Treating asthma in the time of COVID.

The Precision Interventions for Severe and/or Exacerbation-Prone Asthma clinical trials network is actively assessing novel treatments for severe asthma during the coronavirus disease (COVID-19) pandemic and has needed to adapt to various clinical dilemmas posed by the COVID-19 pandemic. Pharmacologic interactions between established asthma therapies and novel drug interventions for COVID-19 infection, including antivirals, biologics, and vaccines, have emerged as a critical and unanticipated issue in the clinical care of asthma. In particular, impaired metabolism of some long-acting beta-2 agonists by the cytochrome P4503A4 enzyme in the setting of antiviral treatment using ritonavir-boosted nirmatrelvir (NVM/r, brand name Paxlovid) may increase risk for adverse cardiovascular events. Although available data have documented the potential for such interactions, these issues are largely unappreciated by clinicians who treat asthma, or those dispensing COVID-19 interventions in patients who happen to have asthma. Because these drug-drug interactions have not previously been relevant to patient care, clinicians have had no guidance on management strategies to reduce potentially serious interactions between treatments for asthma and COVID-19. The Precision Interventions for Severe and/or Exacerbation-Prone Asthma network considered the available literature and product information, and herein share our considerations and plans for treating asthma within the context of these novel COVID-19-related therapies.

Evaluation of choroidal thickness in children with acute asthma attack by optical coherence tomography.

OBJECTIVE: To evaluate the change in central choroidal thickness in children with asthma attack before and after treatment with ß2 agonists. MATERIALS AND METHODS: About 100 eyes of 50 patients (5-17 years old) with visual acuity of 20/20 who had no retinal, choroidal, and systemic comorbidity were examined by enhanced depth optical coherence tomography (EDI-OCT) before and after asthma attack treatment. Sixty eyes of 30 healthy children of similar age and gender were evaluated as the control group. The central choroidal thickness, peak expiratory flow (PEF), forced expiratory volume 1(FEV1), oxygen saturation, and heart rate were evaluated. RESULTS: The mean age of the patients was 9.2 ± 3.1 years, and the mean saturation values of patients was 97.2 ± 1.3 before treatment, and it increased to 98.3 ± 0.9 after treatment with a statistically significant difference. The mean FEV1 values were 80.8 ± 15.2 before, and 92.7 ± 12.9 after the treatment and PEF values were 75.9 ± 18.6 before and 89.3 ± 18.9 after treatment. This differences were statistically significant (p < 0.001). The average choroidal thickness before the treatment were 310.4 ± 34.2 µm and decreased to 302.7 ± 34.4 µm after the treatment, this decrease was statistically significant (p < 0.001). The mean choroidal thickness of the control group was 303.0 ± 7.3 µm and compared to the pre-treatment and post-treatment values, it was more similar to the post-treatment values, although there was no statistically difference. CONCLUSION: In our study, it was shown that choroidal thickness was significantly reduced in children with asthma who received attack treatment with ß2 agonists, and it was similar to the control group after the treatment.

Echocardiographic Evaluation of the Cardiac Chambers in Asthmatic Patients: The BADA (Blood Pressure Levels, Clinical Features and Markers of Subclinical Cardiovascular Damage of Asthma Patients) Study-ECO.

