Safety and Side Effects of Rifampin versus Isoniazid in Children.

BACKGROUND: The treatment of latent infection with Mycobacterium tuberculosis is important in children because of their vulnerability to life-threatening forms of tuberculosis disease. The current standard treatment - 9 months of isoniazid - has been associated with poor adherence and toxic effects, which have hampered the effectiveness of the drug. In adults, treatment with 4 months of rifampin has been shown to be safer and to have higher completion rates than 9 months of isoniazid. METHODS: In this multicenter, open-label trial, we randomly assigned 844 children (<18 years of age) with latent M. tuberculosis infection to receive either 4 months of rifampin or 9 months of isoniazid. The primary outcome was adverse events of grade 1 to 5 that resulted in the permanent discontinuation of a trial drug. Secondary outcomes were treatment adherence, side-effect profile, and efficacy. Independent review panels whose members were unaware of trial-group assignments adjudicated all adverse events and progression to active tuberculosis. RESULTS: Of the children who underwent randomization, 829 were eligible for inclusion in the modified intention-to-treat analysis. A total of 360 of 422 children (85.3%) in the rifampin group completed per-protocol therapy, as compared with 311 of 407 (76.4%) in the isoniazid group (adjusted difference in the rates of treatment completion, 13.4 percentage points; 95% confidence interval [CI], 7.5 to 19.3). There were no significant between-group differences in the rates of adverse events, with fewer than 5% of the children in the combined groups with grade 1 or 2 adverse events that were deemed to be possibly related to a trial drug. Active tuberculosis, including 1 case with resistance to isoniazid, was diagnosed in 2 children in the isoniazid group during 542 person-years of follow-up, as compared with no cases in the rifampin group during 562 person-years (rate difference, -0.37 cases per 100 person-years; 95% CI, -0.88 to 0.14). CONCLUSIONS: Among children under the age of 18 years, treatment with 4 months of rifampin had similar rates of safety and efficacy but a better rate of adherence than 9 months of treatment with isoniazid. (Funded by the Canadian Institutes of Health Research and Conselho Nacional de Pesquisa; ClinicalTrials.gov number, NCT00170209 .).

Four Months of Rifampin or Nine Months of Isoniazid for Latent Tuberculosis in Adults.

BACKGROUND: A 9-month regimen of isoniazid can prevent active tuberculosis in persons with latent tuberculosis infection. However, the regimen has been associated with poor adherence rates and with toxic effects. METHODS: In an open-label trial conducted in nine countries, we randomly assigned adults with latent tuberculosis infection to receive treatment with a 4-month regimen of rifampin or a 9-month regimen of isoniazid for the prevention of confirmed active tuberculosis within 28 months after randomization. Noninferiority and potential superiority were assessed. Secondary outcomes included clinically diagnosed active tuberculosis, adverse events of grades 3 to 5, and completion of the treatment regimen. Outcomes were adjudicated by independent review panels. RESULTS: Among the 3443 patients in the rifampin group, confirmed active tuberculosis developed in 4 and clinically diagnosed active tuberculosis developed in 4 during 7732 person-years of follow-up, as compared with 4 and 5 patients, respectively, among 3416 patients in the isoniazid group during 7652 person-years of follow-up. The rate differences (rifampin minus isoniazid) were less than 0.01 cases per 100 person-years (95% confidence interval [CI], -0.14 to 0.16) for confirmed active tuberculosis and less than 0.01 cases per 100 person-years (95% CI, -0.23 to 0.22) for confirmed or clinically diagnosed tuberculosis. The upper boundaries of the 95% confidence interval for the rate differences of the confirmed cases and for the confirmed or clinically diagnosed cases of tuberculosis were less than the prespecified noninferiority margin of 0.75 percentage points in cumulative incidence; the rifampin regimen was not superior to the isoniazid regimen. The difference in the treatment-completion rates was 15.1 percentage points (95% CI, 12.7 to 17.4). The rate differences for adverse events of grade 3 to 5 occurring within 146 days (120% of the 4-month planned duration of the rifampin regimen) were -1.1 percentage points (95% CI, -1.9 to -0.4) for all events and -1.2 percentage points (95% CI, -1.7 to -0.7) for hepatotoxic events. CONCLUSIONS: The 4-month regimen of rifampin was not inferior to the 9-month regimen of isoniazid for the prevention of active tuberculosis and was associated with a higher rate of treatment completion and better safety. (Funded by the Canadian Institutes of Health Research and the Australian National Health and Medical Research Council; ClinicalTrials.gov number, NCT00931736 .).

