Electrophysiological characteristics of atrial tachycardia recurrence: Relevance to catheter ablation strategies in adults with congenital heart disease.

BACKGROUND: Catheter ablation outcomes for adults with congenital heart disease (ACHD) are described, but recurrence mechanisms remain largely unknown. OBJECTIVE: The purpose of this study was to identify the electrophysiological characteristics of atrial tachycardia (AT) recurrence in ACHD. METHODS: ACHD atrial tachycardia procedures over a 10-year period were explored for AT or atrial fibrillation (AF) recurrence. RESULTS: At 299 procedures in 250 ACHD (mean age 39 ± 15 years; 130 [52%] male), 464 ATs (360 intra-atrial reentrant tachycardia, 104 focal AT; median 2 [IQR 1-3] ATs per procedure) were targeted. Complete (n = 256 [86%]) or partial (n = 37 [12%]) success was achieved in 98% of procedures. Over a median of 3.0 (IQR 1.4-5.3) years of follow-up, 67 patients (27%) developed AT/AF recurrence after the index procedure. Repeat vs index tachycardias were more often focal AT (26/69 [38%] vs 73/378 [19%]; P < .001), demonstrated longer cycle length (325 ms vs 280 ms; P = .003), required isoproterenol (34/69 [50%] vs 121/378 [32%]; P = .03), and involved the pulmonary venous atrium (PVA)/septum (26/69 [38%] vs 67/378 [18%]; P < .001). AF history (hazard ratio [HR] 2.0; interquartile range [IQR] 1.2-3.4; P = .01), incomplete success (HR 3.6; IQR 2.1-6.4; P < .001), and PVA substrate (HR 2.1; IQR 1.2-3.5; P = .006) were independently associated with AT/AF recurrence. With complete index procedure success and no AF history, 5-year actuarial freedom from AT/AF and AT alone were 77% and 80%. CONCLUSION: After catheter ablation in ACHD, repeat ATs were more frequently focal, required isoproterenol administration, or involved intra-atrial reentrant tachycardia within the PVA or atrial septum. Negative factors were partial success, index PVA substrate, and remote history of AF. These data support aggressive pharmacological provocation to eliminate all inducible tachycardias and coexisting PVA substrates at index procedures for ACHD.

Efficacy of isoproterenol in the evaluation of dormant conduction and arrhythmogenic foci identification in atrial fibrillation ablation.

BACKGROUND: Catheter ablation for atrial fibrillation (AF) is an established therapy. However, postoperative recurrence is a serious issue caused by the reconduction of the isolated pulmonary veins (PV) and the onset of non-PV foci. The objectives of this study were to elucidate dormant conduction, confirm PV arrhythmia substrate, induce non-PV foci after PV isolation, and assess the acute efficacy of high dose isoproterenol (ISP) when administered in addition to adenosine. METHODS: The study consisted of 100 patients with drug-refractory AF (paroxysmal and persistent) who underwent ablation therapy (either radio-frequency or cryoballoon ablation) as the first-line of therapy at our hospital. All patients first underwent PV isolation (PVI) and were administered adenosine followed by ISP (6 µg × 5 min). The effects were observed, and the therapeutic strategy was evaluated. RESULTS: Persistent dormant conduction due to ISP administration was observed in 13 patients. In over half of the patients, arrhythmia substrates were identified in the PV. Ten patients presented with persistent PV firing. The ablation of non-PV foci was additionally performed in 23 patients. CONCLUSIONS: We found that dormant conduction, as a result of ISP administration, is persistent and ISP is useful when performing an ablation. In addition, ISP administration is useful for the identification of PV arrhythmia substrates and induction of non-PV foci. However, the effectiveness of ISP may be partially due to the complementary effect of adenosine, and, therefore, a combination of the two drugs seems preferable.

Heat stress-induced deficits in growth, metabolic efficiency, and cardiovascular function coincided with chronic systemic inflammation and hypercatecholaminemia in ractopamine-supplemented feedlot lambs.

Heat stress hinders growth and well-being in livestock, an effect that is perhaps exacerbated by the ß1 agonist ractopamine. Heat stress deficits are mediated in part by reduced feed intake, but other mechanisms involved are less understood. Our objective was to determine the direct impact of heat stress on growth and well-being in ractopamine-supplemented feedlot lambs. Commercial wethers were fed under heat stress (40 °C) for 30 d, and controls (18 °C) were pair-fed. In a 2 × 2 factorial, lambs were also given a daily gavage of 0 or 60 mg ractopamine. Growth, metabolic, cardiovascular, and stress indicators were assessed throughout the study. At necropsy, 9th to 12th rib sections (four-rib), internal organs, and feet were assessed, and sartorius muscles were collected for ex vivo glucose metabolic studies. Heat stress increased (P < 0.05) rectal temperatures and respiration rates throughout the study and reduced (P < 0.05) weight gain and feed efficiency over the first week, ultrasonic loin-eye area and loin depth near the end of the study, and four-rib weight at necropsy. Fat content of the four-rib and loin were also reduced (P < 0.05) by heat stress. Ractopamine increased (P < 0.05) loin weight and fat content and partially moderated the impact of heat stress on rectal temperature and four-rib weight. Heat stress reduced (P < 0.05) spleen weight, increased (P < 0.05) adrenal and lung weights, and was associated with hoof wall overgrowth but not organ lesions. Ractopamine did not affect any measured indicators of well-being. Heat stress reduced (P < 0.05) blood urea nitrogen and increased (P < 0.05) circulating monocytes, granulocytes, and total white blood cells as well as epinephrine, TNFα, cholesterol, and triglycerides. Cortisol and insulin were not affected. Heat stress reduced (P < 0.05) blood pressure and heart rates in all lambs and increased (P < 0.05) left ventricular wall thickness in unsupplemented but not ractopamine-supplemented lambs. No cardiac arrhythmias were observed. Muscle glucose uptake did not differ among groups, but insulin-stimulated glucose oxidation was reduced (P < 0.05) in muscle from heat-stressed lambs. These findings demonstrate that heat stress impairs growth, metabolism, and well-being even when the impact of feed intake is eliminated by pair-feeding and that systemic inflammation and hypercatecholaminemia likely contribute to these deficits. Moreover, ractopamine improved muscle growth indicators without worsening the effects of heat stress.

