Clinical Interventions Following Escalations from a Continuous Respiratory Monitoring Service in Patients With Chronic Obstructive Pulmonary Disease.

Background: Continuous respiratory monitoring can support integrated care for chronic obstructive pulmonary disease (COPD) patients, by coupling them with remote clinical personnel who triage patients in coordination with their health care providers. When deploying such services, there remains uncertainty surrounding outcomes when at-risk patients are proactively identified and escalated for provider evaluation. This study presents findings from a service deployed in a real-world COPD cohort by analyzing the clinical interventions made during in-person and telehealth pulmonary outpatient visits following remote escalations. Methods: A single-center, retrospective, observational study of real-world COPD patients at a multi-site pulmonary practice was conducted. Patients who were enrolled in a continuous respiratory monitoring service for at least one year and were seen by a provider within seven days of an escalation by the service (N=168) were included. To evaluate the potential impact of these escalations on provider and patient burden, medical charts from outpatient visits were manually reviewed and grouped into six categories based on the clinical action(s) taken by the provider. Results: A total of 245 outpatient visits occurred from 168 patients within seven days of escalation. Of the 245 visits, 206 (84.1%) resulted in clinical intervention and 163 (66.5%) resulted in treatment consistent with acute exacerbations of COPD (AECOPDs). 1.6% of the outpatient visits resulted in referral to the emergency room. Conclusion: Provider encounters occurring following the escalation of a patient from a continuous respiratory monitoring service consistently resulted in that provider administering a treatment to the escalated patient.

Clinical perspectives in bronchiectasis management.

Non-cystic fibrosis bronchiectasis is a chronic inflammatory airway disease that results in permanent lung damage and can correlate with considerable clinical and economic burden. There are gaps in knowledge surrounding bronchiectasis, for which there are no published US-based treatment guidelines or FDA-approved therapies. Given the current challenges and gaps in care, the authors of this article convened for an AJMC® roundtable in March 2024. This publication summarizes the main findings of that roundtable and situates them in a scholarly context. Panelists agreed that patients with unexplained chronic cough or fatigue, purulent sputum production, hemoptysis, or repeated infection should undergo CT scanning to assess the presence of bronchiectasis, which has been estimated to affect approximately 364,000 to 558,000 individuals at least 18 years of age. They noted that disease symptoms and treatment burden can considerably diminish patient health-related quality of life (HRQOL) and that an exacerbation uniformly signifies deteriorating health and substantially impacts disease progression, hospitalization rates, and mortality. Absent an FDA-approved therapy, panelists' top management priorities were preventing or reducing exacerbations and maintaining or improving HRQOL. Panelists concluded that providers are ill-equipped to change the course of this heterogenous disease and that there is a real need for options to manage symptoms, for US-based guidelines, and for more research into epidemiology, etiology, and treatment.

Five-Year Outcomes among U.S. Bronchiectasis and NTM Research Registry Patients.

Rationale: Nontuberculous mycobacteria (NTM) are prevalent among patients with bronchiectasis. However, the long-term natural history of patients with NTM and bronchiectasis is not well described. Objectives: To assess the impact of NTM on 5-year clinical outcomes and mortality in patients with bronchiectasis. Methods: Patients in the Bronchiectasis and NTM Research Registry with ⩾5 years of follow-up were eligible. Data were collected for all-cause mortality, lung function, exacerbations, hospitalizations, and disease severity. Outcomes were compared between patients with and without NTM at baseline. Mortality was assessed using Cox proportional hazards models and the log-rank test. Measurements and Main Results: In total, 2,634 patients were included: 1,549 (58.8%) with and 1,085 (41.2%) without NTM at baseline. All-cause mortality (95% confidence interval) at Year 5 was 12.1% (10.5%, 13.7%) overall, 12.6% (10.5%, 14.8%) in patients with NTM, and 11.5% (9.0%, 13.9%) in patients without NTM. Independent predictors of 5-year mortality were baseline FEV1 percent predicted, age, hospitalization within 2 years before baseline, body mass index, and sex (all P < 0.01). The probabilities of acquiring NTM or Pseudomonas aeruginosa were approximately 4% and 3% per year, respectively. Spirometry, exacerbations, and hospitalizations were similar, regardless of NTM status, except that annual exacerbations were lower in patients with NTM (P < 0.05). Conclusions: Outcomes, including exacerbations, hospitalizations, rate of loss of lung function, and mortality rate, were similar across 5 years in patients with bronchiectasis with or without NTM.

