BACKGROUND:BCR-ABL (fusion between the Abelson [Abl] tyrosine kinase gene at chromosome 9 and the break point cluster [Bcr] gene at chromosome 22) tyrosine kinase inhibitors (TKIs) have been increasingly linked to pulmonary arterial hypertension (PAH) since 2009, although supporting evidence is limited. Our objective was to evaluate the risk of PAH associated with second- and third-generation BCR-ABL TKIs compared with imatinib in adults. METHODS:We employed a prevalent new-user design that emulates a randomized trial within the French national health care database population between 2008 and 2024. Thus, subjects initiating a second- and third-generation BCR-ABL TKI were matched on time and propensity score with users of the first-generation BCR-ABL TKI, imatinib. Patients were followed to occurrence of the primary outcome (ie, new onset of PAH), switch to another BCR-ABL TKI, death from any cause, end of registration within the database, or end of the study period, whichever came first. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards regression models, and incidence rates and corresponding 95% CIs were calculated using the Poisson distribution. RESULTS:Six thousand six hundred twenty-five dasatinib (age 59.7±15.2 years, 44.0% women), 5205 nilotinib (age 55.4±15.0 years, 44.2% women), 2421 bosutinib (age 63.8±14.2 years, 42.1% women),1358 ponatinib (age 57.3±14.9 years, 46.1% women), and 922 asciminib (age 64.3±13.8 years, 43.7% female) new users were each matched with the maximum of available imatinib users on time-conditional propensity score and on duration of prior imatinib use (prevalent users). Dasatinib use was associated with a 9-fold increased risk of PAH compared with imatinib (1829 versus 43 events per million persons per year; HR=8.89 [95% CI, 5.30-14.92]). Bosutinib and ponatinib were associated with HRs of 10.76 (95% CI, 4.68-24.73) and 7.74 (95% CI, 2.33-25.70) respectively, with most cases occurring in patients previously exposed to dasatinib. Nilotinib and asciminib were not associated with an increased risk of PAH. CONCLUSIONS:This study, designed to emulate a randomized trial, suggests that, in French patients with chronic myeloid leukemia treated with BCR-ABL TKIs, dasatinib use is associated with a higher risk of PAH compared with imatinib, while bosutinib and ponatinib exposure may aggravate or trigger a recurrence of PAH in patients with preexisting dasatinib exposure. Whether bosutinib and ponatinib could induce PAH without preexposure to dasatinib remains to be explored.

Importance:Dual bronchodilator therapy with a long-acting muscarinic antagonist (LAMA) and a long-acting β2-agonist (LABA) is recommended for most patients with symptomatic chronic obstructive pulmonary disease (COPD). Fixed-dose LAMA-LABA therapies are available in metered-dose, dry powder, and soft mist inhalers. However, metered-dosed inhalers are associated with greater greenhouse gas emissions than either dry powder or soft mist inhalers, and questions persist about potential intraclass differences among LAMA-LABAs given variability in their active ingredients, dosing schedules, and delivery devices. Objective:To evaluate the comparative effectiveness and safety of once-daily umeclidinium-vilanterol dry powder inhalers, twice-daily glycopyrrolate-formoterol metered-dosed inhalers, and once-daily tiotropium-olodaterol soft mist inhalers. Design, Setting, and Participants:This observational active-comparator study analyzed claims of patients (≥40 years) newly treated with LAMA-LABA inhalers and continuously enrolled in a large commercial health insurance or Medicare Advantage plan during the 183-day baseline period. Patients were propensity score