Clinical Factors Influencing Endogenous Carbon Monoxide Production and Carboxyhemoglobin Levels in Neonates.

Carboxyhemoglobin (COHb) is an index of endogenous carbon monoxide formation during the hem degradation process and could be used to confirm hemolysis in neonates. The influence of other clinical factors on COHb values in neonates has not been fully investigated. We aimed to evaluate the influence of hemolysis, sepsis, respiratory distress, and postnatal age on COHb values. We retrospectively analyzed COHb measurements determined with a carbon monoxide-oximeter in 4 groups of term neonates: A-sepsis, B-respiratory distress, C-hemolysis, and D-healthy neonates. The mean COHb values were 1.41% (SD: 0.26), 1.32% (SD: 0.27), 2.5% (SD: 0.69), and 1.27% (SD: 0.19) (P<0.001) in groups A (n=8), B (n=37), C (n=16), and D (n=76), respectively. COHb in group C was significantly higher than in the other groups. There was a negative correlation between postnatal age and COHb in healthy neonates. A cut-off level of 1.7% had 93% (95% confidence interval [CI]: 89%-97%) sensitivity and 94% (95% CI: 90%-98%) specificity for diagnosis of hemolysis. COHb values were higher during the first days of life. We found that COHb levels in neonates with hemolysis were significantly higher and that the influence of sepsis and respiratory distress on COHb values was insignificant.

Secondary polycythemia in chronic obstructive pulmonary disease: prevalence and risk factors.

BACKGROUND: Secondary polycythemia is associated with cigarette smoking and chronic obstructive pulmonary disease (COPD). However, the prevalence of polycythemia in COPD and the contributing risk factors for polycythemia in COPD have not been extensively studied. METHODS: We analyzed the presence of secondary polycythemia in current and former smokers with moderate to very severe COPD at the five-year follow-up visit in the observational COPDGene study. We used logistic regression to evaluate the association of polycythemia with age, sex, race, altitude, current smoking status, spirometry, diffusing capacity for carbon monoxide (DLCO), quantitative chest CT measurements (including emphysema, airway wall thickness, and pulmonary artery to aorta diameter ratio), resting hypoxemia, exercise-induced hypoxemia, and long-term oxygen therapy. RESULTS: In a total of 1928 COPDGene participants with moderate to very severe COPD, secondary polycythemia was found in 97 (9.2%) male and 31 (3.5%) female participants. In a multivariable logistic model, severe resting hypoxemia (OR 3.50, 95% CI 1.41-8.66), impaired DLCO (OR 1.28 for each 10-percent decrease in DLCO % predicted, CI 1.09-1.49), male sex (OR 3.60, CI 2.20-5.90), non-Hispanic white race (OR 3.33, CI 1.71-6.50), current smoking (OR 2.55, CI 1.49-4.38), and enrollment in the Denver clinical center (OR 4.42, CI 2.38-8.21) were associated with higher risk for polycythemia. In addition, continuous (OR 0.13, CI 0.05-0.35) and nocturnal (OR 0.46, CI 0.21-0.97) supplemental oxygen were associated with lower risk for polycythemia. Results were similar after excluding participants with anemia and participants enrolled at the Denver clinical center. CONCLUSIONS: In a large cohort of individuals with moderate to very severe COPD, male sex, current smoking, enrollment at the Denver clinical center, impaired DLCO, and severe hypoxemia were associated with increased risk for secondary polycythemia. Continuous or nocturnal supplemental oxygen use were associated with decreased risk for polycythemia.

Effectiveness of pirfenidone in idiopathic pulmonary fibrosis according to the autoantibody status: a retrospective cohort study.

