Tetanus, a severe and life-threatening illness caused by Clostridium tetani, produces symptoms such as muscle spasms, muscle stiffness and seizures caused by the production of tetanus neurotoxin (TeNT). TeNT causes spastic paralysis through the inhibition of neurotransmission in spinal inhibitory interneurons. This is achieved, in part, through pH-triggered membrane insertion of the translocation (HCT) domain, which delivers the catalytic light-chain (LC) domain to the cytosol. While the function of HCT is well defined, the mechanism by which it accomplishes this task is largely unknown. Based on the crystal structure of tetanus neurotoxin, we identified potential polar interactions between arginine 711, tryptophan 715 and aspartate 821 that appear to be evolutionarily conserved across the clostridial neurotoxin family. We show that the disruption of the Asp-Arg pair in a beltless HCT variant (bHCT) results in changes in thermal stability without significant alterations to the overall secondary structure. ANS (1-anilino-8-napthalene sulfonate) binding studies, in conjunction with liposome permeabilization assays, demonstrate that mutations at R711 or D821 trigger interactions with the membrane at higher pH values compared to wildtype bHCT. Interestingly, we show that the introduction of the D821N mutation into LHNT (LC-HCT only), but not the holotoxin, resulted in the increased cleavage of VAMP 2 in cortical neurons relative to the wildtype protein. This suggests that, as observed for botulinum toxin A, the receptor-binding domain is not necessary for LC translocation but rather helps determine the pH threshold of membrane insertion. The mutation of W715 did not result in detectable changes in the activity of either bHCT or the holotoxin, suggesting that it plays only a minor role in stabilizing the structure of the toxin. We conclude that the protonation of D821 at low pH disrupts interactions with R711 and W715, helping to drive the conformational refolding of HCT needed for membrane insertion and the subsequent translocation of the LC.

Traditionally, the sperm genome is thought to be packaged by protamines into a uniformly compact and inert chromatin structure. Here, we challenge this long-standing view by demonstrating that protamine post-translational modifications (PTMs) present on distinct protamine molecules create discrete protamine-DNA chromatin states, ranging from weak to tightly associated chromatin configurations. Loss of these modifications alters protamine-DNA interactions in vitro and in vivo , compromising sperm chromatin integrity and impairing fertility. Therefore, these findings demonstrate that protamines do not merely serve as inert packaging proteins; rather protamine PTMs establish functional heterogeneity within sperm chromatin, creating compartment-like domains analogous to those in somatic cells. Thus, PTMs allow protamines to do more than simply compact the paternal genome-they likely encode a molecular blueprint that orchestrates the timely unpacking and reorganization of the paternal genome after fertilization.

Abstract Background Cough remains a persistent symptom in patients with idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases (ILDs). To inform future research, treatment and care models, we conducted the first systematic synthesis of evidence on its associated burden. Methods A literature search was performed for articles published between January 2010 and October 2023 using databases including Embase, MEDLINE and the Cochrane Library. Studies in patients with IPF and other ILDs reporting cough-related measures were eligible for inclusion. Included studies were categorised based on the types of ILD they examined and their design. Study details, patient characteristics and outcomes were extracted, and the risk of bias was assessed. A narrative synthesis approach was employed to interpret the findings. Results Sixty-one studies were included: 33 in IPF, 18 in mixed-ILDs, six in connective tissue disease-associated-ILDs and four in sarcoidosis. Across the studies, a range of tools to assess cough and its impact were used. The most frequently used measures of cough were cough severity visual analogue scale (VAS) and objective cough counts, whereas the most frequently used health-related quality of life (HRQoL)/impact measures were the St. George’s Respiratory Questionnaire (SGRQ) and Leicester Cough Questionnaire (LCQ). In IPF, studies consistently reported correlations between various cough and HRQoL measures, including between cough VAS scores and objective cough counts, LCQ scores and SGRQ scores. Similar correlations were observed in studies in other ILDs, but data were more limited. Qualitative studies in both IPF and other ILDs consistently highlighted the significant cough-related burden experienced by patients, including disruption of daily activities, fatigue and social embarrassment. Although there were no studies specifically investigating the economic burden of cough, one study in patients with fibrotic ILD found cough severity was associated with workplace productivity loss. Conclusions Our study underscores the heterogeneity in assessing cough and its impact in IPF and other ILDs. The findings confirm the negative impact of cough on HRQoL in IPF and suggest a comparable impact in other ILDs. Our synthesis highlights the need for standardised assessment tools, along with dedicated studies, particularly in non-IPF ILDs and on the economic burden of cough.