Investigating the effect of pretreatment with azithromycin on inflammatory mediators in bronchial epithelial cells exposed to cigarette smoke.

Purpose of the study: Macrolide therapy is effective in reducing chronic obstructive pulmonary disease (COPD) exacerbations. Our recent study has shown the effectiveness of taking azithromycin in COPD patients, not only ex-smokers but also current smokers. Beyond their anti-microbial effects, macrolides have anti-inflammatory and immunomodulatory properties. The aim of this study was to determine if pretreatment with azithromycin modulates cigarette smoke-induced inflammation in airway epithelial cells. We hypothesized that pretreatment with azithromycin decreases exacerbation frequency by modulating inflammation in human airway epithelial cells exposed to cigarette smoke. Materials and methods: BEAS-2B bronchial epithelial cells were incubated with 5% cigarette smoke extract (CSE) for 3 h, 6 h, and 24 h. Then, airway epithelial cells were pretreated with azithromycin and exposed to 5% CSE. In each stage, the expression and release of IL-6 and IL-8 mRNA were analyzed by quantitative real-time PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Results: There was a significant increase of IL-6 and IL-8 mRNA, as well as an increase in extracellular IL-8 protein following exposure to 5% CSE. When cells were pretreated with azithromycin and exposed to 5% CSE for 3 h, there was a significant dose-dependent decrease in the expression of IL-6 mRNA. A final concentration of 9 µg/mL of azithromycin was sufficient to decrease IL-6, IL-8 mRNA, and extracellular IL-8 levels. Conclusion: Pretreatment with azithromycin decreased the expression of IL-6 and IL-8 mRNA and the release of IL-8 in bronchial epithelial cells exposed to cigarette smoke. These results demonstrate the direct effect of azithromycin on inflammatory mediators in bronchial epithelial cells exposed to cigarette smoke.

Granularity of SERPINA1 alleles by DNA sequencing in CanCOLD.

DNA sequencing of the SERPINA1 gene to detect α1-antitrypsin (AAT) deficiency (AATD) may provide a better appreciation of the individual and cumulative impact of genetic variants on AAT serum levels and COPD phenotypes.AAT serum level and DNA sequencing of the coding regions of SERPINA1 were performed in 1359 participants of the Canadian Cohort Obstructive Lung Disease (CanCOLD) study. Clinical assessment for COPD included questionnaires, pulmonary function testing and computed tomography (CT) imaging. Phenotypes were tested for association with SERPINA1 genotypes collated into four groups: normal (MM), mild (MS and MI), intermediate (heterozygote MZ, non-S/non-Z/non-I, compound IS, and homozygote SS) and severe (ZZ and SZ) deficiency. Smoking strata and MZ-only analyses were also performed.34 genetic variants were identified including 25 missense mutations. Overall, 8.1% of alleles in this Canadian cohort were deficient and 15.5% of 1359 individuals were carriers of at least one deficient allele. Four AATD subjects were identified and had statistically lower diffusion capacity and greater CT-based emphysema. No COPD phenotypes were associated with mild and intermediate AATD in the overall cohort or stratified by smoking status. MZ heterozygotes had similar CT-based emphysema, but lowered diffusion capacity compared with normal and mild deficiency.In this Canadian population-based cohort, comprehensive genetic testing for AATD reveals a variety of deficient alleles affecting 15.5% of subjects. COPD phenotype was demonstrated in severe deficiency and MZ heterozygotes. This study shows the feasibility of implementing a diagnostic test for AATD using DNA sequencing in a large cohort.

Standardised shorter regimens versus individualised longer regimens for rifampin- or multidrug-resistant tuberculosis.