BACKGROUND: Pirfenidone is an anti-fibrotic agent shown to slow the progression of idiopathic pulmonary fibrosis (IPF). However, its effectiveness in association with serological autoimmune features in IPF remains unclear. METHODS: We retrospectively reviewed the medical records of patients with IPF treated at a tertiary care hospital in South Korea. The autoantibody status was defined as positive if we detected autoantibodies meeting the serological domain criteria for interstitial pneumonia with autoimmune features or anti-neutrophil cytoplasmic antibodies. RESULTS: We included 142 patients with IPF treated with pirfenidone for over six months (93 were autoantibody-positive and 49 were autoantibody-negative). The mean age was 69.5 ± 7.3 years, and 77.5% of the patients were male. The adjusted mean changes over one year were - 34.4 and - 112.2 mL (p = 0.168) in forced vital capacity (FVC), and - 0.53 and - 0.72 mL/mmHg/min (p = 0.356) in the lungs diffusion capacity for carbon monoxide (DLCO) in the autoantibody-negative and autoantibody-positive groups, respectively. CONCLUSIONS: Reductions in FVC and DLCO were similar in autoantibody-positive and autoantibody-negative patients with IPF treated with pirfenidone. Pirfenidone is effective in attenuating the progression of IPF, irrespective of the autoantibody status.

Changes in nitric oxide, carbon monoxide, hydrogen sulfide and male reproductive hormones in response to chronic restraint stress in rats.

Gasotrasmitters are endogenously synthesized gaseous molecules that are engaged in cellular physiological and pathological processes. Stress influences various physiological aspects of an organism and amends a normal system's functions, including those of the reproductive system. This study aims to investigate the effect of long-term exposure to restraint stress on the male reproductive system as well as the possible impact of stress on the levels of nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S), and the expression of their producing-enzymes. In this study, rats were subjected to the restraint condition for 2 h per day and 7 days per week for 8 consecutive weeks. The results revealed decreases in the serum levels of kisspeptin-1(Kiss-1), gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone and dehydroepiandrosterone sulfate (DHEA-s); however, corticosterone, gonadotropin-inhibitory hormone (GnIH), estradiol (E2) and prolactin levels increased following restraint stress. The mRNA expression levels of NO synthases (NOSs); neuronal NOS (nNOS), inducible NOS (iNOS) and H2S synthases; cystathionine-γ-lyase- (CSE), 3-mercaptopyruvate-sulfurtransferase- (3MST) and CO-producing enzyme; heme oxygenase-2 (HO-2) were upregulated in the hypothalamus of restraint rats. Testicular mRNA expression levels of endothelial NOS (eNOS), nNOS, HO-1 and HO-2 were upregulated whereas cystathionine ß-synthase (CBS), CSE and 3MST expression levels were downregulated following restraint stress. Concentrations of NO increased in the testes but decreased in the semen of restraint rats. On the contrary, CO levels were reduced in the testes while they were elevated in the semen, whereas H2S concentrations decreased in both testes and semen of restraint rats. Concentrations of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX), as well as total antioxidant capacity (TAC) rose in the testes, while they declined in the semen of the restraint group. Restraint stress decreases the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) in the testes while increasing them in the semen. Collectively, restraint stress negatively impacts male reproductive functions and modulates gasotransmitters producing-enzymes expression in the hypothalamus and testes.

Efficacy, safety, and tolerability of combined pirfenidone and N-acetylcysteine therapy: a systematic review and meta-analysis.

BACKGROUND: While antifibrotic drugs significantly decrease lung function decline in idiopathic pulmonary fibrosis (IPF), there is still an unmet need to halt disease progression. Antioxidative therapy with N-acetylcysteine (NAC) is considered a potential additional therapy that can be combined with antifibrotics in some patients in clinical practice. However, data on the efficacy, tolerability, and safety of this combination are scarce. We performed a systematic review and meta-analysis to appraise the safety, tolerability, and efficacy of the combination compared to treatment with pirfenidone alone. METHODS: We systematically reviewed all the published studies with combined pirfenidone (PFD) and NAC (PFD + NAC) treatment in IPF patients. The primary outcomes referred to decline in pulmonary function tests (PFTs) and the rates of IPF patients with side effects. RESULTS: In the meta-analysis, 6 studies with 319 total IPF patients were included. The PFD + NAC group was comparable to the PFD alone group in terms of the predicted forced vital capacity (FVC%) and predicted diffusion capacity for carbon monoxide (DLco%) from treatment start to week 24. Side effects and treatment discontinuation rates were also comparable in both groups. CONCLUSION: This systematic review and meta-analysis suggests that combination with NAC does not alter the efficacy, safety, or tolerability of PFD in comparison to PFD alone in IPF patients.

Valuable Serum Markers in Pulmonary Alveolar Proteinosis.

