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Results | PMC10403822 |
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Participant recruitment and retention | RECRUITMENT | Thirty-one participants who attended the memory clinic were screened for inclusion in the present pilot study, of which 21 were included in the study and provided baseline data. The reasons for exclusion at the screening stage are included in the flow diagram in Fig.
Recruitment flow diagram.
Participant characteristics of N = 21 participants enrolled in pilot studyData are presented as mean ± standard deviation apart from SPPB, which is presented as median (interquartile range). MMSE; Mini-Mental State Examination, SPPB; Short Physical Performance Battery MET; Metabolic equivalent* Mean ± SD for those with at least 6 valid days of data (n = 13) are 5175.2 ± 2663.0 steps per day, and 32.6 ± 1.1 MET.hour activity score | PMC10403822 |
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Completeness of data | Of the 18 participants who completed the follow-up assessment, all provided physical function, cognitive function, and health, wellbeing and psychological outcome data across all tests. Sixteen of the 18 participants returned their exercise snacking logbooks, which showed a reported adherence rate of 80% of all exercise snacks completed across the whole group. One participant elected to discontinue the exercise snacking intervention after one week but attended the follow-up assessment and the follow-up interview. Of the 15 participants who attempted 28 days of the intervention, reported adherence was 85%. Half of participants who returned their logbooks completed all exercise snacking sessions over the 28 days. Three accelerometers that were distributed at baseline (n = 21) were misplaced by participants and not returned to the research team, and a further three provided no data owing to technical faults with the device (n = 2) or were removed by the participant. Of the remaining 15 accelerometers, 11 returned complete seven days of valid data, and four had partially complete data (three with six days, and one with three days due to battery fault). | PMC10403822 |
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Acceptability | The quantitative scores indicated an overall acceptability rating from the exercise snacking intervention by completers of the study of 4.6 out of 5. The highest rated aspects of the TFA by study participants were self-efficacy (4.3) and affective response (4.1), followed by ethicality (3.9), coherence (3.8) and effectiveness (3.7). Burden (2.1) and opportunity cost (1.8) were scored low (scores closer to 1 represent a favourable appraisal), demonstrating strong all-round acceptability of the intervention. Similarly, the qualitative interviews indicated a generally positive view of the exercise snacking intervention and insight into some improvements that may enhance the acceptability further (Table
Qualitative analysis organised using the theoretical framework of acceptability domains, with implications for future implementation
Screen participants based on existing activity levels or exercise behaviour.Tailor the programme to include progression to avoid tedium.
Suggest that participants find times when they feel most rested or energised to do the snacksReiterate that they do not need to wait to the evening.
Where noted in quotes, I = Interviewer; R = respondent | PMC10403822 |
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Exploratory analysis of outcome data | SECONDARY | Changes were observed from baseline to follow-up for total SPPB score (8 (1) vs. 9 (3),
Individual changes in (a) total Short Physical Performance Battery (SPPB) score, (b) 60-second sit-to-stand score, (c) timed up and go (TUG) time following 28-days of exercise snacking, and (d) left leg single balance time (to 60 s). *denotes a significant difference in median (SPPB, TUG, left leg single balance time) or mean (60-second sit-to-stand) from baseline to follow-up (
Aggregated descriptive data for secondary outcomes in study completers (n = 18)SPPB = short physical performance battery; MoCA = Montreal Cognitive Assessment; SD = standard deviation; IQR = interquartile range | PMC10403822 |
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Discussion | cognitive impairment | This study provides preliminary evidence that a simple homebased, twice daily exercise snacking programme appears to be acceptable to pre-frail older adult memory clinic attendees. Qualitative data from 15 of the 18 completers suggested that the simplicity of the exercises, and the short, simple to do nature of exercise snacking is a useful feature of this programme, with many non-exercising participants seeing value of continued practice of these exercises. Participants generally found the exercise snacking programme easy to implement, not burdensome, and worthwhile, and for participants who returned follow-up data we observed potential improvements in basic tests of physical function and single leg balance.Together, these findings offer encouragement for the utility of exercise snacking as an intervention for inactive, older adult, memory clinic attendees, with a large effect size for improvement in the SPPB (Self-reported adherence to the exercise snacking intervention was higher than in other exercise studies in people with cognitive impairment (80% of all participants who completed follow up assessment in the present study compared to typical adherence rates around 70%) [Based on our data, exercise snacking may be of particular benefit for those who express common barriers to engagement with more comprehensive exercise provision or formats (such as group-based classes and intensive instructor led interventions), and certainly act as a gateway programme to improve baseline strength and balance and self-efficacy for regular exercise. The process outcomes displayed in Table The results indicate several aspects of the protocol and intervention that warrant further consideration prior to full scale testing to improve acceptability, such as the need to develop adaptations of the snacking exercises to make them easier or more challenging as required, or making the logging and performance of exercise snacks simpler and more habitual (Table Consistent with the other evaluations of exercise snacking in general non-patient populations [There are also several limitations with the study design that warrant consideration. It should be emphasised that the single-group design and lack of a non-exercise control group means that we cannot conclusively state the observed improvements in physical function were a product of the exercise snacking intervention. Whilst the SPPB and TUG are well established with reported reference ranges, the 60-second strength and balance tests used in the present study lack data on their validity and reliability. Furthermore, the present study lacks mechanistic data to explain what physiological adaptations might have contributed to a change in function, for example improved maximum force or power generating capacity [Considering the findings of this study in light of these limitations, we conclude that the utilisation of a simple exercise snacking intervention could be an acceptable and beneficial way to improve the physical function of pre-frail memory clinic patients and warrants further evaluation to establish the efficacy of this approach. Whilst our data demonstrate an encouraging pattern of overall improvement in functional tests, this is not a robust study design to demonstrate efficacy of the intervention and further research employing a randomised controlled trial study design is required. Nonetheless, these initial findings suggest the exercise snacking format is acceptable, low burden, and engaging in this target population. | PMC10403822 |
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Electronic supplementary material | Below is the link to the electronic supplementary material.