We sought to compare the effectiveness of two World Health Organization (WHO)-recommended regimens for the treatment of rifampin- or multidrug-resistant (RR/MDR) tuberculosis (TB): a standardised regimen of 9-12 months (the "shorter regimen") and individualised regimens of ≥20 months ("longer regimens").We collected individual patient data from observational studies identified through systematic reviews and a public call for data. We included patients meeting WHO eligibility criteria for the shorter regimen: not previously treated with second-line drugs, and with fluoroquinolone- and second-line injectable agent-susceptible RR/MDR-TB. We used propensity score matched, mixed effects meta-regression to calculate adjusted odds ratios and adjusted risk differences (aRDs) for failure or relapse, death within 12 months of treatment initiation and loss to follow-up.We included 2625 out of 3378 (77.7%) individuals from nine studies of shorter regimens and 2717 out of 13 104 (20.7%) individuals from 53 studies of longer regimens. Treatment success was higher with the shorter regimen than with longer regimens (pooled proportions 80.0% versus 75.3%), due to less loss to follow-up with the former (aRD -0.15, 95% CI -0.17- -0.12). The risk difference for failure or relapse was slightly higher with the shorter regimen overall (aRD 0.02, 95% CI 0-0.05) and greater in magnitude with baseline resistance to pyrazinamide (aRD 0.12, 95% CI 0.07-0.16), prothionamide/ethionamide (aRD 0.07, 95% CI -0.01-0.16) or ethambutol (aRD 0.09, 95% CI 0.04-0.13).In patients meeting WHO criteria for its use, the standardised shorter regimen was associated with substantially less loss to follow-up during treatment compared with individualised longer regimens and with more failure or relapse in the presence of resistance to component medications. Our findings support the need to improve access to reliable drug susceptibility testing.

Fractional Exhaled Nitric Oxide as an Inflammatory Biomarker in Chronic Obstructive Pulmonary Disease (COPD) with or without Concurrent Diagnosis of Asthma: The Canadian Cohort Obstructive Lung Disease (CanCOLD).

We studied whether fractional exhaled nitric oxide (FENO) can differentiate chronic obstructive pulmonary disease (COPD) with concurrent diagnosis of asthma from COPD-only as well as its ability to predict disease severity and progression. This study was embedded in the Canadian Cohort Obstructive Lung Disease (CanCOLD). Subjects of ≥40 years old completed FENO measurements were subdivided into four groups, including COPD (N = 86 [COPD-only (N = 35) and COPD with concurrent diagnosis of asthma (N = 51)], healthy (N = 72), and at risk (N = 151). Three of the most common clinical definitions were used for characterizing COPD with concurrent diagnosis of asthma: 1) atopy and self-reported physician diagnosis of asthma, 2) ≥12% and ≥200 ml post-bronchodilator FEV1; 3) self-reported physician diagnosis of asthma. FENO values were classified using quartiles and the American Thoracic Society (ATS) guideline 2011. Compared to COPD-only, more COPD with concurrent diagnosis of asthma had a significant FENO50 level of [Formula: see text] 33.5 ppb (fourth quartile) than COPD-only (p = 0.045, 0.011, and 0.006, for definition 1, 2, and 3, respectively). Considering the ATS guideline 2011, fewer COPD with concurrent diagnosis of asthma had FENO50 < 25 than COPD-only, which was statistically significant with definition 1 and 3 (p = 0.038 and 0.026, respectively). FENO as a biomarker has the potential to be used as a complementary value for differentiating COPD with concurrent diagnosis of asthma from COPD-only. Further studies should be conducted on validated definitions of COPD with concurrent diagnosis of asthma, which may include a reference to the type of airway inflammation in addition to the clinical definition.

Dysbacteriosis-Derived Lipopolysaccharide Causes Embryonic Osteopenia through Retinoic-Acid-Regulated DLX5 Expression.

Growing evidence suggests an adverse impact of gut microbiota dysbiosis on human health. However, it remains unclear whether embryonic osteogenesis is affected by maternal gut dysbacteriosis. In this study, we observed that elevated lipopolysaccharide (LPS) levels led to skeletal developmental retardation in an established mouse model of gut microbiota dysbiosis. Using chick embryos exposed to dysbacteriosis-derived LPS, we found restriction in the development of long bones as demonstrated by Alcian blue and alizarin red staining. Micro-CT and histological analysis exhibited decreased trabecular volume, bone mineral density, and collagen production, as well as suppressed osteoblastic gene expression (Ocn, Runx2, Osx, and Dlx5) in chick embryonic phalanges following LPS treatment. Atomic force microscopy manifested decreased roughness of MC3T3-E1 cells and poorly developed matrix vesicles (MVs) in presence of LPS. The expression of the aforementioned osteoblastic genes was suppressed in MC3T3-E1 cells as well. High-throughput RNA sequencing indicated that retinoic acid (RA) may play an important role in LPS-induced osteopenia. The addition of RA suppressed Dlx5 expression in MC3T3-E1 cells, as was also seen when exposed to LPS. Quantitative PCR, Western blot, and immunofluorescent staining showed that retinoic acid receptor α (RARα) was upregulated by LPS or RA treatment, while the expression of DLX5 was downregulated. CYP1B1 expression was increased by LPS treatment in MC3T3-E1 cells, which might be attributed to the increased inflammatory factors and subsequently activated NF-κB signaling. Eventually, blocking RA signals with AGN193109 successfully restored LPS-inhibited osteoblastic gene expression. Taken together, our data reveals that maternal gut microbiota dysbiosis can interfere with bone ossification, in which Dlx5 expression regulated by RA signaling plays an important role.