OBJECTIVE: Several serum markers were reported to reflect the severity of pulmonary alveolar proteinosis (PAP). The aim of this study is to investigate a reliable and facile marker to access and monitor the clinical course of PAP in a large cohort. METHODS: PAP patients from January 2010 to June 2018 were enrolled. Hospital records were used as data sources. The levels of various serum indicators were detected. We evaluated the correlation between pulmonary function test results and clinical variables. RESULTS: Diffusion capacity for carbon monoxide (DLCO) level was positively correlated with the level of high-density lipoprotein cholesterol (HDL-C) (P < 0.05) in 122 patients of PAP at baseline. The levels of HDL-C and DLCO significantly increased while carcinoembryonic antigen (CEA), CYFRA21-1, neuron-specific enolase (NSE), and lactic dehydrogenase (LDH) levels decreased six months after granulocyte-macrophage colony-stimulating factor (GM-CSF) inhalation therapy between 14 patients with PAP. Nevertheless, the increased DLCO was significantly correlated with decreased CEA (r = -0.579, P = 0.031) and CYFRA 21-1 (r = -0.632, P = 0.015). In 10 PAP patients without GM-CSF inhalation therapy, HDL-C and DLCO significantly decreased while NSE and LDH levels increased after six months of follow-up. The decreased DLCO was significantly correlated with increased LDH (r = -0.694, P = 0.026). CONCLUSIONS: Serum CEA, CYFRA21-1, and LDH are valuable serum markers for the evaluation of disease activity of PAP and may predict the response to treatment of PAP.

Phenomenological and Thermodynamic Model of Gas Exchanges in the Placenta during Pregnancy: A Case Study of Intoxication of Carbon Monoxide.

The present work simulates the transport of oxygen, carbon dioxide, and carbon monoxide between a fetus's circulatory system and the mother's. The organ responsible for this exchange is the placenta. Carbon monoxide is a common air pollutant, and it impacts the physiological conditions even in low concentration. The impacts of carbon monoxide are especially dangerous for pregnant women, fetuses, and newborn babies. A model of carbon monoxide transport, from the literature, is modified to simulate a pregnant woman (original model was a male), therefore changing some parameters to express the adjusted respiratory system. It was considered the gas exchange in the placenta, to evaluate the concentration of these different gases in the fetus arterial and venous blood. Three methods of the exergy analysis are implemented for both mother and fetus respiratory systems, aiming at the comparison with the respiratory system of a male adult. The destroyed exergy of the literature did not have the same trend as the models proposed in this article, taking into consideration the hemoglobin reactions. In contrast, the entropy generation associated only with the diffusion transport phenomena was one order of magnitude lower than the other methods. The placenta destroyed exergy rate is significantly higher compared to the irreversibilities of the mother's respiratory system. One possible explanation is the fact that the placenta has other physiological functions than gas transportation.

Modification of the CO-rebreathing method to determine haemoglobin mass and blood volume in patients suffering from chronic mountain sickness.

NEW FINDINGS: What is the central question of this study? Is it necessary to modify the CO-rebreathing method to acquire reliable measurements of haemoglobin mass in patients with chronic mountain sickness? What is the main finding and its importance? The CO-rebreathing method must be modified because of the prolonged CO-mixing time in patients with chronic mountain sickness. After adaptation of the blood sampling method, reliable and valid results were attained. With this modification, it is possible to quantify the extent of polycythaemia and to distinguish between a haemoconcentration and an exclusive enhancement of erythrocyte volume. ABSTRACT: Patients suffering from chronic mountain sickness (CMS) exhibit extremely high haemoglobin concentrations. Their haemoglobin mass (Hbmass), however, has rarely been investigated. The CO-rebreathing protocol for Hbmass determination in those patients might need to be modified because of restricted peripheral perfusion. The aim of this study was to evaluate the CO uptake and carboxyhaemoglobin-mixing time in the blood of CMS patients and to adapt the CO-rebreathing method for this group. Twenty-five male CMS patients living at elevations between 3600 and 4100 m above sea level were compared with ethnically matched healthy control subjects from identical elevations (n = 11) and near sea level (n = 9) and with a Caucasian group from sea level (n = 6). CO rebreathing was performed for 2 min, and blood samples were taken for the subsequent 30 min. After the method was modified, its reliability was evaluated in test-retest experiments (n = 28), and validity was investigated by measuring the Hbmass before and after the phlebotomy of 500 ml (n = 4). CO uptake was not affected by CMS. The carboxyhaemoglobin mixing was completed after 8 min in the Caucasian group but after 14 min in the groups living at altitude. When blood was sampled 14-20 min after inhalation, the typical error of the method was 1.6% (confidence limits 1.2-2.5%). After phlebotomy, Hbmass decreased from 1779 ± 123 to 1650 ± 129 g, and no difference was found between the measured and calculated Hbmass (1666 ± 122 g). When the time of blood sampling was adapted to accommodate a prolonged carboxyhaemoglobin-mixing time, the CO-rebreathing method became a reliable and valid tool to determine Hbmass in CMS patients.