matched 1:1 into 3 cohorts with index dates ranging from May 1, 2016, to February 28, 2025. Data were analyzed from July to August 2025. Exposures:Patients treated with umeclidinium-vilanterol, glycopyrrolate-formoterol, or tiotropium-olodaterol fixed-dose inhalers. Main Outcomes and Measures:Time to the first moderate or severe COPD exacerbation, major adverse cardiovascular event, urinary tract infection, and pneumonia hospitalization. Results:The cohorts included 9479 matched pairs of patients receiving umeclidinium-vilanterol vs glycopyrrolate-formoterol (mean age, 68.9 [SD, 9.0] years; 10 319 women [54.4%]; 8636 men [45.6%]), 9598 receiving tiotropium-olodaterol vs glycopyrrolate-formoterol (mean age, 69.2 [SD, 8.7] years; 10 513 women [54.8%]; 8680 men [45.2%]), and 36 740 receiving umeclidinium-vilanterol vs tiotropium-olodaterol (mean age, 71.5 [SD, 8.4] years; 39 429 women [53.7%]; 34 044 men [46.3%]). Umeclidinium-vilanterol was associated with a 14% lower hazard of a first moderate or severe COPD exacerbation than glycopyrrolate-formoterol (hazard ratio [HR], 0.86; 95% CI, 0.81-0.91; number needed to treat [NNT], 17) and was associated with a 3% lower hazard than tiotropium-olodaterol (HR, 0.97; 95% CI, 0.94-0.99; NNT, 100). Tiotropium-olodaterol was associated with a 6% lower hazard of a first moderate or severe COPD exacerbation than glycopyrrolate-formoterol (HR, 0.94; 95% CI, 0.89-1.00). Similar risks of first major adverse cardiovascular event, urinary tract infection, and pneumonia hospitalization were observed among patients in all 3 cohorts. Conclusions and Relevance:This cohort study found that umeclidinium-vilanterol was associated with improved clinical outcomes compared with glycopyrrolate-formoterol and tiotropium-olodaterol. Patients, prescribers, and health systems may consider once-daily umeclidinium-vilanterol dry powder inhalers over alternatives among new users of LAMA-LABA therapy.

PURPOSE:Our objective was to estimate the effect of initiating an inhaled corticosteroids-containing single-inhaler triple agent (ICS-LABA-LAMA) compared with a single-inhaler LABA-LAMA dual bronchodilator in patients with COPD on the risk of severe COVID-19 prior to the roll-out of vaccines. METHODS:We conducted a cohort study emulating a randomized trial, among patients with COPD aged 40 years or more in the UK, comparing those who initiated a triple inhaler with those who initiated a dual bronchodilator inhaler between March 1 and December 31, 2020. Weighting by fine stratification of the propensity score was used to account for confounders. The risk of hospitalized COVID-19 was compared with a Cox proportional hazards model in an as-treated analysis with a 30-day grace period. RESULTS:The study cohort included 876 patients initiating a triple inhaler and 5010 initiating a dual LABA-LAMA inhaler. The adjusted incidence rate of hospitalized COVID-19 was 5.6 per 100 person-years in the triple inhaler group and 2.9 per 100 person-years in the dual inhaler group, with a corresponding hazard ratio (HR) of 1.96 (95% confidence interval 1.01-3.77). Sensitivity analyses on the duration of the grace period, using an intent-to-treat exposure classification, or starting follow-up 14 days after treatment initiation (accounting for treatment initiation for an undocumented SARS-CoV-2 infection) were generally consistent with the main analysis. CONCLUSIONS:Patients with COPD prescribed an ICS-containing triple inhaler were potentially exposed to an increased risk of severe COVID-19 prior to the vaccine era. As SARS-CoV-2 continues to cause significant burden, these findings should be considered when determining initiation of inhaled treatment in COPD.