Cold Flow Evaluation in Transdermal Drug Delivery Systems by Measuring the Width of the Oozed Adhesive.

The objective of this study was to develop a simpler and more practical quantitative evaluation method of cold flow (CF) in transdermal drug delivery systems (TDDSs). CF was forcibly induced by loading a weight on a punched-out sample (bisoprolol and tulobuterol tapes). When the extent of CF was analyzed using the area of oozed adhesive as following a previously reported method, the CF profiles were looked different between the samples 12 mm in diameter subjected to a 0.5-kg weight and samples 24 mm in diameter subjected to a 2.0-kg weight despite an equal load per unit area (4.42 g/mm2). The width of oozed adhesive around the original sample was suggested to be an index that properly describes the relationship between the load per unit area and the extent of CF. Further, it was clarified that the average CF width over the entire circumference of the sample was the same whether the samples were round or square as long as the sample area and load were the same. We also observed a linear relationship between the CF width and the aspect ratio of oval and rectangular samples. These results indicated that the CF properties of typical TDDS products lacking CF-proof processing at the edges could be determined by testing samples cut from the product rather than the whole TDDS patch. The proposed width measuring method was simple and useful for optimizing the composition of the adhesive and for testing the quality of the product.

The risk of higenamine adverse analytical findings following oral administration of plumula nelumbinis capsules.

Higenamine is a ß2-agonist that has been included in the Prohibited List of the World Anti-Doping Agency (WADA) since 2017. Meanwhile, it exists in plumula nelumbinis, a part of the lotus seed, and is commonly used as an ingredient in cuisines, herbal medicines, and nutritional supplements in China and other countries in East Asia. Therefore, an evaluation of the risk of an adverse analytical finding (AAF) of higenamine caused by plumula nelumbinis products is necessary in doping control. In this study, 14 volunteers took plumula nelumbinis capsules orally (0.34 g/caplet, 6 caplets/day, 7 days), and another 11 volunteers ingested higenamine tablets (three 5 mg tablets/day for 7 days). Urine samples were collected over a period of 14 days. All urine samples were subjected to quantitative dilute-and-shoot analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The analytical results showed that urinary higenamine concentrations exceeded the WADA reporting limit (10 ng/mL) during the drug period in most sample groups. The maximum higenamine concentration observed in the plumula nelumbinis capsule group was 500 ng/mL. Based on confidence interval theory, appropriate data were used to establish mathematical models. The models reflected that the higenamine concentration in urine can exceed the WADA reporting limit with a high probability after taking plumula nelumbinis capsules. In conclusion, oral administration of plumula nelumbinis capsules showed a high risk of an AAF due to higenamine.

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.

Hypertrophic muscle growth and metabolic efficiency were impaired by chronic heat stress, improved by zilpaterol supplementation, and not affected by ractopamine supplementation in feedlot lambs1.

Feedlot performance is reduced by heat stress and improved by ß adrenergic agonists (ßAA). However, the physiological mechanisms underlying these outcomes are not well characterized, and anecdotal reports suggest that ßAA may confound the effects of heat stress on wellbeing. Thus, we sought to determine how heat stress and ßAA affect growth, metabolic efficiency, and health indicators in lambs on a feedlot diet. Wethers (38.6 ± 1.9 kg) were housed under thermoneutral (controls; n = 25) or heat stress (n = 24) conditions for 21 d. In a 2 × 3 factorial, their diets contained no supplement (unsupplemented), ractopamine (ß1AA), or zilpaterol (ß2AA). Blood was collected on days -3, 3, 9, and 21. On day 22, lambs were harvested and ex vivo skeletal muscle glucose oxidation was determined to gauge metabolic efficiency. Feet and organ tissue damage was assessed by veterinary pathologists. Heat stress reduced (P < 0.05) feed intake by 21%, final bodyweight (BW) by 2.6 kg, and flexor digitorum superficialis (FDS) muscle mass by 5%. ß2AA increased (P < 0.05) FDS mass/BW by 9% and average muscle fiber area by 13% compared with unsupplemented lambs. Blood lymphocytes and monocytes were greater (P < 0.05) in heat-stressed lambs, consistent with systemic inflammation. Plasma insulin was 22% greater (P < 0.05) and glucose/insulin was 16% less (P < 0.05) in heat-stressed lambs than controls. Blood plasma urea nitrogen was increased (P < 0.05) by heat stress on day 3 but reduced (P < 0.05) on days 9 and 21. Plasma lipase and lactate dehydrogenase were reduced (P < 0.05) by heat stress. Glucose oxidation was 17% less (P < 0.05) in muscle from heat-stressed lambs compared with controls and 15% greater (P < 0.05) for ß2AA-supplemented compared with unsupplemented lambs. Environment and supplement interacted (P < 0.05) for rectal temperature, which was increased (P < 0.05) by heat stress on all days but more so (P < 0.05) in ß2AA-supplemented lambs on days 4, 9, and 16. Heat stress increased (P < 0.05) the frequency of hoof wall overgrowth, but ßAA did not produce any pathologies. We conclude that reduced performance in heat-stressed lambs was mediated by reduced feed intake, muscle growth, and metabolic efficiency. ß2AA increased muscle growth and improved metabolic efficiency by increasing muscle glucose oxidation, but no such effects were observed with ractopamine. Finally, ßAA supplementation was not detrimental to health indicators in this study, nor did it worsen the effects of heat stress.

