Interchanging Reusable and Disposable Nebulizers Used with Home-Based Compressors May Result in Inconsistent Dosing: A Laboratory Investigation with Device Combinations Supplied to the US Healthcare Environment.

INTRODUCTION: Reusable nebulizer-compressor combinations deliver inhaled medications for patients with chronic lung diseases. On hospital discharge, the patient may take home the disposable nebulizer that was packaged and combine it with their home compressor. Though this practice may reduce waste, it can increase variability in medication delivery. Our study compared several reusable and disposable nebulizers packaged with compressor kits used in the US. We included a common disposable hospital nebulizer that may not be supplied with popular home kits but may be brought home after a hospitalization or emergency department visit. We focused on fine droplet mass < 4.7 µm aerodynamic diameter (FDM<4.7 µm), associated with medication delivery to the airways of the lungs. METHODS: We evaluated the following nebulizer-compressor combinations (n = 5 replicates): 1. OMBRA® Table Top Compressor with MC 300® reusable and Airlife™ MistyMax™ 10® disposable nebulizer, 2. Sami-the-Seal® compressor with SideStream® reusable and disposable nebulizers and Airlife™ MistyMax 10™ disposable nebulizer, 3. VIOS® compressor with LC Sprint® reusable, and VixOne® and Airlife™ MistyMax™ disposable nebulizers, 4. Innospire® Elegance® compressor with SideStream® reusable and disposable nebulizers and Airlife™ MistyMax 10™ disposable nebulizer, 5. Willis-the-Whale® compressor with SideStream® reusable and disposable nebulizers and Airlife™ MistyMax 10™ disposable nebulizer, 6. Pari PRONEB® Max compressor with LC Sprint® reusable and Airlife™ MistyMax 10™ disposable nebulizer. We placed a 3-ml albuterol solution (0.833 mg/ml) in each nebulizer. A bacterial/viral filter was attached to the nebulizer mouthpiece to capture emitted medication, with the filter exit coupled to a simulator of a tidal breathing adult (rate = 10 cycles/min; Vt = 600 ml; I/E ratio = 1:2). The filter was replaced at 1-min intervals until onset of sputter. Droplet size distributions (n = 5 replicates/system) were determined in parallel by laser diffractometry. RESULTS: Cumulative FDM<4.7 µm varied from 381 ± 33 µg for the best performing combination (Proneb/LC-Sprint) to 150 ± 21 µg for the system with the lowest output (VIOS®/MistyMax 10™). CONCLUSIONS: Substituting one nebulizer for another can result in large differences in medication delivery to the lungs.

Guidance on Mitigating the Risk of Transmitting Respiratory Infections During Nebulization by the COPD Foundation Nebulizer Consortium.

BACKGROUND: Nebulizers are used commonly for inhaled drug delivery. Because they deliver medication through aerosol generation, clarification is needed on what constitutes safe aerosol delivery in infectious respiratory disease settings. The COVID-19 pandemic highlighted the importance of understanding the safety and potential risks of aerosol-generating procedures. However, evidence supporting the increased risk of disease transmission with nebulized treatments is inconclusive, and inconsistent guidelines and differing opinions have left uncertainty regarding their use. Many clinicians opt for alternative devices, but this practice could impact outcomes negatively, especially for patients who may not derive full treatment benefit from handheld inhalers. Therefore, it is prudent to develop strategies that can be used during nebulized treatment to minimize the emission of fugitive aerosols, these comprising bioaerosols exhaled by infected individuals and medical aerosols generated by the device that also may be contaminated. This is particularly relevant for patient care in the context of a highly transmissible virus. RESEARCH QUESTION: How can potential risks of infections during nebulization be mitigated? STUDY DESIGN AND METHODS: The COPD Foundation Nebulizer Consortium (CNC) was formed in 2020 to address uncertainties surrounding administration of nebulized medication. The CNC is an international, multidisciplinary collaboration of patient advocates, pulmonary physicians, critical care physicians, respiratory therapists, clinical scientists, and pharmacists from research centers, medical centers, professional societies, industry, and government agencies. The CNC developed this expert guidance to inform the safe use of nebulized therapies for patients and providers and to answer key questions surrounding medication delivery with nebulizers during pandemics or when exposure to common respiratory pathogens is anticipated. RESULTS: CNC members reviewed literature and guidelines regarding nebulization and developed two sets of guidance statements: one for the health care setting and one for the home environment. INTERPRETATION: Future studies need to explore the risk of disease transmission with fugitive aerosols associated with different nebulizer types in real patient care situations and to evaluate the effectiveness of mitigation strategies.