Importance:Inhaled corticosteroid (ICS)-long-acting β-agonist (LABA) inhalers are generally considered therapeutically equivalent when treating chronic obstructive pulmonary disease (COPD). However, metered-dose inhalers in the class are associated with substantially higher greenhouse gas emissions than dry powder formulations, and studies have raised questions about potential intraclass differences in clinical outcomes among patients receiving ICS-LABAs. Objective:To analyze COPD exacerbations and pneumonia hospitalizations associated with once-daily fluticasone furoate-vilanterol dry powder inhalers, twice-daily fluticasone propionate-salmeterol dry powder inhalers, and twice-daily budesonide-formoterol metered-dose inhalers in adults with COPD. Design, Setting, and Participants:This cohort study was conducted using longitudinal commercial claims data of US adults aged 40 years or older with COPD. Patients were 1:1 pairwise propensity score matched into 3 cohorts: (1) new users receiving fluticasone furoate-vilanterol vs budesonide-formoterol between January 1, 2014, and February 29, 2024; (2) new users receiving fluticasone furoate-vilanterol vs fluticasone propionate-salmeterol between January 1, 2014, and February 29, 2024; and (3) new users receiving fluticasone propionate-salmeterol vs budesonide-formoterol between January 1, 2007, and February 29, 2024. Exposures:Receipt of a once-daily fluticasone furoate-vilanterol dry powder inhaler (Breo Ellipta; GSK), twice-daily fluticasone propionate-salmeterol dry powder inhaler (Advair Diskus; GSK), or twice-daily budesonide-formoterol metered-dose inhaler (Symbicort; AstraZeneca). Main Outcomes and Measures:The primary outcomes were first moderate or severe COPD exacerbation and first pneumonia hospitalization. Hazard ratios and 95% CIs were estimated using Cox proportional hazards regression models. Results:The cohorts included 38 070 matched pairs of patients receiving fluticasone furoate-vilanterol vs budesonide-formoterol (58.8% women; mean [SD] age, 71.0 [9.0] years), 20 471 matched pairs of patients receiving fluticasone furoate-vilanterol vs fluticasone propionate-salmeterol (58.3% women; mean [SD] age, 69.9 [9.2] years), and 55 627 matched pairs of patients receiving fluticasone propionate-salmeterol vs budesonide-formoterol (56.2% women; mean [SD] age, 68.3 [9.0] years). Patients receiving fluticasone furoate-vilanterol had a 9% lower risk of moderate or severe COPD exacerbations compared with those receiving budesonide-formoterol (hazard ratio [HR], 0.91 [95% CI, 0.88-0.94]; number needed to treat [NNT] = 40) and a 6% lower risk compared with those receiving fluticasone propionate-salmeterol (HR, 0.94 [95% CI, 0.89-0.98]; NNT = 40). The risk of moderate or severe COPD exacerbation was similar for patients receiving fluticasone propionate-salmeterol and budesonide-formoterol (HR, 0.98 [95% CI, 0.95-1.01]). No differences were observed in the risk of pneumonia hospitalization across the 3 cohorts (fluticasone furoate-vilanterol vs budesonide-formoterol: HR, 1.03 [95% CI, 0.96-1.11]; fluticasone furoate-vilanterol vs fluticasone propionate-salmeterol: HR, 0.93 [95% CI, 0.85-1.03]; and fluticasone propionate-salmeterol vs budesonide-formoterol: HR, 1.04 [95% CI, 0.98-1.10]). Conclusions and Relevance:In this cohort study of new ICS-LABA users with COPD, once-daily dry powder fluticasone furoate-vilanterol inhalers were associated with slightly improved clinical outcomes compared with twice-daily metered-dose budesonide-formoterol inhalers and twice-daily dry powder fluticasone propionate-salmeterol inhalers. Further studies are needed to explore potential intraclass differences among inhalers used to treat COPD.