Conventional dogma presumes that protamine-mediated DNA compaction in sperm is achieved by electrostatic interactions between DNA and the arginine-rich core of protamines. Phylogenetic analysis reveals several non-arginine residues conserved within, but not across species. The significance of these residues and their post-translational modifications are poorly understood. Here, we investigated the role of K49, a rodent-specific lysine residue in protamine 1 (P1) that is acetylated early in spermiogenesis and retained in sperm. In sperm, alanine substitution (P1(K49A)) decreases sperm motility and male fertility—defects that are not rescued by arginine substitution (P1(K49R)). In zygotes, P1(K49A) leads to premature male pronuclear decompaction, altered DNA replication, and embryonic arrest. In vitro, P1(K49A) decreases protamine–DNA binding and alters DNA compaction and decompaction kinetics. Hence, a single amino acid substitution outside the P1 arginine core is sufficient to profoundly alter protein function and developmental outcomes, suggesting that protamine non-arginine residues are essential for reproductive fitness.

PDF file - 68K, Positional information and effect sizes of the 24 patient/LCL overlap SNPs.

PDF file, 288K, Supplemental data showing study design, quality control, and replication results.

Background Dyspnoea and cough can have a profound impact on the lives of patients with pulmonary fibrosis. We investigated the effects of nintedanib on the symptoms and impact of pulmonary fibrosis in patients with progressive pulmonary fibrosis (PPF) in the INBUILD trial using the Living with Pulmonary Fibrosis (L-PF) questionnaire. Methods Patients had a fibrosing interstitial lung disease (ILD) (other than idiopathic pulmonary fibrosis) of >10% extent on high-resolution computed tomography (HRCT) and met criteria for ILD progression within the prior 24 months. Patients were randomised 1:1 to receive nintedanib or placebo. Changes in L-PF questionnaire scores from baseline to week 52 were assessed using mixed models for repeated measures. Results In total, 663 patients were treated. Compared with placebo, there were significantly smaller increases (worsenings) in adjusted mean L-PF questionnaire total (0.5 versus 5.1), symptoms (1.3 versus 5.3), dyspnoea (4.3 versus 7.8) and fatigue (0.7 versus 4.0) scores in the nintedanib group at week 52. L-PF questionnaire cough score decreased in the nintedanib group and increased in the placebo group (−1.8 versus 4.3). L-PF questionnaire impacts score decreased slightly in the nintedanib group and increased in the placebo group (−0.2 versus 4.6). Similar findings were observed in patients with a usual interstitial pneumonia-like fibrotic pattern on HRCT and in patients with other fibrotic patterns on HRCT. Conclusion Based on changes in L-PF questionnaire scores, nintedanib reduced worsening of dyspnoea, fatigue and cough and the impacts of ILD over 52 weeks in patients with PPF.

We aimed to describe healthcare resource utilization (HCRU) patterns and costs in patients with fibrosing interstitial lung disease (ILD) and those with a progressive phenotype of fibrosing ILD in a US claims database. Data from the IBM® MarketScan® databases (1 October 2011–30 September 2015) were used. Diagnosis codes documented on medical claims on two occasions (without any claims during the 12 months prior) identified patients with incident fibrosing ILD. Patients with chronic fibrosing ILD with a progressive phenotype were identified by proxies for progression. Patients aged ≥ 18 years with 365 days of continuous coverage before the index date were eligible for inclusion. Data were analyzed for 12 months prior to identification of fibrosing ILD/progressive phenotype (baseline) and 12 months after (follow-up). Outcomes included treatment patterns, outpatient and inpatient claims, and costs. We identified 23,577 patients with incident fibrosing ILD and 14,722 with the progressive phenotype. Follow-up data were available for 9986 and 5840 patients, respectively. The most frequent ILD-related medications during baseline were corticosteroids (49.4% and 56.6%). Mean (± standard deviation [SD]) annualized number of outpatient claims was 30.0 (± 26.4) and 34.1 (± 27.7) in the baseline period and 36.2 (± 28.6) and 41.9 (± 30.2) in the follow-up in fibrosing ILD and with a progressive phenotype, respectively. Mean (SD) number of all-cause hospitalizations was 0.5 (± 1.1) and 0.7 (± 1.2) during baseline and 0.6 (± 1.1) and 0.7 (± 1.2) during follow-up. Mean (SD) total costs were $40,907 (± 92,496) and $49,561 (± 98,647) during baseline and $46,157 (± 102,858) and $54,215 (± 116,833) during follow-up. Inpatient mortality during follow-up was 53.50 and 77.44 per 1000 patient-years. HCRU and costs were high in patients with chronic fibrosing ILD with a progressive phenotype, likely reflecting the disease severity and the need for close monitoring and acute care. Outpatient claims accounted for a substantial proportion of the total costs. Some patients with lung diseases have inflammation or scarring of the lung tissues (interstitial lung diseases, or ILDs). In some patients with lung scarring, the scarring may become progressive (i.e., it worsens over time). In this study, we looked at these patients identified in US health insurance records. We counted how many times patients visited a doctor, were admitted to hospital, or needed medications or tests. We also looked at the total cost of all this medical care. Overall, we concluded that patients with ILDs with progressive lung scarring had a high number of visits to the doctor, and the total costs of their medical care were high.