Non-Pharmaceutical Techniques for Obstructive Airway Clearance Focusing on the Role of Oscillating Positive Expiratory Pressure (OPEP): A Narrative Review.

Mucus secretion in the lungs is a natural process that protects the airways from inhaled insoluble particle accumulation by capture and removal via the mucociliary escalator. Diseases such as cystic fibrosis (CF) and associated bronchiectasis, as well as chronic obstructive pulmonary disease (COPD), result in mucus layer thickening, associated with high viscosity in CF, which can eventually lead to complete airway obstruction. These processes severely impair the delivery of inhaled medications to obstructed regions of the lungs, resulting in poorly controlled disease with associated increased morbidity and mortality. This narrative review article focuses on the use of non-pharmacological airway clearance therapies (ACTs) that promote mechanical movement from the obstructed airway. Particular attention is given to the evolving application of oscillating positive expiratory pressure (OPEP) therapy via a variety of devices. Advice is provided as to the features that appear to be the most effective at mucus mobilization.

Impact of Oscillating Positive Expiratory Pressure Device Use on Post-Discharge Hospitalizations: A Retrospective Cohort Study Comparing Patients with COPD or Chronic Bronchitis Using the Aerobika® and Acapella® Devices.

Purpose: Managing and preventing disease exacerbations are key goals of COPD care. Oscillating positive expiratory pressure (OPEP) devices have been shown to improve clinical outcomes when added to COPD standard of care. This retrospective database study compared real-world resource use and disease exacerbation among patients with COPD or chronic bronchitis prescribed either of two commonly used OPEP devices. Patients and methods: Patients using the Aerobika® (Trudell Medical International, London, ON, Canada) or Acapella® (Smiths Medical, Wampsville, New York, USA) OPEP device for COPD or chronic bronchitis were identified from hospital claims linked to medical and prescription claims between September 2013 and April 2018; the index date was the first hospital visit with an OPEP device. Severe disease exacerbation, defined as an inpatient visit with a COPD or chronic bronchitis diagnosis, and all-cause healthcare resource utilization over 30 days and 12 months post-discharge were compared in propensity score (PS)-matched Aerobika device and Acapella device users. Results: In total, 619 Aerobika device and 1857 Acapella device users remained after PS matching. After discharge from the index visit, Aerobika device users were less likely to have ≥1 severe exacerbation within 30 days (12.0% vs 17.4%, p=0.01) and/or 12 months (39.6% vs 45.3%, p=0.01) and had fewer 12-month severe exacerbations (mean, 0.7 vs 0.9 per patient per year, p=0.01), with significantly longer time to first severe exacerbation than Acapella users (log-rank p=0.01). Aerobika device users were also less likely to have ≥1 all-cause inpatient visit within 30 days (13.9% vs 20.3%, p<0.001) and 12 months (44.9% vs 51.8%, p=0.003) than Acapella users. Conclusion: Patients receiving the Aerobika OPEP device, compared to the Acapella device, had lower rates of subsequent severe disease exacerbation and all-cause inpatient admission. This suggests that Aerobika OPEP device may be a beneficial add-on to usual care and that OPEP devices may vary in clinical effectiveness.

Corrigendum to "Cost-Effectiveness of the Aerobika® Oscillating Positive Expiratory Pressure Device in the Management of Chronic Obstructive Pulmonary Disease Exacerbations in Canada".

[This corrects the article DOI: 10.1155/2019/9176504.].

Cost-Effectiveness of the Aerobika® Oscillating Positive Expiratory Pressure Device in the Management of Chronic Obstructive Pulmonary Disease Exacerbations in Canada.