Additional file 1 | PMC10403822 |
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Acknowledgements | We are extremely grateful to the participants, and the RICE research staff Melissa Nolan and Bethany Fine for their support with the study. Financial support for this work came from an NIHR Research Capability Funding award distributed by the Royal United Hospitals, Bath. | PMC10403822 |
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Authors’ contributions | RECRUITMENT | MW, OP, and TW conceived and designed the study, and obtained funding. VB and KK were responsible for participant recruitment and data collection. MW and OP analysed data and prepared the manuscript, and all authors read and approved the final manuscript. | PMC10403822 |
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Funding | This study was funded by a Research Capability Fund award from the Royal United Hospitals, Bath. The funding body were not involved in the design of the study, the collection, analysis, or interpretation of data, or in writing the manuscript. | PMC10403822 |
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Data Availability | The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. | PMC10403822 |
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Declarations | PMC10403822 |
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Ethics approval and consent to participate | WEST | The protocol was approved by the National Health Service (NHS) South West – Frenchay Research Ethics Committee (Ref: 22/SW/0084), conducted in accordance with the Helsinki Declaration of 1975, as revised in 2000, and registered on ClinicalTrials.gov (Identifier: NCT05439252, 30/06/2022). Informed consent was obtained from all the participants. | PMC10403822 |
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Consent for publication | Informed consent from all subjects and/or their legal guardian(s) was received for publication of identifying information/images in an online open-access publication. | PMC10403822 |
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Competing interests | The authors declare no competing interests. | PMC10403822 |
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References | PMC10403822 |
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Background | inflammation | INFLAMMATION, LUNG DISEASES, NON-CYSTIC FIBROSIS BRONCHIECTASIS | Brensocatib is an oral, selective, reversible inhibitor of dipeptidyl peptidase-1 (DPP-1), responsible for activating neutrophil serine proteases (NSPs) including neutrophil elastase (NE), proteinase 3 (PR3), and cathepsin G (CatG). In chronic inflammatory lung diseases such as non-cystic fibrosis bronchiectasis (NCFBE), neutrophils accumulate in the airways resulting in excess active NSPs that cause damaging inflammation and lung destruction. | PMC10189992 |
Methods | The 24-week WILLOW trial (NCT03218917) was a randomized, double-blind, placebo-controlled, parallel-group trial in patients with NCFBE conducted at 116 sites across 14 countries. In this trial, treatment with brensocatib was associated with improvements in clinical outcomes including time to first exacerbation, reduction in exacerbation frequency and a reduction in NE activity in sputum. An exploratory analysis of NE activity in white blood cell (WBC) extracts and NE, PR3 and CatG activity in sputum was conducted to further characterize brensocatib’s effect and identify potential correlated effects. | PMC10189992 |
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Results | POSITIVE | NE, PR3 and CatG activities were reduced in sputum and NE activity was reduced in WBC extracts in a dose-dependent manner after four weeks of brensocatib treatment, with a return to baseline four weeks after the end of treatment. Brensocatib produced the greatest reduction in the sputum activity of CatG, followed by NE and then PR3. Positive correlations among the sputum NSPs were observed both at baseline and in response to treatment, with the strongest correlation among the sputum NSPs for NE and CatG. | PMC10189992 |
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Supplementary Information | The online version contains supplementary material available at 10.1186/s12931-023-02444-z. | PMC10189992 |
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Keywords | PMC10189992 |
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Background | respiratory disease | RESPIRATORY DISEASE, NON-CYSTIC FIBROSIS BRONCHIECTASIS | Non-cystic fibrosis bronchiectasis (NCFBE) is a chronic, progressive respiratory disease defined by permanent dilatation of the bronchi [Dipeptidyl peptidase-1 (DPP-1, EC 3.4.14.1), also known as cathepsin C, is an enzyme responsible for activating NE, PR3, and CatG zymogens in promyelocytes during neutrophil differentiation in the bone marrow [Brensocatib is an investigational, oral, selective, reversible inhibitor of DPP-1 [In a phase 2b, randomized, double-blind, placebo-controlled trial in 256 patients with NCFBE (WILLOW), 24 weeks of treatment with 10 or 25 mg brensocatib was associated with improvements in clinical outcomes including prolongation in the time to first exacerbation and reduction in the frequency of exacerbations [In this manuscript, we conducted an exploratory analysis to evaluate the effect of brensocatib on PR3 and CatG activity in sputum, and NE activity in white blood cell (WBC) extracts, which were not previously reported in the phase 2b trial in NCFBE [ | PMC10189992 |
Methods | PMC10189992 |
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Trial design and data analysis | alpha1-antitrypsin deficiency, bronchiectasis, asthma | ALPHA1-ANTITRYPSIN DEFICIENCY, BRONCHIECTASIS, HYPOGAMMAGLOBULINEMIA, PERIODONTITIS, CYSTIC FIBROSIS, COMMON VARIABLE IMMUNODEFICIENCY, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, SECONDARY, ASTHMA | The WILLOW trial (ClinicalTrials.gov: NCT03218917; EudraCT: 2017-002533-32) was a randomized, double-blind, placebo-controlled, parallel-group trial conducted at 116 sites across 14 countries [Key exclusion criteria included bronchiectasis due to a clinical diagnosis of cystic fibrosis, hypogammaglobulinemia, common variable immunodeficiency, or alpha1-antitrypsin deficiency, as well as an investigator-determined primary diagnosis of chronic obstructive pulmonary disease or asthma (secondary diagnoses were allowed). Because of potential dental side effects of treatment with brensocatib, exclusion criteria were structured to avoid the enrollment of patients with severe periodontitis.The WILLOW Statistical Analysis Plan (SAP) is discussed in the Additional file | PMC10189992 |
WBC collection procedure | BLOOD | Blood was collected from participating patients at each of the following visits: Day 1 (pre-dose), weeks 2, 4, 12, 24 (the end of the treatment period), and at week 28 (4 weeks after the end of the treatment period) [ | PMC10189992 |
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NE extraction from WBC pellets | agitation | An NSP extraction methodology utilizing surfactant and mechanical agitation has previously been described and qualified [ | PMC10189992 |
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Quantitation of WBC NE activities | To quantify the activity of NE in the WBC pellets, kinetic enzymatic assays were applied to the WBC lysate samples as previously described [For the data analyses, only patients with baseline WBC extract NE values were evaluated to enable a determination of the change in NE activity from baseline. There were patients with missing WBC extract NE values at baseline (and at subsequent time points) due to misapplication of the WBC pellet procedure by the clinical sites leading to samples becoming compromised and unable to be assayed. | PMC10189992 |