The "Blood pressure levels, clinical features and markers of subclinical cardiovascular Damage of Asthma patients" (BADA) study is aimed at defining the cardiovascular risk profile and the markers of subclinical and clinical vascular and cardiac damage in asthmatic patients. Very few studies have assessed asthmatic patients without concomitant heart disease through a transthoracic echocardiogram. The goal of the present study is to investigate the prevalence of morphology and/or function changes in the cardiac chambers of a sample of 86 patients with chronic asthma, referred to the dedicated outpatient unit of the Division of Respiratory Diseases of the AOUP "P. Giaccone" of the University of Palermo, and the results obtained were compared with those of a control group without respiratory or cardiovascular diseases. Patients with asthma showed a marked and widespread involvement of the four cardiac chambers compared with the controls: enlargement of the two atria, greater left ventricular remodeling with interventricular septal thickening, increased indexed left ventricular mass with a significantly greater percentage of patients with overt left ventricular hypertrophy, worse left ventricular diastolic function proven by the significant difference in the E/A ratio, and worse right ventricular systolic function with global right ventricular dysfunction estimated by the Myocardial Performance Index (Tei Index). Multivariate regression analysis, after adjustment for essential hypertension, hypertension severity, diabetes, Body Mass Index, and creatinine clearance, seems to indicate that the indexed left ventricular mass, right atrial volume, and right ventricular Tei index (but not left ventricular hypertrophy) correlate significantly with asthma, severe asthma, and FEV1 (and to a lesser extent with asthma duration). No correlation is apparent between inhaled therapy (ICS, SABA) and myocardial involvement. These results seem to confirm that a more in-depth cardiovascular evaluation in patients with chronic respiratory disease allows the identification of unrecognized cardiovascular involvement. A transthoracic echocardiogram performed in asthmatic patients without clinically overt signs or symptoms of cardiovascular impairment has identified some features indicative of an early subclinical cardiac impairment not found in the control group. These findings, considering also the higher frequency of hypertension in the asthma group, deserve further validation in the future.

Effects of zinc propionate supplementation on growth performance, skeletal muscle fiber, and receptor characteristics in beef steers.

A randomized complete block design experiment with 32 yearling crossbred steers (average body weight [BW] = 442 ± 17.0 kg) fed a steam-flaked corn-based diet was used to evaluate the effects of dietary Zn (KemTRACE Zn propionate 27; Kemin Industries, Inc., Des Moines, IA) supplementation on live growth performance, skeletal muscle fiber, and beta-adrenergic receptor (ß-AR) characteristics during the finishing phase. Steers were blocked by BW (n = 4 blocks; 8 steers/block), assigned to pens (n = 4 steers/pen), and randomly assigned to the following treatments: control (CON; 0.0 g/[head (hd) · d] of additional Zn) or additional dietary Zn (ZnP; 1.0 g/[hd · d] additional Zn). The basal diet contained Zn (60 ppm dry matter basis) from ZnSO4; additional Zn was top-dressed at feeding. Ractopamine hydrochloride (RH; Optaflexx: Elanco Animal Health, Greenfield, IN) was included at 300 mg/(hd · d) for the final 28 d of the 111-d feeding period. Longissimus muscle biopsy samples, BW, and blood were obtained on days 0, 42, 79, and 107. Final BW was collected prior to shipping on day 111. Biopsy samples were used for immunohistochemical (IHC), mRNA, and protein analysis. Serum urea nitrogen (SUN) and nonesterified fatty acid (NEFA) concentrations were measured. Steers fed ZnP had a greater average daily gain (P = 0.02) and gain to feed ratio (G:F; P = 0.03) during the RH feeding period compared with CON. There were no differences (P > 0.05) in other growth performance variables, carcass traits, mRNA abundance, or relative protein concentration for fiber type and ß-AR. Fiber types I and IIA had no differences in the cross-sectional area; however, the IIX area was greater for CON (P < 0.04) compared with ZnP and increased (P < 0.02) over time. There were no differences between treatments for the ß1-AR density (P > 0.05) in skeletal muscle tissue throughout the study. A treatment × day interaction was observed in ß2-AR density (P = 0.02) and ß3-AR density (P = 0.02) during the RH feeding period, where the abundance of the receptors increased with ZnP but did not change in CON. Compared with CON, ZnP had greater (P < 0.01) mean NEFA concentrations. Mean SUN concentrations did increase by day (P < 0.01). Additional dietary Zn, supplied as Zn propionate, upregulates ß2-AR and ß3-AR and improves growth performance in feedlot steers during the RH feeding period, likely through a shift of resource utilization from lipogenesis to muscle maintenance and hypertrophy.

