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Background Foot and Mouth Disease (FMD) is an important disease in livestock in Bhutan due to its significant social and economic impacts to the farmers as well as to the government. FMD outbreaks continue to occur every year with greater frequency in some parts of the country despite the implementation of control measures. It is imperative to understand the current patterns of the disease for planning effective control programs. Therefore, this study aimed to investigate the spatial and temporal patterns of FMD in Bhutan since the most recent national survey. Methodology Nine year’s (2011–2019) of national FMD outbreak data was used for this study. An investigation of global spatial autocorrelation was undertaken using the K difference function statistic and local spatial clusters of FMD outbreaks using Kulldorff’s spatial scan statistic. Retrospective spatio-temporal analysis was conducted using a Bernoulli probability model with monthly aggregation of data. A non-stationary cosinor model was used to examine seasonality and trend of outbreaks. Results The K function statistic detected significant global spatial autocorrelation of FMD outbreaks ( p  < 0.02) and Kulldorff’s spatial scan statistic identified two outbreak clusters in west Bhutan- the first primary cluster ( p  < 0.002) with relative risk (RR) of 5.22 and radius of 19.77 km in Paro and Thimphu districts and the second primary cluster ( p  < 0.006, RR = 8.44 radius: 8.98 km) in Punakha and Wangdue Phodrang districts. The spatio-temporal scan test detected a single significant ( P  < 0.001) space–time cluster of 22 FMD outbreaks centred in south-west Bhutan with a radius of 60 km over an 8-month period in 2018—2019. The temporal analysis indicated that, on an average there were 0.5 (95% CI: 0.2—0.8) additional outbreaks per month in the seasonal winter peaks at 1.9 months (95% CI: 12.55 -3.64) compared with the overall monthly average. Conclusion The western and southern regions of Bhutan have experienced the greatest overall incidence and significant spatial and spatio-temporal clusters of outbreaks of FMD during the period 2011—2019, These findings in districts in the western medium FMD risk surveillance zone threaten progress to control of FMD in Bhutan.

This study tested the hypothesis that increasing the duration and/or frequency of antimicrobial treatment of subclinical mastitis would result in a higher bacteriological cure rate. Glands with a positive California mastitis test (CMT) from cows with an elevated somatic cell count (>500,000 cells/mL) that had an intramammary infection were randomly assigned at cow level to no treatment (Control; n = 80 glands), intramammary infusion of 200 mg cloxacillin sodium on three occasions at 48 h intervals (3 × 48 h; n = 273 glands), five occasions at 24 h intervals (5 × 24 h; n = 279 glands), or on five occasions at 48 h intervals (5 × 48 h; n = 72 glands). Glands were resampled at 21 (±3) and 28 (±3) days after initiation of treatment. The gland-level cure rate for any pathogen was 5/80 (6.2%), 139/173 (49.8%), 172/297 (61.6%) and 58/72 (80.6%) for Control, 3 × 48 h, 5 × 24 h and 5 × 48 h, respectively. The cure rate for major pathogens (defined as Staphylococcus aureus or Streptococcus spp.) was 4/52 (7.7%), 84/197 (42.6%), 96/183 (52.5%) and 36/48 (75%) for Control, 3 × 48 h, 5 × 24 h and 5 × 48 h, respectively. We conclude that treatment was superior to no treatment, and bacteriological cure rate was higher with the 5 × 24 h protocol than for the 3 × 48 h protocol and was higher with the 5 × 48 h than the 5 × 24 h protocol.