OBJECTIVE:To compare the risk of moderate or severe exacerbations of chronic obstructive pulmonary disease (COPD) among new users of azithromycin versus roflumilast in a population of patients with active COPD treated in routine clinical practice. DESIGN:Target trial emulation. DATA SOURCE:Optum Clinformatics Data Mart Database from 1 March 2011 to 31 August 2024. PARTICIPANTS:Patients aged >40 years with active COPD and at least 183 days of continuous insurance enrolment who initiated a new oral prescription for maintenance azithromycin or roflumilast. Those with evidence of other pulmonary conditions or alternative indications for azithromycin were excluded. Propensity score matching was used between treatment groups. MAIN OUTCOME MEASURES:The primary outcome was time to first moderate or severe COPD exacerbation. Cox proportional hazards models estimated hazard ratios. RESULTS:A total of 7550 matched pairs of patients initiating azithromycin versus roflumilast were included in the cohort. The mean age of patients was 70 years, and 56% were women. The unadjusted incidence of a first moderate or severe COPD exacerbation among patients in the cohort receiving azithromycin or roflumilast was 1.2 per person year. Compared with roflumilast, azithromycin was associated with a 17% reduction in the hazard of first moderate or severe COPD exacerbation (hazard ratio 0.83, 95% confidence interval (CI) 0.79 to 0.87; number needed to treat 15, 95% CI 12 to 21). These results were robust across a range of prespecified sensitivity and subgroup analyses. CONCLUSIONS:Among patients with active COPD, azithromycin use was associated with a reduced likelihood of moderate or severe COPD exacerbations compared with roflumilast use. Although this study did not assess the comparative safety of these agents, it provides evidence on treatment outcomes that may complement forthcoming data from a large randomised controlled trial. STUDY REGISTRATION:Centre for Open Science Real-World Evidence Registry https://osf.io/95d2v.

Objective: To estimate the effect of initiating glucagon-like peptide-1 receptor agonists (GLP-1 RAs) versus dipeptidyl peptidase-4 (DPP-4) inhibitors on incident nonarteritic anterior ischemic optic neuropathy (NAION) among adults with type 2 diabetes. Research Design and Methods: This active-comparator, new-user cohort emulated a pragmatic target trial using the Clinical Practice Research Datalink in United Kingdom. Patients aged ≥18 years with a physician diagnosis of type 2 diabetes, who newly initiated a GLP-1 RA or a DPP-4 inhibitor, were included. DPP-4 inhibitors were selected as the comparator because they may be used as second-line treatment, like GLP-1 RAs, and have no established association with NAION. We estimated risks, risk differences (RDs), and risk ratios (RRs) of incident NAION adjusted using propensity score fine stratification weighting. Results: At one year, there were 14 NAION events among 106,858 GLP-1 RA initiators (18.5 per 100,000) and 53 among 416,369 DPP-4 inhibitor initiators (7.2 per 100,000): GLP-1 RAs were associated with an increased risk of NAION compared with DPP-4 inhibitors (RR: 2.56, 95% CI: 1.44-4.86; RD: 11.3 per 100,000). The risk of NAION was higher during the first six months and diminished with longer durations of use, and was higher in patients aged <50 years, men, ever-smokers, and those with ≥ 1% hemoglobin A1c reduction. Conclusions: GLP-1 RAs were associated with an increased one-year risk of NAION compared with DPP-4 inhibitors among adults with type 2 diabetes, particularly in younger patients, men, ever-smokers, and patients with a marked hemoglobin A1c reduction.

BACKGROUND:Although beta-blockers are effective at reducing mortality in certain cardiovascular diseases (CVDs), their effectiveness in patients with COPD and CVD is uncertain, particularly with the concurrent use of long-acting beta2-agonists (LABAs). RESEARCH QUESTION:Is the initiation of beta-blockers in patients with COPD and CVD associated with reduced mortality, and is this effect influenced by concurrent use of LABAs? STUDY DESIGN AND METHODS:The United Kingdom's Clinical Practice Research Datalink (CPRD) Aurum network was used to form a cohort of patients with COPD and CVD from January 2002 to March 2021 who were aged ≥ 40 years. A prevalent new-user design, conceived to emulate a trial, was used, matching initiators of beta-blockers with nonusers on time and propensity score as well as CVD indication, namely heart failure (HF), ischemic heart disease (IHD), atrial fibrillation, and hypertension. Hazard ratios (HRs) and 95% CIs of all-cause mortality were estimated by using an as-treated approach. RESULTS:The study cohort included 11,594 initiators of beta-blockers and 11,594 matched nonusers. The HR of death with beta-blocker use relative to nonuse was 0.88 (95% CI, 0.81-0.95). The HR was 0.95 (95% CI, 0.85-1.05) among concurrent LABA users and 0.80 (95% CI, 0.71-0.91) among LABA nonusers (Pinteraction = .04), an effect driven by patients with IHD (Pinteraction = .01). The HR was 0.77 (95% CI, 0.66-0.89) among patients with HF, 0.84 (95% CI, 0.73-0.98) for IHD, 0.96 (95% CI, 0.83-1.11) for atrial fibrillation, and 1.10 (95% CI, 0.87-1.38) for hypertension. INTERPRETATION:This large population-based study, designed to emulate a trial, suggests that beta-blocker use is effective at reducing all-cause mortality in patients with COPD and CVD but only in those with HF or IHD, not in those with atrial fibrillation or hypertension. The concurrent use of LABAs could mitigate the effectiveness of beta-blockers at reducing mortality.