Ractopamine-induced fiber type-specific gene expression in porcine skeletal muscles is independent of growth.

Feeding ractopamine (RAC), a ß-adrenergic agonist (BAA), to pigs increases type IIB muscle fiber type-specific protein and mRNA expression. However, increases in the abundance of these fast-twitch fiber types occur with other forms of muscle hypertrophy and thus BAA-induced changes in myosin heavy chain (MyHC) composition may simply be associated with increased muscle growth known to occur in response to BAA feeding. The objective of this study was to determine whether RAC feeding could change the MyHC gene expression in the absence of maximal muscle growth. Pigs were fed either an adequate diet that supported maximal muscle hypertrophy or a low nutrient diet that limited muscle growth. RAC was included in diets at 0 or 20 mg/kg for 1, 2, or 4 wk. Backfat depth was less (P < 0.05) in pigs fed the low nutrient diet compared with the adequate diet but was not affected by RAC. Loin eye area was greater (P < 0.05) in pigs fed an adequate diet plus RAC at 1 wk but did not differ among remaining pigs. At 2 and 4 wk, however, pigs fed the adequate diet had greater loin eye areas (P < 0.05) than pigs fed the low nutrient diet regardless of RAC feeding. Gene expression of the MyHC isoforms, I, IIA, IIX, and IIB, as well as glycogen synthase, citrate synthase, ß 1-adrenergic receptor (AR), and ß 2-AR were determined in longissimus dorsi (LD) and red (RST) and white (WST) portions of the semitendinosus muscles. MyHC type I gene expression was not altered by RAC or diet. Feeding RAC decreased (P < 0.01) MyHC type IIA gene expression in all muscles, but to a greater extent in WST and LD. MyHC type IIX gene expression was lower (P < 0.05) in WST and LD muscles in response to RAC but was not altered in RST muscles. RAC increased (P < 0.05) MyHC type IIB gene expression in all muscles, but to a greater extent in RST. ß 1-AR gene expression was unaffected by RAC or diet, whereas the expression of the ß 2-AR gene was decreased (P < 0.001) by RAC. No significant RAC * diet interactions were observed in gene expression in this study, indicating that RAC altered MyHC and ß 2-AR gene expression in porcine skeletal muscles independent of growth.

Growth, performance, and carcass characteristics of feedlot Holstein steers fed ractopamine hydrochloride.

Growth-promoting technologies such as implants, ionophores, and ß-agonists improve feedlot performance, efficiency, and carcass characteristics of cattle. The objective of this experiment was to determine the effects of dose and duration of ractopamine hydrochloride (RH) on feedlot performance and carcass characteristics when fed to Holstein steers. A randomized complete block design was used with a 3 × 3 factorial arrangement of treatments with 3 RH doses (0, 300, or 400 mg∙steer-1∙d-1) fed for 3 durations (28, 35, or 42 d). Holstein steers (n = 855; initial body weight [BW] = 448 ± 37 kg) were blocked by BW and randomly allocated to 1 of 9 pens (15 blocks; 9 dose × duration treatment combinations) approximately 72 d before harvest. Weekly pen weights, chute temperament scores, and animal mobility were determined during the RH feeding period. At harvest, carcass data were collected on all steers, and tenderness was measured on steaks from 3 or 4 randomly selected steers from each pen and slice shear force (SSF) was determined on one steak selected from each side of the carcass after aging for 14 or 21 d. For feedlot performance, carcass characteristics, and SSF, no dose × duration interactions were observed (P ≥ 0.11). With increasing RH dose, average daily gain (ADG) and gain-to-feed ratio (G:F) increased linearly (P ≤ 0.01), whereas BW gain increased linearly with RH dose and duration (P ≤ 0.01). Hot carcass weight (P = 0.02) and longissimus muscle (LM) area (P ≤ 0.01) increased linearly with increasing RH dose. The percentage of carcasses in the USDA Yield Grade 2 category increased linearly (P ≤ 0.01) and percentage of carcasses in the USDA Yield Grade 4 category tended (P = 0.08) to decrease linearly as RH dose increased. In the 14-d aged steaks, the percentage of steaks with SSF ≤ 15.3 kg decreased linearly (P ≤ 0.01), whereas the percentage of steaks with ≥20.0 kg SSF increased linearly (P ≤ 0.01) with increasing RH dose. After 21-d aging, there was a tendency (P = 0.06) for a greater percentage of steaks from steers fed RH to have SSF ≥ 20.0 kg (2% of total steaks), but no difference (P ≥ 0.12) in the percentage of steaks with SSF ≤ 19.9 kg. Final chute temperament (P ≥ 0.45) and animal mobility (P ≥ 0.67) scores were not affected by feeding RH. Increasing the dose of RH (300 or 400 mg∙steer-1∙d-1) fed for 28 to 42 d before harvest increased ADG, G:F, hot carcass weight, and LM area when fed to Holstein steers with no negative effects on behavior or mobility. The percentage of steaks classified as not tender improved when steaks were aged for 21 d from steers treated with RH.