Background There is a lack of fully validated patient-reported outcome measures for progressive fibrosing interstitial lung disease (ILD). We aimed to validate the King's Brief Interstitial Lung Disease (K-BILD) questionnaire for measuring health-related quality of life (HRQoL) in these patients. We also aimed to estimate the meaningful change threshold for interpreting stabilisation of HRQoL as a clinical end-point in progressive fibrosing ILD, where the current goal of treatment is disease stability and slowing progression. Methods This analysis evaluated data from 663 patients with progressive fibrosing ILD other than idiopathic pulmonary fibrosis from the INBUILD trial. Validation of the measurement properties was assessed for internal consistency, test–retest reliability, construct validity, known-groups validity and responsiveness. We calculated meaningful change thresholds for treatment response using anchor-based (within-patient) and distribution-based methods. Results K-BILD had strong internal consistency (Cronbach's α was 0.94 for total score, 0.88 for breathlessness and activities, 0.91 for psychological, and 0.79 for chest symptoms). The test–retest reliability intraclass correlation coefficient was 0.74 for K-BILD total score. K-BILD demonstrated weak correlations with forced vital capacity (FVC) percent predicted. Known-groups validity showed significant differences in K-BILD scores for patient groups with different disease severity based on use of supplemental oxygen or baseline FVC % pred (≤70% or >70%). We estimated a meaningful change threshold of ≥ –2 units for K-BILD total score for defining patients who remain stable/improved versus those with progressive deterioration. Conclusions Our results validate K-BILD as a tool for assessing HRQoL in patients with progressive fibrosing ILD and set a meaningful change threshold of ≥ –2 units for K-BILD total score.

The Living with Idiopathic Pulmonary Fibrosis (L-IPF) questionnaire was developed with substantial input from patients with idiopathic pulmonary fibrosis (IPF) to assess symptoms and health-related quality of life (HRQoL). Because IPF is the prototypical chronic fibrosing interstitial lung disease (ILD) with a progressive phenotype, we expanded applicability of the L-IPF by deleting the word “idiopathic”, creating the L-PF (Living with Pulmonary Fibrosis) questionnaire, and then assessed its relevance among patients with progressive fibrosing ILDs in one-to-one interviews. Patients in the USA and Germany with any progressive fibrosing ILD other than IPF were asked about their disease and symptoms, completed the 44-item L-PF questionnaire (comprising two modules that assess symptoms and impacts of disease) and then answered a series of debriefing questions. Interviews were recorded, transcribed and coded for qualitative content analysis. 20 patients were interviewed, but time constraints meant not all were asked about all items. The most frequent diagnoses were rheumatoid arthritis-associated ILD (25%) and mixed connective tissue disease-associated ILD (20%). Almost all patients endorsed the symptoms assessed by the L-PF: shortness of breath (19 out of 20 patients), cough (19 out of 20) and fatigue (18 out of 20). Most patients endorsed impacts of progressive fibrosing ILD on activities of daily living, physical well-being, sleep, emotional well-being, and social aspects of their lives. Most patients had an overall positive impression of the Symptoms module and understood items as intended. All seven patients asked understood the items of the Impacts module. The L-PF contains concepts relevant and important to patients with progressive fibrosing ILD, and items are understood as intended.