Medication adherence and persistence in chronic obstructive pulmonary disease patients receiving triple therapy in a USA commercially insured population.

INTRODUCTION: This longitudinal, retrospective cohort study of patients with COPD describes baseline characteristics, adherence, and persistence following initiation of inhaled corticosteroids (ICS)/long-acting ß2-agonists (LABA)/long-acting muscarinic antagonists (LAMA) from multiple inhaler triple therapy (MITT). METHODS: Patients aged ≥40 years receiving MITT between January 2012 and September 2015 were identified from the IQVIA™ Real-world Data Adjudicated Claims-USA database. MITT was defined as subjects with ≥1 overlapping days' supply of three COPD medications (ICS, LABA, and LAMA). Adherence (proportion of days covered, PDC) and discontinuation (defined as a gap of 1, 30, 60, or 90 days of supply in any of the three components of the triple therapy) were calculated for each patient over 12 months of follow-up. In addition, analyses were stratified by number of inhalers. RESULTS: In total, 14,635 MITT users were identified (mean age, 62 years). Mean PDC for MITT at 12 months was 0.37%. Mean PDC for the ICS/LABA and LAMA component at 12 months was 49% (0.49±0.31; median, 0.47) and 54% (0.54±0.33; 0.56), respectively. The proportion of adherent patients (PDC ≥0.8) at 12 months was 14% for MITT. Allowing for a 30-day gap from last day of therapy, 86% of MITT users discontinued therapy during follow-up. CONCLUSION: Patients with COPD had low adherence to and persistence with MITT in a real-world setting. Mean PDC for each single inhaler component was higher than the mean PDC observed with MITT. Reducing the number of inhalers may improve overall adherence to intended triple therapy.

Treatment of asthma in smokers: A questionnaire survey in Japanese clinical practice.

BACKGROUND: Cigarette smoking in patients with asthma leads to poor symptom control. As patients who are current smokers have been excluded from enrollment in many clinical trials on asthma, there are few reports on the treatment in current smokers with asthma. In this study, we aimed to assess how respiratory physicians manage asthma in current smokers in Japan. METHODS: Respiratory physicians in 16 Japanese hospitals answered a questionnaire on treatment for patients with asthma between December 2014 and February 2015. Medical records were reviewed for 1756 patients with asthma. RESULTS: The mean patient age was 61.1 years, and 62.9% of the patients were female. A total of 102 patients (5.8%) were current smokers, and 546 patients (31.1%) were former smokers. Long-acting muscarinic antagonists (LAMA) were prescribed more frequently for current smokers with asthma than for former smokers and never smokers with asthma (10.8% vs 4.6%, p = 0.01, 10.8% vs 3.8%, p < 0.01). In contrast, macrolides were prescribed more frequently for former smokers and never smokers with asthma than for current smokers with asthma (7.7% vs 1.0%, p = 0.01, 6.4% vs 1.0%, p = 0.03). Triple therapy, i.e., inhaled corticosteroids, long-acting beta agonists, and LAMA concomitantly, was prescribed for current smokers with asthma more frequently than for former smokers and never smokers with asthma (9.8% vs 4.0%, p = 0.01, 9.8% vs 3.3%, p < 0.01). CONCLUSIONS: According to this survey, current smokers with asthma received more intensive therapy, including LAMA, than did former smokers with asthma.

Is adenosine useful for the identification of atrial fibrillation triggers?