Effect of tocolytic drugs on fetal heart rate variability: a systematic review.

INTRODUCTION: Tocolytics may cause changes in fetal heart rate (HR) pattern, while fetal heart rate variability (HRV) is an important marker of fetal well-being. We aim to systematically review the literature on how tocolytic drugs affect fetal HRV. MATERIALS AND METHODS: We searched CENTRAL, PubMed and EMBASE up to June 2016. Studies published in English, using computerized or visual analysis to describe the effect of tocolytics on HRV in human fetuses were included. Studies describing tocolytics during labor, external cephalic version, pre-eclampsia and infection were excluded. Eventually, we included six studies, describing 169 pregnant women. RESULTS: Nifedipine, atosiban and indomethacin administration show no clinically important effect on fetal HRV. Following administration of magnesium sulfate decreased variability and cases of bradycardia are described. Fenoterol administration results in a slight increase in fetal HR with no changes in variability. After ritodrine administration increased fetal HR and decreased variability is seen. The effect of co-administration of corticosteroids should be taken into account. CONCLUSION: In order to prevent iatrogenic preterm labor, the effects of tocolytic drugs on fetal HRV should be taken into account when monitoring these fetuses.

Zilpaterol hydrochloride improves beef yield, changes palatability traits, and increases calpain-calpastatin gene expression in Nellore heifers.

This research aimed to evaluate the effects of the beta-agonist zilpaterol hydrochloride (ZH) on carcass traits, subprimal yield, meat quality, palatability traits, and gene expression in Nellore heifers. Zilpaterol increased Longissimus lumborum area and did not change back fat thickness, meat color, and cooking loss. Heifers fed ZH had greater hindquarter weight and carcass percentage. Muscles from hindquarter were heavier for animals fed ZH. Forequarter (% of carcass) decreased and brisket did not change with ZH supplementation. There were no differences between treatments for steak aroma, beef flavor, and off-flavor. However, tenderness and juiciness were reduced by ZH, depending on postmortem aging. Zilpaterol increased Calpain-1, Calpain-2, and calpastatin mRNA expression, with no effect of day of slaughter or ZH×Day interaction. In conclusion, ZH supplementation improved hypertrophy, meat production, and debone yield in Nellore heifers, which led to decreased tenderness and to increased mRNA expression in the calpain-calpastatin system.

The effects of beta-2 adrenergic agonist and antagonist on human bone metabolism: a randomized controlled trial.