Acute Carbon Monoxide Poisoning Secondary to Cigarette Smoking in a 40-Year-Old Man: A Case Report.

BACKGROUND AND OBJECTIVES: Carbon monoxide is one of the most common causes of fatal intoxications in the United States, and multiple previous studies have demonstrated that cigarette smokers have higher levels of carbon monoxide in their blood. However, the potential negative effects due to acute carbon monoxide poisoning from excessive cigarette smoking have not been well established. METHODS: This is a single patient case report. RESULTS: In this case report, a 40-year-old male with a past medical history of depression, anxiety, panic attacks, and substance use disorder developed symptomatic, acute carbon monoxide poisoning secondary to heavy cigarette smoking in a confined space. In this patient, the cessation of clonazepam therapy coincided with increasing anxiety and panic disorder with agoraphobia triggering an escalation in his cigarette smoking. The patient smoked three packs of cigarettes in 3 hours and developed worsening of his symptoms. He required inpatient treatment with benzodiazepines and hyperbaric oxygen. DISCUSSION AND CONCLUSIONS: Therefore, it is important to recognize cigarette smoke as a significant source of carbon monoxide exposure. SCIENTIFIC SIGNIFICANCE: While the negative effects of cigarette smoking are often perceived as being chronic and only coming to fruition after numerous years of exposure, it is important for both physicians and patients to recognize the possibility for potentially life-threatening acute toxicity secondary to carbon monoxide exposure. (Am J Addict 2019;28:413-415).

A Pilot Study of E-Cigarette Naïve Cigarette Smokers and the Effects on Craving After Acute Exposure to E-Cigarettes in the Laboratory.

BACKGROUND AND OBJECTIVES: Recent surveys confirm continued increases in the use of electronic-cigarettes (e-cigarettes) in adolescents and adults. Users often state that e-cigarettes reduce tobacco craving and withdrawal symptoms in addition to their smoking. Data from laboratory studies and clinical trials have confirmed these statements, though there are inconsistencies in the outcomes. In this pilot study, we set out to evaluate the effects of e-cigarettes, as compared to the participants' own cigarettes, on baseline craving and smoking severity. METHODS: Using a within-subjects, placebo-controlled study design, 15 tobacco-dependent, e-cigarette naïve participants sustained abstinence overnight. They completed distinct phases of this protocol during four separate study sessions. Participants were randomized to an e-cigarette device containing one of three doses of nicotine (0, 18, or 36 mg/ml) or their own cigarette. Each study visit was ~3 hours long and separated by at least 7 days. Visits included assessments of craving and smoking severity. RESULTS: The data showed that after 10 puffs in both the Own cigarette and e-cigarette conditions, breath carbon monoxide levels increased significantly in the former but not the latter. Questionnaire of Smoking Urges and Choices to Smoke scores were not statistically different across groups after two distinct bouts of 10 puffs each. Additionally, E-cigarette Perceptions Questionnaire responses were not significantly different according to dose. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: This experiment provides data demonstrating that e-cigarettes did not reduce craving or smoking severity in e-cigarette naïve users. However, since this was a pilot study, the conclusions that can be drawn are limited. (Am J Addict 2019;28:361-366).

Acute respiratory responses to the use of e-cigarette: an intervention study.