Background: The Aerobika® oscillating positive expiratory pressure (OPEP) device is a hand-held, drug-free medical device that has been shown to improve lung function and improve health-related quality of life in patients with chronic obstructive pulmonary disease (COPD). We estimated the cost-effectiveness of this device among postexacerbation COPD patients in the Canadian healthcare system. Methods: We performed a cost-utility analysis using a Markov model to compare both costs and outcome of patients with COPD who had recently experienced an exacerbation between 2 treatment arms: patients who used the Aerobika® device and patients who did not use the Aerobika® device. This cost-utility analysis included costs based on the Alberta healthcare system perspective as these represent Canadian experience. A one-year horizon with 12 monthly cycles was used. Results: For a patient after 1 year, the use of the Aerobika® device would save $694 in healthcare costs and produce 0.04 more in quality-adjusted life years (QALYs) in comparison with no positive expiratory pressure (PEP)/OPEP therapy. In other words, the economic outcome of the device was dominant (i.e., more effective and less costly). The probability for this device to be the dominant strategy was 72%. With a willingness to pay (WTP) threshold of $50,000 per QALY gained, the probability for the Aerobika® device to be cost-effective was 77%. Conclusions: Given one of the major treatment goals in the GOLD guidelines is to minimize the negative impact of exacerbations and prevent re-exacerbations, the Aerobika® OPEP device should be viewed as a potential component of a treatment strategy to improve symptom control and reduce the risk of re-exacerbations in patients with COPD.

In vitro and clinical characterization of the valved holding chamber AeroChamber Plus® Flow-Vu® for administrating tiotropium Respimat® in 1-5-year-old children with persistent asthmatic symptoms.

BACKGROUND: When characterizing inhalation products, a comprehensive assessment including in vitro, pharmacokinetic (PK), and clinical data is required. We conducted a characterization of tiotropium Respimat® when administered with AeroChamber Plus® Flow-Vu® anti-static valved holding chamber (test VHC) with face mask in 1-5-year-olds with persistent asthmatic symptoms. METHODS: In vitro tiotropium dose and particle size distribution delivered into a cascade impactor were evaluated under fixed paediatric and adult flow rates between actuation and samplings. The tiotropium mass likely to reach children's lungs was assessed by tidal breathing simulations and an ADAM-III Child Model. PK exposure to tiotropium in preschool children with persistent asthmatic symptoms (using test VHC) was compared with pooled data from nine Phase 2/3 trials in older children, adolescents, and adults with symptomatic persistent asthma not using test VHC. RESULTS: At fixed inspiratory flow rates, emitted mass and fine particle dose decreased under lower flow conditions; dose reduction was observed when Respimat® was administered by test VHC at paediatric flow rates. In <5-year-old children, such a dose reduction is appropriate. In terms of dose per kg/body weight, in vitro-delivered dosing in children was comparable with adults. Transmission and aerosol holding properties of Respimat® when administered with test VHC were fully sufficient for aerosol delivery to patients. At zero delay, particles <5 µm (most relevant fraction) exhibited a transfer efficacy of ≥60%. The half-time was>10 s, allowing multiple breaths. Standardized tidal inhalation resulted in an emitted mass from the test VHC of approximately one-third of labelled dose, independent of coordination and face mask use, indicating predictable tiotropium administration by test VHC with Respimat®. Tiotropium exposure in 1-5-year-old patients using the test VHC, when adjusted by height or body surface, was comparable with that in older age groups without VHCs; no overexposure was observed. Adverse events were less frequent with tiotropium (2.5 µg, n = 20 [55.6%]; 5 µg, n = 18 [58.1%]) than placebo (n = 25 [73.5%]). CONCLUSIONS: Our findings provide good initial evidence to suggest that tiotropium Respimat® may be administered with AeroChamber Plus® Flow-Vu® VHC in 1-5-year-old patients with persistent asthmatic symptoms. To confirm the clinical efficacy and safety in these patients, additional trials are required. CLINICAL TRIALS REGISTRY NUMBER: The trial was registered under NCT01634113 at http://www.clinicaltrials.gov.

A review of the in vitro and in vivo valved holding chamber (VHC) literature with a focus on the AeroChamber Plus Flow-Vu Anti-static VHC.

Valved holding chambers (VHCs) reduce the need for inhalation-actuation coordination with pressurized metered dose inhalers (pMDIs), reduce oropharyngeal drug deposition and may improve lung deposition and clinical outcomes compared to pMDIs used alone. While VHCs are thus widely advocated for use in vulnerable patient groups within clinical and regulatory guidelines, there is less consensus as to whether the performance differences between different VHCs have clinical implications. This review evaluates the VHC literature, in particular the data pertaining to large- versus small-volume chambers, aerosol performance with a VHC adjunct versus a pMDI alone, charge dissipative/conducting versus non-conducting VHCs, and facemasks, to ascertain whether potentially meaningful differences between VHCs exist. Inconsistencies in the literature are examined and explained, and relationships between in vitro and in vivo data are discussed. A particular focus of this review is the AeroChamber Plus® Flow-Vu® Anti-static VHC, the most recent iteration of the AeroChamber VHC family.

