Maleimide functionalized polycaprolactone micelles for glutathione quenching and doxorubicin delivery.

High glutathione production is known to be one of the defense mechanisms by which many cancer cells survive elevated oxidative stress. By explicitly targeting glutathione in these cancer cells and diminishing its levels, oxidative stress can be intensified, ultimately triggering apoptosis or programmed cell death. Herein, we developed a novel approach by creating maleimide-functionalized polycaprolactone polymers, specifically using 2,3-diiodomaleimide functionality to reduce the level of glutathione in cancer cells. Polycaprolactone was chosen to conjugate the 2,3-diiodomaleimide functionality due to its biodegradable and biocompatible properties. The amphiphilic block copolymer was synthesized using PEG as a macroinitiator to make corresponding polymeric micelles. The resulting 2,3-diiodomaleimide-conjugated polycaprolactone micelles effectively quenched glutathione, even at low concentrations (0.01 mg mL-1). Furthermore, we loaded these micelles with the anticancer drug doxorubicin (DOX), which exhibited pH-dependent drug release. We obtained a loading capacity (LC) of 3.5% for the micelles, one of the highest LC reported among functional PCL-based micelles. Moreover, the enhanced LC doesn't affect their release profile. Cytotoxicity experiments demonstrated that empty and DOX-loaded micelles inhibited cancer cell growth, with the DOX-loaded micelles displaying the highest cytotoxicity. The ability of the polymer to quench intracellular GSH was also confirmed. This approach of attaching maleimide to polycaprolactone polymers shows promise in depleting elevated glutathione levels in cancer cells, potentially improving cancer treatment efficacy.

Effect of aromatic substituents on thermoresponsive functional polycaprolactone micellar carriers for doxorubicin delivery.

Amphiphilic functional polycaprolactone (PCL) diblock copolymers are excellent candidates for micellar drug delivery. The functional groups on the backbone significantly affect the properties of PCL. A systematic investigation of the effect of aromatic substituents on the self-assembly of γ-functionalized PCLs and the delivery of doxorubicin (DOX) is presented in this work. Three thermoresponsive amphiphilic diblock copolymers with poly(γ-benzyloxy-ε-caprolactone) (PBnCL), poly(γ-phenyl- ε-caprolactone) (PPhCL), poly(γ-(4-ethoxyphenyl)-ε-caprolactone) (PEtOPhCL), respectively, as hydrophobic block and γ-tri(ethylene glycol) functionalized PCL (PME3CL) as hydrophilic block were prepared through ring-opening polymerization (ROP). The thermoresponsivity, thermodynamic stability, micelle size, morphology, DOX-loading, and release profile were determined. The LCST values of amphiphilic diblock copolymers PME3CL-b-PBnCL, PME3CL-b-PPhCL, and PME3CL-b-PEtOPhCL are 74.2°C, 43.3°C, and 37.3°C, respectively. All three copolymers formed spherical micelles in phosphate-buffered saline (PBS, 1×, pH = 7.4) at low concentrations ranging from 8.7 × 10-4 g/L to 8.9 × 10-4 g/L. PME3CL-b-PBnCL micelles showed the highest DOX loading capacity of 3.01 ± 0.18 (wt%) and the lowest drug release, while PME3CL-b-PEtOPhCL micelles exhibited the lowest DOX loading capacity of 1.95 ± 0.05 (wt%) and the highest drug release. Cytotoxicity and cellular uptake of all three micelles were assessed in vitro using MDA-MB-231 breast cancer cells. All three empty micelles did not show significant toxicity to the cells at concentrations high up to 0.5 mg/mL. All three DOX-loaded micelles were uptaken into the cells, and DOX was internalized into the nucleus of the cells.

Reversible Cross-linked Thermoresponsive Polycaprolactone Micelles for Enhanced Stability and Controlled Release.