The goal of our study was to assess acute respiratory responses to using e-cigarettes in exclusive e-cigarette users (E-Group) and dual users (T/E-Group) and to compare these effects with responses to smoking tobacco-cigarettes in tobacco smokers (T-Group). The study included 120 adults (age: 21.7 ± 2.1 years) divided into 4 groups (n = 30 each): Controls, T-, E-, T/E-Group. Spirometric status, O2 saturation, exhaled FeNO levels, exhaled CO levels, and airway temperature were assessed before the use of an e-cigarette (E-, T/E-Group) or tobacco cigarette as well as 'minute 1' and 'minute 30' after smoking. Controls used an e-cigarette without e-liquid. Lower (p < 0.05) baseline values of FeNO were found in T-Group (15.4 ppb) and in T/E-Group (15.0 ppb) than in Controls (19.6 ppb). Following exposure, and compared with Controls, T-, and T/E-Group had a significant decrease (p < 0.05) in PEF and MEF75. Mean FeNO values decreased on 'minute 1' in T-Group (by 2.1 ppb), E-Group (by 1.5 ppb) and in T/E-Group (by 2.2 ppb). Other effects included increase in temperature of exhaled air (p < 0.05). The use of e-cigarettes is associated with decreased FeNO and airflow indices (PEF, MEF75), but an increase in airway temperature. These changes are similar to those after exposure to tobacco cigarette smoke.

Epidemiology and forensic aspects of carbon monoxide intoxication in Portugal: A three years' analysis.

The presented manuscript describes the carbon monoxide (CO) related deaths in Portugal over a period of 3 years, based on autopsies carried out at the National Institute of Legal Medicine and Forensic Sciences, from January 2012 to December 2014. Three hundred and forty-seven forensic autopsy reports with carboxyhaemoglobin (COHb) analysis requests were analysed and subdivided into three main groups: (1) improbable CO intoxication; (2) possible CO intoxication; (3) highly probable CO intoxication. In group 1, COHb analysis was negative, and the death circumstances, as well as the post mortem findings, didn't corroborate an exposition to CO. In group 2, with COHb positive in 1/3 of the cases, the death circumstances corroborated an exposition to CO, but the post mortem findings weren't enough to confirm an exposition to this substance. In group 3, the results of COHb were positive, and both circumstances of death and post mortem findings corroborated an exposition to CO. The first group (113 cases) had no specific suspicion of a CO intoxication and, thus, the request of a COHb analysis had no particular basis, reflected in the low COHb achieved percentage (between 0 and 12). In the second group (164 cases), 29% of the cases were directly or indirectly related to CO exposure (between 0% and 94%). In the third group (70 cases), 56 deaths were due to CO intoxication and 14 due to burns after CO inhalation (between 18% and 91%). This study intended to do, not only a 3-year assessment of CO poisoning, but also to enhance the fact that circumstantial information, as well as a correct evaluation at the forensic autopsy data are crucial, and allow an enhanced diagnosis of possible intoxication, as well as a better guidance for the consequent toxicological analysis requests.

Comprehensive effects of left ventricular assist device speed changes on alveolar gas exchange, sleep ventilatory pattern, and exercise performance.

BACKGROUND: Increasing left ventricular assist device (LVAD) pump speed according to the patient's activity is a fascinating hypothesis. This study analyzed the short-term effects of LVAD speed increase on cardiopulmonary exercise test (CPET) performance, muscle oxygenation (near-infrared spectroscopy), diffusion capacity of the lung for carbon monoxide (Dlco) and nitric oxide (Dlno), and sleep quality. METHODS: We analyzed CPET, Dlco and Dlno, and sleep in 33 patients supported with the Jarvik 2000 (Jarvik Heart Inc., New York, NY). After a maximal CPET (n = 28), patients underwent 2 maximal CPETs with LVAD speed randomly set at 3 or increased from 3 to 5 during effort (n = 15). Then, at LVAD speed randomly set at 2 or 4, we performed (1) constant workload CPETs assessing O2 kinetics, cardiac output (CO), and muscle oxygenation (n = 15); (2) resting Dlco and Dlno (n = 18); and (3) nocturnal cardiorespiratory monitoring (n = 29). RESULTS: The progressive pump speed increase raised peak volume of oxygen consumption (12.5 ± 2.5 ml/min/kg vs 11.7 ± 2.8 ml/min/kg at speed 3; p = 0.001). During constant workload, from speed 2 to 4, CO increased (at rest: 3.18 ± 0.76 liters/min vs 3.69 ± 0.75 liters/min, p = 0.015; during exercise: 5.91 ± 1.31 liters/min vs 6.69 ± 0.99 liters/min, p = 0.014), and system efficiency (τ = 65.8 ± 15.1 seconds vs 49.9 ± 14.8 seconds, p = 0.002) and muscle oxygenation improved. At speed 4, Dlco decreased, and obstructive apneas increased despite a significant apnea/hypopnea index and a reduction of central apneas. CONCLUSIONS: Short-term LVAD speed increase improves exercise performance, CO, O2 kinetics, and muscle oxygenation. However, it deteriorates lung diffusion and increases obstructive apneas, likely due to an increase of intrathoracic fluids. Self-adjusting LVAD speed is a fascinating but possibly unsafe option, probably requiring a monitoring of intrathoracic fluids.