Microbiota-derived lipopolysaccharide retards chondrocyte hypertrophy in the growth plate through elevating Sox9 expression.

Accumulating data show that the cytotoxicity of bacterial lipopolysaccharides (LPS) from microbiota or infection is associated with many disorders observed in the clinics. However, it is still obscure whether or not embryonic osteogenesis is affected by the LPS exposure during gestation. Using the early chicken embryo model, we could demonstrate that LPS exposure inhibits chondrogenesis of the 8-day chicken embryos by Alcian Blue-staining and osteogenesis of 17-day by Alcian Blue and Alizarin Red staining. Further analysis of the growth plates showed that the length of the proliferating zone (PZ) increases whereas that of the hypertrophic zone (HZ) decreased following LPS exposure. However there is no significant change on cell proliferation in the growth plates. Immunofluorescent staining, western blot analysis, and quantitive polymerase chain reaction revealed that Sox9 and Col2a1 are highly expressed at the messenger RNA level and their protein products are also abundant. LPS exposure causes a downregulation of Runx2 and Col10a1 expression in 8-day hindlimbs, and a suppression of Runx2, Col10a1, and Vegfa expression in 17-day phalanges. Knocking down Sox9 in ATDC5 cells by small interfering RNA transfection lead to the expression reduction of Col2a1, Runx2, and Col10a1, implying the vital role of Sox9 in the process of LPS-induced delay in the transition from proliferating chondrocytes to hypertrophic chondrocytes in the growth plate. In the presence of LPS, the antioxidant defense regulator nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is highly expressed, and the activities of superoxide dismutase 1 (SOD1), SOD2, and glutaredoxin rise in 17-day phalanges and ADTC5 cells. Simultaneously, an increase of intracellular ROS is observed. When Nrf2 expression was knocked down in ATDC5 cells, the expressions of Sox9, Col2a1, Runx2, Col10a1, and Vegfa were also going down as well. Taken together, our current data suggest that LPS exposure during gestation could restrict the chondrocytes conversion from proliferating to hypertrophic in the growth plate, in which LPS-induced Sox9 plays a crucial role to trigger the cascade of downstream genes by excessive ROS production and Nrf2 elevation.

Dexamethasone interferes with osteoblasts formation during osteogenesis through altering IGF-1-mediated angiogenesis.

Dexamethasone (Dex), a synthetic glucocorticoid (GC) with long-lasting treatment effects, has been proved to exert a modulatory effect on osteoblast proliferation and differentiation during embryonic osteogenesis. However, it is still controversial if Dex exposure influences endochondral ossification and the underlying mechanism. In this study, chick embryos in vivo and preosteoblast cell cultures in vitro were utilized to investigate the effects of Dex on osteoblast formation and differentiation during the skeletal development. We first demonstrated that Dex exposure could shorten the long bones of 17-day chick embryos in vivo, and also downregulated the expressions of osteogenesis-related genes. Next, we established that Dex exposure inhibited the proliferation and viability of preosteoblasts-MC3TC-E1 cells, and the addition of insulin-like growth factor 1 (IGF-1) could dramatically rescue these negative effects. On the basis of remarkable changes in the rescue experiments, we next verified the important role of angiogenesis in osteogenesis by culturing isolated embryonic phalanges in Dulbecco's modified Eagle's medium culture or on the chick chorioallantoic membrane (CAM). Then, we transplanted MC3T3-E1 cell masses onto the CAM. The data showed that Dex exposure reduced the vessel density within the developed cell mass, concomitantly with the downregulation of IGF-1 pathway. We verified that the inhibition of blood vessel formation caused by Dex could be rescued by IGF-1 treatment using the CAM angiogenesis model. Eventually, we demonstrated that the shortened length of the phalanges in the presence of Dex could be reversed by IGF-1 addition. In summary, these findings suggested that the inhibition of Igf-1 signal caused by Dex exposure exerts a detrimental impact on the formation of osteoblasts and angiogenesis, which consequently shortens long bones during osteogenesis.

Cell survival controlled by lens-derived Sema3A-Nrp1 is vital on caffeine-suppressed corneal innervation during chick organogenesis.