Thermoresponsive amphiphilic poly(ε-caprolactone)s (PCL)s are excellent candidates for drug delivery due to their biodegradability, biocompatibility, and controlled release. However, the thermoresponsivity of modified PCL can often lead to premature drug release because their lower critical solution temperature (LCST) is close to physiological temperature conditions. To address this issue, we developed a novel approach that involves functionalizing redox-responsive lipoic acid to the hydrophobic block of PCL. Lipoic acid has disulfide bonds that undergo reversible cross-linking after encapsulating the drug. Herein, we synthesized an ether-linked propargyl-substituted PCL as the hydrophobic block of an amphiphilic copolymer along with unsubstituted PCL. The propargyl group was used to attach lipoic acid through a postpolymerization modification reaction. The hydrophilic block is composed of an ether-linked, thermoresponsive tri(ethylene glycol)-substituted PCL. Anticancer drug doxorubicin (DOX) was encapsulated within the core of the micelles and induced cross-linking in the presence of a reducing agent, dithiothreitol. The developed micelles are thermodynamically stable and demonstrated thermoresponsivity with an LCST value of 37.5 °C but shifted to 40.5 °C after cross-linking. The stability and release of both uncross-linked (LA-PCL) and cross-linked (CLA-PCL) micelles were studied at physiological temperatures. The results indicated that CLA-PCL was stable, and only 35% release was observed after 46 h at 37 °C while LA-PCL released more than 70% drug at the same condition. Furthermore, CLA-PCL was able to release a higher amount of DOX in the presence of glutathione and above the LCST condition (42 °C). Cytotoxicity experiments revealed that CLA-PCL micelles are more toxic toward MDA-MB-231 breast cancer cells at 42 °C than at 37 °C, which supported the thermoresponsive release of the drug. These results indicate that the use of reversible cross-linking is a great approach toward synthesizing stable thermoresponsive micelles with reduced premature drug leakage.

Chalcogenopheno[3,2-b]pyrrole-Containing Donor-Acceptor-Donor Organic Semiconducting Small Molecules for Organic Field-Effect Transistors.

A group of chalcogenopheno[3,2-b]pyrroles, including thieno[3,2-b]pyrrole (TP), furo[3,2-b]pyrrole (FP), and selenopheno[3,2-b]pyrrole (SeP), and thieno[3,2-b]thiophene (TT) electron-donating units were coupled with a thiophene-flanked diketopyrrolo[3,4-c]pyrrole (ThDPP) acceptor to generate four donor-acceptor-donor (D-A-D) semiconducting small molecules (ThDPP-TT, ThDPP-FP, ThDPP-TP, and ThDPP-SeP). This study systematically investigated the differences between chalcogenopheno[3,2-b]pyrroles and TT. From the characterizations, chalcogenopheno[3,2-b]pyrrole-containing molecules showed lower band gaps and binding-energy cold crystallization behavior. The enthalpies of cold crystallization were correlated with the weight of the chalcogen in ThDPP-FP, ThDPP-TP, and ThDPP-SeP, which were evaluated as intermolecular chalcogen-bond interactions between chalcogen and pyrrole nitrogen in chalcogenopheno[3,2-b]pyrroles. A stronger chalcogen bond interaction resulted in stronger self-aggregation in thin films with thermal treatment, which resulted in a polycrystalline structure in chalcogenopheno[3,2-b]pyrrole-containing molecules. For the application in an organic field-effect transistor, all four molecules showed good performance with the highest hole mobilities as 6.33 × 10-3 cm2 V-1 s-1 for ThDPP-TT, 2.08 × 10-2 cm2 V-1 s-1 for ThDPP-FP, 1.87 × 10-2 cm2 V-1 s-1 for ThDPP-TP, and 6.32 × 10-3 cm2 V-1 s-1 for ThDPP-SeP, and the change of mobility is well correlated to the root-mean-square roughness of the thin films. Overall, all the chalcogenopheno[3,2-b]pyrrole-containing molecules showed lower band gaps, polymorphism, and better charge transport properties compared to TT-containing molecules, which motivates replacing TT with chalcogenopheno[3,2-b]pyrroles in conjugated polymers, non-fullerene small molecular acceptors, and narrow-band-gap donors.

Regioselective Direct C-H Bond Heteroarylation of Thiazoles Enabled by an Iminopyridine-Based α-Diimine Nickel(II) Complex Evaluated by DFT Studies.