INTRODUCTION: Both isoproterenol (Iso) and adenosine (Ado) are used to induce atrial fibrillation (AF) in the electrophysiology lab. However, the utility of Ado has not been systematically established. OBJECTIVE: The purpose of this study was to compare Ado to Iso for the induction of paroxysmal AF. METHODS: Forty patients (16 women; mean age, 60 ± 12 years) with paroxysmal AF, presenting for ablation were prospectively included of whom 36 (90%) received Ado (18-36 mg) and/or Iso (3-20 µg/min incremental dose) in a randomized order (26 [72%] received both drugs). RESULTS: AF was induced with Iso in 15 of 32 (47%) and with Ado in 12 of 30 (40%) patients (P = 0.9). Iso-triggered AF started from the left pulmonary veins (PVs) in 11 of 15 (73%), from the right PVs in 3 of 15 (20%), and from the coronary sinus (CS) in 1 of 15 (7%) cases. Ado-induced AF episodes originated from the left PVs in 6 of 12 (50%), from the right atrium (RA) in 4 of 12 (33%), and from the CS in 2 of 12 (17%) cases. Altogether, Iso-induced AF was more likely initiated from the PVs (93%) compared with Ado (50%) ( P = 0.02). Ado-induced non-PV triggers were not predictive of arrhythmia recurrence after PV isolation. CONCLUSION: Ado much more frequently induces non-PV triggers, especially from the RA. The clinical significance of these foci, however, is questionable.

Trends in the utilisation of COPD therapeutic regimens before and after the introduction of LAMA/LABA combination products: A population-based study.

INTRODUCTION: Long-acting muscarinic antagonist/long-acting beta agonist (LAMA/LABA) combination products have recently been introduced. We sought to describe the impact of these products on patterns of chronic obstructive pulmonary disease (COPD) therapy. MATERIALS AND METHODS: We used administrative healthcare data from Ontario, Canada, to identify all residents aged ≥ 65 years who were dispensed a product to treat COPD at least once between January 2010 and May 2016, and to calculate the monthly prevalence of use of 11 mutually exclusive therapeutic regimens. We also compared the characteristics of new users of LAMA/LABA and LAMA + LABA regimens. RESULTS: Overall use of any COPD regimen remained stable in the year following the formulary listing of LAMA/LABA combination products in May 2015, as did the use of LABA/ICS (most commonly-used regimen). Use of LAMA/LABA and LAMA/LABA + ICS (inhaled corticosteroid) regimens rose rapidly to 283 and 56 users per 100,000 population, respectively, while concurrent falls were seen for LAMA + LABA/ICS (2047 to 1944), LAMA + LABA + ICS (30-19), and LAMA + LABA (103-63). LAMA and LABA monotherapy use declined (1764 to 1669 and 57 to 51, respectively). New users of LAMA/LABA were more likely to be male, urban-dwelling, and to have transitioned from LABA/ICS therapy than new users of LAMA + LABA, and less likely to have transitioned from LAMA or LABA monotherapy, or LAMA + ICS. They were also more likely to have visited a respirologist, and less likely to have been hospitalised, at least once in the preceding 180 days. CONCLUSIONS: The introduction of LAMA/LABA combination products led to population-level changes in regimens used for COPD therapy, but no overall increase in long-acting therapy use. New users of LAMA/LABA and LAMA + LABA regimens transitioned to dual LAMA and LABA therapy through different treatment pathways.

Characteristics and health care resource use of subjects with COPD in the year before initiating LAMA monotherapy or LAMA+LABA combination therapy: A U.S. database study.

PURPOSE: To characterize subjects with chronic obstructive pulmonary disease (COPD) newly initiated on long-acting muscarinic antagonists (LAMA) or dual LAMA/long-acting ß2-adrenergic agonist (LABA) therapy. DESIGN: This pilot/preliminary analysis was a retrospective crosssectional study of subjects with COPD from the Optum Impact National Managed Care Benchmark Database. METHODOLOGY: Subjects with at least one LAMA prescription in the index period (July 2008-June 2009) were included and stratified by treatment. Data were collected in the year before the index date and included comorbidities, medication use, COPD-related costs, health care resource use, and exacerbations. RESULTS: Of 5,311 eligible subjects, 2,057 initiated LAMA therapy (LAMA cohort) and 191 initiated LAMA+LABA therapy (LAMA+LABA cohort). The Charlson comorbidity index was slightly lower in the LAMA+LABA cohort than the LAMA cohort (mean±SD: 0.63±1.13 vs. 0.66±1.28), but the number of prescriptions was higher (mean±SD: 42.9±23.2 vs. 30.5±27.2). The LAMA+LABA cohort had higher short-acting inhaled ß2 agonist (56.0% vs. 35.7%), oral corticosteroid (37.7% vs. 32.6%), and home oxygen therapy use (14.1% vs. 3.2%) than the LAMA cohort. Total medical costs were greater in the LAMA+LABA cohort than the LAMA cohort (mean±SD: $3,320.40±4085.9 vs. $1,226.20±3602.9), although emergency department ($11.00±66.8 vs. $30.70±259.2) and outpatient visit ($39.60±163.1 vs. $41.70±424.3) costs were lower. Resource use and exacerbation incidence were similar between cohorts. CONCLUSION: In this first look, subjects with COPD initiating LAMA or LAMA+LABA therapy exhibited different clinical and resource use characteristics in the year before treatment. Subjects receiving LAMA+LABA were older, with higher COPD co-medication use, more prescriptions, and associated higher pharmacy costs compared with subjects initiating LAMA. These differences may reflect a higher severity of COPD in those starting LABA+LAMA treatment.

The Beneficial Effects of Electroacupuncture at PC6 Acupoints (Neiguan) on Myocardial Ischemia in ASIC3 -/- mice.