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Sputum collection procedure | Sputum was collected from participating patients at each of the following visits: Screening Visit, Day 1 (pre-dose), weeks 2, 4, 12, 24 (the end of the treatment period), and at week 28 (4 weeks after the end of the treatment period) [ | PMC10189992 |
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Quantitation of sputum NSP activity | ® | SECONDARY | To measure the activity of NE, PR3, and CatG in sputum, the ProAxsis ProteaseTag® Active NSP Immunoassays (ProAxsis, Belfast, UK) were used as a sandwich ELISA assay. Immunoassay plates were coated with a capture tag which allowed selective bindings to the active form of the specific NSP (NE, PR3 or CatG) on the plates. Phosphate buffered saline was added to the sputum at a 1:4 V:W ratio (volume added (mL) = mass of sample (g) × 4 mL) to homogenize the sputum samples. Sputum aliquots were then diluted with assay diluent (200-fold, 50-fold, tenfold, undiluted) and incubated in the ProAxsis plates. Then a primary antibody against each NSP was added to the plate and incubated to allow binding to the captured NSP. If the primary antibody was not conjugated, then a secondary horse radish peroxidase (HRP) conjugated antibody was added to the plate and incubated to allow binding to the primary antibody. A color forming substrate containing tetramethylbenzidine was also added to generate a colored product via an enzymatic reaction with the HRP, which was followed by an immediate absorbance reading using a Molecular Devices plate reader. Increases in NSP activity yielded increased amounts of absorbance in each of these assays. | PMC10189992 |
Sputum NSP data analysis criteria | The baseline sputum NSP values represented the average of the sputum NSP values from the subject’s Screening visit and Day 1 (pre-dose) visit as both visits were prior to the initiation of treatment. If one of the Screening or the Day 1 NSP values was below the quantification limit (BQL), then the non-BQL value was used as the Baseline value. If both values at the Screening visit and Day 1 (pre-dose) visit were BQL, then the baseline value was represented by a value of zero.Every subject with a non-zero baseline sputum NSP value was included for further data analysis where comparison to baseline was performed. For those subjects with a non-zero baseline value, if any post-baseline value was BQL, then for each visit with a BQL value, the value of the BQL character field was converted to zero. Due to the lognormal distribution nature of the sputum NSP data set, a data transformation method using Log transformation replaced each numeric number x with log | PMC10189992 |
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Correlation of sputum NSPs | The correlation of sputum NSP activities was determined for all patients combined, irrespective of treatment arms at baseline and for all timepoints. The correlations of sputum NSP activities were further analyzed according to treatment group: placebo, 10 mg brensocatib, or 25 mg brensocatib at baseline and for each timepoint: week 2, week 4, week 12, week 24 and week 28. | PMC10189992 |
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Results | PMC10189992 |
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Distribution analysis of WBC and sputum NSP activities | The WILLOW trial randomized 256 patients, and 89, 81 and 85 had sputum NSP activity data in the 25 mg brensocatib, 10 mg brensocatib, and placebo groups, respectively. Baseline and post-baseline NE activity data in blood was reportable for 37, 30 and 35 patients, respectively. The prespecified analysis of sputum NSP activities assumed that they followed a lognormal distribution profile. This assumption was confirmed for NE, PR3 and CatG. The WBC NE activity followed a normal distribution profile. These analyses are shown in Additional file | PMC10189992 |
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Effect of brensocatib treatment on active NE levels in WBCs | ± | The total number of reportable NE activities from the blood samples at baseline and over the course of the trial was 256 for placebo, 239 for 10 mg brensocatib, and 299 for 25 mg brensocatib. The effect of treatment on NE activity in WBCs was also evaluated. Active NE levels in WBC extracts were reduced by brensocatib by week 4 in a dose-dependent manner, which was maintained over the 24 weeks, with a recovery to baseline levels 4 weeks after the end of treatment (Fig. NE activity in WBCs on study. Change from baseline is presented as mean (± SEM) for NE. * P < 0.05 vs placebo at the same timepoint | PMC10189992 |
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Correlation of effect on active sputum NSP levels | REGRESSION | We were further interested in understanding any possible correlations among the sputum NSP activities. The three pairs of sputum NSP biomarkers are plotted in Fig. Correlation of sputum NSP activities from all treatment arms. Pearson correlation analysis within sputum NSPs at (The slightly less positive NSP correlation values post baseline suggested that there may have been an effect of treatment. Thus, the correlation analysis was repeated for each of the three dosing groups to identify if the NSP correlations for patients on brensocatib differed compared to those on placebo over the course of the trial: at baseline (Fig. Correlation of sputum NSPs in separate dosing arms at baseline only. NSP sputum correlation analysis was performed for placebo, 10 mg brensocatib and 25 mg brensocatib. Simple linear regression was plotted with the best-fit line plus 95% confidence intervalsCorrelation of sputum NSPs in separate dosing arms at Week 2. NSP sputum correlation analysis was performed for placebo, 10 mg brensocatib and 25 mg brensocatib. Simple linear regression was plotted with the best-fit line plus 95% confidence intervalsCorrelation of sputum NSPs in separate dosing arms at Week 4. NSP sputum correlation analysis was performed for placebo, 10 mg brensocatib and 25 mg brensocatib. Simple linear regression was plotted with the best-fit line plus 95% confidence intervalsCorrelation of sputum NSPs in separate dosing arms at Week 12. NSP sputum correlation analysis was performed for placebo, 10 mg brensocatib and 25 mg brensocatib. Simple linear regression was plotted with the best-fit line plus 95% confidence intervalsCorrelation of sputum NSPs in separate dosing arms at Week 24. NSP sputum correlation analysis was performed for placebo, 10 mg brensocatib and 25 mg brensocatib. Simple linear regression was plotted with the best-fit line plus 95% confidence intervalsCorrelation of sputum NSPs in separate dosing arms at Week 28. NSP sputum correlation analysis was performed for placebo, 10 mg brensocatib and 25 mg brensocatib. Simple linear regression was plotted with the best-fit line plus 95% confidence intervalsPearson correlation coefficients (r) for each pair of sputum NSP activities over the trial duration. Pearson correlation coefficients (r) are presented as mean for ( | PMC10189992 |