In severe, uncontrolled asthma, tezepelumab reduced exacerbations over 1 y regardless of type 2 inflammation level.

SOURCE CITATION: Corren J, Menzies-Gow A, Chupp G, et al. Efficacy of tezepelumab in severe, uncontrolled asthma: pooled analysis of the PATHWAY and NAVIGATOR clinical trials. Am J Respir Crit Care Med. 2023;208:13-24. 37015033.

Exposure of Mycobacterium tuberculosis to human alveolar lining fluid shows temporal and strain-specific adaptation to the lung environment.

Upon infection, Mycobacterium tuberculosis ( M.tb ) reaches the alveolar space and comes in close contact with human alveolar lining fluid (ALF) for an uncertain period of time prior to its encounter with alveolar cells. We showed that homeostatic ALF hydrolytic enzymes modify the M.tb cell envelope, driving M.tb -host cell interactions. Still, the contribution of ALF during M.tb infection is poorly understood. Here, we exposed 4 M.tb strains with different levels of virulence, transmissibility, and drug resistance (DR) to physiological concentrations of human ALF for 15-min and 12-h, and performed RNA sequencing. Gene expression analysis showed a temporal and strain-specific adaptation to human ALF. Differential expression (DE) of ALF-exposed vs. unexposed M.tb revealed a total of 397 DE genes associated with lipid metabolism, cell envelope and processes, intermediary metabolism and respiration, and regulatory proteins, among others. Most DE genes were detected at 12-h post-ALF exposure, with DR- M.tb strain W-7642 having the highest number of DE genes. Interestingly, genes from the KstR2 regulon, which controls the degradation of cholesterol C and D rings, were significantly upregulated in all strains post-ALF exposure. These results indicate that M.tb -ALF contact drives initial metabolic and physiologic changes in M.tb , with potential implications in infection outcome. IMPORTANCE: Tuberculosis, caused by airborne pathogen Mycobacterium tuberculosis ( M.tb ), is one of the leading causes of mortality worldwide. Upon infection, M.tb reaches the alveoli and gets in contact with human alveolar lining fluid (ALF), where ALF hydrolases modify the M.tb cell envelope driving subsequent M.tb -host cell interactions. Still, the contributions of ALF during infection are poorly understood. We exposed 4 M.tb strains to ALF for 15-min and 12-h and performed RNA sequencing, demonstrating a temporal and strain-specific adaptation of M.tb to ALF. Interestingly, genes associated with cholesterol degradation were highly upregulated in all strains. This study shows for the first time that ALF drives global metabolic changes in M.tb during the initial stages of the infection, with potential implications in disease outcome. Biologically relevant networks and common and strain-specific bacterial determinants derived from this study could be further investigated as potential therapeutic candidates.

Suspected Bronchiectasis and Mortality in Adults With a History of Smoking Who Have Normal and Impaired Lung Function : A Cohort Study.