This study aims to investigate the possible mechanisms of electroacupuncture (EA) at PC6 to improve myocardial ischemia (MI) by regulating the cardiac transient outward potassium current channel (Ito). According to the random number table, the mice were divided into six groups of six mice each: control group, MI group, PC6, LU7 (Lieque-point), ST36 (Zusanli-point), and nonacupoint group. Mice in the control group were injected with saline (20 mg/kg, 24 hours interval), and the other ASIC3 -/- mice were injected subcutaneously twice with isoproterenol (ISO) (20 mg/kg, 24 hours interval). In the preexperiment, 5 mg/kg, 10 mg/kg, 20 mg/kg, and 30 mg/kg of ISO were used, and the results showed that 5 mg/kg and 10 mg/kg of ISO both could induce acute MI, but shorter duration of sustained MI. On the other hand, an injection of 30 mg/kg can make the mice experience arrhythmia or die immediately, and EA was operated at PC6, LU7, ST36 acupoints, and nonacupoint in the mice of PC6, LU7, ST36, and nonacupoint groups, respectively, after injecting twice. Then Western blotting techniques (Western Blot) were used to analyze the protein expressions of Kv1.4, Kv4.2, Kv4.3, and KchIP2. The results of this experiment showed that the protein expressions of Kv1.4, Kv4.2, Kv4.3, and KChIP2 in MI group were significantly lower than those in the control group (p < 0.01). Compared with MI group, the results of PC6, LU7, and ST36 groups obviously increased (p < 0.05). Furthermore, the expressions of PC6 group were higher than LU7 group and ST36 group (p < 0.05). And electrocardiogram's T-waves showed obvious pathological changes in the MI group compared to the control group (p < 0.01). After EA, the abnormal T-waves voltage of ECG in PC6, LU7, and ST36 groups was improved (p < 0.05). In addition, the rate change of PC6 group was larger than that of both LU7 and ST36 groups (p < 0.05). But the T-waves voltage of the nonacupoint group was not significantly different than that of the MI group (p > 0.05).

Once-Daily Single-Inhaler Triple versus Dual Therapy in Patients with COPD.

BACKGROUND: The benefits of triple therapy for chronic obstructive pulmonary disease (COPD) with an inhaled glucocorticoid, a long-acting muscarinic antagonist (LAMA), and a long-acting ß2-agonist (LABA), as compared with dual therapy (either inhaled glucocorticoid-LABA or LAMA-LABA), are uncertain. METHODS: In this randomized trial involving 10,355 patients with COPD, we compared 52 weeks of a once-daily combination of fluticasone furoate (an inhaled glucocorticoid) at a dose of 100 µg, umeclidinium (a LAMA) at a dose of 62.5 µg, and vilanterol (a LABA) at a dose of 25 µg (triple therapy) with fluticasone furoate-vilanterol (at doses of 100 µg and 25 µg, respectively) and umeclidinium-vilanterol (at doses of 62.5 µg and 25 µg, respectively). Each regimen was administered in a single Ellipta inhaler. The primary outcome was the annual rate of moderate or severe COPD exacerbations during treatment. RESULTS: The rate of moderate or severe exacerbations in the triple-therapy group was 0.91 per year, as compared with 1.07 per year in the fluticasone furoate-vilanterol group (rate ratio with triple therapy, 0.85; 95% confidence interval [CI], 0.80 to 0.90; 15% difference; P<0.001) and 1.21 per year in the umeclidinium-vilanterol group (rate ratio with triple therapy, 0.75; 95% CI, 0.70 to 0.81; 25% difference; P<0.001). The annual rate of severe exacerbations resulting in hospitalization in the triple-therapy group was 0.13, as compared with 0.19 in the umeclidinium-vilanterol group (rate ratio, 0.66; 95% CI, 0.56 to 0.78; 34% difference; P<0.001). There was a higher incidence of pneumonia in the inhaled-glucocorticoid groups than in the umeclidinium-vilanterol group, and the risk of clinician-diagnosed pneumonia was significantly higher with triple therapy than with umeclidinium-vilanterol, as assessed in a time-to-first-event analysis (hazard ratio, 1.53; 95% CI, 1.22 to 1.92; P<0.001). CONCLUSIONS: Triple therapy with fluticasone furoate, umeclidinium, and vilanterol resulted in a lower rate of moderate or severe COPD exacerbations than fluticasone furoate-vilanterol or umeclidinium-vilanterol in this population. Triple therapy also resulted in a lower rate of hospitalization due to COPD than umeclidinium-vilanterol. (Funded by GlaxoSmithKline; IMPACT ClinicalTrials.gov number, NCT02164513 .).

[Persistence to treatment and resources use with inhaled fixed-dose combinations of corticosteroids and long-acting ß-adrenergic agonists for the treatment of asthma: A population-based retrospective study]. / Persistencia al tratamiento y uso de recursos con corticosteroides y agonistas ß-adrenérgicos de larga duración inhalados a dosis fijas para el tratamiento del asma: estudio retrospectivo de base poblacional.