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Discussion | bronchiectasis, bacterial infection, reductions in airway inflammation, inflammatory disorder, A1AT, reductions in lung inflammation | LUNG INFLAMMATION, BRONCHIECTASIS, INFLAMMATORY RESPONSE, BACTERIAL INFECTION, RECRUITMENT, INFLAMMATORY DISORDER, AIRWAY DISEASE, BRONCHIECTASIS | Bronchiectasis is an inflammatory disorder and neutrophils dominate the airway inflammatory profile in the majority of bronchiectasis patients. NSPs such as NE, PR3 and CatG are released from neutrophil granules when neutrophils are activated and during the formation of neutrophil extracellular traps [There are currently no approved treatments for bronchiectasis, and there is a need for non-antibiotic treatments that can reduce lung inflammation. To that end, inhibition of DPP-1 represents a novel therapeutic strategy to reduce NSP activity and lung inflammation [Interestingly, a greater reduction of NE activity was observed in sputum than in WBCs (Table There are several plausible explanations for a greater effect in the lung than in the circulation. Reduced NSP activity may directly or indirectly reduce neutrophil recruitment to the lung, or the inflammatory stimulus for NSP release including potentially impacting bacterial infection through restoration of antimicrobial peptides. This theoretically generates a “virtuous cycle”, the counterpoint to the vicious cycle, whereby reductions in lung inflammation improve other aspects of airway disease, leading to larger and more sustained reductions in airway inflammation. These reductions in NSP activity in the lung may allow for a return to homeostatic balance of NSPs with their inhibitors: alpha-1 antitrypsin (A1AT), elafin and secretory leukocyte peptidase inhibitor (SLPI).The positing of a virtuous cycle in response to brensocatib suggests that once brensocatib treatment is removed, NSP activities in the lung may take longer to return to baseline levels than for those in the circulation (i.e., WBC extracts). Indeed, four weeks after termination of brensocatib treatment, NE activity in the WBCs returned to baseline levels, while NE, PR3 and CatG activities in sputum did not.Sputum NE, PR3 and CatG activities were strongly correlated at baseline and positive correlations were observed on study treatment at all timepoints, suggesting that brensocatib’s effect on all three NSP activities is interrelated. This does not appear to be a surprising result given that the mechanism of action of DPP-1 is to activate all three NSPs. However, while the NSP correlations remained positive on treatment, the strength of those correlations decreased somewhat for those on brensocatib, and more so for those on the higher 25 mg dose of brensocatib. The explanation may be related to the differential reduction in the NSP activities to brensocatib treatment, with CatG being reduced to the greatest extent, followed closely by NE, with a lower reduction in PR3 activity in sputum. Thus, it may not be unexpected that the very strong correlation between NE and CatG at baseline showed the least change in response to brensocatib treatment, since both biomarkers were more likely to have been reduced comparably. In contrast, the positive correlations between PR3 and both NE and CatG declined on brensocatib treatment (but not on placebo), which may be explained by the lower reduction in PR3 activity relative to both NE and CatG. The residual reductions in the NSP correlations that cannot be explained by differential impact of brensocatib on the individual NSP biomarkers may be related to the increased appearance of NSP activity values below the quantification limit. Notably, four weeks after the end of brensocatib treatment, the sputum NSP correlations all recovered close to their initial values.DPP-1 inhibition with brensocatib had the greatest effect in reducing CatG activity in sputum and the least effect on PR3 activity. There may be multiple factors accounting for the differential response in NSP activity to DPP-1 inhibition. In the absence of a DPP-1 inhibitor, nearly all of the NSPs zymogens are converted to active forms during neutrophil maturation [Brensocatib reduced all three NSP biomarkers in sputum illustrating the unique mechanism of action of DPP-1 inhibitors that simultaneously reduce several key inflammatory mediators linked to exacerbation. In contrast, specific inhibitors to NE ([The thesis that PR3 and CatG are also important regulators of the local inflammatory response is supported by the literature [ | PMC10189992 |
Conclusions | reductions in blood NE | Brensocatib demonstrated dose dependent reductions in blood NE and sputum NSP activity in the WILLOW study. These data suggest a broad anti-inflammatory effect of brensocatib underlying its clinical efficacy observed in NCFBE patients. | PMC10189992 |
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Acknowledgements | The authors acknowledge Jun Zou who supported the biostats analysis for the WILLOW study and the following Insmed colleagues who contributed to the analysis of the NE activity in the WILLOW blood samples: Amruta Sabnis, Arielle Dorfman, Kuan-Ju Chen, Franziska Leifer, Xizhe Zhao, Jeong Yeong Kang, Mary Atalla, Sadikul Islam, and Yang Deng. | PMC10189992 |
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Author contributions | JZ, BK, JDC, CF, KCM, WRP, EJS, and DC provided the concept for this manuscript. JZ, JB, DL, CF, KCM, WRP, EJS, and DC designed the methodology. JZ, JB, DL and DC conducted the formal analysis and data curation. Writing—Original Draft Preparation: JZ and DC authored the original manuscript. JZ, BK, JDC, JB, DL, CF, AT, KCM, WRP, EJS, and DC edited the manuscript. All authors read and approved the final manuscript. | PMC10189992 |
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Funding | This research was funded by Insmed Incorporated. | PMC10189992 |
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Availability of data and materials | All data generated or analysed during this study are included in this published article [and its Additional information files]. | PMC10189992 |
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Declarations | PMC10189992 |
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Ethics approval and consent to participate | The WILLOW trial was performed in accordance with the ethical principles of the Declaration of Helsinki, International Conference on Harmonisation Good Clinical Practice guidelines, and applicable regulatory requirements. Approvals from independent ethics committees were obtained. Informed consent was obtained from all subjects involved in the study. | PMC10189992 |
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Consent for publication | Not applicable. | PMC10189992 |
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Competing interests | Zambon | DC, JS, DL, CF, AT, KGM, JZ, WP and EJS are employees of Insmed Incorporated, Bridgewater, New Jersey. JDC has received grants and personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Zambon, and Insmed Incorporated; a grant from Gilead; and personal fees from Novartis and Chiesi. BK has received personal fees from Insmed Incorporated. | PMC10189992 |
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References | PMC10189992 |
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Key Points | PMC10755607 |
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Question | insomnia | Which first-stage treatment is optimal for improving daytime functions among patients with insomnia, and which second-stage treatment offers the best added value for patients whose insomnia has not remitted? | PMC10755607 |
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Findings | depressive symptoms, fatigue, insomnia disorder | In a randomized clinical trial of 211 adults with insomnia disorder, first-stage treatment with behavioral therapy (BT) or zolpidem produced significant improvements for various daytime outcomes, including depressive symptoms, fatigue, functional impairments, and mental health, that were no different between groups. Adding a second-stage therapy offered an added value for further improving daytime functions with immediate and delayed effects observed for treatment sequences starting with zolpidem and BT, respectively. | PMC10755607 |