Direct C-H bond arylation is a highly effective method for synthesizing arylated heteroaromatics. This method reduces the number of synthetic steps and minimizes the formation of impurities. We report an air- and moisture-stable iminopyridine-based α-diimine nickel(II) complex for direct C5-H bond arylation of thiazole derivatives. Under a low catalyst loading and performing the reactions at lower temperatures (80 °C) under aerobic conditions, we produced mono- and diarylated thiazole units. Competition experiments and density functional theory calculations revealed that the mechanism of C-H activation in 4-methylthiazole involves an electrophilic aromatic substitution.

Recent Advances in Polycaprolactones for Anticancer Drug Delivery.

Poly(ε-Caprolactone)s are biodegradable and biocompatible polyesters that have gained considerable attention for drug delivery applications due to their slow degradation and ease of functionalization. One of the significant advantages of polycaprolactone is its ability to attach various functionalities to its backbone, which is commonly accomplished through ring-opening polymerization (ROP) of functionalized caprolactone monomer. In this review, we aim to summarize some of the most recent advances in polycaprolactones and their potential application in drug delivery. We will discuss different types of polycaprolactone-based drug delivery systems and their behavior in response to different stimuli, their ability to target specific locations, morphology, as well as their drug loading and release capabilities.

Variation in Risk-Standardized Acute Admission Rates Among Patients With Heart Failure in Accountable Care Organizations: Implications for Quality Measurement.

Background Accountable care organizations (ACOs) aim to improve health care quality and reduce costs, including among patients with heart failure (HF). However, variation across ACOs in admission rates for patients with HF and associated factors are not well described. Methods and Results We identified Medicare fee-for-service beneficiaries with HF who were assigned to a Medicare Shared Savings Program ACO in 2017 and survived ≥30 days into 2018. We calculated risk-standardized acute admission rates across ACOs, assigned ACOs to 1 of 3 performance categories, and examined associations between ACO characteristics and performance categories. Among 1 232 222 beneficiaries with HF, 283 795 (mean age, 81 years; 54% women; 86% White; 78% urban) were assigned to 1 of 467 Medicare Shared Savings Program ACOs. Across ACOs, the median risk-standardized acute admission rate was 87 admissions per 100 people, ranging from 61 (minimum) to 109 (maximum) admissions per 100 beneficiaries. Compared to the overall average, 13% of ACOs performed better on risk-standardized acute admission rates, 72% were no different, and 14% performed worse. Most ACOs with better performance had fewer Black beneficiaries and were not hospital affiliated. Most ACOs that performed worse than average were large, located in the Northeast, had a hospital affiliation, and had a lower proportion of primary care providers. Conclusions Admissions are common among beneficiaries with HF in ACOs, and there is variation in risk-standardized acute admission rates across ACOs. ACO performance was associated with certain ACO characteristics. Future studies should attempt to elucidate the relationship between ACO structure and characteristics and admission risk.

Promoting Participation in Pulmonary Rehabilitation after Hospitalization for Chronic Obstructive Pulmonary Disease, Strategies of Top-performing Systems: A Qualitative Study.