In this study, we investigated the effect of caffeine overexposure on corneal innervation in the early chicken embryo. Caffeine administration restricted corneal innervation by affecting trigeminal nerve development. Immunohistochemistry for phospho-Histone3 (pHIS3) and C-caspase3 revealed that cell survival was repressed by caffeine administration. Whole-mount in situ hybridization against semaphorin 3A (Sema3A) and neuropilin-1 (Nrp1) showed that both caffeine and 2,2'-azobis(2-methylpropionamidine) dihydrochloride (AAPH, a free radical generator) administration upregulates the expression of both Sema3A and Nrp1. Next, we demonstrated that lens ablation in the developing chicken embryos significantly affected NF-labeled periocular nerve fascicles and innervation to the central eye region. Subsequently, we used a neuroblastoma cell line to investigate in vitro whether or not Sema3A-Nrp1 signaling exerts a key role on the caffeine-suppressed neuron survival. Knocking-down Sema3A through transfection with Sema3A-siRNA dramatically decreased the responsiveness of cells to caffeine administration, as well as cell apoptosis. We suggest that Sema3A-Nrp1 signaling regulates Trp53 and Cdkn1a through Slit2-Robo1 and Ephb2. Taken together, we speculate here that caffeine-enhanced reactive oxygen species upregulates Sema3A-Nrp1 expression in the lens and periocular tissues, resulting in corneal cell apoptosis, accompanied by its chemorepellent role on the invasion of the developing cornea by trigeminal sensory fibers.

Are there specific clinical characteristics associated with physician's treatment choices in COPD?

BACKGROUND: The number of pharmacological agents and guidelines available for COPD has increased markedly but guidelines remain poorly followed. Understanding underlying clinical reasoning is challenging and could be informed by clinical characteristics associated with treatment prescriptions. METHODS: To determine whether COPD treatment choices by respiratory physicians correspond to specific patients' features, this study was performed in 1171 patients who had complete treatment and clinical characterisation data. Multiple statistical models were applied to explain five treatment categories: A: no COPD treatment or short-acting bronchodilator(s) only; B: one long-acting bronchodilator (beta2 agonist, LABA or anticholinergic agent, LAMA); C: LABA+LAMA; D: a LABA or LAMA + inhaled corticosteroid (ICS); E: triple therapy (LABA+LAMA+ICS). RESULTS: Mean FEV1 was 60% predicted. Triple therapy was prescribed to 32.9% (treatment category E) of patients and 29.8% received a combination of two treatments (treatment categories C or D); ICS-containing regimen were present for 44% of patients altogether. Single or dual bronchodilation were less frequently used (treatment categories B and C: 19% each). While lung function was associated with all treatment decisions, exacerbation history, scores of clinical impact and gender were associated with the prescription of > 1 maintenance treatment. Statistical models could predict treatment decisions with a < 35% error rate. CONCLUSION: In COPD, contrary to what has been previously reported in some studies, treatment choices by respiratory physicians appear rather rational since they can be largely explained by the patients' characteristics proposed to guide them in most recommendations.

Lipopolysaccharides (LPS) Induced Angiogenesis During Chicken Embryogenesis is Abolished by Combined ETA/ETB Receptor Blockade.

BACKGROUND/AIMS: Angiogenesis plays a key role during embryonic development. The vascular endothelin (ET) system is involved in the regulation of angiogenesis. Lipopolysaccharides (LPS) could induce angiogenesis. The effects of ET blockers on baseline and LPS-stimulated angiogenesis during embryonic development remain unknown so far. METHODS: The blood vessel density (BVD) of chorioallantoic membranes (CAMs), which were treated with saline (control), LPS, and/or BQ123 and the ETB blocker BQ788, were quantified and analyzed using an IPP 6.0 image analysis program. Moreover, the expressions of ET-1, ET-2, ET3, ET receptor A (ETRA), ET receptor B (ETRB) and VEGFR2 mRNA during embryogenesis were analyzed by semi-quantitative RT-PCR. RESULTS: All components of the ET system are detectable during chicken embryogenesis. LPS increased angiogenesis substantially. This process was completely blocked by the treatment of a combination of the ETA receptor blockers-BQ123 and the ETB receptor blocker BQ788. This effect was accompanied by a decrease in ETRA, ETRB, and VEGFR2 gene expression. However, the baseline angiogenesis was not affected by combined ETA/ETB receptor blockade. CONCLUSION: During chicken embryogenesis, the LPS-stimulated angiogenesis, but not baseline angiogenesis, is sensitive to combined ETA/ETB receptor blockade.