In Western studies, lung microbiome changes are reported in patients with chronic obstructive pulmonary disease (COPD) and are associated with poorer outcomes, but similar studies in Asian patients or those with less severe COPD are limited. The Acute Exacerbation and Respiratory InfectionS in COPD Japan (AERIS-J; jRCT1080224632/NCT03957577) was a prospective, non-interventional study to evaluate sputum microbiome diversity at baseline and after 12 months (V2; exploratory analysis), in patients aged 40-80 years with stable COPD (June 2019-June 2022). Baseline sputum potentially pathogenic organisms (PPOs) were identified. Blood cell counts and COPD Assessment Test (CAT) scores were collected at baseline and COPD symptoms measured over 12 months using the Evaluating Respiratory Symptoms in COPD and EXAcerbations of Chronic pulmonary disease Tool, collected by eDiary. Patients (N=63) had a mean age of 72.8 years, and percent predicted post-bronchodilator forced expiratory volume in 1 second was 58.3%; 92% were male. Across 62 baseline sputum samples, microbiome composition was similar between 16S rRNA/metagenomic datasets. Patients graded Global Initiative for Chronic Obstructive Lung Disease (GOLD) III versus GOLD I/II had minimal differences in their microbial taxonomic profile and no differences in microbial diversity (Wilcoxon =0.71). Alpha diversity (Shannon index) positively correlated with blood basophils (rho=0.41; =0.0019) and negatively correlated with CAT score (rho=0.36; =0.0069). Alpha diversity and sputum (rho: -0.0637; =0.7836) or blood (rho: 0.1739; =0.2043) eosinophils were not correlated. No difference in alpha ( =0.5) or beta ( =0.3) diversity or Operational Taxonomic Unit (Anosim R=-0.024; =0.892) was observed between PPO-positive or -negative sputum. A less diverse microbiome correlated with poorer health status and lower blood basophils in patients with COPD and moderate airflow limitation. There was no relationship between PPO presence and microbiome diversity.

Background Patients with chronic obstructive pulmonary disease (COPD) are at risk of exacerbations and pneumonia; how the risk factors interact is unclear. Methods This post-hoc, pooled analysis included studies of COPD patients treated with inhaled corticosteroid (ICS)/long-acting β 2 agonist (LABA) combinations and comparator arms of ICS, LABA, and/or placebo. Backward elimination via Cox’s proportional hazards regression modelling evaluated which combination of risk factors best predicts time to first (a) pneumonia, and (b) moderate/severe COPD exacerbation. Results Five studies contributed: NCT01009463, NCT01017952, NCT00144911, NCT00115492, and NCT00268216. Low body mass index (BMI), exacerbation history, worsening lung function (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage), and ICS treatment were identified as factors increasing pneumonia risk. BMI was the only pneumonia risk factor influenced by ICS treatment, with ICS further increasing risk for those with BMI <25 kg/m 2 . The modelled probability of pneumonia varied between 3 and 12% during the first year. Higher exacerbation risk was associated with a history of exacerbations, poorer lung function (GOLD stage), female sex and absence of ICS treatment. The influence of the other exacerbation risk factors was not modified by ICS treatment. Modelled probabilities of an exacerbation varied between 31 and 82% during the first year. Conclusions The probability of an exacerbation was considerably higher than for pneumonia. ICS reduced exacerbations but did not influence the effect of risks associated with prior exacerbation history, GOLD stage, or female sex. The only identified risk factor for ICS-induced pneumonia was BMI <25 kg/m 2 . Analyses of this type may help the development of COPD risk equations.