BACKGROUND: Bronchiectasis in adults with chronic obstructive pulmonary disease (COPD) is associated with greater mortality. However, whether suspected bronchiectasis-defined as incidental bronchiectasis on computed tomography (CT) images plus clinical manifestation-is associated with increased mortality in adults with a history of smoking with normal spirometry and preserved ratio impaired spirometry (PRISm) is unknown. OBJECTIVE: To determine the association between suspected bronchiectasis and mortality in adults with normal spirometry, PRISm, and obstructive spirometry. DESIGN: Prospective, observational cohort. SETTING: The COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) study. PARTICIPANTS: 7662 non-Hispanic Black or White adults, aged 45 to 80 years, with 10 or more pack-years of smoking history. Participants who were former and current smokers were stratified into normal spirometry (n = 3277), PRISm (n = 986), and obstructive spirometry (n = 3399). MEASUREMENTS: Bronchiectasis identified by CT was ascertained using artificial intelligence-based measurements of an airway-to-artery ratio (AAR) greater than 1 (AAR >1), a measure of bronchial dilatation. The primary outcome of "suspected bronchiectasis" was defined as an AAR >1 of greater than 1% plus 2 of the following: cough, phlegm, dyspnea, and history of 2 or more exacerbations. RESULTS: Among the 7662 participants (mean age, 60 years; 52% women), 1352 (17.6%) had suspected bronchiectasis. During a median follow-up of 11 years, 2095 (27.3%) died. Ten-year mortality risk was higher in participants with suspected bronchiectasis, compared with those without suspected bronchiectasis (normal spirometry: difference in mortality probability [Pr], 0.15 [95% CI, 0.09 to 0.21]; PRISm: Pr, 0.07 [CI, -0.003 to 0.15]; obstructive spirometry: Pr, 0.06 [CI, 0.03 to 0.09]). When only CT was used to identify bronchiectasis, the differences were attenuated in the normal spirometry (Pr, 0.04 [CI, -0.001 to 0.08]). LIMITATIONS: Only 2 racial groups were studied. Only 1 measurement was used to define bronchiectasis on CT. Symptoms of suspected bronchiectasis were nonspecific. CONCLUSION: Suspected bronchiectasis was associated with a heightened risk for mortality in adults with normal and obstructive spirometry. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute.

In COPD with type 2 inflammation despite inhaled triple therapy, dupilumab safely reduced exacerbations.

SOURCE CITATION: Bhatt SP, Rabe KF, Hanania NA, et al; BOREAS Investigators. Dupilumab for COPD with type 2 inflammation indicated by eosinophil counts. N Engl J Med. 2023;389;205-214.37272521.

Impact of benralizumab on asthma exacerbation-related medical healthcare resource utilization and medical costs: results from the ZEPHYR 2 study.

BACKGROUND AND AIM: Benralizumab is a biologic add-on treatment for severe eosinophilic asthma that can reduce the rate of asthma exacerbations, but data on the associated medical utilization are scarce. This retrospective study evaluated the economic value of benralizumab by analyzing healthcare resource utilization (HRU) and medical costs in a large patient population in the US. METHODS: Insurance claims data (11/2016-6/2020) were analyzed. A pre-post design was used to compare asthma exacerbation rates, medical HRU and medical costs in the 12 months pre vs. post index (day after benralizumab initiation). Patients were aged ≥12 years, with ≥2 records of benralizumab and ≥2 asthma exacerbations pre index, and constituted non-mutually exclusive cohorts: biologic-naïve, biologic-experienced (switched from omalizumab or mepolizumab to benralizumab), or with extended follow-up (18 or 24 months). RESULTS: In all cohorts (mean age 51-53 years; 67-70% female; biologic-naïve, N = 1,292; biologic-experienced, N = 349; 18-month follow-up, N = 419; 24-month follow-up, N = 156), benralizumab treatment reduced the rate of asthma exacerbation by 53-68% (p < .001). In the biologic-naïve cohort, inpatient admissions decreased by 58%, emergency department visits by 54%, and outpatient visits by 58% post index (all p < .001), with similar reductions in exacerbation-related medical HRU in other cohorts. Exacerbation-related mean total medical costs decreased by 51% in the biologic-naïve cohort ($4691 pre-index, $2289 post-index), with cost differences ranging from 16% to 64% across other cohorts (prior omalizumab: $2686 to $1600; prior mepolizumab: $5990 to $5008; 18-month: $3636 to $1667; 24-month: $4014 to $1449; all p < .001). Medical HRU and cost reductions were durable, decreasing by 64% in year 1 and 66% in year 2 in the 24 month follow-up cohort. CONCLUSION: Patients treated with benralizumab with prior exacerbations experienced reductions in asthma exacerbations and exacerbation-related medical HRU and medical costs regardless of prior biologic use, with the benefits observed for up to 24 months after treatment initiation.