The Quebec Respiratory Health Education Network: Integrating a model of self-management education in COPD primary care.

The objective of this study is to evaluate whether a chronic obstructive pulmonary disease (COPD) self-management education program with coaching of a case manager improves patient-related outcomes and leads to practice changes in primary care. COPD patients from six family medicine clinics (FMCs) participated in a 1-year educational program offered by trained case managers who focused on treatment adherence, inhaler techniques, smoking cessation, and the use of an action plan for exacerbations. Health-care utilization, health-related quality of life (HRQL), treatment adherence, inhaler technique, and COPD knowledge were assessed at each visit with validated questionnaires. We also evaluated whether the use of spirometry and the assessment of individual patient needs led to a more COPD-targeted treatment by primary care physicians, based on changes in prescriptions for COPD (medication, immunization, and written action plan). Fifty-four patients completed the follow-up visits and were included in the analysis. The number of unscheduled physician visits went from 40 the year before intervention to 17 after 1 year of educational intervention ( p = 0.033). Emergency room visits went from five to two and hospitalizations from two to three (NS). Significant improvements were observed in HRQL ( p = 0.0001), treatment adherence ( p = 0.025), adequate inhaler technique ( p < 0.0001), and COPD knowledge ( p < 0.001). Primary care physicians increased their prescriptions for long-acting bronchodilators with/without inhaled corticosteroid, flu immunizations, and COPD action plans in the event patient had an exacerbation. The COPD self-management educational intervention in FMCs reduced unscheduled visits to the clinic and improved patients' quality of life, self-management skills, and knowledge. The program had a positive impact on COPD-related practices by primary care physicians in the FMCs.

Effect of morphine on breathlessness and exercise endurance in advanced COPD: a randomised crossover trial.

The objective of the present study was to evaluate the effect of morphine on exertional breathlessness and exercise endurance in advanced chronic obstructive pulmonary disease (COPD).In a randomised crossover trial, we compared the acute effect of immediate-release oral morphine versus placebo on physiological and perceptual responses during constant-load cardiopulmonary cycle exercise testing (CPET) in 20 adults with advanced COPD and chronic breathlessness syndrome.Compared with placebo, morphine reduced exertional breathlessness at isotime by 1.2±0.4 Borg units and increased exercise endurance time by 2.5±0.9 min (both p≤0.014). During exercise at isotime, morphine decreased ventilation by 1.3±0.5 L·min-1 and breathing frequency by 2.0±0.9 breaths·min-1 (both p≤0.041). Compared with placebo, morphine decreased exertional breathlessness at isotime by ≥1 Borg unit in 11 participants (responders) and by <1 Borg unit in nine participants (non-responders). Baseline participant characteristics, including pulmonary function and cardiorespiratory fitness, were similar between responders and non-responders. A higher percentage of responders versus non-responders stopped incremental CPET due to intolerable breathlessness: 82 versus 33% (p=0.028).Immediate-release oral morphine improved exertional breathlessness and exercise endurance in some, but not all, adults with advanced COPD. The locus of symptom-limitation on laboratory-based CPET may help to identify patients most likely to benefit from morphine.

Early COPD Exacerbation Treatment with Combination of ICS and LABA for Patients Presenting with Mild-to-Moderate Worsening of Dyspnea.

This is a proof of concept study that aims to establish feasibility and safety of a new strategy that includes an action plan for early treatment of acute exacerbations of COPD (AECOPD) with doubling dose of a combination of a long-acting beta2 agonist and an inhaled corticosteroid, and to explore its potential for avoiding the requirement of prednisone and its safety. Thirty-seven COPD outpatients with previous exacerbations were enrolled and followed-up for 12 months. The written action plan included a standing prescription to be used in the event of an AECOPD: Antibiotic, for 5 days (for purulent exacerbations) and doubling a combination of Salmeterol and Fluticasone Propionate for 10 days. The primary outcome was "treatment success" defined as "no need of prednisone within 30 days of the onset." Twenty-seven patients experienced an AECOPD and doubled their combination dose. Among the 27 patients, there were 21 patients (78%) who did not require prednisone, and none of those had cardiovascular events, pneumonia, ER and hospital admissions. We have assessed that an early treatment of AECOPD with doubling the dose of a combination of Salmeterol and Fluticasone Propionate appears to be safe, well-tolerated and adhered to, and results in no requirement of systemic corticosteroid in a large proportion of patients presenting with mild-to-moderate worsening of dyspnea. This trial has the potential to change the approach of treatment of AECOPD and reduce the use of oral corticosteroids.