Background Prospective evidence is lacking regarding incremental benefits of long-acting dual- versus mono-bronchodilation in improving symptoms and preventing short-term disease worsening/treatment failure in low exacerbation risk patients with chronic obstructive pulmonary disease (COPD) not receiving inhaled corticosteroids. Methods The 24-week, double-blind, double-dummy, parallel-group Early MAXimisation of bronchodilation for improving COPD stability (EMAX) trial randomised patients at low exacerbation risk not receiving inhaled corticosteroids, to umeclidinium/vilanterol 62.5/25 μg once-daily, umeclidinium 62.5 μg once-daily or salmeterol 50 μg twice-daily. The primary endpoint was trough forced expiratory volume in 1 s (FEV 1 ) at Week 24. The study was also powered for the secondary endpoint of Transition Dyspnoea Index at Week 24. Other efficacy assessments included spirometry, symptoms, heath status and short-term disease worsening measured by the composite endpoint of clinically important deterioration using three definitions. Results Change from baseline in trough FEV 1 at Week 24 was 66 mL (95% confidence interval [CI]: 43, 89) and 141 mL (95% CI: 118, 164) greater with umeclidinium/vilanterol versus umeclidinium and salmeterol, respectively (both p  < 0.001). Umeclidinium/vilanterol demonstrated consistent improvements in Transition Dyspnoea Index versus both monotherapies at Week 24 (vs umeclidinium: 0.37 [95% CI: 0.06, 0.68], p  = 0.018; vs salmeterol: 0.45 [95% CI: 0.15, 0.76], p  = 0.004) and all other symptom measures at all time points. Regardless of the clinically important deterioration definition considered, umeclidinium/vilanterol significantly reduced the risk of a first clinically important deterioration compared with umeclidinium (by 16–25% [ p  < 0.01]) and salmeterol (by 26–41% [ p  < 0.001]). Safety profiles were similar between treatments. Conclusions Umeclidinium/vilanterol consistently provides early and sustained improvements in lung function and symptoms and reduces the risk of deterioration/treatment failure versus umeclidinium or salmeterol in symptomatic patients with low exacerbation risk not receiving inhaled corticosteroids. These findings suggest a potential for early use of dual bronchodilators to help optimise therapy in this patient group.

Task-dependent changes in inhibition may explain why supraspinal excitability is higher during arm cycling than an intensity- and position-matched tonic contraction. The present study investigated whether interhemispheric inhibition (IHI) associated with biceps brachii activity was different during arm cycling, a locomotor output, compared to a tonic contraction. IHI was quantified using an ipsilateral silent period (iSP) evoked via transcranial magnetic stimulation (TMS) of the ipsilateral motor cortex. TMS was delivered at 120% resting motor threshold during the mid-elbow flexion phase of arm cycling (6 o’clock position, made relative to a clock face) and during a position- and intensity-matched tonic contraction. In total, 36 participants took part in the study. However, only 14 participants demonstrated IHI during arm cycling and 10 participants during tonic contraction. Of these participants, eight displayed clear iSPs during arm cycling and tonic contraction. The iSP duration was longer during arm cycling than tonic contraction (p  <  0.05), while iSP EMG amplitude and area were not different between tasks (p  >  05 for both comparisons). The main finding from this study is that IHI appears to be stronger during arm cycling than an intensity- and position-matched tonic contraction. This does not support previous findings of higher supraspinal excitability during arm cycling.

Ewe wastage is the combination of on-farm mortality and premature culling. Internationally, there is limited research on actual wastage incidence and causes in commercial sheep flocks. To the authors’ knowledge, this is the first study that reports both lifetime wastage and detailed annual wastage in a sample of commercial New Zealand flocks. This study utilized data collected from 13,142 ewes from four cohorts on three commercial New Zealand farms (Farm A 2010-born, Farm A 2011-born, Farm B, Farm C), during the period 2011–2017, as they aged from replacement hoggets to 6-year-old ewes (Farm A and Farm B) or 3-year-old ewes (Farm C). Data collection visits occurred at three or four key management times each year, namely pre-mating, pregnancy diagnosis, pre-lambing and weaning. At each visit, body condition score (BCS) was assessed and any ewes that were culled or had died on farm were recorded. As this was a lifetime study, each ewe was assigned an outcome and corresponding ‘exit age’. By the end of the study, all ewes that had exited their respective flocks, were classified as either prematurely culled, or dead/missing, or if still in the flock, as censored, and either the exact date or interval in which they exited the flock was recorded. Semi-parametric competing risk (premature culling vs. dead/missing), interval-censored survival models were developed to: 1. describe the association between hogget reproductive outcomes and risk of subsequent wastage, and 2. assess pre-mating BCS as a predictor of wastage in that production year. Of the 13,142 enrolled ewes, 50.4% exited their respective flocks due to premature culling and 40.0% due to on-farm dead/missing, giving a total of 90.4% that exited due to wastage. Annual mortality incidence ranged from 3.5 to 40.2%. As a hogget, wastage incidence ranged from 7.6 to 45.4%. Pregnancy or rearing a lamb as a hogget did not increase risk of subsequent wastage. In all years, pre-mating BCS was a predictor of ewe wastage, with odds of wastage lower with increasing BCS. Therefore, farmers should focus on improving pre-mating BCS to 3.5/5.0 by assessing ewe BCS at weaning, allowing poorer-BCS ewes to be managed to gain BCS before re-breeding.

