BACKGROUND:Although cardiovascular disease is common in patients with chronic obstructive pulmonary disease (COPD), the efficacy and safety of β blockers in reducing cardiac events and mortality is uncertain. This study was designed to assess whether the cardioselective β blocker, bisoprolol, improves cardiorespiratory outcomes when added to usual COPD care. METHODS:This double-blind, randomised, controlled, phase 3 trial was done across 22 hospital and research institute sites selected by research experience and resources to conduct the study in Australia, India, New Zealand, and Sri Lanka. Participants aged 40-85 years with COPD, post-bronchodilator FEV1 30-70% predicted, and at least one COPD exacerbation in the previous 2 years were randomly assigned to receive bisoprolol (1·25-5 mg) or matched placebo, orally, once daily, for 2 years, with both groups continuing to receive usual COPD care. Randomisation was with a concealed, computer-generated sequence, stratified by site, smoking status, and previous diagnosis of cardiovascular disease requiring treatment. Participants, site personnel, and investigators remained masked to study treatment throughout the trial. The primary outcome was a composite of cardiac and respiratory effects, starting with the most important outcome (death), then cardiac or respiratory hospital admissions, exacerbations, quality-of-life measures, and FEV1. Analysis was by intention-to-treat (ITT) in all randomly assigned patients, using a country-stratified win ratio. Adverse events were analysed from the ITT population using all available data. Missing data were not used to determine wins, but regarded as a tie on that level of the hierarchy. The trial was prospectively registered on ClinicalTrials.gov (NCT03917914), Clinical Trial Registry - India (CTRI/2020/08/027322), and the Sri Lanka Clinical Trials Registry (SLCTR/2021/033). The study is complete. FINDINGS:Of 360 participants screened for eligibility between June 30, 2020, and March 20, 2023, 280 were randomly assigned to bisoprolol (n=143) or placebo (n=137), with 249 completing 2 years of follow-up. 233 patients (83%) were male and 47 (17%) were female; mean age was 68 years (SD 8). Mean post-bronchodilator FEV1 was 45% (SD 11) predicted at baseline. According to the hierarchy of outcomes, bisoprolol was associated with better cardiorespiratory health for 3041 (45%) of 6763 comparisons and placebo for 3240 (48%), with 482 (7%) showing no difference, giving a win ratio of 0·95 (95% CI 0·72 to 1·25, p=0·72) and a net benefit of -2% (95% CI -15 to 10) with bisoprolol. No significant differences were seen between bisoprolol and placebo in all-cause mortality, cardiorespiratory hospitalisations, major adverse cardiac events, or moderate or severe COPD exacerbations. Additionally, no significant differences were seen in FEV1, COPD symptoms, or quality of life, or adverse events. The most common adverse events were COPD exacerbations, occuring in 83 (58%) participants in the bisoprolol group and 87 (64%) in the placebo group. 15 (10%) participants in the bisoprolol group and 11 (8%) in the placebo group died. None of these deaths were attributed to the treatment. INTERPRETATION:In patients with moderately severe COPD, treatment with bisoprolol made no difference to overall cardiorespiratory health, all-cause mortality, or serious cardiorespiratory events. FUNDING:National Health and Medical Research Council of Australia and the Health Research Council of New Zealand.
A new species of the genus Lepechinelloides is described from the Clarion-Clipperton Zone in the Pacific Ocean. Lepechinelloides polymetallica sp. nov . is distinguished from the other two species in this genus by the ventrally directed midventral extensions on pleonites 1 to 3, widened propodi of both gnathopods, and small upright pointing extensions on all pereonites. This species is both morphologically and molecularly defined and compared to the other two species in the genus.
Globally rising female labour force participation represents one of the most noteworthy economic developments of the last century. Despite this rise, little is known about the individual and broader economic costs tied to women's experiences of problematic menstrual symptoms such as period pain (dysmenorrhea) and heavy menstrual bleeding. This study quantifies the economic burden of menstrual symptoms on Australian working women using a human capital approach. A cross-sectional online survey was conducted among women in Australia who had been employed for at least 3 months. Lost productivity associated with menstrual symptoms is estimated at $4882 Int (AUD $7176) per person annually, with an estimated annual economic burden of $9.527 billion Int ($14.005 billion AUD) in Australia based on a 90% prevalence rate for one or more menstrual symptoms. Presenteeism was the predominant cost driver, accounting for 46% of total productivity loss. Over the counter and prescribed analgesic use were significantly correlated with greater pain and productivity impairment, despite not reducing productivity impacts. Pain severity demonstrated a strong positive correlation with absenteeism and presenteeism (r = 0.97). Women aged 35-44 reported significantly higher lost productivity than their counterparts. These findings highlight the substantial economic rationale for government and workplace interventions supporting menstrual symptom management.