Abnormal Exertional Breathlessness on Cardiopulmonary Cycle Exercise Testing in Relation to Self-Reported and Physiologic Responses in Chronic Airflow Limitation.

BACKGROUND: Exertional breathlessness is a cardinal symptom of cardiorespiratory disease. RESEARCH QUESTION: How does breathlessness abnormality, graded using normative reference equations during cardiopulmonary exercise testing (CPET), relate to self-reported and physiologic responses in people with chronic airflow limitation (CAL)? STUDY DESIGN AND METHODS: An analysis was done of people aged ≥ 40 years with CAL undergoing CPET in the Canadian Cohort Obstructive Lung Disease study. Breathlessness intensity ratings (Borg CR10 scale [0-10 category-ratio scale for breathlessness intensity rating]) were evaluated in relation to power output, rate of oxygen uptake, and minute ventilation at peak exercise, using normative reference equations as follows: (1) probability of breathlessness normality (probability of having an equal or greater Borg CR10 rating among healthy people; lower probability reflecting more severe breathlessness) and (2) presence of abnormal breathlessness (rating above the upper limit of normal). Associations with relevant participant-reported and physiologic outcomes were evaluated. RESULTS: We included 330 participants (44% women): mean ± SD age, 64 ± 10 years (range, 40-89 years); FEV1/FVC, 57.3% ± 8.2%; FEV1, 75.6% ± 17.9% predicted. Abnormally low exercise capacity (peak rate of oxygen uptake < lower limit of normal) was present in 26%. Relative to peak power output, rate of oxygen uptake, and minute ventilation, abnormally high breathlessness was present in 26%, 25%, and 18% of participants. For all equations, abnormally high exertional breathlessness was associated with worse lung function, exercise capacity, self-reported symptom burden, physical activity, and health-related quality of life; and greater physiologic abnormalities during CPET. INTERPRETATION: Abnormal breathlessness graded using CPET normative reference equations was associated with worse clinical, physiological, and functional outcomes in people with CAL, supporting construct validity of abnormal exertional breathlessness.

Normative Reference Equations for Breathlessness Intensity during Incremental Cardiopulmonary Cycle Exercise Testing.

Rationale: Cardiopulmonary exercise testing (CPET) is the gold standard to evaluate exertional breathlessness, a common and disabling symptom. However, the interpretation of breathlessness responses to CPET is limited by a scarcity of normative data. Objectives: We aimed to develop normative reference equations for breathlessness intensity (Borg 0-10 category ratio) response in men and women aged ⩾40 years during CPET, in relation to power output (watts), oxygen uptake, and minute ventilation. Methods: Analysis of ostensibly healthy people aged ⩾40 years undergoing symptom-limited incremental cycle CPET (10 W/min) in the CanCOLD (Canadian Cohort Obstructive Lung Disease) study. Participants had smoking histories <5 pack-years and normal lung function and exercise capacity. The probability of each Borg 0-10 category ratio breathlessness intensity rating by power output, oxygen uptake, and minute ventilation (as an absolute or a relative value [percentage of predicted maximum]) was predicted using ordinal multinomial logistic regression. Model performance was evaluated by fit, calibration, and discrimination (C statistic) and externally validated in an independent sample (n = 86) of healthy Canadian adults. Results: We included 156 participants (43% women) from CanCOLD; the mean age was 65 (range, 42-91) years, and the mean body mass index was 26.3 (standard deviation, 3.8) kg/m2. Reference equations were developed for women and men separately, accounting for age and/or body mass. Model performance was high across all equations, including in the validation sample (C statistic for men = 0.81-0.92, C statistic for women = 0.81-0.96). Conclusions: Normative reference equations are provided to compare exertional breathlessness intensity ratings among individuals or groups and to identify and quantify abnormal breathlessness responses (scores greater than the upper limit of normal) during CPET.

Biological Anti-IL-5/IL-5R Therapeutics for Chronic Obstructive Pulmonary Disease (COPD) with Specific Treatable Traits: A Real-World Retrospective Analysis.

