fitness tests may be used to aid preparation for high-altitude travel.

Case study on the utility of hepatic global gene expression profiling in the risk assessment of the carcinogen furan.

Furan is a chemical hepatocarcinogen in mice and rats. Its previously postulated cancer mode of action (MOA) is chronic cytotoxicity followed by sustained regenerative proliferation; however, its molecular basis is unknown. To this end, we conducted toxicogenomic analysis of B3C6F1 mouse livers following three week exposures to non-carcinogenic (0, 1, 2mg/kgbw) or carcinogenic (4 and 8mg/kgbw) doses of furan. We saw enrichment for pathways responsible for cytotoxicity: stress-activated protein kinase (SAPK) and death receptor (DR5 and TNF-alpha) signaling, and proliferation: extracellular signal-regulated kinases (ERKs) and TNF-alpha. We also noted the involvement of NF-kappaB and c-Jun in response to furan, which are genes that are known to be required for liver regeneration. Furan metabolism by CYP2E1 produces cis-2-butene-1,4-dial (BDA), which is required for ensuing cytotoxicity and oxidative stress. NRF2 is a master regulator of gene expression during oxidative stress and we suggest that chronic NFR2 activity and chronic inflammation may represent critical transition events between the adaptive (regeneration) and adverse (cancer) outcomes. Another objective of this study was to demonstrate the applicability of toxicogenomics data in quantitative risk assessment. We modeled benchmark doses for our transcriptional data and previously published cancer data, and observed consistency between the two. Margin of exposure values for both transcriptional and cancer endpoints were also similar. In conclusion, using furan as a case study we have demonstrated the value of toxicogenomics data in elucidating dose-dependent MOA transitions and in quantitative risk assessment.

Differential expression of long noncoding RNAs in the livers of female B6C3F1 mice exposed to the carcinogen furan.

The mammalian genome is transcribed into mRNAs that code for protein and a broad spectrum of other noncoding (nc) RNA products. Long ncRNAs (lncRNA), defined as ncRNA species > 200 nucleotides long, are emerging as important epigenetic regulators of gene expression that are involved in a spectrum of biological processes of relevance to toxicology. We conducted a gene expression profiling study in the livers of female B6C3F1 mice exposed to the carcinogen furan at 0.0, 1.0, and 2.0mg/kg (noncarcinogenic doses) and at 4.0 and 8.0mg/kg (carcinogenic doses) for 3 weeks. LncRNA differential expression showed a nonlinear dose response with none differentially expressed at 1.0 or 2.0mg/kg, 2 lncRNAs at 4.0mg/kg furan, and 83 at 8mg/kg, representing 13.3% (83/632) of the total number of differentially expressed transcripts. Among the lncRNAs observed, two lncRNAs examined showed transcriptional clustering with nearby protein-coding genes. LincRNA-p21 is an antisense transcript that is 15kb downstream from Cdkn1a locus and appears to be cotranscribed with the protein coding gene Cdkn1a at 8.0mg/kg furan. In a separate independent study, RNA samples from the livers of mice administered benzo(a)pyrene also demonstrated increased levels of Cdkn1a and the antisense lincRNA-p21 transcript. These data demonstrate that lncRNAs are transcriptional targets of furan exposures associated with levels of furan that are cytotoxic and induce cell proliferation. In addition, certain lncRNA transcripts are associated with the expression of nearby coding protein genes. We hypothesize that lncRNAs have potential as epigenetic biomarkers of carcinogenic exposures.