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Meaning | insomnia | These findings support the comparable efficacy between sequential treatments starting with BT and zolpidem for addressing the daytime consequences of insomnia. | PMC10755607 |
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Importance | insomnia, Daytime functional impairments | Daytime functional impairments are the primary reasons for patients with insomnia to seek treatment, yet little is known about what the optimal treatment is for improving daytime functions and how best to proceed with treatment for patients whose insomnia has not remitted. | PMC10755607 |
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Objectives | insomnia | To compare the efficacy of behavioral therapy (BT) and zolpidem as initial therapies for improving daytime functions among patients with insomnia and evaluate the added value of a second treatment for patients whose insomnia has not remitted. | PMC10755607 |
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Design, Setting, and Participants | DISORDER, MAY, CHRONIC INSOMNIA | In this sequential multiple-assignment randomized clinical trial conducted at institutions in Canada and the US, 211 adults with chronic insomnia disorder were enrolled between May 1, 2012, and December 31, 2015, and followed up for 12 months. Statistical analyses were performed on an intention-to-treat basis in April and October 2023. | PMC10755607 |
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Interventions | insomnia | Participants were randomly assigned to either BT or zolpidem as first-stage therapy, and those whose insomnia had not remitted received a second-stage psychological therapy (BT or cognitive therapy) or medication therapy (zolpidem or trazodone). | PMC10755607 |
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Main Outcomes and Measures | mood disturbances, insomnia, fatigue | Study outcomes were daytime symptoms of insomnia, including mood disturbances, fatigue, functional impairments of insomnia, and scores on the 36-item Short-Form Health Survey (SF-36) physical and mental health components. | PMC10755607 |
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Results | −7.3, Anxiety, fatigue, anxiety, insomnia, depressive symptoms, −6.7, Depression, −4.7, Fatigue | Among 211 adults with insomnia (132 women [63%]; mean [SD] age, 45.6 [14.9] years), 104 were allocated to BT and 107 to zolpidem at the first stage. First-stage treatment with BT or zolpidem yielded significant and equivalent benefits for most of the daytime outcomes, including depressive symptoms (Beck Depression Inventory-II mean score change, −3.5 [95% CI, −4.7 to −2.3] vs −4.3 [95% CI, −5.7 to −2.9]), fatigue (Multidimensional Fatigue Inventory mean score change, −4.7 [95% CI, −7.3 to −2.2] vs −5.2 [95% CI, −7.9 to −2.5]), functional impairments (Work and Social Adjustment Scale mean score change, −5.0 [95% CI, −6.7 to −3.3] vs −5.1 [95% CI, −7.2 to −2.9]), and mental health (SF-36 mental health subscale mean score change, 3.5 [95% CI, 1.9-5.1] vs 2.5 [95% CI, 0.4-4.5]), while BT produced larger improvements for anxiety symptoms relative to zolpidem (State-Trait Anxiety Inventory mean score change, −4.1 [95% CI, –5.8 to –2.4] vs −1.2 [95% CI, −3.0 to 0.5]; | PMC10755607 |
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Conclusions and Relevance | insomnia, insomnia disorder | In this randomized clinical trial of adults with insomnia disorder, BT and zolpidem produced improvements for various daytime symptoms of insomnia that were no different between treatments. Adding a second treatment offered an added value with further improvements of daytime functions. | PMC10755607 |
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Trial Registration | insomnia | ClinicalTrials.gov Identifier: This randomized clinical trial compares the efficacy of behavioral therapy and zolpidem as initial therapies for improving daytime functions among patients with insomnia and evaluates the added value of a second treatment for patients whose insomnia has not remitted. | PMC10755607 |
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Introduction | insomnia, Insomnia, sleep disorder | SECONDARY | Insomnia is a highly prevalent sleep disorder that tends to be persistent or recurrentCurrent recommended treatments for insomnia in clinical practice guidelines include 2 major approaches: psychological therapies (ie, cognitive behavioral therapy [CBT]) and medications (eg, benzodiazepine-receptor agonists and sedating antidepressants).Only a few studies have directly compared the efficacy of CBT and medications for daytime symptoms in insomnia, with mixed findings. In a randomized clinical trial (RCT) of young and middle-aged patients with chronic sleep-onset insomnia, no significant differences were found among CBT, medications, and combination therapy on mood-related changes after intervention.The main objectives of this study were to compare short-term and long-term changes in daytime functions of 4 treatment sequences using psychological (behavioral and cognitive) and pharmacologic therapies (zolpidem and trazodone) for insomnia. In particular, the study aimed to compare the efficacy of behavioral therapy (BT) and zolpidem as first-stage therapies for improvement of daytime functions. For those whose insomnia did not remit after first-stage therapy, the added value of a second treatment was evaluated. Daytime functions investigated in the current study were among the predefined secondary outcomes of a previously published trial. | PMC10755607 |
Methods | PMC10755607 |
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Study Design | insomnia, comorbid psychiatric disorder | This study is part of an RCT that aimed to examine the comparative efficacy of 4 treatment sequences involving psychological and medication therapies for insomnia with and without comorbid psychiatric disorder (trial protocol in This project adopted a sequential multiple assignment randomized trial (SMART) design with 2 treatment stages and 2 treatment modalities for each stage ( | PMC10755607 |
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Participant Flow in the Sequential Treatment for Insomnia | Reprinted with permission from Morin et al. | PMC10755607 |
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Participants | psychiatric disorders | CHRONIC INSOMNIA | A total of 211 adults with chronic insomnia were recruited from the community through media advertisements and physician referrals. All participants included in the study met the following criteria: (1) aged 21 years or older, (2) persistent (>1 month) difficulties initiating or maintaining sleep despite adequate opportunity for sleep, (3) sleep onset latency or wake time after sleep onset of 30 minutes or more for 3 or more nights per week during 2 weeks of sleep diary monitoring, (4) ISI total score more than 10, (5) score of 2 or more on either the interference or distress item of the screening ISI. Participants were excluded if they had untreated psychiatric disorders or uncontrolled medical conditions or had conditions that interfered with sleep quality and sleep continuity. Additional details about exclusion criteria can be found in a previous publication. | PMC10755607 |
Outcome Measures | mood disturbances, insomnia, fatigue | The current study focused on changes in daytime functional outcomes, including mood disturbances, fatigue, functional impairments of insomnia, and the 36-item Short-Form Health Survey (SF-36) physical and mental health components. | PMC10755607 |