A Real-World Evidence Study Assessing the Impact of Adding the Aerobika Oscillating Positive Expiratory Pressure Device to Standard of Care Upon Healthcare Resource Utilization and Costs in Post-Operative Patients.

INTRODUCTION: The aim of this real-world study was to measure the benefit of the Aerobika oscillating positive expiratory pressure (OPEP) device when added to standard of care (defined as incentive spirometry [IS]) for post-operative patients. METHODS: Adults aged ≥ 18 years who were hospitalized for cardiac, thoracic or upper abdominal surgery between 1 September 2013 and 30 April 2017 were identified from IQVIA's Hospital Charge Detail Master (CDM) database; the index date was the date of the first hospitalization for surgery. The control cohort (IS) included patients who had ≥ 1 CDM record within 12 months prior to the index date and ≥ 1 record after discharge, evidence of IS use during index hospitalization and no evidence of use of a PEP or OPEP device at any time during the study period. The Aerobika OPEP cohort was selected in a similar manner, except that patients were required to have evidence of Aerobika OPEP use during the index hospitalization. Aerobika OPEP patients were 1:1 matched to IS patients using propensity score (PS) matching. Hospital readmissions and costs were measured at 30 days post-discharge from the index hospitalization. RESULTS: After PS matching, 144 patients were included in each cohort. At 30 days post-discharge, compared to the control (IS) cohort there were significantly fewer patients in the Aerobika OPEP cohort with ≥ 1 all-cause re-hospitalizations (13.9 vs. 22.9%; p = 0.042). The patients in the Aerobika OPEP cohort also had a shorter mean length of stay (± standard deviation) (1.25 ± 4.04 vs. 2.60 ± 8.24 days; p = 0.047) and lower total unadjusted mean all-cause cost per patient ($3670 ± $13,894 vs. $13,775 ± $84,238; p = 0.057). Adjusted analyses suggested that hospitalization costs were 80% lower for the Aerobika OPEP cohort versus the IS cohort (p = 0.001). CONCLUSION: Our results suggest that the addition of the Aerobika OPEP device to standard of care (IS) is beneficial in the post-operative setting. FUNDING: Trudell Medical International.

Are valved holding chambers (VHCs) interchangeable? An in vitro evaluation of VHC equivalence.

INTRODUCTION: The European Medicines Agency (EMA) requires that a specific valved holding chamber (VHC) is designated for use with a given pressurised metered dose inhaler (pMDI). No other regulatory authorities impose similar requirements, implying that VHCs are interchangeable. This in vitro study, employing EMA assessment criteria, assessed the equivalence of four anti-static VHCs (aVHCs) versus the non-conducting VHC most widely referenced in pMDI monographs, the AeroChamber Plus™ (AC+) VHC. MATERIAL & METHODS: The "reference" AC + VHC was prepared by soaking in detergent solution. The four test aVHCs (AeroChamber Plus™ Flow-Vu™ [AC + FV]; Compact Space Chamber Plus [CSC+]; InspiraChamber [IC]; OptiChamber Diamond™ [OCD]) were tested "out-of-packet". Twenty devices of each type were evaluated. A salbutamol pMDI was actuated into each VHC with a 2-s delay between actuation and Andersen Cascade Impactor (ACI) sampling. Drug deposition in four ACI particle size groups was assessed: Group 1, >5.8-10 µm; Group 2, >3.3-5.8 µm; Group 3, >1.1-3.3 µm; Group 4, ≤1.1 µm. Equivalence versus the reference VHC was demonstrated where the 90% confidence interval for the test/reference mass ratio was within 85-118%. RESULTS: The mass retained within the VHC was similar for the AC + VHC and AC + FV aVHC, but was approximately twice as great for the other aVHCs. Salbutamol deposition in all ACI groups with the AC + FV aVHC was equivalent to the reference AC + VHC. By contrast, deposition in ACI groups 1 to 3 with the CSC+, IC and OCD aVHCs was inequivalent to (approximately half that of) the reference VHC. Inter-device variability for each VHC type was greatest for the IC and least for the AC + VHC and AC + FV aVHC. CONCLUSIONS: The performance of VHCs that superficially resemble one another may differ markedly. Thus, as implied by EMA guidelines, VHCs should not automatically be considered to be interchangeable.