Rationale: Pulmonary rehabilitation (PR) after hospitalization for chronic obstructive pulmonary disease (COPD) is recommended by guidelines; however, few patients participate, and rates vary between hospitals. Objectives: To identify contextual factors and strategies that may promote participation in PR after hospitalization for COPD. Methods: Using a positive-deviance approach, we calculated hospital-specific rates of PR after hospitalization for COPD among a cohort of Medicare beneficiaries. At a purposive sample of high-performing and innovative hospitals in the United States, we conducted in-depth interviews with key stakeholders. We defined high-performing hospitals as having a PR rate above the 95th percentile, at least 6.58%. To learn from hospitals that demonstrated a commitment to improving rates of PR, regardless of PR rates after discharge, we identified innovative hospitals on the basis of a review of American Thoracic Society conference research presentations from prior years. Interviews were audio-recorded and transcribed verbatim. Using a directed content analysis approach, transcripts were coded iteratively to identify themes. Results: Interviews were conducted with 38 stakeholders at nine hospitals (seven high-performers and two innovators). Hospitals were diverse regarding size, teaching status, PR program characteristics, and geographic location. Participants included PR medical directors, PR managers, respiratory therapists, inpatient and outpatient providers, and others. We found that high-performing hospitals were broadly focused on improving care for patients with COPD, and several had recently implemented new initiatives to reduce rehospitalizations after admission for COPD in response to the Centers for Medicare and Medicaid Services/Medicare's Hospital Readmission Reduction Program. Innovative and high-performing hospitals had systems in place to identify patients with COPD that enabled them to provide patient education and targeted discharge planning. Strategies took several forms, including the use of a COPD navigator or educator. In addition, we found that high-performing hospitals reported effective interprofessional and patient communication, had clinical champions or external change agents, and received support from hospital leadership. Specific strategies to promote PR included education of referring providers, education of patients to increase awareness of PR and its benefits, and direct assistance in overcoming barriers. Conclusions: Our findings suggest that successful efforts to increase participation in PR may be most effective when part of a larger strategy to improve outcomes for patients with COPD. Further research is necessary to test the generalizability of our findings.

Analysis of shared cognitive tasks in the application of non-invasive ventilation to patients with COPD exacerbation.

Interprofessional teamwork plays a key role in the uptake of evidence-based interventions, such as noninvasive ventilation (NIV) for patients with exacerbated Chronic Obstructive Pulmonary Disease (COPD). We aimed to identify the shared cognitive tasks in interprofessional teams using NIV for patients with COPD exacerbation. We used a cognitive task analysis approach (CTA) to engage nurses, rapid response team members, respiratory therapists, and physicians involved in the use of NIV to treat patients with COPD exacerbation. Clinicians participated in a semi-structured interview (n = 21) that elicited cognitions needed to treat COPD exacerbation. Three shared cognitive tasks were identified: Complete a thorough assessment, Formulate a care plan, and Continuously monitor patient status. Findings attest to the importance of having access to up-to-date information and expertise necessary to make accurate clinical inferences for patient assessment. Shared understanding of the formulated care plan among all members of the care team was important to its execution. Continuous monitoring was crucial; however, this cognitive task relied on patient assessment skills and ongoing collaboration within the clinical care team. Application of NIV for patients with COPD exacerbation may require enhancing collaboration through nontechnical skills and interprofessional training.

Identifying themes to inform nursing decisions when caring for patients with acute exacerbation of chronic obstructive pulmonary disease on noninvasive ventilation: A qualitative descriptive study.

Prior studies analyzing patient experience with noninvasive ventilation (NIV) found the most impactful interaction that patients remembered was with nurses, however a survey of nurses regarding the management of patients treated with NIV has shown that most nurses felt unprepared to care for these sick patients. Our qualitative descriptive study explored the current nursing experience using NIV as a treatment for acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Nine (n = 9) subject matter expert nurses practicing in a variety of clinical settings participated in semi-structured interviews. The COnsolidated criteria for REporting Qualitative research checklist was followed for interview development. Interview transcripts were subsequently analyzed using deductive thematic analysis. Themes identified from the interviews pertained to patient assessment, novice nurses' need for clinical support, team communication, and nursing education. Improving interprofessional team communication and collaboration skills, and implementing guidelines for NIV utilization were specified as essential components of NIV education for nurses. Even though the nursing role in the care of AECOPD NIV patient could be institution dependent, the themes presented in our study are useful in identifying opportunities for NIV nursing education and areas for further research. Patient or Public Contribution: Nurses served as interviewees for this study.

Supervised preoperative walking on increasing early postoperative stamina and mobility in older adults with frailty traits: A pilot and feasibility study.