Benralizumab is a biologic approved as an add-on treatment for severe eosinophilic asthma. Previous real-world studies and clinical trials have shown that benralizumab can reduce the rate of asthma exacerbations and systemic corticosteroid use. However, there is little information on the economic value of benralizumab in real-world patient populations. This study showed that patients with severe asthma in the United States had lower rates of asthma exacerbations after starting treatment with benralizumab. The patients also had fewer asthma exacerbation-related hospitalizations, emergency department visits, and outpatient visits as well as lower medical costs related to asthma exacerbations compared with before the treatment. These benefits were observed in patients who had never taken and those who had been previously treated with biologic therapies, and for up to 24 months after starting benralizumab treatment. These results show that the clinical value of benralizumab translates into reduced medical utilization for patients with severe asthma.

Real-World Effectiveness Study of Benralizumab for Severe Eosinophilic Asthma: ZEPHYR 2.

BACKGROUND: Benralizumab is an mAb therapy for severe eosinophilic asthma. Real-world data on its clinical impact in various patient populations such as patients with varying eosinophil levels, previous biologic use, and extended follow-up in the United States are limited. OBJECTIVE: To determine the effectiveness of benralizumab in different asthmatic patient cohorts and its long-term clinical impact. METHODS: Patients with asthma treated with benralizumab from November 2017 to June 2019 with 2 or more exacerbations in the 12 months before benralizumab initiation (index) were included in this pre-post cohort study that used medical, laboratory, and pharmacy US insurance claims. Asthma exacerbation rates in the 12 months pre and post index were compared. Nonmutually exclusive patient cohorts were defined by blood eosinophil counts (<150, ≥150, 150-<300, <300, and ≥300 cells/µL), a switch from another biologic, or follow-up for 18 or 24 months post index. RESULTS: There were 429 patients in the eosinophil cohort, 349 in the biologic-experienced cohort, and 419 in the extended follow-up cohort. In all eosinophil cohort subgroups, the asthma exacerbation rate decreased from 3.10-3.55 per patient-year (PPY) pre index to 1.11-1.72 PPY post index (52%-64% decrease; P < .001). Similar decreases were observed in patients switching from omalizumab (3.25 to 1.25 PPY [62%]) or mepolizumab (3.81 to 1.78 PPY [53%]) to benralizumab and those followed up for 18 months (3.38 to 1.18 PPY [65%]) or 24 months (3.38 to 1.08 PPY [68%]) (all P < .001). In the extended follow-up cohort, 39% and 49% had no exacerbations in the 0 to 12 months and the 12 to 24 months post index, respectively. CONCLUSIONS: Benralizumab achieved significantly improved asthma control in real-world patients with different blood eosinophil counts, including eosinophil counts ranging from less than 150 to greater than or equal to 300 cells/µL, switching from other biologics, or treated for up to 24 months.

Use of Remote Cardiorespiratory Monitoring is Associated with a Reduction in Hospitalizations for Subjects with COPD.

Background: Chronic obstructive pulmonary disease (COPD) is prevalent and results in high healthcare resource utilization. The largest impact on health status and proportion of healthcare costs in COPD are related to hospitalizations for acute exacerbations. Accordingly, the Centers for Medicare & Medicaid Services have advocated for remote patient monitoring (RPM) to aid in chronic disease management. However, there has been a lack of evidence for the effectiveness of RPM in reducing the need for unplanned hospitalizations for patients with COPD. Methods: This pre/post study was a retrospective analysis of unplanned hospitalizations in a cohort of COPD subjects started on RPM at a large, outpatient pulmonary practice. The study included all subjects with at least one unplanned, all-cause hospitalization or emergency room visit in the prior year, who had elected to enroll in an RPM service for assistance with clinical management. Additional inclusion criteria included being on RPM for at least 12 months and a patient of the practice for at least two years (12 months pre- and post-initiation of RPM). Results: The study included 126 subjects. RPM was associated with a significantly lower rate of unplanned hospitalizations per patient per year (1.09 ± 0.07 versus 0.38 ± 0.06, P<0.001). Conclusion: Unplanned, all-cause hospitalization rates were lower in subjects started on RPM for COPD when compared to their prior year. These results support the potential of RPM to improve the long-term management of COPD.