PURPOSE: Genetic knockout or pharmacological inhibition of the beta-2 adrenergic receptor (B2AR) increased bone mass, whereas stimulation decreased bone mass in rodents. In humans, observational studies support sympathetic nervous system regulation of bone metabolism, but intervention studies are lacking. We aimed to determine the effects of a selective beta-2 adrenergic agonist and non-selective antagonist on human bone metabolism. METHODS: 32 healthy postmenopausal women were included in a randomized controlled trial conducted in the Academic Medical Center Amsterdam. Participants were randomized to receive treatment with 17-ß estradiol 2mg/day; 17-ß estradiol 2mg/day and terbutaline 5mg/day (selective B2AR agonist); propranolol 80mg/day (non-selective B-AR antagonist); or no treatment during 12weeks. Main outcome measure was the change in serum concentrations of procollagen type I N propeptide (P1NP) and C-terminal crosslinking telopeptides of collagen type I (CTx) as markers of bone formation and resorption after 12weeks compared between the treatment groups. Data were analyzed with mixed model analysis. RESULTS: 17-ß estradiol decreased bone turnover compared to control (P1NP p<0.001, CTx p=0.003), but terbutaline combined with 17-ß estradiol failed to increase bone turnover compared to 17-ß estradiol alone (P1NP p=0.135, CTx p=0.406). Propranolol did not affect bone turnover compared to control (P1NP p=0.709, CTx p=0.981). CONCLUSION: Selective beta-2 adrenergic agonists and non-selective beta-antagonists do not affect human bone turnover although we cannot exclude small changes below the detection limit of this study.

A step-up ractopamine feeding program for finishing pigs / Niveles incrementales de ractopamina para cerdos en ceba / Plano de níveis aumentados de ractopamina para suínos em terminação

Abstract Background: Ractopamine (RAC) supplementation in the feed has been evaluated as a strategy to increase productive efficiency in finishing pigs. Objective: To evaluate the effects of different RAC dietary levels on performance, carcass traits, efficiency of lysine (ELU) and energy (EEU) utilization, and economic viability in finishing pig. Methods: A total of 40 barrows (74.75 ± 5.22 kg) were fed four RAC levels (0, 5, 10 and 5-10 mg/kg step-up program) from 0-14, 15-31 and 0-31 days. Performance, carcass characteristics, ELU, EEU, cost per unit of weight gain (CWG), payment and profit parameters were measured. The animals were distributed in a completely randomized design in four treatments, with ten replicates per treatment. The experimental unit was each animal. Results: Pigs fed RAC diets showed increased body weights at 14 and 31 days, average daily gain (ADG) at 0-14 and 0-31 days, ELU at 0-14 days, and hot carcass weight as compared with those fed the control diet. The step-up program as compared to the 10 mg/kg RAC concentration resulted in increased body weight, feed/gain ratio (FGR), ADG, ELU, EEU and CWG at 0-14 days. Payment by weight and bonus payment were better for treatments with RAC as compared to control. Conclusions: Pigs fed RAC improved performance, carcass weight, ELU, EEU and economic viability. The results were better for the step-up program compared with the intermittent use of 10 mg/kg RAC.

Resumen Antecedentes: La suplementación de cerdos con ractopamina (RAC) es una estrategia para aumentar la eficiencia productiva en ceba. Objetivo: Evaluar el efecto de diferentes planes de suplementación con RAC en dietas de cerdos en ceba sobre el rendimiento productivo, características de la canal, eficiencia de utilización de lisina (ELU) y energía (EEU), y viabilidad económica. Métodos: Un total de 40 machos castrados (74,75 ± 5,22 kg) fueron alimentados con cuatro niveles de RAC (0, 5, 10 y 5-10 mg/kg de plano escalonado) de 0-14, 15-31 y 0-31 días. Se evaluó el rendimiento, características de la canal, ELU, EEU, el costo por unidad de ganancia de peso (CWG), los tipos de pago y ganancias. Los animales se distribuyeron en un diseño completamente aleatorizado en cuatro tratamientos, con diez repeticiones por tratamiento. La unidad experimental fue cada animal. Resultados: Los animales suplementados con RAC tuvieron mayor peso corporal a los 14 y 31 días, ganancia de peso diaria (ADG) de 0-14 y 0-31 días, ELU de 0-14 días y peso de la canal caliente en comparación con el grupo control. En comparación con la concentración de 10 mg/kg de RAC, el plano escalonado resultó en un aumento de peso corporal, conversión alimenticia (FGR), ADG, ELU, EEU y CWG a los 0-14 días. El pago por peso y el pago por bonificación fueron mejores para los tratamientos con RAC en comparación con el control. Conclusiones: Los cerdos en ceba alimentados con RAC tienen mejor rendimiento, peso de la canal, ELU, EEU y viabilidad económica. Los resultados de los parámetros estudiados son mejores con el uso del plano escalonado en comparación con el uso continuo de 10 mg/kg de RAC.