Carbon monoxide analysis method in human blood by Airtight Gas Syringe - Gas Chromatography - Mass Spectrometry (AGS-GC-MS): Relevance for postmortem poisoning diagnosis.

Carbon monoxide is one of the most abundant toxic air pollutants. Symptoms of a CO intoxication are non-specific, leading to a high number of misdiagnosed CO poisoning cases that are missing in the disease statistics. The chemical nature of the molecule makes it difficult to detect for long periods and at low levels, thus requiring a very accurate and sensitive method. Current methods capable of accurate and sensitive analyses are available, however an inconsistency between results and symptoms are frequently reported. Therefore, an improved method for the analysis of carbon monoxide in blood and in the headspace (HS) of the sampling tube with the use of Airtight Gas Syringe - Gas Chromatography - Mass Spectrometry (AGS-GC-MS) is hereby presented and validated, for CO concentrations in a range of 10-200 nmol/mL HS (2-40 µmol/mL blood). Analytical LOQ is found at 0.9 nmol/mL HS (0.18 µmol/mL blood) and LOD at 0.1 nmol/mL gas. Application to intoxicated samples from autopsies and comparison to previously published methods show that this method is more appropriate, since performed under fully controlled conditions. Results show higher CO concentrations compared to previous approaches, indicating that results might have been underestimating the true blood CO burden. Therefore, this approach has the potential to help reduce the misdiagnosed cases and the gap between measurement and diagnosis of CO poisonings.

Rates of change in FEV1 and DLCO as potential indicators for mTOR inhibitor therapy in premenopausal lymphangioleiomyomatosis patients.

The value of rates of change in forced expiratory volume in 1 s (FEV1) and diffusing capacity of the lung for carbon monoxide (DLCO) to predict disease progression, and initiation of mTOR (mechanistic target of rapamycin) inhibitor therapy has not been evaluated.In 84 premenopausal lymphangioleiomyomatosis patients, individual rates of change in FEV1 and DLCO and their 95% confidence intervals were used to derive subsequent lowest values of FEV1 and DLCO that would prompt initiation of sirolimus therapy. These treatment criteria were compared with a criterion based on FEV1 or DLCO ≤70% predicted. In 12 patients undergoing sirolimus therapy both methods for determining the optimal point for initiation of therapy were evaluated.27 and 35 patients who experienced greater than expected rates of change in FEV1 and DLCO, respectively, would have been excluded from therapy based on an FEV1 or DLCO >70% pred. 25 of the 84 patients were eventually treated, but only when FEV1 or DLCO were ≤70% pred. Applying such treatment criteria to 12 patients undergoing sirolimus therapy would have delayed treatment for many years.Premenopausal females in whom FEV1 or DLCO are declining at rates above the expected based on their individual rates of decline, should be considered for sirolimus therapy before the FEV1 or DLCO falls to ≤70% pred.

Effects of Varenicline Alone and in Combination With Low-dose Naltrexone on Alcohol-primed Smoking in Heavy-drinking Tobacco Users: A Preliminary Laboratory Study.