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Treatments | PMC10755607 |
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Cognitive Behavioral Therapy | The first-stage psychological therapy consisted of BT, which included sleep restriction | PMC10755607 |
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Medication | depressive symptoms | The first-stage medication treatment involved sublingual zolpidem, 5 mg to 10 mg, taken nightly at bedtime. The second-stage pharmacotherapy consisted of trazodone, 50 to 150 mg, taken 30 minutes before bedtime. As a serotonin receptor antagonist and reuptake inhibitor antidepressant, trazodone can alleviate a wide range of depressive symptoms with an additional sedative effect of sleep, | PMC10755607 |
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Statistical Analysis | The intention-to-treat analyses were performed in April and October 2023. To evaluate each treatment sequence while taking into account the nature of the SMART design (ie, 2 randomizations, where the second is conditional on the response to the first), the analytic strategy was based on recommendations from Nahum-Shani et al. | PMC10755607 |
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Results | PMC10755607 |
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Participants | insomnia disorder | A total of 211 adults (132 women [63%]; mean [SD] age, 45.6 [14.9] years; 14 Black participants [7%], 11 Hispanic participants [5%], 182 White participants [86%], and 4 participants [2%] of other race or ethnicity [Asian (n = 2), Middle Eastern origin (n = 1), and not specified (n = 1)]) who met criteria for insomnia disorder (mean [SD] duration, 13.2 [12.5] years) were randomly allocated to BT (n = 104) or zolpidem treatment (n = 107) ( | PMC10755607 |
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Sociodemographic and Clinical Characteristics of Participants | Reprinted with permission from Morin et al.Asian (n = 2), Middle Eastern origin (n = 1), and not specified (n = 1).Percentages do not total 100 due to missing data.Of the 211 randomized participants, 168 completed first-stage therapy ( | PMC10755607 |
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Follow-Up Assessments | anxiety | Both conditions starting with BT showed significant improvements from post2 to 12-month follow-up for anxiety symptoms (mean change in STAI-Trait score: BT plus zolpidem, −4.6 [95% CI, −7.7 to −1.5]; | PMC10755607 |
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Subgroup Analysis for Participants With Psychiatric Comorbidity | psychiatric comorbidity | The findings in the subgroup analysis by psychiatric comorbidity (absent vs present) were similar to those from the main analysis for most of the outcomes. However, they are not reported in detail here due to the small sample sizes and reduced power for those analyses. | PMC10755607 |
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Discussion | depressive, insomnia, depressive symptoms | The current study showed that first-stage treatment with BT or zolpidem was effective in reducing daytime symptoms of insomnia, with no significant differences between groups. The addition of a second-stage therapy resulted in an added value in enhancing daytime functions. In particular, immediate effects of second-stage therapies were observed for sequences that used zolpidem as the initial treatment, while delayed effects were made with sequences starting with BT at 12-month follow-up. Overall, these findings provide further support for the efficacy of CBT and sleep-promoting medication for improving daytime functions among patients with insomnia.Although some studies have previously reported benefits of CBT on daytime outcomes,At the end of second-stage therapy, although patients in the 2 groups starting with zolpidem showed further improvements for most daytime outcomes, only patients who switched from pharmacotherapy to psychological treatment (from zolpidem to BT) reported greater reductions in depressive severity. This finding aligned with our hypothesis that switching treatment modalities would lead to greater treatment benefits, although it needs to be interpreted cautiously given the smaller sample size for the treatment sequence involving 2 medications and the mild range of depressive symptoms. In the treatment sequences starting with BT, patients who received 2 treatments within the same modality (from BT to CT) had slightly better outcomes than those who switched modality (from BT to zolpidem) at 12-month follow-up, which may be partially attributed to the broader action of CT by targeting psychological and mood symptoms compared with zolpidem. | PMC10755607 |
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Limitations | mood disturbances, daytime impairments, insomnia, fatigue | REMISSION | Some of the findings need to be interpreted cautiously given some methodological limitations. First, the lack of a control condition and the relatively small sample sizes for each treatment sequence may reduce the statistical power to detect more significant group differences. Second, only patients whose insomnia did not remit received second-stage therapy, while patients with insomnia who achieve remission can still have residual daytime impairments (eg, fatigue and mood disturbances) that are associated with future relapse | PMC10755607 |
Conclusions | insomnia, anxiety | The present study documented the efficacy of BT and zolpidem for improving daytime functional outcomes among patients with insomnia and the effect of BT on reducing anxiety symptoms. Adding a second treatment offered an added value for further improvements of daytime functions. Future developments of insomnia treatment strategies should take into account the daytime consequences of insomnia. Additional studies are needed to further investigate the potential benefits of switching treatment modalities and incorporating a therapeutic component that can address psychological and mood disturbances. | PMC10755607 |
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1. Introduction | cough, throat | COLD, FLU | These authors contributed equally to this work.There is wide variation in how individuals perceive the chemosensory attributes of liquid formulations of ibuprofen, encompassing both adults and children. To understand personal variation in the taste and chemesthesis properties of this medicine, and how to measure it, our first scientific strategy centered on utilizing trained adult panelists, due to the complex and time-consuming psychophysical tasks needed at this initial stage. We conducted a double-blind cohort study in which panelists underwent whole-genome-wide genotyping and psychophysically evaluated an over-the-counter pediatric medicine containing ibuprofen. Associations between sensory phenotypes and genetic variation near/within irritant and taste receptor genes were determined. Panelists who experienced the urge to cough or throat sensations found the medicine less palatable and sweet, and more irritating. Perceptions varied with genetic ancestry; panelists of African genetic ancestry had fewer chemesthetic sensations, rating the medicine sweeter, less irritating, and more palatable than did those of European genetic ancestry. We discovered a novel association between How medications are delivered often differs between children and adults. While adults typically take medicine as solid formulations, encapsulating unpleasant-tasting active pharmaceutical ingredients (APIs), young children, unable or unwilling to swallow pills or capsules, are treated with liquid