OBJECTIVE: To determine the persistence, exacerbations, and use of resources in patients who use inhaler treatment with fluticasone propionate/formoterol (PF/Form) in relation with other combinations of inhaled corticosteroid/long-acting ß-adrenergic (ICS/LABA) at fixed doses, for the treatment of asthma in real-life practice. MATERIAL AND METHODS: Observational study conducted by reviewing medical records. The study included subjects ≥18 years of age who started treatment with ICS/LABA and who met certain inclusion/exclusion criteria. The follow-up was carried out for one year. Study groups: a) PF/Form and b) Other-combinations (Other-ICS/LABA). MAIN MEASUREMENTS: Persistence, medication possession ratio (MPR), exacerbations, and costs (direct/indirect). The statistical analysis was performed using regression models, with a P<.05. RESULTS: A total of 3,203 patients were included in the study. By groups: a) FP/Form: 7.0% and b) Other-ICS/LABA: 93.0%. The mean age was 52.2 years, and 60.8% were women. A total of 44.9% of patients had persistent-moderate asthma. Patients under treatment with FP/Form were associated with greater persistence (67.6 vs. 61.2%, P=.043), a higher RPM (80.6 vs. 74.3%, P=.002), and less exacerbations (16.0 vs. 21.9%, P=.021), particularly severe-exacerbations (4.0 vs. 7.7%, P=.043). The mean/unit of the total cost (ANCOVA) was lower in patients under treatment with PF/Form (2,033 vs. € 2,486, P=.012), respectively. The total cost was associated with: Exacerbations (ß=0.618), asthma-severity (ß=0.214), age (ß=0.073), and lack-adherence (RPM: ß=-0.031), P<.01. CONCLUSIONS: Patients undergoing treatment with PF/Form were associated with greater adherence to treatment (persistence, RPM), a circumstance that leads to less severe exacerbations and total costs for the national health system. These differences could be due to the pharmacological properties of the drug or other factors not measured.

Inhaled magnesium sulfate in the treatment of acute asthma.

BACKGROUND: Asthma exacerbations can be frequent and range in severity from mild to life-threatening. The use of magnesium sulfate (MgSO4) is one of numerous treatment options available during acute exacerbations. While the efficacy of intravenous MgSO4 has been demonstrated, the role of inhaled MgSO4 is less clear. OBJECTIVES: To determine the efficacy and safety of inhaled MgSO4 administered in acute asthma. SPECIFIC AIMS: to quantify the effects of inhaled MgSO4 I) in addition to combination treatment with inhaled ß2-agonist and ipratropium bromide; ii) in addition to inhaled ß2-agonist; and iii) in comparison to inhaled ß2-agonist. SEARCH METHODS: We identified randomised controlled trials (RCTs) from the Cochrane Airways Group register of trials and online trials registries in September 2017. We supplemented these with searches of the reference lists of published studies and by contact with trialists. SELECTION CRITERIA: RCTs including adults or children with acute asthma were eligible for inclusion in the review. We included studies if patients were treated with nebulised MgSO4 alone or in combination with ß2-agonist or ipratropium bromide or both, and were compared with the same co-intervention alone or inactive control. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial selection, data extraction and risk of bias. We made efforts to collect missing data from authors. We present results, with their 95% confidence intervals (CIs), as mean differences (MDs) or standardised mean differences (SMDs) for pulmonary function, clinical severity scores and vital signs; and risk ratios (RRs) for hospital admission. We used risk differences (RDs) to analyse adverse events because events were rare. MAIN RESULTS: Twenty-five trials (43 references) of varying methodological quality were eligible; they included 2907 randomised patients (2777 patients completed). Nine of the 25 included studies involved adults; four included adult and paediatric patients; eight studies enrolled paediatric patients; and in the remaining four studies the age of participants was not stated. The design, definitions, intervention and outcomes were different in all 25 studies; this heterogeneity made direct comparisons difficult. The quality of the evidence presented ranged from high to very low, with most outcomes graded as low or very low. This was largely due to concerns about the methodological quality of the included studies and imprecision in the pooled effect estimates. Inhaled magnesium sulfate in addition to inhaled ß2-agonist and ipratropiumWe included seven studies in this comparison. Although some individual studies reported improvement in lung function indices favouring the intervention group, results were inconsistent overall and the largest study reporting this outcome found no between-group difference at 60 minutes (MD -0.3 % predicted peak expiratory flow rate (PEFR), 95% CI -2.71% to 2.11%). Admissions to hospital at initial presentation may be reduced by the addition of inhaled magnesium sulfate (RR 0.95, 95% CI 0.91 to 1.00; participants = 1308; studies = 4; I² = 52%) but no difference was detected for re-admissions or escalation of care to ITU/HDU. Serious adverse events during admission were rare. There was no difference between groups for all adverse events during admission (RD 0.01, 95% CI -0.03 to 0.05; participants = 1197; studies = 2). Inhaled magnesium sulfate in addition to inhaled ß2-agonistWe included 13 studies in this comparison. Although some individual studies reported improvement in lung function indices favouring the intervention group, none of the pooled results showed a conclusive benefit as measured by FEV1 or PEFR. Pooled results for hospital admission showed a point estimate that favoured the combination of MgSO4 and ß2-agonist, but the confidence interval includes the possibility of admissions increasing in the intervention group (RR 0.78, 95% CI 0.52 to 1.15; participants = 375; studies = 6; I² = 0%). There were no serious adverse events reported by any of the included studies and no between-group difference for all adverse events (RD -0.01, 95% CI -0.05 to 0.03; participants = 694; studies = 5). Inhaled magnesium sulfate versus inhaled ß2-agonistWe included four studies in this comparison. The evidence for the efficacy of ß2-agonists in acute asthma is well-established and therefore this could be considered a historical comparison. Two studies reported a benefit of ß2-agonist over MgSO4 alone for PEFR and two studies reported no difference; we did not pool these results. Admissions to hospital were only reported by one small study and events were rare, leading to an uncertain result. No serious adverse events were reported in any of the studies in this comparison; one small study reported mild to moderate adverse events but the result is imprecise. AUTHORS' CONCLUSIONS: Treatment with nebulised MgSO4 may result in modest additional benefits for lung function and hospital admission when added to inhaled ß2-agonists and ipratropium bromide, but our confidence in the evidence is low and there remains substantial uncertainty. The recent large, well-designed trials have generally not demonstrated clinically important benefits. Nebulised MgSO4 does not appear to be associated with an increase in serious adverse events. Individual studies suggest that those with more severe attacks and attacks of shorter duration may experience a greater benefit but further research into subgroups is warranted.Despite including 24 trials in this review update we were unable to pool data for all outcomes of interest and this has limited the strength of the conclusions reached. A core outcomes set for studies in acute asthma is needed. This is particularly important in paediatric studies where measuring lung function at the time of an exacerbation may not be possible. Placebo-controlled trials in patients not responding to standard maximal treatment, including inhaled ß2-agonists and ipratropium bromide and systemic steroids, may help establish if nebulised MgSO4 has a role in acute asthma. However, the accumulating evidence suggests that a substantial benefit may be unlikely.