BACKGROUND:Recommendations for the use of inhaled corticosteroid-formoterol reliever-based regimens are limited by the absence of randomised controlled trials (RCTs) in patients with asthma using maintenance inhaled corticosteroids, and scarce evidence for the effect on type 2 airway inflammation. We aimed to examine the clinical efficacy and safety of maintenance inhaled corticosteroids plus budesonide-formoterol reliever or terbutaline reliever in patients with mild-to-moderate asthma. METHODS:This open-label, parallel-group, randomised, controlled, phase 4 trial was conducted at Wellington Hospital and two community-based primary care facilities in New Zealand. Eligible participants were aged 16-75 years, had a self-reported doctor's diagnosis of asthma, were using reliever only therapy or maintenance inhaled corticosteroids with short-acting β2-agonist reliever therapy, and were registered with a general practitioner. Participants had to have reported mean reliever use on two or more occasions per week in the 12 weeks before enrolment and had evidence of airway inflammation (FeNO ≥25 parts per billion [ppb]) at screening. Participants were randomly assigned (1:1) to budesonide-formoterol (budesonide 200 μg and formoterol 6 μg) reliever or terbutaline 250 μg reliever therapy using a computer-generated sequence in block sizes of four and six, stratified by region, baseline inhaled corticosteroids maintenance dose, and history of severe asthma exacerbation in the previous 12 months. All participants received maintenance budesonide 200 μg. During a 26-week treatment period, participants attended visits at weeks 0 (screening and randomisation), 13, and 26. The primary outcome was FeNO at week 26, measured in the intention-to-treat (ITT) population. This trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12622001304729 (completed). FINDINGS:Between March 28, 2023, and Aug 27, 2024, 290 participants were assessed for eligibility, 109 were ineligible, and 181 were randomly assigned to budesonide-formoterol (n=93) or terbutaline reliever therapy (n=88; ITT population). Participants had a mean age of 33·91 years (SD 15·54). 119 (66%) of 181 participants were female and 62 (34%) were male. Geometric mean FeNO was 62·18 ppb (SD 1·86) at baseline and 39·65 ppb (2·12) at week 26, for the budesonide-formoterol group and 68·03 ppb (1·97) at baseline and 52·98 ppb (2·27) at week 26 for the terbutaline group. Budesonide-formoterol reliever therapy resulted in a mean reduction in geometric mean FeNO of 18·50% (95% CI 2·72-31·73; p=0·024) at week 26 compared with terbutaline reliever therapy. 77 (83%) of 93 participants in the budesonide-formoterol group versus 69 (78%) of 88 in the terbutaline group had at least one adverse event (relative risk 1·06 [95% CI 0·91-1·22]; p=0·46). There were no deaths in the study. INTERPRETATION:Budesonide-formoterol reliever therapy resulted in a reduction in FeNO compared with terbutaline reliever in adults with asthma using maintenance inhaled corticosteroids. Budesonide-formoterol reliever is a safe and effective alternative to short-acting β2-agonist reliever therapy for adults using maintenance inhaled corticosteroids. FUNDING:AstraZeneca.
Background and objective:Recent observational data suggest that cardioselective β-blockers like bisoprolol are safe and beneficial for patients with COPD. However, the acute effects of bisoprolol on lung and cardiovascular function in these patients is unclear, a gap that this study aimed to address. Methods:This was a subanalysis of pre-randomisation screening visit data from the ongoing Preventing Adverse Cardiac Events (PACE) in COPD randomised controlled trial. If all other eligibility criteria were met, participants were orally administered an unblinded 1.25 mg tablet of bisoprolol. Post-bronchodilator spirometry, heart rate and blood pressure were monitored at 0, 30 (cardiovascular parameters only), 60 and 120 min. For this subanalysis, respiratory intolerance was defined as a decrease in forced expiratory volume in 1 s (FEV1) (L) ≥200 mL and ≥12% from the 0-min FEV1 (L) value; and cardiovascular intolerance was defined as systolic blood pressure (SBP) falling below 100 mmHg at 1 or 2 h. Results:Of 359 consented participants, 292 conducted the test-dose procedure. 13 (4.5%) were respiratory intolerant and six (2.1%) were cardiovascular intolerant at 1 or 2 h. No participant was intolerant for both. There was no significant difference in FEV1 (L) or SBP at baseline At 120 min the intolerant group's mean FEV1 had significantly decreased to 1.05 L (95% CI 0.86-1.25 L; p<0.0001); the tolerant group experienced no change (1.10, 1.05-1.14 L; p=0.33). Conclusion:The administration of 1.25 mg bisoprolol was acutely well tolerated in >95% of COPD patients.