Background An understanding of the experience of patients with progressive fibrosing interstitial lung disease (PF-ILD) is needed to select appropriate patient-reported outcome measures (PROMs) to evaluate treatment effect in clinical trials. Methods A systematic literature review was conducted to develop a preliminary conceptual model of the symptoms experienced by patients with PF-ILD and the impacts the disease has on them. An online survey and consensus meetings were then conducted with 12-14 stakeholders (patients, clinicians, regulatory and payer advisors) to refine the conceptual model and critically appraise how key concepts should be measured by PROMs. PROMs assessed included Living with Idiopathic Pulmonary Fibrosis, Living with Pulmonary Fibrosis, the King's Brief Interstitial Lung Disease questionnaire, Cough and Sputum Assessment Questionnaire, Evaluating Respiratory Symptoms, Leicester Cough Questionnaire, Functional Assessment of Chronic Illness Therapy (Dyspnoea/Fatigue) and St George's Respiratory Questionnaire for Idiopathic Pulmonary Fibrosis. Results The literature review identified 36 signs/symptoms and 43 impacts directly or indirectly related to pulmonary aspects of PF-ILD. The most relevant symptoms identified by participants included shortness of breath on exertion, fatigue and cough; relevant impacts included effects on physical functioning, activities of daily living and emotional wellbeing. These are presented in a conceptual model. Consensus opinion was that existing PROMs need further modification and validation before use in clinical trials. Conclusions The conceptual model improves understanding of the symptoms and impacts that living with PF-ILD has on patients' wellbeing. It can help to inform the choice of PROMs in clinical trials and highlight aspects to assess in the clinical care of patients with PF-ILD.

Introduction Among the various types of progressive fibrosing interstitial lung diseases (PF-ILDs), substantial survival data exist for idiopathic pulmonary fibrosis (IPF) but not for other types. This hinders evidence-based decisions about treatment and management, as well as the economic modelling needed to justify research into new treatments and reimbursement approvals. Given the clinical similarities between IPF and other PF-ILDs, we reasoned that patient survival data from four major IPF trials could be used to estimate long-term survival in other PF-ILDs. Methods We used propensity score matching to match patients with IPF taking either nintedanib or placebo in the TOMORROW, INPULSIS-1, INPULSIS-2 and INPULSIS-ON trials to patients with PF-ILDs other than IPF in the INBUILD trial. Seven models were fitted to the survival data for the matched patients with IPF, and the three best-fitting models were used to generate informative priors in a Bayesian framework to extrapolate patient survival of the INBUILD population. Results After propensity score matching, the analysis included data from 1099 patients with IPF (640 nintedanib patients; 459 placebo patients) and 654 patients with other PF-ILDs (326 nintedanib patients; 328 placebo patients). Gamma, log-logistic and Weibull models best fit the survival of the matched patients with IPF. All three models led to consistent Bayesian estimates of survival for the matched patients with other PF-ILDs, with median rates of overall survival ranging from 6.34 to 6.50 years after starting nintedanib. The corresponding control group survival estimates were 3.42 to 3.76 years. Conclusion We provide the first estimates of long-term overall survival for patients with PF-ILDs other than IPF, and our analysis suggests that nintedanib may prolong their survival. Our Bayesian approach to estimating survival of one disease based on clinical trial data from a similar disease may help inform economic modelling of rare, orphan and newly defined disorders.

Tetanus neurotoxin (TeNT) is an A-B toxin with three functional domains: endopeptidase, translocation (HCT), and receptor binding. Endosomal acidification triggers HCT to interact with and insert into the membrane, translocating the endopeptidase across the bilayer. Although the function of HCT is well defined, the mechanism by which it accomplishes this task is unknown. To gain insight into the HCT membrane interaction on both local and global scales, we utilized an isolated, beltless HCT variant (bHCT), which retained the ability to release potassium ions from vesicles. To examine which bHCT residues interact with the membrane, we widely sampled the surface of bHCT using 47 single-cysteine variants labeled with the environmentally sensitive fluorophore NBD. At neutral pH, no interaction was observed for any variant. In contrast, all NBD-labeled positions reported environmental change in the presence of acidic pH and membranes containing anionic lipids. We then examined the conformation of inserted bHCT using circular dichroism and intrinsic fluorescence. Upon entering the membrane, bHCT retained predominantly α-helical secondary structure, whereas the tertiary structure exhibited substantial refolding. The use of lipid-attached quenchers revealed that at least one of the three tryptophan residues penetrated deep into the hydrocarbon core of the membrane, suggesting formation of a bHCT transmembrane conformation. The possible conformational topology was further explored with the hydropathy analysis webtool MPEx, which identified a large, potential α-helical transmembrane region. Altogether, the spectroscopic evidence supports a model in which, upon acidification, the majority of TeNT bHCT entered the membrane with a concurrent change in tertiary structure.