Introduction: We describe the use of anti-IL-5 monoclonal antibodies from a COPD clinic, a source other than traditional clinical trials. The objectives were to characterize the patient subgroup prescribed anti-IL-5 monoclonal antibodies and to report potential benefits. Methods: This is a retrospective case series study of 17 patients treated in a COPD subspecialty clinic. All patients had a diagnosis of COPD (post-bronchodilator FEV1/FVC <0.7) and had been prescribed an anti-IL-5 biologic for at least 8 months. Acute exacerbations of COPD (AECOPDs) were collected as reported in electronic medical records. Results: All patients (17) enrolled were treated with biologics for ≥8 months, and 13 (76%) for ≥1 year. Patients were characterized by severe disease traits, FEV1 <50% predicted, recurrent exacerbations (3.5 moderate-to-severe AECOPDs in the year before treatment), high peripheral blood eosinophil counts (≥250 cells/µL in the previous year), all on inhaled triple therapy, and only 1 patient with a diagnosis of asthma prior to smoking. There was a statistically significant decrease in the exacerbation rate compared with baseline after 8 and 12 months of anti-IL-5 treatment, respectively, yielding the equivalent of a 2-3x reduction in exacerbation rate. Absolute FEV1 decreased, and the decline in FEV1 % of predicted reached statistical significance (p<0.05); CAT score improved (p<0.05). Discussion: This real-world evidence data aligns with existing studies suggesting the potential benefit of anti-IL-5 treatment for specific patients with COPD and therefore advocates for further investigation of RCTs on the use of anti-IL-5 biologics for well-characterized patients with COPD.

Single-Cell Sequencing Reveals MYOF-Enriched Monocyte/Macrophage Subcluster as a Favorable Prognostic Factor in Sepsis.

This research utilized single-cell RNA sequencing to map the immune cell landscape in sepsis, revealing 28 distinct cell clusters and categorizing them into nine major types. Delving into the monocyte/macrophage subclusters, 12 unique subclusters are identified and pathway enrichment analyses are conducted using KEGG and GO, discovering enriched pathways such as oxidative phosphorylation and antigen processing. Further GSVA and AUCell assessments show varied activation of interferon pathways, especially in subclusters 4 and 11. The clinical correlation analysis reveals genes significantly linked to survival outcomes. Additionally, cellular differentiation in these subclusters is explored. Building on these insights, the differential gene expression within these subclusters is specifically scrutinized, which reveal MYOF as a key gene with elevated expression levels in the survivor group. This finding is further supported by in-depth pathway enrichment analysis and the examination of cellular differentiation trajectories, where MYOF's role became evident in the context of immune response regulation and sepsis progression. Validating the role of the MYOF gene in sepsis, a dose-dependent response to LPS in THP-1 cells and C57 mice is observed. Finally, inter-cellular communications are analyzed, particularly focusing on the MYOF+Mono/Macro subcluster, which indicates a pivotal role in immune regulation and potential therapeutic targeting.

Glycogen synthase kinase 3 inhibitor attenuates endotoxin-induced liver injury.

BACKGROUND/AIMS: Endotoxin (lipopolysaccharide, LPS)-induced acute liver injury was attenuated by endotoxin tolerance (ET), which is characterized by phosphatidylinositol 3-kinase pathway/Akt signaling. Glycogen synthase kinase 3 (GSK-3) acts downstream of phosphatidylinositol 3-kinase pathway/Akt and GSK-3 inhibitor protects against organic injury. This study evaluates the hypothesis that ET attenuated LPS-induced liver injury through inhibiting GSK-3 functional activity and downstream signaling. METHODS: Sprague-Dawley rats with or without low-dose LPS pretreatment were challenged with or without large dose of LPS and subsequently received studies. Serum tumor necrosis factor-alpha, interleukin-10, alanine aminotransferase, lactate dehydrogenase, and total bilirubin levels were analyzed, morphology of liver tissue was performed, glycogen content, myeloperoxidase content, phagocytosis activity of Kupffer cells, and the expression and inhibitory phosphorylation as well as kinase activity of GSK-3 were examined. Survival after LPS administration was also determined. RESULTS: LPS induced significant increases of serum TNF-α, alanine aminotransferase, lactate dehydrogenase, and total bilirubin (P < 0.05), which were companied by obvious alterations in liver: the injury of liver tissue, the decrease of glycogen, the infiltration of neutrophils, and the enhancement of phagocytosis of Kupffer cells (P < 0.05). LPS pretreatment significantly attenuated these alterations, promoted the inhibitory phosphorylation of GSK-3 and inhibited its kinase activity, and improved the survival rate (P < 0.05). CONCLUSIONS: ET attenuated LPS-induced acute liver injury through inhibiting GSK-3 functional activity and its downstream signaling.