Evaluation of Commercial ß-Agonists, Dietary Protein, and Shade on Fecal Shedding of Escherichia coli O157:H7 from Feedlot Cattle.

Escherichia coli O157:H7 is a foodborne pathogen commonly associated with cattle feces. Diet, including dietary supplements such as ß-agonists, may impact fecal shedding of this pathogen. A series of three experiments were conducted to determine if the ß-agonists ractopamine hydrochloride (RAC) or zilpaterol hydrochloride (ZH) would impact the level or prevalence of fecal E. coli O157:H7 shedding. In Experiment 1, dietary RAC did not impact fecal shedding of E. coli O157:H7 based on the level or prevalence, but the addition of dietary soybean meal (SBM) in the study did reduce E. coli O157:H7 shedding. In Experiments 2 and 3, dietary ZH did not affect fecal E. coli O157:H7 shedding as determined by enumeration or prevalence, but in Experiment 2 the addition of 30% (dry matter basis) wet distillers grains with solubles (WDGS) in the diet tended to increase E. coli O157:H7 shedding. Shade is a potential management tool to reduce heat stress in cattle, and in Experiment 3 the presence of shade over the feedlot pens did not affect E. coli O157:H7 shedding. The use of ß-agonists in cattle diets did not significantly affect fecal shedding of E. coli O157:H7, and in particular the percentage of animals shedding enumerable levels of the pathogen did not change, indicating that there was not a change in colonization. As has been reported previously and indicated again in this study, the use of WDGS in the diet may increase E. coli O157:H7 shedding. In contrast, the addition of SBM to cattle diets, to increase the dietary crude protein, appeared to reduce E. coli O157:H7 shedding, but this potential dietary intervention needs to be confirmed with additional research.

Nitric oxide synthase and cyclooxygenase modulate ß-adrenergic cutaneous vasodilatation and sweating in young men.

KEY POINTS: ß-Adrenergic receptor agonists such as isoproterenol induce cutaneous vasodilatation and sweating in humans, but the mechanisms underpinning this response remain unresolved. Using intradermal microdialysis, we evaluated the roles of nitric oxide synthase (NOS) and cyclooxygenase (COX) in ß-adrenergic cutaneous vasodilatation and sweating elicited by administration of isoproterenol. We show that while NOS contributes to ß-adrenergic cutaneous vasodilatation, COX restricts cutaneous vasodilatation. We also show that combined inhibition of NOS and COX augments ß-adrenergic sweating These new findings advance our basic knowledge regarding the physiological control of cutaneous blood flow and sweating, and provide important and new information to better understand the physiological significance of ß-adrenergic receptors in the skin. ABSTRACT: ß-Adrenergic receptor agonists such as isoproterenol can induce cutaneous vasodilatation and sweating in humans, but the mechanisms underpinning this response remain unresolved. We evaluated the hypotheses that (1) nitric oxide synthase (NOS) contributes to ß-adrenergic cutaneous vasodilatation, whereas cyclooxygenase (COX) limits the vasodilatation, and (2) COX contributes to ß-adrenergic sweating. In 10 young males (25 ± 5 years), cutaneous vascular conductance (CVC) and sweat rate were evaluated at four intradermal forearm skin sites infused with (1) lactated Ringer solution (control), (2) 10 mm Nω -nitro-l-arginine (l-NNA), a non-specific NOS inhibitor, (3) 10 mm ketorolac, a non-specific COX inhibitor, or (4) a combination of l-NNA and ketorolac. All sites were co-administered with a high dose of isoproterenol (100 µm) for 3 min to maximally induce ß-adrenergic sweating (ß-adrenergic sweating is significantly blunted by subsequent activations). Approximately 60 min after the washout period, three incremental doses of isoproterenol were co-administered (1, 10 and 100 µm each for 25 min). Increases in CVC induced by the first and second 100 µm isoproterenol were attenuated by l-NNA alone, and those in response to all doses of isoproterenol were reduced by l-NNA with co-infusion of ketorolac (all P ≤ 0.05). Ketorolac alone augmented increases in CVC induced by 10 µm and by the second 100 µm isoproterenol (both P ≤ 0.05). While isoproterenol-induced sweating was not affected by the separate administration of l-NNA or ketorolac (all P > 0.05), their combined administration augmented sweating elicited by the first 3 min of 100 µm isoproterenol (P = 0.05). We show that while NOS contributes to ß-adrenergic cutaneous vasodilatation, COX restrains the vasodilatation. Finally, combined inhibition of NOS and COX augments ß-adrenergic sweating.