Background: Further validation of K-BILD questionnaire content is needed in PF-ILD. Aim: Assess relevance and comprehension of K-BILD questionnaire content in PF-ILD. Methods: 20 adult ILD patients (US [n=15]; Germany [n=5]) with prespecified PF-ILD criteria (eg, ≥10% relative decline in FVC%pred) were interviewed. After concept elicitation, participants completed the 15-item K-BILD questionnaire assessing 3 domains (breathlessness/activities, psychological and chest symptoms) within the past 2 weeks, followed by an interview. Interviews were audio-recorded, transcribed and coded for qualitative content analysis using ATLAS.ti. Results: Reporting values as median (range), participants were aged 73 (48–81) years with 67% (47–95) FVC%pred. Rheumatoid arthritis-associated (25%), hypersensitivity pneumonitis (20%) and other fibrosing (30%) ILD were amongst the underlying ILD diagnoses for this cohort. Breathlessness was one of the most frequent and impactful K-BILD items reported by patients. Comprehension of K-BILD time period was high, with most participants stating they were thinking of the past 2 weeks (n=14/20, 70%) and 100% (n=19/19) reporting ability to recall 2 weeks’ time. K-BILD items were well understood by participants, capturing relevant aspects of PF-ILD affecting most participants (Figure). Conclusion: For patients with PF-ILD, K-BILD is well understood and contains relevant concepts.

Ampreloxetine is a novel norepinephrine reuptake inhibitor in development for the treatment of symptomatic neurogenic orthostatic hypotension. The objectives of this analysis were to define the pharmacokinetics of once-daily oral ampreloxetine and provide dose recommendations for clinical development. We fitted a population pharmacokinetic model to ampreloxetine plasma concentrations from single- and multiple-ascending dose trials in healthy subjects and two phase II studies in adult subjects with attention-deficit/hyperactive disorder or fibromyalgia at doses of 2–50 mg. Ampreloxetine pharmacokinetics was best described by a two-compartment model with first-order absorption and elimination. The terminal half-life was 30–40 h, resulting in sustained drug concentrations for the entire 24-h dosing interval at steady state. Covariates of age, weight, or renal impairment did not impact ampreloxetine exposure. Cytochrome P450 2D6 phenotype had no influence on ampreloxetine exposure. Sex and smoking status were identified as statistically significant covariates, suggesting a role for cytochrome P450 1A2 in the elimination of ampreloxetine. Despite statistical significance, differences in ampreloxetine exposure in male vs female subjects and smokers vs non-smokers were not clinically meaningful at the recommended dose. At the 10-mg dose, > 75% norepinephrine transporter inhibition and < 50% serotonin transporter inhibition are anticipated for adult subjects. The population pharmacokinetic model effectively described the plasma concentration–time profile of ampreloxetine after single and multiple doses. Population pharmacokinetic/pharmacodynamic analysis justified using a fixed dosing regimen with no dose adjustments across a broad population and can be used to inform dosing strategies in future clinical studies. ClinicalTrials.gov identifier numbers NCT01693692 (fibromyalgia); NCT01458340 (attention-deficit/hyperactive disorder).

Bacteria produce and secrete various toxins under specific circumstances. One class of these bacterial toxins, including the clostridial neurotoxins, are a special class of proteins which begin in a globular, soluble form and convert to an integral membrane protein. The clostridial neurotoxins have a three globular domain structure with each portion responsible for one aspect of its function. During intoxication, it inserts into the endosomal membrane and concurrently translocates a portion of the protein into the mammalian cytosol, where it has toxic activities. The middle 50kDa domain is the translocation domain. This domain is responsible for the switch from globular soluble to integral membrane and translocating a second domain across the endosomal membrane, in response to the acidic low pH of the endosomal lumen. However, the exact residues which enter the membrane are not known. By putting an environmentally sensitive fluorescent probe at various positions and controlling the environment through the addition of membranes and then low pH, the local environment of each position can be monitored. From our studies, we have identified residues which are membrane inserted and further differentiated their depth into the membrane bilayer.