Background and Aims: Frail older adults are more than twice as likely to experience postoperative complications. Preoperative exercise may better prepare these patients through improved stamina and mobility experienced in the days following surgery. We measured the impact of a walking intervention using an activity tracker and coaching on postoperative stamina, and mobility in older adults with frailty traits. Methods: We included patients aged 60+ and scoring 4+ on the Edmonton Frailty Scale. We then randomized patients to intervention versus control stratified by anticipated hospital stay (1 night vs. 2+ night) and baseline stamina (i.e., 6-min walk distance [6MWD]). Intervention patients received an activity tracker and linked smart phone. An athletic trainer (AT) prescribed a daily step count goal and titrated this up after checking in with patients during weekly telephone calls. Controls received general walking recommendations. We then measured postoperative 6MWD 1-3 days after surgery. We also assessed postoperative mobility by measuring steps walked the day after surgery using a thigh-worn monitor. Because many patients could not walk postoperatively, we compared intervention-control difference in both 6MWD and steps using Wilcoxon rank testing and Tobit and ordinal logistic regression adjusting for several patient characteristics. Results: We randomized 104 eligible patients; 80 patients remained for final analysis. There was no difference in intervention versus control postoperative 6MWD (median 72 vs. 74 m Wilcoxon p = 0.54) or postoperative steps taken (median 128 vs. 51 steps Wilcoxon p = 0.76). Analysis adjusting for patient characteristics was consistent with these findings. Conclusion: Our intervention consisting of goal setting with an activity tracker and telephonic coaching by an AT did not appear to improve stamina or mobility measured in the days after surgery. Small sample size limited our ability to examine this impact in subsets defined by surgical specialty or baseline stamina.

Death among patients hospitalized with symptomatic COVID-19: Implications for high-risk patients.

BACKGROUND: We aimed to examine the role played by the COVID-19 infection in patients' death and to determine the proportion of patients for whom it was a major contributor to death. METHODS: We included patients ≥50 years old who were hospitalized with COVID-19 infection and died between March 1, 2020 and September 30, 2020 in a tertiary medical center. We considered COVID-19 infection to be a major cause for death if the patient had well-controlled medical conditions and death was improbable without coronavirus infection, and a minor cause for death if the patient had serious illnesses and had an indication for palliative care. RESULTS: Among 243 patients, median age was 80 (interquartile intervals: 72-86) and 40% were female. One in two had moderate or severe frailty and 41% had dementia. Nearly 60% of the patients were classified as having advanced, serious illnesses present prior to the hospitalization, with death being expected within 12 months, and among this group 39% were full code at admission. In the remaining 40% of patients, deaths were classified as unexpected based on patients' prior conditions, suggesting that COVID-19 infection complications were the primary contributor to death. CONCLUSIONS: For slightly less than half (40%) of patients who died of complications of COVID-19, death was an unexpected event. Among the 60% of patients for whom death was not a surprise, our findings identify opportunities to improve end-of-life discussions and implement shared decision-making in high-risk patients early on or prior to hospitalization.

Efficacy of models of palliative care delivered beyond the traditional physician-led, subspecialty consultation service model: a systematic review and meta-analysis.

OBJECTIVE: This meta-analysis aimed to determine the effectiveness of non-physician provider-led palliative care (PC) interventions in the management of adults with advanced illnesses on patient-reported outcomes and advance care planning (ACP). METHODS: We included randomised trials and cluster trials published in MEDLINE, EMBASE, CINAHL, PsycINFO, Cochrane Register of Controlled Trials and ClinicalTrials.gov searched until July 2021 that examined individuals ≥18 years with a diagnosis of advanced, life-limiting illness and received a PC intervention led by a non-physician (nurse, advance practitioner or social worker). Our primary outcome was quality of life (QOL), which was extracted as unadjusted or adjusted estimates and measures of variability. Secondary outcomes included anxiety, depression and ACP. RESULTS: Among the 21 studies (2370 subjects), 13 included patients with cancer, 3 with heart failure, 4 with chronic respiratory disease and 1 with chronic kidney disease. The interventions were diverse and varied with respect to team composition and services offered. For QOL, the standardised mean differences suggested null effects of PC interventions compared with usual care at 1-2 months (0.04; 95% CI=-0.14 to 0.23, n=10 randomised controlled trials (RCTs)) and 6-7 months (0.10; 95% CI=-0.15 to 0.34, n=6 RCTs). The results for anxiety and depression were not significant also. For the ACP, there was a strong benefit for the PC intervention (absolute increase of 0.32% (95% CI=0.06 to 0.57). CONCLUSIONS: In this meta-analysis, PC interventions delivered by non-physician were not associated with improvement in QOL, anxiety or depression but demonstrated an impact on the ACP discussion and documentation.