Purpose:Multiple guidelines recommend single-inhaler triple therapy (SITT) for some patients with COPD. The first two SITTs approved for COPD were beclomethasone-glycopyrronium-formoterol (BEGF, twice daily) and fluticasone-umeclidinium-vilanterol (FUV, once daily). No study has compared the effectiveness and safety of these SITTs on major outcomes. Patients and Methods:We identified a cohort of patients with COPD, 40 years of age or older, from the United Kingdom's Clinical Practice Research Datalink. The patients who initiated treatment with FUV or BEGF were compared on the incidence of moderate or severe COPD exacerbations, and of pneumonia, over one year, after balancing baseline characteristics by propensity score weighting. Results:The study cohort included 34,825 initiators of FUV and 39,288 initiators of BEGF, well balanced after weighing. The adjusted hazard ratio (HR) of a first moderate or severe exacerbation with FUV compared with BEGF was 0.91 (95% CI: 0.89-0.93), while for severe exacerbation it was 0.92 (95% CI: 0.86-0.97), corresponding to 27.9 fewer subjects with a moderate or severe exacerbation and 1.0 fewer with a severe exacerbation per 100 treated with FUV for one year. The HR of pneumonia requiring hospitalisation, comparing FUV with BEGF, was 1.06 (95% CI 0.99-1.13), over all patients. It was 1.14 (95% CI 1.06-1.24) among those classified as GOLD Group E, and 1.10 (95% CI 1.02-1.19) among those with a blood eosinophil count ≤ 300 cells/µL, corresponding to increases of 1.7 and 1.0 more subjects with a severe pneumonia per 100 treated with FUV for one year, respectively. Conclusion:In a real-world clinical practice setting of COPD treatment, initiating triple therapy with FUV was associated with a lower incidence of moderate and severe exacerbations than with BEGF. On the other hand, the incidence of a severe pneumonia requiring hospitalisation was higher with FUV among GOLD Group E subjects or those whose blood eosinophil count is not elevated.