Cost-effectiveness of the Aerobika* oscillating positive expiratory pressure device in the management of COPD exacerbations.

INTRODUCTION: COPD places a huge clinical and economic burden on the US health care system, with acute exacerbations representing a key driver of direct medical costs. Current treatments, although effective in reducing symptoms and limiting exacerbations, do not adequately target the underlying disease processes that drive exacerbation development. The Aerobika* oscillating positive expiratory pressure (OPEP) device has been shown in a real-world effectiveness study to lower the frequency of moderate-to-severe exacerbations during a 30-day post-exacerbation period. This study sought to determine the impact on exacerbations and costs and to determine the cost-effectiveness of the Aerobika* device. METHODS: Data from published literature and national fee schedules were used to model the cost-effectiveness of the Aerobika* device in patients who had experienced an exacerbation in the previous month, or a post-exacerbation care population. Exacerbation trends and the impact of the Aerobika* device on reducing exacerbation frequency were modeled using a one-year Markov model with monthly cycles and three health states: (i) no exacerbation, (ii) exacerbation, and (iii) death. Scenario analysis and one-way sensitivity analysis (OWSA) were also performed. RESULTS: When the effect of Aerobika* device was assumed to last 30 days, use of the device resulted in cost-savings ($553 per patient) and improved outcomes (ie, six fewer exacerbations per 100 patients per year) compared to no OPEP/positive expiratory pressure therapy. When the effect of the Aerobika* device was assumed to extend beyond the conservative 30-day time frame, the Aerobika* device remained the dominant strategy (21 fewer exacerbations per 100 patients per year; cost savings of $1,952 per patient). Consistency in findings after performing OWSAs indicates the robustness of results. CONCLUSION: The Aerobika* device is a cost-effective treatment option that provides clinical benefit and results in direct medical cost savings in a post-exacerbation care COPD population.

Development and Evaluation of a Family of Human Face and Upper Airway Models for the Laboratory Testing of Orally Inhaled Products.

Many orally inhaled products are supplied with a facemask instead of a mouthpiece, enabling aerosolized medication to be transferred from the inhaler to the lungs when the user lacks the capability to use a mouthpiece. Until recently, laboratory evaluation of an orally inhaled product-facemask was frequently undertaken by removing the facemask, treating the facemask adapter as being equivalent to a mouthpiece. Measurements of delivered drug mass were therefore subject to bias arising from the absence of dead volume, had the facemask been present. We have described the development of the Aerosol Delivery to an Anatomic Model (ADAM) infant, small child, and adult faces and upper airways, and their subsequent evaluation. Each model possesses physical features of appropriate size, and the soft tissues are also simulated. Rudimentary underlying bony structure is also present, because its purpose is only to provide support, enabling the mechanical response of the facial soft tissues when a facemask is applied to be realized. A realistic upper airway (nasopharynx for the infant model, naso- and oropharynx for the child and oropharynx for the adult models) is also incorporated, so that each model can be used to determine the mass of inhaled medication likely to penetrate as far as the lungs where therapy is intended to be applied. Measurements of the mass of pressurized metered-dose inhaler-delivered salbutamol at a filter distal to the upper airway of each model, simulating age-appropriate tidal breathing, were remarkably consistent, almost all being in the range 0.3 to 1.0 µg/kg across the model age ranges, when expressed as a fraction of body weight.

A Retrospective Study of the Effectiveness of the AeroChamber Plus® Flow-Vu® Antistatic Valved Holding Chamber for Asthma Control.