Exploring the Patient Experience with Noninvasive Ventilation: A Human-Centered Design Analysis to Inform Planning for Better Tolerance.

BACKGROUND: This study brings a human-centered design (HCD) perspective to understanding the patient experience when using noninvasive ventilation (NIV) with the goal of creating better strategies to improve NIV comfort and tolerance. METHODS: Using an HCD motivational approach, we created a semi-structured interview to uncover the patients' journey while being treated with NIV. We interviewed 16 patients with chronic obstructive pulmonary disease (COPD) treated with NIV while hospitalized. Patients' experiences were captured in a stepwise narrative creating a journey map as a framework describing the overall experience and highlighting the key processes, tensions, and flows. We broke the journey into phases, steps, emotions, and themes to get a clear picture of the overall experience levers for patients. RESULTS: The following themes promoted NIV tolerance: trust in the providers, the favorable impression of the facility and staff, understanding why the mask was needed, how NIV works and how long it will be needed, immediate relief of the threatening suffocating sensation, familiarity with similar treatments, use of meditation and mindfulness, and the realization that treatment was useful. The following themes deterred NIV tolerance: physical and psychological discomfort with the mask, impaired control, feeling of loss of control, and being misinformed. CONCLUSIONS: Understanding the reality of patients with COPD treated with NIV will help refine strategies that can improve their experience and tolerance with NIV. Future research should test ideas with the best potential and generate prototypes and design iterations to be tested with patients.

The Association of Frailty With Long-Term Outcomes in Patients With Acute Respiratory Failure Treated With Noninvasive Ventilation.

The objective of this study was to investigate the prevalence and impact of frailty on mortality in patients with acute respiratory failure (ARF) treated with noninvasive ventilation (NIV). This was a single-center, prospective study of patients who developed ARF (irrespective of etiology) and were treated with NIV support. Frailty was assessed using the Clinical Frailty Scale (CFS). We modeled the relationship of CFS with one-year mortality using Cox proportional hazards regression, adjusting for other clinical and demographic characteristics. Of the 166 patients enrolled, 48% had moderate to severe frailty. These patients were more likely to be female (67% versus 33%) and on oxygen therapy at home (46% versus 28%). The median CFS score was 5 (interquartile range (IQR): 5-6). Moderate to severe frailty was associated with a 60% higher risk of one-year mortality (hazard ratio (HR): 1.63, 95% confidence interval (CI): 1.15-2.31). Frailty assessment may identify patients in need of ventilatory support who are at increased risk of mortality and may be an important factor to consider when discussing goals of care in this vulnerable population.

Association of Palliative Care with Days at Home and Healthcare Use in Patients with Advanced Chronic Obstructive Pulmonary Disease: A Cohort Study.

Rationale: Palliative care focuses on improving quality of life for patients with life-limiting conditions. Although previous studies have shown palliative care to be associated with reduced acute healthcare use in people with cancer and other illnesses, these findings may not generalize to patients with chronic obstructive pulmonary disease (COPD). Objectives: We examined the association between palliative care and rates of days at home, locations of death, and acute healthcare use in patients with COPD. Methods: We used health administrative databases in Ontario, Canada, to identify patients with advanced COPD hospitalized between April 2010 and March 2017 and followed up until March 2018. Patients who received palliative care were matched 1:1 with those who did not receive palliative care in terms of age, sex, long-term oxygen, previous COPD hospitalizations and propensity scores. Rate ratios (RR) were estimated by using Poisson models with generalized estimating equations to account for matching. Results: Among 35,492 patients, 1,788 (5%) received palliative care. In the matched cohort (1,721 pairs), people with COPD receiving palliative care had similar rates of days at home (RR, 1.01; 95% confidence interval [CI], 0.97-1.05) but were more likely to die at home (16.4% vs. 10.0%; P < 0.001) compared with those who did not receive palliative care. Rates of healthcare use were similar except for increased hospitalizations in the palliative care group (RR, 1.09; 95% CI, 1.01-1.18). Conclusions: Receipt of palliative care did not reduce days at home or healthcare use but was associated with a modest increase in the proportion who died at home. Future work should evaluate palliative care strategies designed specifically for patients with COPD.