Resumo Antecedentes: Suplementação de ractopamina (RAC) em dietas para suínos foi avaliada como uma estratégia para aumentar eficiência de produção de suínos em terminação. Objetivo: Avaliar os efeitos de diferentes planos de suplementação de RAC em dietas para suínos em terminação sobre o desempenho, características de carcaça, eficiência de utilização de lisina (ELU) e energia (EEU), e viabilidade econômica. Métodos: Um total de 40 machos castrados (74.75 ± 5.22 kg) foram alimentados com quatro níveis de RAC (0, 5, 10 e 5-10 mg/kg plano escalonado) em 0-14, 15-31 e 0-31 dias. Desempenho, características de carcaça, ELU, EEU, custo por unidade de ganho de peso (CWG), tipos de pagamento e lucro foram mensurados. Os animais foram distribuídos em um delineamento inteiramente casualizado em quatro tratamentos, dez repetições para cada tratamento. A unidade experimental foi cada animal. Resultados: Os animais alimentados com dietas contendo RAC mostraram aumento de peso corporal aos 14 e 31 dias, ganho de peso diário (ADG) de 0-14 e 0-31 dias, ELU de 0-14 dias e peso de carcaça quente comparado ao grupo controle. O plano escalonado comparado ao nível de 10 mg/kg de RAC mostrou maior peso corporal, conversão alimentar (FGR), ADG, ELU, EEU e CWG de 0-14 dias. Pagamento por peso e pagamento por bonificação foram melhor para tratamentos com RAC em comparação ao controle. Conclusões: Suínos alimentados com RAC mostram melhor desempenho, peso de carcaça, ELU, EEU e viabilidade econômica. Os resultados dos parâmetros estudados foram melhores com uso do plano escalonado quando comparado com uso constante de 10 mg/kg de RAC para suínos em terminação.

Assessment of bronchodilator responsiveness following methacholine-induced bronchoconstriction in children with asthma.

PURPOSE: The aim of this study was to investigate bronchodilator responsiveness (BDR) following methacholine-induced bronchoconstriction and to determine differences in BDR according to clinical parameters in children with asthma. METHODS: The methacholine challenge test was performed in 145 children with mild to moderate asthma, and the provocative concentration causing a 20% decline in FEV1 (PC20) was determined. Immediately after the challenge test, patients were asked to inhale short-acting ß2-agonists (SABAs) to achieve BDR, which was assessed as the change in FEV1% predicted×100/post-methacholine FEV1% predicted. For each subject, the asthma medication, blood eosinophil count, serum total IgE, serum eosinophil cationic protein level, and skin prick test result were assessed. RESULTS: The FEV1 (mean±SD) values of the 145 patients were 90.5±10.9% predicted, 64.2±11.5% predicted, and 86.2±11.2% predicted before and after methacholine inhalation, and following the administration of a SABA, respectively. The BDR did not differ significantly according to asthma medication, age, or gender. However, BDR in the atopy group (37.4±17.7%) was significantly higher than that in the non-atopy group (30.5±10.7%; P=0.037). Patients with blood eosinophilia (38.6±18.1%) displayed increased BDR compared with patients without eosinophilia (32.0±13.8%; P=0.037). CONCLUSIONS: In children with mild to moderate asthma, the responsiveness to short-acting bronchodilators after methacholine-induced bronchoconstriction was not related to asthma medication, but was higher in children with atopy and/or peripheral blood eosinophilia.