OBJECTIVES: Heavy-drinking tobacco users are less likely to successfully quit smoking than their moderate-drinking counterparts, even when they are prescribed smoking cessation medication. One strategy for improving treatment outcomes in this subgroup of tobacco users may be to combine medication therapies to target both alcohol and tobacco use simultaneously. Adding naltrexone to frontline smoking cessation treatments may improve treatment outcomes in this group. METHOD: This double-blind, placebo-controlled human laboratory study examined the effects of varenicline (2 mg/d) and varenicline (2 mg/d), combined with a low dose of naltrexone (25 mg/d) on alcohol-primed smoking behavior in a laboratory model of smoking relapse in heavy-drinking tobacco users (n = 30). Participants attended a laboratory session and received an alcohol challenge (target breath alcohol concentration = 0.030 g/dL). They completed a smoking delay task that assessed their ability to resist smoking followed by an ad libitum smoking phase (primary outcomes). They also provided ratings of subjective drug effects and craving, and carbon monoxide levels were measured after smoking (secondary outcomes). RESULTS: Participants receiving varenicline monotherapy delayed smoking longer and smoked fewer cigarettes than those on placebo. Participants receiving varenicline + low-dose naltrexone did not delay smoking longer than those receiving varenicline alone. Participants in both active medication arms smoked fewer cigarettes ad libitum than those receiving placebo. CONCLUSIONS: Varenicline can improve smoking outcomes even after an alcohol prime, supporting its use in heavy drinkers who wish to quit smoking. Findings did not support increased efficacy of combined varenicline + low-dose naltrexone relative to varenicline monotherapy.

Physiological predictors of Hypoxic Challenge Testing (HCT) outcomes in Interstitial Lung Disease (ILD).

BACKGROUND: Pre-flight risk assessments are currently recommended for all Interstitial Lung Disease (ILD) patients. Hypoxic challenge testing (HCT) can inform regarding the need for supplemental in-flight oxygen but variables which might predict the outcome of HCT and thus guide referral for assessment, are unknown. METHODS: A retrospective analysis of ILD patients attending for HCT at three tertiary care ILD referral centres was undertaken to investigate the concordance between HCT and existing predictive equations for prediction of in-flight hypoxia. Physiological variables that might predict a hypoxaemic response to HCT were also explored with the aim of developing a practical pre-flight assessment algorithm for ILD patients. RESULTS: A total of 106 ILD patients (69 of whom (65%) had Idiopathic Pulmonary Fibrosis (IPF)) underwent HCT. Of these, 54 (51%) patients (of whom 37 (69%) had IPF) failed HCT and were recommended supplemental in-flight oxygen. Existing predictive equations were unable to accurately predict the outcome of HCT. ILD patients who failed HCT had significantly lower resting SpO2, baseline PaO2, reduced walking distance, FEV1, FVC and TLCO, but higher GAP index than those who passed HCT. CONCLUSIONS: TLCO >50% predicted and PaO2 >9.42 kPa were independent predictors for passing HCT. Using these discriminators, a novel, practical pre-flight algorithm for evaluation of ILD patients is proposed.

FGF21 induced by carbon monoxide mediates metabolic homeostasis via the PERK/ATF4 pathway.

The prevalence of metabolic diseases, including type 2 diabetes, obesity, and cardiovascular disease, has rapidly increased, yet the molecular mechanisms underlying the metabolic syndrome, a primary risk factor, remain incompletely understood. The small, gaseous molecule carbon monoxide (CO) has well-known anti-inflammatory, antiproliferative, and antiapoptotic effects in a variety of cellular- and tissue-injury models, whereas its potential effects on the complex pathways of metabolic disease remain unknown. We demonstrate here that CO can alleviate metabolic dysfunction in vivo and in vitro. We show that CO increased the expression and section of the fibroblast growth factor 21 (FGF21) in hepatocytes and liver. CO-stimulated PERK activation and enhanced the levels of FGF21 via the eIF2α-ATF4 signaling pathway. The induction of FGF21 by CO attenuated endoreticulum stress- or diet-induced, obesity-dependent hepatic steatosis. Moreover, CO inhalation lowered blood glucose levels, enhanced insulin sensitivity, and promoted energy expenditure by stimulating the emergence of beige adipose cells from white adipose cells. In conclusion, we suggest that CO acts as a potent inducer of FGF21 expression and that CO critically depends on FGF21 to regulate metabolic homeostasis.-Joe, Y., Kim, S., Kim, H. J., Park, J., Chen, Y., Park, H.-J., Jekal, S.-J., Ryter, S. W., Kim, U. H., Chung, H. T. FGF21 induced by carbon monoxide mediates metabolic homeostasis via the PERK/ATF4 pathway.