Uncertainty as a critical determinant of antibiotic prescribing in patients with an asthma exacerbation: a qualitative study.

OBJECTIVE: To identify factors that influence providers' decisions to prescribe antibiotics in patients presenting to the hospital with an asthma exacerbation. METHODS: We performed semi-structured interviews with a purposive sample of providers including sixteen hospitalists, emergency room providers, or pulmonologists, and one focus group with internal medicine residents recruited from one large, urban, teaching hospital and one small, rural, community hospital. Questions were informed by the Theoretical Domains Framework to determine factors that may influence behaviors. Directed content analysis was used to code and analyze transcripts of the interviews. RESULTS: Uncertainty regarding the diagnostic (asthma vs. COPD) and the cause of exacerbation (bacterial vs. viral infection) emerged as the main driver for prescribing behavior. Provider response to uncertainty included: "watchful waiting" or immediate antibiotic prescribing. The following factors played important roles in providers' prescribing decision: 1) awareness/agreement with existing guidelines 2) confidence in their ability to apply the guidelines in challenging cases; 3) perceived risk of patient deterioration without antibiotics; 4) fear of litigation; 5) habit and clinical inertia 6) prescribing within the group 7) lack of information of antibiotic prescribing rates and 8) lack of time and/or resources. CONCLUSIONS: We identified diagnostic uncertainty as the primary determinant of antibiotic prescribing in asthma exacerbations and developed a conceptual model to explain provider responses and factors that influenced their responses. These results enhance our understanding of the factors that can contribute to low-value and wasteful practices like superfluous antibiotic prescribing and will support the development of interventions to de-implement such practices.

Update to the study protocol for an implementation-effectiveness trial comparing two education strategies for improving the uptake of noninvasive ventilation in patients with severe COPD exacerbation.

BACKGROUND: There is strong evidence that noninvasive ventilation (NIV) improves the outcomes of patients hospitalized with severe COPD exacerbation, and NIV is recommended as the first-line therapy for these patients. Yet, several studies have demonstrated substantial variation in NIV use across hospitals, leading to preventable morbidity and mortality. In addition, prior studies suggested that efforts to increase NIV use in COPD need to account for the complex and interdisciplinary nature of NIV delivery and the need for team coordination. Therefore, our initial project aimed to compare two educational strategies: online education (OLE) and interprofessional education (IPE), which targets complex team-based care in NIV delivery. Due to the impact of the COVID-19 pandemic on recruitment and planned intervention, we had made several changes in the study design, statistical analysis, and implementation strategies delivery as outlined in the methods. METHODS: We originally proposed a two-arm, pragmatic, cluster, randomized hybrid implementation-effectiveness trial comparing two education strategies to improve NIV uptake in patients with severe COPD exacerbation in 20 hospitals with a low baseline rate of NIV use. Due to logistical constrains and slow recruitment, we changed the study design to an opened cohort stepped-wedge design with three steps which will allow the institutions to enroll when they are ready to participate. Only the IPE strategy will be implemented, and the education will be provided in an online virtual format. Our primary outcome will be the hospital-level risk-standardized NIV proportion for the period post-IPE training, along with the change in rate from the period prior to training. Aim 1 will compare the change over time of NIV use among patients with COPD in the step-wedged design. Aim 2 will explore the mediators' role (respiratory therapist autonomy and team functionality) on the relationship between the implementation strategies and effectiveness. Finally, in Aim 3, through interviews with providers, we will assess the acceptability and feasibility of the educational training. CONCLUSION: The changes in study design will result in several limitation. Most importantly, the hospitals in the three cohorts are not randomized as they enroll based on their readiness. Second, the delivery of the IPE is virtual, and it is not known if remote education is conducive to team building. However, this study will be among the first to test the impact of IPE in the inpatient setting carefully and may generalize to other interventions directed to seriously ill patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT04206735 . Registered on December 20, 2019.