The effects of increasing supplementation of zinc-amino acid complex on growth performance, carcass characteristics, and inflammatory response of beef cattle fed ractopamine hydrochloride.

Forty-two Angus crossbred steers (380 ± 5.3 kg) were enrolled in a finishing study to evaluate the influence of a supplemental Zn amino-acid complex (ZnAA; Availa-Zn) on performance and carcass characteristics of finishing steers in combination with ractopamine hydrochloride (RAC). Steers were stratified by BW into 7 pens of 6 steers each, and individual feed intake was measured. Steers were assigned to 1 of 4 treatments for 86 d (pre-RAC period): a dry-rolled corn-based diet supplemented with 60 mg Zn/kg DM from ZnSO and no supplemental ZnAA (CON; analyzed 88 mg Zn/kg DM; = 6) or CON diet supplemented with 30 (Zn30; = 12), 60 (Zn60; = 12), or 90 (Zn90; = 11) mg Zn/kg DM from ZnAA. Day 86 BW and G:F displayed a quadratic tendency ( = 0.09) with Zn60 steers being greater than the other treatments. Plasma cyclic adenosine monophosphate tended to linearly increase with increasing ZnAA ( = 0.10). On d 88, 6 of 12 steers (one of the 2 pens) receiving supplemental ZnAA was randomly selected to be supplemented with RAC at 300 mg∙steer∙d for the final 28 d of the experiment (RAC period). This created 7 final treatments: CON: no supplemental ZnAA, no RAC ( = 5); Zn30: Zn30, no RAC ( = 5); Zn30R: Zn30 + RAC ( = 6); Zn60: Zn60, no RAC ( = 6); Zn60R: Zn60 + RAC ( = 6); Zn90: Zn90, no RAC ( = 5); and Zn90R: Zn90 + RAC ( = 6). During the RAC period, as supplemental ZnAA increased within RAC-supplemented treatments, there was a linear increase in final BW, ADG, and G:F ( < 0.05). However, there was no effect of supplemental ZnAA on BW, ADG, or G:F during this period in non-RAC fed steers ( ≥ 0.44). Day 111 plasma Cu was increased, plasma Fe decreased, and leukocyte counts and serum interleukin-8 concentrations were greater ( < 0.05) in RAC-fed steers suggesting that RAC may elicit a mild inflammatory response. There was a tendency for increasing Zn supplementation to decrease plasma haptoglobin within RAC-fed steers ( = 0.07), suggesting that Zn may alter the inflammatory response. Overall, Zn60 improved growth performance during the pre-RAC period. Zinc supplemented as ZnAA appears to improve growth in combination with RAC supplementation, suggesting that Zn may enhance or support the biological function of RAC. Additionally, these results indicate that feeding RAC impacts trace mineral status, and potentially causes a non-specific inflammatory response, but further research is required to define this response.

Effect of ractopamine hydrochloride and zilpaterol hydrochloride on cardiac electrophysiologic and hematologic variables in finishing steers.

OBJECTIVE To investigate the effects of dietary supplementation with the ß-adrenoceptor agonists ractopamine hydrochloride and zilpaterol hydrochloride on ECG and clinicopathologic variables of finishing beef steers. DESIGN Randomized controlled trial. ANIMALS 30 Angus steers. PROCEDURES Steers were grouped by body weight and randomly assigned to receive 1 of 3 diets for 23 days: a diet containing no additive (control diet) or a diet containing ractopamine hydrochloride (300 mg/steer/d) or zilpaterol hydrochloride (8.3 mg/kg [3.8 mg/lb] of feed on a dry-matter basis), beginning on day 0. Steers were instrumented with an ambulatory ECG monitor on days -2, 6, 13, and 23, and continuous recordings were obtained for 72, 24, 24, and 96 hours, respectively. At the time of instrumentation, blood samples were obtained for CBC and serum biochemical and blood lactate analysis. Electrocardiographic recordings were evaluated for mean heart rate and arrhythmia rates. RESULTS Steers fed zilpaterol or ractopamine had greater mean heart rates than those fed the control diet. Mean heart rates were within reference limits for all steers, with the exception of those in the ractopamine group on day 14, in which mean heart rate was high. No differences in arrhythmia rates were identified among the groups, nor were any differences identified when arrhythmias were classified as single, paired, or multiple (> 2) beats. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that dietary supplementation of cattle with ractopamine or zilpaterol at FDA-approved doses had no effect on arrhythmia rates but caused an increase in heart rate that remained within reference limits.