Sustained exposure to oral corticosteroids (OCS) increases the risk of upper gastrointestinal bleeding (UGIB). It is uncertain whether short-term OCS treatment of asthma exacerbations increases this risk. This study aims to estimate the risk of acute UGIB after transient OCS use in patients with mild-to-moderate asthma. We used a case-crossover design within a cohort of patients with mild-to-moderate asthma, aged 18–40 years during 2000–2023, from the UK’s Clinical Practice Research Datalink. Subjects who experienced a first severe UGIB formed the case series. Short-term OCS was defined by a prescription for ≤ 14 days, with a 30-day residual effect period. For each case, the UGIB event date and 6 control dates, selected at 45-day intervals in the prior year, were considered exposed if the prescription spanned the date. The odds ratio (OR) of UGIB was estimated using conditional logistic regression, adjusted for time-varying use of asthma inhalers and medications related to bleeding risks. Findings The cohort involved 655,217 patients with mild-to-moderate asthma, with 743 experiencing a first UGIB who received 1160 OCS prescriptions in the past year. The crude and adjusted ORs of UGIB after OCS use versus non-use was 1.12 (95

Respiratory societies now advocate for long-acting beta2-agonist (LABA) and long-acting muscarinic antagonist (LAMA) combinations (LABA-LAMA) as initial pharmacological treatment of COPD patients with multiple exacerbations or significant symptoms. However, the evidence comes from trials involving treatment-experienced patients. We identified a cohort of newly diagnosed COPD patients, 40 years of age or older, from the UK's Clinical Practice Research Datalink over 2014-2021. Treatment-naïve initiators of single-inhaler LABA-LAMA or LAMA were compared on the incidence of COPD exacerbation and major adverse cardiovascular events (MACE) over one year, after adjustment by propensity score weighting. The cohort included 16,804 initiators of LABA-LAMA and 57,295 of LAMA. The adjusted hazard ratio (HR) of a first moderate or severe exacerbation with LABA-LAMA relative to LAMA was 1.00 (95% confidence interval (CI): 0.96-1.05). This HR was 0.93 (95% CI: 0.86-1.00) among GOLD group E patients, 1.07 (95% CI: 0.99-1.15) among GOLD group B patients, and 0.91 (95% CI: 0.83-0.99) for patients with FEV1 < 50% predicted. The HR of MACE was 1.13 (95% CI: 1.02-1.25) overall and 1.03 (95% CI: 0.83-1.28) among patients with FEV1 < 50% predicted. In a real-world clinical practice setting of COPD treatment, initiating therapy with LABA-LAMA may be more effective at exacerbation reduction than LAMA among patients with multiple exacerbations and those with FEV1<50% predicted. The small increase in MACE risk with LABA-LAMA should be considered when initiating bronchodilator therapy in newly diagnosed COPD, particularly those with FEV1≥50% predicted. This study supports a targeted approach to initial COPD therapy.

OBJECTIVES:To conduct a systematic review of observational studies examining the association between sodium-glucose cotransporter 2 (SGLT2) inhibitors and the risk of mortality and of hospitalization compared with the use of other antidiabetic medications in patients with type two diabetes and COVID-19, with a focus on the methodological quality. We also describe how such studies can be improved when addressing a public health emergency. STUDY DESIGN AND SETTING:We conducted a systematic review by searching Embase, MEDLINE, and the WHO COVID-19 research article databases up to March 2025. Observational studies reporting on the risk of mortality and of hospitalization with the use of SGLT2 inhibitors among patients with type two diabetes and COVID-19 were included and study quality was assessed using the ROBINS-I tool. Our systematic review focused on the methodological assessment of the literature. RESULTS:We included 20 cohort studies, with 18 reporting on all-cause mortality and eight on COVID-19-related hospitalization. Five studies reported a decreased risk of all-cause mortality (range of effects estimates: 0.25 to 0.82), compared with nonuse or use of other drugs, and four studies reported a decreased risk of hospitalization (range: 0.79 to 0.92); the others reported no association. Overall, 14 studies were at serious risk of bias and six were at critical risk. We identified several methodological issues related to the selection of participants, inadequate control of confounding, and assessment of exposure and outcomes. No meta-analysis was conducted due to the low quality and heterogeneity of the included studies. CONCLUSIONS:The observational studies examining the effectiveness of SGLT2 inhibitors among patients with type two diabetes and COVID-19 outcomes have important methodological issues that limit the conclusions that can be drawn from this knowledge base. Although public health emergencies require rapid responses, methodological rigor remains essential to generate actionable evidence.