INTRODUCTION: Electrostatic charge in valved holding chambers (VHCs) may lead to inconsistent metered-dose inhaler (MDI) asthma drug delivery. We compared the AeroChamber Plus® Flow Vu® Antistatic Valved Holding Chamber (AC+FV AVHC) with non-antistatic control VHCs in terms of asthma exacerbations, resource use, and cost in an asthma population. METHODS: Patients included in an adjudicated claims database with AC+FV AVHC or non-antistatic VHC (control VHC) use between 1/2010 and 8/2015 (index) who were treated with an inhaled corticosteroid (ICS) or a combination of an ICS and a long-acting ß2 agonist MDI within 60 days before or after the index date, were diagnosed with asthma, and had ≥12 months of pre- and ≥30 days of post-index health plan enrollment were included. Cohorts were matched 1:1 using propensity scores. We compared incidence rates (IR) of exacerbation, time to first exacerbation using Kaplan-Meier survival analysis, occurrence of exacerbations, and healthcare resource use and costs using generalized linear models. RESULTS: 9325 patients in each cohort were identified. The IR of exacerbations per 100 person-days (95% CI) was significantly higher in the control VHC cohort than the AC+FV AVHC cohort [0.161 (0.150-0.172) vs. 0.137 (0.128-0.147)]. A higher proportion of exacerbation-free patients was observed in the AC+FV AVHC cohort. Among the 4293 patients in each cohort with ≥12 months of follow-up, AC+FV AVHC patients were found to be 10-12% less likely than control VHC patients to experience an exacerbation throughout the study period. A lower proportion of the AC+FV AVHC patients had an ED visit compared to the control VHC patients (10.8% vs. 12.4%). Exacerbation-related costs for the AC+FV AVHC cohort were 23%, 25%, 20%, and 12% lower than those for the control VHC cohort at 1, 6, 9, and 12 months, respectively. CONCLUSIONS: The AC+FV AVHC was associated with lower exacerbation rates, delayed time to first exacerbation, and lower exacerbation-related costs when compared to control non-antistatic VHCs.

Clinically Relevant In Vitro Testing of Orally Inhaled Products-Bridging the Gap Between the Lab and the Patient.

Current pharmacopeial methods for in vitro orally inhaled product (OIP) performance testing were developed primarily to support requirements for drug product registration and quality control. In addition, separate clinical studies are undertaken in order to quantify safety and efficacy in the hands of the patient. However, both laboratory and clinical studies are time-consuming and expensive and generally do not investigate either the effects of misuse or the severity of the respiratory disease being treated. The following modifications to laboratory evaluation methodologies can be incorporated without difficulty to provide a better linkage from in vitro testing to clinical reality: (1) examine all types of OIP with patient-representative breathing profiles which represent normal inhaler operation in accordance with the instructions for use (IFU); (2) evaluate OIP misuse, prioritizing the importance of such testing on the basis of (a) probability of occurrence and (b) consequential impact in terms of drug delivery in accordance with the label claim; and (3) use age-appropriate patient-simulated face and upper airway models for the evaluation of OIPs with a facemask. Although it is not necessarily foreseen that these suggestions would form part of future routine quality control testing of inhalers, they should provide a closer approximation to the clinical setting and therefore be useful in the preparation for in vivo studies and in improving guidance for correct use.

Developing ways to evaluate in the laboratory how inhalation devices will be used by patients and care-givers: the need for clinically appropriate testing.

The design of methods in the pharmaceutical compendia for the laboratory-based evaluation of orally inhaled product (OIP) performance is intentionally aimed for simplicity and robustness in order to achieve the high degree of accuracy and precision required for the assurance of product quality in a regulated environment. Consequently, performance of the inhaler when used or even misused by the patient or care-giver has often not been assessed. Indeed, patient-use-based methodology has been developed in a somewhat piecemeal basis when a need has been perceived by the developing organization. There is, therefore, a lack of in-use test standardization across OIP platforms, and often important details have remained undisclosed beyond the sponsoring organization. The advent of international standards, such as ISO 20072:2009, that focus specifically on the OIP development process, together with the need to make these drug delivery devices more patient-friendly as an aid to improving compliance, is necessitating that clinically appropriate test procedures be standardized at the OIP class level. It is also important that their capabilities and limitations are well understood by stakeholders involved in the process. This article outlines how this process might take place, drawing on current examples in which significant advances in methodology have been achieved. Ideally, it is hoped that such procedures, once appropriately validated, might eventually become incorporated into the pharmacopeial literature as a resource for future inhaler developers, regulatory agencies, and clinicians seeking to understand how these devices will perform in use to augment ongoing product quality testing which is adequately served by existing methods.