formulations that contain sugars, salts, and flavor volatiles to improve palatability [In the United Kingdom, a popular cold and flu medicine for adults is formulated as a powder, containing APIs and excipients such as lemon flavors and sweeteners [For pediatric populations, ibuprofen is often delivered as a sweetened suspension because sweetness is not only a preferred taste but also effective in masking unpleasant tastes [The primary goal of the present study was (1) to begin addressing this hypothesis by (a) determining the degree of personal variation in the palatability of a popular over-the-counter (OTC) sweetened formulation of ibuprofen via detailed measurements of chemosensory perceptions in a trained adult sensory panel and (b) comparing these results with panelists’ genetics, by conducting a candidate gene association study on selected variants in/near sweet and bitter taste receptors (TAS1Rs and TAS2Rs) and related chemosensory transient receptor potential (TRP) channels. For this initial study, we did not test children because the psychophysical tasks needed were complex and lengthy, and because, as reported above, variation in the perception of ibuprofen exists in both adults and children [ | PMC10487938 |
2. Results | PMC10487938 |
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2.1. Panel Characteristics | The 154 panelists (64 males; 90 females) who met the inclusion criteria had a mean age of 34 ± 1 years and represented the diversity of the city where they lived: Philadelphia, PA, USA [ | PMC10487938 |
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2.2. Chemosensory Phenotypes | cough, throat, epiglottis | As shown in Psychophysical ratings varied widely across panelists for all conditions. Sip-and-spit ratings for sweetness, irritation, bitterness, and palatability were predictors of ratings after swallowing (A greater proportion of panelists experienced the urge to cough and throat tingling/scratching in the swallow condition than in the sip-and-spit condition, and had these sensations localized in the epiglottis, larynx, trachea, hypopharynx, and hypopharynx areas ( | PMC10487938 |
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3. Discussion | Chemesthetic sensations, throat, human immunodeficiency virus | HUMAN IMMUNODEFICIENCY VIRUS | We found reproducible individual differences among adults in the taste and palatability of a popular OTC ibuprofen-containing pediatric formulation and two of its sweetening excipients, and genetic variation contributed to some of these differences. Swallowing the formulation intensified perceived irritation and bitterness and diminished sweetness and palatability compared to the sip-and-spit condition. Chemesthetic sensations lingered in the throat, confirming prior reports of an aftertaste [While some evidence suggested that ibuprofen is a chemesthetic irritant, particularly in the throat [Trained in psychophysical methods, adult panelists rated an OTC sweetened formulation that contained the API ibuprofen and common sweetening excipients, providing a more complex flavor than do aqueous solutions of ibuprofen that are previously used [The present study is not without limitations. Although we identified a novel association between Other taste psychophysical studies conducted in adults, which allow for more complex taste ratings and longer testing duration, have revealed personal variation in taste, irritation, and the palatability of pediatric medicines, including the first-line treatment for young children infected with human immunodeficiency virus [Needs for Pediatric Research. We caution that the data generated from trained adults are not generalizable to children, and we emphasize that fundamental challenges and the need for more research in children remain, including the need for validated methods to assess the palatability and chemesthetic properties of medicines among young children, who are prone to attention lapses, tend to answer questions in the affirmative, and have limited language capabilities [While much attention has been paid to improving the taste of the medicine, since taste is the key factor in children’s acceptance and medication adherence [ | PMC10487938 |
4. Materials and Methods | PMC10487938 |
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4.1. Participants and Stimuli | Healthy adults trained as sensory panelists were enrolled in a multisession study as trained sensory panelists to evaluate the taste of a variety of pediatric liquid formulations and excipients, one of which was an over-the-counter (OTC) sweetened suspension containing ibuprofen (100 mg/5 mL, 2% The study was temporarily halted from March to July 2020 due to the COVID-19-related discontinuation of nonessential human subject research in Philadelphia. Upon study resumption in August 2020, we adapted the testing facility and received IRB approval to implement several procedures to reduce risks to study staff and participants. In addition to screening for COVID-19 symptomatology, we administered the National Institute of Health Olfaction Toolbox test [ | PMC10487938 |
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4.2. Phenotyping | numbing, stinging, taste sensations, sneeze, throat, cough, palate, epiglottis | Using a double-blind study design, panelists were tested in closed rooms designed specifically for sensory testing, with red light illumination to eliminate the effect of the color of the solution, if any, on sensory ratings. During the first session, panelists were trained individually to identify basic taste sensations and were familiarized with rating taste and irritation sensations on the general labeled magnitude scale (gLMS) and palatability on the hedonic gLMS, on a computer with Compusense five™ Plus software (version 5) (Compusense, Inc., Guelph, Ontario, Canada). The gLMS visually spaces verbal descriptors of intensity for chemosensory perceptions (e.g., bitterness, sweetness, and irritation) as no sensation (0), barely detectable (1.4), weak (5.8), moderate (16), strong (35), very strong (53), and strongest imaginable (100) [After swishing it in their mouth for 5 s, panelists rated taste, irritation, and palatability on a computer. One minute separated the presentation of each stimulus, during which panelists rinsed their mouths with water. Stimuli were presented in a quasi-randomized order since during the sessions in which they rated the ibuprofen medicine, it was presented last since it was the only stimulus that was swallowed. This formulation was evaluated under three conditions and in the following order: (a) swishing in mouth for 5 sec and spitting out without swallowing (sip-and-spit condition); (b) after a one-minute pause, swishing in the mouth for 5 sec and then swallowing (swallow condition); and (c) five minutes post-swallowing (delay condition). Immediately after rating the intensity of taste, irritation, and hedonics, panelists were presented with a checklist of eight chemesthetic sensations—burning, tingling, stinging, numbing, cooling, scratching, urge to cough, and urge to sneeze—and indicated which, if any, they experienced. They were then presented with a diagram of the sagittal section of the head and throat areas (i.e., tongue, hard palate, soft palate, oropharynx, nasopharynx, hypopharynx, larynx, trachea, esophagus, and epiglottis as shown in | PMC10487938 |
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4.3. Genotyping, Genetic Ancestry, and Candidate Single-Nucleotide Polymorphisms (SNPs) | Saliva samples were collected from each enrolled panelist (Kinship analysis was performed with KING (version 2.2.7) [The imputation of genotypes to a greater portion of the human genome was performed on Michigan Imputation Server ( | PMC10487938 |