Purpose: Triple therapy comprising a long-acting muscarinic antagonist, long-acting [[beta].sub.2]-agonist and inhaled corticosteroid is recommended for patients with chronic obstructive pulmonary disease (COPD) who continue to experience frequent exacerbations or symptoms whilst receiving dual therapy. Adherence and persistence to multiple-inhaler triple therapy (MITT) is known to be poor. This study assessed comparative adherence to single-inhaler triple therapy (SITT) versus MITT in a real-world setting in England. Patients and Methods: This was a retrospective cohort study using linked primary care (Clinical Practice Research Datalink Aurum) and secondary care (Hospital Episode Statistics [HES] Admitted Patient Care) data to identify patients with COPD who were newly initiated on SITT or MITT between November 2017 and June 2019. Eligible patients were aged [greater than or equal to] 35 years and had a forced expiratory volume in 1 second/forced vital capacity <0.7, linkage to HES and continuous registration with a general practitioner for 12 months preand 6 months post-initiation. Inverse probability of treatment weighting was used to balance baseline characteristics between cohorts. Adherence was measured using the proportion of days covered by days' supply of SITT or MITT prescriptions. Persistence was measured with a gap of >30 days between the end of a prescription and the following refill used to determine non-persistence. Results: Overall, 4080 SITT and 6579 MITT users comprised the study cohort. After weighting, the baseline characteristics between the cohorts were comparable (absolute standardized mean difference <10%). SITT users had significantly higher adherence than MITT users at 6, 12, and 18 months post-initiation (p<0.001 for all comparisons). Median persistence was higher among SITT users than MITT users (5.09 months vs 0.99 months). Conclusion: Patients with COPD in England initiating SITT had significantly better adherence and persistence compared with MITT initiators. These improvements continued at least 18 months following treatment initiation. Keywords: COPD, Clinical Practice Research Datalink, Hospital Episode Statistics, MITT, proportion of days covered, SITT

Background There is a need for real-world data describing the frequency and impact of moderate asthma exacerbations in patients receiving inhaled corticosteroids/long-acting β 2 -agonists (ICS/LABA). The Salford Lung Study (SLS) and associated extension study (Ext-SLS) evaluated ICS/LABA versus existing maintenance therapy in adults with asthma. This analysis assessed the impact of moderate exacerbations in patients from the Ext-SLS. Methods This retrospective cohort study analysed linked primary and secondary care and patient questionnaire data from patients enrolled in the Ext-SLS (indexed April 2018–May 2019). Primary outcome was number of self-reported moderate asthma exacerbations 12 months pre-index, overall, by maintenance treatment class and asthma control status at index, using the Asthma Control Test (ACT; poor [< 16], somewhat controlled [16–18], and controlled [> 19]) and 6-item Asthma Control Questionnaire (ACQ-6; uncontrolled [≥ 1.50], partially controlled [> 0.75–<1.50], and controlled [≤ 0.75]). Secondary outcomes included index ACT and ACQ-6 score, healthcare resource utilisation (HCRU) and direct costs 12 months pre- and post-index, stratified by self-reported moderate exacerbation frequency pre-index. Results Of 485 patients with ≥ 12 months’ pre-index data, 86.6% (n = 420) self-reported moderate exacerbations, with similar frequency irrespective of maintenance treatment class (66.7–100.0%; ICS/LABA: 85.4%). Numerically greater proportions of patients self-reported a moderate exacerbation in the 12 months pre-index in ACT poor-control (n = 110/115 [95.7%]) and ACQ-6-uncontrolled (n = 200/210 [95.3%]) versus ACT- and ACQ-6-controlled (n = 205/260 [78.8%], n = 105/145 [72.4%]) groups. Symptom control worsened with increasing exacerbation frequency: mean (SD) ACT scores were 21.8 (3.3) and 15.7 (4.4) for patients with 0 or ≥ 7 events, respectively; mean (SD) ACQ-6 scores followed the same trend. Direct costs and HCRU increased with pre-index exacerbation frequency; mean (SD) all-cause and asthma-related total costs were £1509 (£2384) and £717 (£1459) for patients with no moderate exacerbations 12 months pre-index and £2002 (£2058) and £1086 (£1538) for patients with ≥ 7 exacerbations; similar trends occurred over 12 months post-index. Conclusions Patients with asthma experience frequent moderate exacerbations, which are associated with poor asthma control, increased HCRU and costs, emphasising the poor quality of life patients experience. Tackling poor adherence, risk behaviour, and comorbidities as well as holistic management and medication review are needed. Clinical trial details Registered on clinicaltrials.gov: NCT03152669, 12 May 2017