AlkB is a bacterial Fe(II)- and 2-oxoglutarate-dependent dioxygenase that repairs a wide range of alkylated nucleobases in DNA and RNA as part of the adaptive response to exogenous nucleic acid-alkylating agents. Although there has been longstanding interest in the structure and specificity of Escherichia coli AlkB and its homologs, difficulties in assaying their repair activities have limited our understanding of their substrate specificities and kinetic mechanisms. Here, we used quantitative kinetic approaches to determine the transient kinetics of recognition and repair of alkylated DNA by AlkB. These experiments revealed that AlkB is a much faster alkylation repair enzyme than previously reported and that it is significantly faster than DNA repair glycosylases that recognize and excise some of the same base lesions. We observed that whereas 1,N6-ethenoadenine can be repaired by AlkB with similar efficiencies in both single- and double-stranded DNA, 1-methyladenine is preferentially repaired in single-stranded DNA. Our results lay the groundwork for future studies of AlkB and its human homologs ALKBH2 and ALKBH3.

TD‐0714 is an orally active, potent, and selective inhibitor of human neprilysin (NEP) in development for the treatment of chronic heart failure. Oral administration of TD‐0714 in rats resulted in dose‐dependent and sustained increases in plasma cyclic guanosine monophosphate (cGMP) over 24 hours consistent with NEP target engagement. Randomized, double‐blind, placebo controlled, single ascending dose (50–600 mg TD‐0714) and multiple ascending dose (10–200 mg TD‐0714 q.d. for 14 days) studies were conducted in healthy volunteers. TD‐0714 was generally well‐tolerated and no serious adverse events or clinically significant effects on vital signs or electrocardiogram parameters were observed. TD‐0714 exhibited dose‐proportional pharmacokinetics (PKs) with high oral bioavailability, minimal accumulation after once daily dosing, and negligible renal elimination. Pharmacodynamic (PD) responses were observed at all dose levels studied, as reflected by statistically significant increases in plasma cGMP concentrations. The increases in cGMP were significantly above the baseline (~ 50–100%) on day 14 for the entire 24‐hour interval indicating that sustained cGMP elevations are achieved at steady‐state. Maximal steady‐state cGMP response was observed in plasma and urine at doses ≥ 50 mg. The TD‐0714 PK‐PD relationship and safety profile were similar in elderly vs. younger adult subjects. The TD‐0714 PK and PD profiles support further clinical development of TD‐0714 and suggest the potential for once‐daily administration and predictable exposure in patients with cardiorenal diseases regardless of their renal function.

Objectives: Understanding inhaler preferences may contribute to improving adherence in COPD patients and improving long-term outcomes. This study aims to identify and quantify preferences for convenience-related inhaler attributes in French moderate-to-severe COPD patients, with discrete choice experiment (DCE) methodology. Methods: Attributes were defined from a literature search, clinician and patient interviews: shape, dose insertion, dose preparation, dose release, dose confirmation, dose counter and reusability. An online DCE was conducted in respondents with self-reported COPD stage 2-4 recruited through a panel. The study questionnaire included twelve choice scenarios per respondent and questions on patient characteristics, treatment and disease severity. Statistical analyses used a mixed logit regression model with random effects. Utility scores were estimated for four types of inhalers: Inhaler A - soft mist inhaler; Inhaler B - reusable soft mist inhaler; Inhaler C - multi-dose dry powder inhaler; and Inhaler D - single dose dry powder inhaler. Results: The study was completed by 153 patients (50 females); respondents were 50.4 years old on average; 13 different inhaler devices were reported. The most preferred inhaler is L-shaped, has dose preparation with capsule insertion and a dose counter, and is reusable. Inhaler profiles A and B had the highest utilities (mean of 1.2533 and 0.9578 respectively) compared to inhaler C (0.6315) and D (0.2200). Conclusions: This study showed statistically significant results that the strongest drivers of preference in French users of inhalation devices for COPD are shape, dose counter and reusability. Convenience-related characteristics are important to patients and should be taken into account by clinicians prescribing these devices.