BACKGROUND: Recent treatment guidelines for COPD have replaced the long-acting beta2agonist (LABA) and inhaled corticosteroid (ICS) combination with single-inhaler triple therapy that adds a long-acting muscarinic antagonist (LAMA). However, the corresponding trials reported numerically higher incidences of cardiovascular adverse events with triple therapy compared with LABA-ICS. RESEARCH QUESTION: Does single-inhaler triple therapy increase the incidence of major adverse cardiovascular events, compared with LABA-ICS, in a real-world clinical practice setting? STUDY DESIGN AND METHODS: We identified a cohort of patients with COPD aged $ 40 years treated during 2017-2021 from the UK's Clinical Practice Research Datalink. Among LAMAnaive patients, initiators of single-inhaler triple therapy were matched 1:1 to LABA-ICS users on time-conditional propensity scores. They were compared on the incidence of major adverse cardiovascular events (MACEs), defined as hospitalization for myocardial infarction or stroke, or all-cause-mortality, over 1 year. RESULTS: The cohort included 10,255 initiators of triple therapy and 10,255 matched users of LABA-ICS. The incidence rate of MACEs was 11.3 per 100 per year with triple therapy compared with 8.8 per 100 per year for LABA-ICS. The corresponding adjusted hazard ratio (HR) of MACEs with triple therapy was 1.28 (95% CI, 1.05-1.55), relative to LABA-ICS; however, the increase was mainly in the first 4 months (HR, 1.41; 95% CI, 1.14-1.74). The HR of all-cause death was 1.31 (95% CI, 1.06-1.62), whereas for acute myocardial infarction and stroke hospitalization it was 1.00 (95% CI, 0.56-1.79) and 1.06 (95% CI, 0.48-2.36), respectively, with triple therapy, relative to LABA-ICS. INTERPRETATION: In a real-world setting of COPD treatment, patients who initiated singleinhaler triple therapy had an increased incidence of MACEs compared with similar patients treated with an LABA-ICS inhaler. This small increase was due to the all-cause mortality component, occurring mainly in the first 4 months after treatment initiation.

BACKGROUND:Observational studies of the association between antibiotics and preterm delivery report conflicting findings, with some potentially affected by immortal time bias. We assessed the effects of third-trimester antibiotic use on preterm delivery and low birthweight, using a study design that accounts for immortal time bias. METHODS:We used the UK's Clinical Practice Research Datalink to identify pregnant females aged 12-50, over the period 2002 to 2016, reaching 27 weeks of gestation without antibiotic use until that point. We applied the prevalent new-user design, matching each third-trimester antibiotic initiator with a reference nonuser at the same gestational day, using time-conditional propensity scores. The 2 matched groups were compared on the incidence of preterm delivery and low birthweight. The full cohort was also analyzed with antibiotic use considered as time-fixed and time-varying exposures. RESULTS:The cohort included 207,027 pregnancies, with 16,865 initiating antibiotics matched to 16,865 nonusers. The hazard ratio (HR) of preterm delivery with third-trimester antibiotic use was 1.14 [95% confidence interval (CI): 1.04, 1.24], compared with nonuse. With time-fixed exposure, subject to immortal time bias, the HR was 0.78 (95% CI: 0.73, 0.83), while with time-varying exposure, the HR was 1.23 (95% CI: 1.16, 1.32). The HR of low birthweight with antibiotic initiation was 1.07 (95% CI: 0.93, 1.25) compared with 0.91 (95% CI: 0.83, 1.00) under the time-fixed approach. CONCLUSIONS:Using the prevalent new-user design, which emulates a randomized trial, antibiotic use late in pregnancy was associated with a modestly increased incidence of preterm delivery. Previous inconclusive studies may have resulted from observational methods that introduced, or insufficiently addressed, immortal time bias.