Background The comparative efficacy of inhaled corticosteroid/long-acting muscarinic antagonist/long-acting β 2 -agonist (ICS/LAMA/LABA) triple therapy administered via single or multiple inhalers in patients with chronic obstructive pulmonary disease (COPD) has not been evaluated comprehensively. We conducted two replicate trials comparing single- with multiple-inhaler ICS/LAMA/LABA combination in COPD. Methods 207608 and 207609 were Phase IV, 12-week, randomized, double-blind, triple-dummy non-inferiority trials comparing once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 μg via Ellipta inhaler, with twice-daily budesonide/formoterol (BUD/FOR) 400/12 μg via metered-dose inhaler plus once-daily tiotropium (TIO) 18 μg via HandiHaler. Patients had symptomatic COPD and forced expiratory volume in 1 s (FEV 1 ) < 50% predicted, or FEV 1  < 80% predicted and ≥ 2 moderate or 1 severe exacerbations in the prior year. The primary endpoint in both trials was weighted mean change from baseline (wmCFB) in 0–24-h FEV 1 at Week 12. Secondary endpoints included CFB in trough FEV 1 at Day 84 and 85. Other endpoints included serial FEV 1 and health status outcomes at Week 12. Safety was evaluated descriptively. Results The modified per-protocol population included 720 and 711 patients in studies 207608 and 207609 (intent-to-treat population: 728 and 732). FF/UMEC/VI was non-inferior to BUD/FOR+TIO for wmCFB in 0–24-h FEV 1 at Week 12 (Study 207608 treatment difference [95% confidence interval]: 15 mL [− 13, 43]; Study 207609: 11 mL [− 20, 41]). FF/UMEC/VI improved trough FEV 1 CFB versus BUD/FOR+TIO at Day 84 and 85 (Day 85 treatment difference: Study 207608: 38 mL [10, 66]; Study 207609: 51 mL [21, 82]) and FEV 1 at 12 and 24 h post-morning dose at Week 12 in both studies. No treatment differences were seen in health status outcomes. Safety profiles were similar between treatments; pneumonia occurred in 7 (< 1%) patients with FF/UMEC/VI and 9 (1%) patients with BUD/FOR+TIO, across both studies. Conclusions FF/UMEC/VI was non-inferior to BUD/FOR+TIO for wmCFB in 0–24-h FEV 1 at Week 12 in patients with COPD. Greater improvements in trough and serial FEV 1 measurements at Week 12 with FF/UMEC/VI versus BUD/FOR+TIO, together with similar health status improvements and safety outcomes including the incidence of pneumonia, suggest that once-daily single-inhaler FF/UMEC/VI triple therapy is a viable option for patients looking to simplify their treatment regimen. Trial registration GSK (207608/207609; NCT03478683 / NCT03478696 ).