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4.4. Statistical Analyses | Salty | We computed descriptive statistics and used the Shapiro–Wilk test to assess for normality. Salty and savory ratings were rarely provided and therefore eliminated from the analysis. The gLMS ratings for sweetness were normally distributed (First, we focused on phenotyping data from 154 panelists. Separate ANOVA tests determined whether ratings intensified and the number and locations of sensations increased upon swallowing (sip-and-spit vs. swallow) and whether or not panelists experienced an aftertaste (sip-and-spit vs. delay), which was deemed to have occurred only when the taste or irritation ratings were greater in the delay condition than in the sip-and-spit condition. Separate correlational analyses were conducted to determine whether or not gLMS ratings in the sip-and-spit condition were predictive of ratings in the swallow condition. Dichotomous groupings were formed based on whether the individual experienced certain chemesthetic sensations or not and we determined whether or not the taste and palatability differed between groups using Fisher’s exact tests.Second, we investigated the genetic associations with chemosensory phenotypes but analyses focused on the 141 unrelated individuals with successful genotyping and the determination of genetic ancestry ( | PMC10487938 |
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Supplementary Materials | The supporting information can be downloaded at Click here for additional data file. | PMC10487938 |
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Author Contributions | Study concept and design, and project administration: J.A.M. and E.D.L.; methodology: J.A.M.; acquisition, analysis, or interpretation of data: J.A.M., M.K., M.Y.P., B.E.H., E.D.L., L.R.S. and J.D.M.; writing—original draft preparation: J.A.M. and M.K.; writing—review and editing: J.A.M., M.K., M.Y.P., B.E.H., L.R.S. and E.D.L.; statistical analysis: J.A.M., M.K., M.Y.P. and B.E.H.; funding acquisition: J.A.M. and E.D.L. All authors have read and agreed to the published version of the manuscript. | PMC10487938 |
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Institutional Review Board Statement | The study complied with the Declaration of Helsinki for Medical Research involving Human Subjects and was approved by the Office of Regulatory Affairs at the University of Pennsylvania and the Institutional Review Board of the Children’s Hospital of Philadelphia (protocol number 829945; date of approval: 28 June 2018). | PMC10487938 |
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Informed Consent Statement | Written informed consent was obtained from all subjects involved in the study. | PMC10487938 |
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Data Availability Statement | Summary statistics for SNP–phenotype associations and R codes for statistical analysis are available upon reasonable request and the Data Usage Agreement should be sent to corresponding authors Julie A. Mennella ( | PMC10487938 |
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Conflicts of Interest | The authors declare no conflict of interest. The funder had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. | PMC10487938 |
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Appendix A | allergies | ALLERGIES | Study flow chart. The study population consisted of women and men who were non-smokers; had no known allergies or sensitivities to any of the medications or stimuli included in the taste panel; and who were not taking and had not taken in the recent past any medication that was contraindicated to those included in the taste panel. Biological females had to have a negative urine pregnancy test on each testing day. We based our sample size calculation using prior adult sensory panel data reported by Mennella et al. (Reprinted/adapted with permission from Ref. [ | PMC10487938 |
Background | Scientists often make cognitive claims (eg, the results of their work) and normative claims (eg, what should be done based on those results). Yet, these types of statements contain very different information and implications. This randomized controlled trial sought to characterize the granular effects of using normative language in science communication. | PMC10131812 |
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Objective | Our study examined whether viewing a social media post containing scientific claims about face masks for COVID-19 using both normative and cognitive language (intervention arm) would reduce perceptions of trust and credibility in science and scientists compared with an identical post using only cognitive language (control arm). We also examined whether effects were mediated by political orientation. | PMC10131812 |
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Methods | This was a 2-arm, parallel group, randomized controlled trial. We aimed to recruit 1500 US adults (age 18+) from the Prolific platform who were representative of the US population census by cross sections of age, race/ethnicity, and gender. Participants were randomly assigned to view 1 of 2 images of a social media post about face masks to prevent COVID-19. The control image described the results of a real study (cognitive language), and the intervention image was identical, but also included recommendations from the same study about what people should do based on the results (normative language). Primary outcomes were trust in science and scientists (21-item scale) and 4 individual items related to trust and credibility; 9 additional covariates (eg, sociodemographics, political orientation) were measured and included in analyses. | PMC10131812 |
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Results | From September 4, 2022, to September 6, 2022, 1526 individuals completed the study. For the sample as a whole (eg, without interaction terms), there was no evidence that a single exposure to normative language affected perceptions of trust or credibility in science or scientists. When including the interaction term (study arm × political orientation), there was some evidence of differential effects, such that individuals with liberal political orientation were more likely to trust scientific information from the social media post’s author if the post included normative language, and political conservatives were more likely to trust scientific information from the post’s author if the post included only cognitive language (β=0.05, 95% CI 0.00 to 0.10; | PMC10131812 |
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Conclusions | SECONDARY | This study does not support the authors’ original hypotheses that single exposures to normative language can reduce perceptions of trust or credibility in science or scientists for all people. However, the secondary preregistered analyses indicate the possibility that political orientation may differentially mediate the effect of normative and cognitive language from scientists on people’s perceptions. We do not submit this paper as definitive evidence thereof but do believe that there is sufficient evidence to support additional research into this topic, which may have implications for effective scientific communication. | PMC10131812 |
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Trial Registration | OSF | OSF Registries osf.io/kb3yh; https://osf.io/kb3yh | PMC10131812 |
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International Registered Report Identifier (IRRID) | RR2-10.2196/41747 | PMC10131812 |
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