Importance:Influenza infection could be associated with a long-term increase in the risk of Parkinson disease (PD). However, the benefit of influenza immunization as a preventive measure for PD remains unknown. Objective:To assess whether immunization for influenza at midlife (between age 40 and 50 years) is associated with a decreased risk of PD. Design, Setting, and Participants:This cohort study used electronic medical records from the UK's Clinical Practice Research Datalink Aurum. The study cohort comprised individuals vaccinated for influenza between 40 and 50 years of age (hereafter, with influenza immunization at midlife) from 1995 to 2017 and unvaccinated controls (hereafter, without influenza immunization at midlife) matched 1:1 on age, sex, socioeconomic status, and calendar month of the vaccination. All analyses were conducted between January and May 2025. Main Outcomes and Measures:The primary outcome was incident PD. A modified intention-to-treat exposure definition with a 2-year lag period was applied to assess the risk of incident PD associated with influenza immunization at midlife vs no influenza immunization at midlife. Cox proportional hazards regression models estimated hazard ratios (HRs) and 95% CIs of the study outcome. Inverse probability of censoring weighting was used to account for selection bias, and propensity score matching was used for confounding control. Secondary analyses assessed potential effect size modifiers. Sensitivity analyses explored the implications of different potential biases. Results:The study cohort included 1 191 209 individuals (mean [SD] age, 44 [3] years; 673 920 females [56.6%]), of whom 612 974 received influenza immunization at midlife and 578 235 did not receive influenza immunization at midlife . Influenza immunization at midlife vs lack thereof was not associated with the risk of PD overall (crude incidence rates per 1000 person-years, 0.16 vs 0.10; matched HR, 0.96; 95% CI, 0.76-1.22). Results varied over time, with the lowest point estimate approximately 8 years after vaccination (HR, 0.75; 95% CI, 0.52-1.08), but none of the differences were statistically significant. Results also varied by seasonality, with a lower point estimate for those vaccinated during influenza season (matched HR, 0.62; 95% CI, 0.33-1.15) compared with those vaccinated outside of influenza season (matched HR, 1.07; 95% CI, 0.81-1.42). Stratification by age, sex, or vaccination prior to cohort entry did not modify the association. Sensitivity analyses supported the findings of the primary analysis. Conclusions and Relevance:This cohort study found that influenza immunization at midlife was not associated with the risk of PD in the overall population. Potential benefits for PD risk occurring several years after vaccination or in specific patient subgroups require further investigation.

Background The 2023 Global initiative for chronic Obstructive Lung Disease (GOLD) recommendations advocate long-acting beta2 agonist (LABA) and long-acting muscarinic antagonist (LAMA) combinations (LABA-LAMA) for the initial pharmacological treatment of patients with chronic obstructive pulmonary disease (COPD) with multiple exacerbations. However, this choice, rather than combinations of LABA and inhaled corticosteroids (LABA-ICS), no longer recommended in GOLD, was based on randomised trials that excluded patients with multiple prior exacerbations.Research question What is the comparative effectiveness of initiating COPD treatment with LABA-ICS versus LABA-LAMA inhalers, particularly in patients with multiple COPD exacerbations, in a real-world clinical practice setting?Study design and methods We identified a cohort of patients with COPD, 40 years of age or older, from the United Kingdom’s Clinical Practice Research Datalink. Treatment-naïve initiators of single-inhaler LABA-ICS or LABA-LAMA, with no prior asthma, LABA, LAMA or ICS use, were compared on the incidence of moderate or severe COPD exacerbation over 1 year, after adjustment by propensity score weighting.Results The study cohort included 20 750 initiators of LABA-ICS inhalers and 16 594 of LABA-LAMA. The overall adjusted HR of a first moderate or severe exacerbation with LABA-ICS relative to LABA-LAMA was 1.03 (95% CI 0.98 to 1.08). Among patients with two or more prior exacerbations, the HR of exacerbation with LABA-ICS versus LABA-LAMA was 0.89 (95% CI 0.81 to 0.97), while it was 1.07 (95% CI 1.00 to 1.15) among patients with no prior exacerbations. The HR was 0.92 (95% CI 0.86 to 0.99) among those with forced expiratory volume in 1 s (FEV1)≥50% predicted.Interpretation In a real-world clinical practice setting of COPD treatment, initiating therapy with LABA-ICS inhalers may be more effective than LABA-LAMA inhalers among patients with multiple exacerbations, particularly those with FEV1≥50% predicted, but less effective among those with no prior exacerbations and FEV1<50% predicted. This study supports a targeted approach to initial therapy for COPD.