Risk of Coronavirus Disease 2019-Associated Pulmonary Aspergillosis Based on Corticosteroid Duration in Intensive Care Patients.

Background: Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) is a potential complication in critically ill COVID-19 patients. Corticosteroids are standard of care for hospitalized COVID-19 patients but carry an increased risk of secondary infections including CAPA. The objective of this study was to evaluate if duration of corticosteroid therapy ≤10 days versus >10 days affects the risk of developing CAPA. Methods: This was a retrospective cohort study of adult patients with severe COVID-19 pneumonia requiring mechanical ventilation who received at least 3 days of corticosteroid treatment. Incidence of CAPA and secondary outcomes were compared using appropriate bivariable analyses. Steroid duration was evaluated as an independent predictor in a logistic regression model. Results: A total of 278 patients were included (n = 169 for ≤10 days' steroid duration; n = 109 for >10 days). CAPA developed in 20 of 278 (7.2%) patients. Patients treated with >10 days of corticosteroid therapy had significantly higher incidence of CAPA (11.9% vs 4.1%; P = .0156), and steroid duration >10 days was independently associated with CAPA (odds ratio, 3.17 [95% confidence interval, 1.02-9.83]). Secondary outcomes including inpatient mortality (77.1% vs 43.2%; P < .0001), mechanical ventilation-free days at 28 days (0 vs 1.5; P < .0001), and secondary infections (44.9% vs 28.4% P = .0220) were worse in the >10 days cohort. Conclusions: Corticosteroid treatment >10 days in critically ill COVID-19 patients is associated with an increased risk of CAPA. Patients may require corticosteroids for reasons beyond COVID-19 and clinicians should be cognizant of risk of CAPA with prolonged courses.

Safety and efficacy of methylprednisolone versus dexamethasone in critically ill patients with COVID-19 acute respiratory distress syndrome: a retrospective study.

Background: Corticosteroids (CSs), specifically dexamethasone (DEX), are the treatment of choice for severe acute respiratory distress syndrome (ARDS) due to COVID-19 pneumonia (CARDS). However, data from both ARDS and relatively small CARDS clinical trials have suggested improved outcomes with methylprednisolone (MP) versus DEX. The objective of this retrospective cohort study was to compare the safety and effectiveness of MP and DEX in critically ill CARDS patients. Methods: The study cohort included CARDS patients admitted to a tertiary referral intensive care unit (ICU) between April and September 2020 who received at least 5 days of CSs for CARDS. Results: The cohort was notable for a high severity of illness (overall, 88.5% of patients required mechanical ventilation and 16% required vasopressors on admission). The DEX group (n = 62) was significantly older with a higher illness severity [Sequential Organ Failure Assessment (SOFA) 6 (4.75-8) versus 4.5 (3-7), p = 0.008], while the MP group (n = 51) received significantly more loading doses [19 (37.3%) versus 4 (6.5%), p < 0.0001]. MP was associated with a shorter time to intubation and more rapid progression to mortality [days to death: 18 (15-23) versus 27 (15-34), p = 0.026]. After correction for baseline imbalances in age and SOFA score, DEX was associated with improved mortality at 90 days compared with MP [hazard ratio (HR) = 0.43, 95% confidence interval (CI) = 0.23-0.80, p = 0.008]. However, there were no differences between rates of secondary infections during hospitalization or insulin requirements at 7 and 14 days. Conclusion: In this cohort of critically ill CARDS, choice of CS was associated with mortality but not adverse event profile, and thus warrants further investigation.

Artificial Intelligence-based CT Assessment of Bronchiectasis: The COPDGene Study.

Background CT is the standard method used to assess bronchiectasis. A higher airway-to-artery diameter ratio (AAR) is typically used to identify enlarged bronchi and bronchiectasis; however, current imaging methods are limited in assessing the extent of this metric in CT scans. Purpose To determine the extent of AARs using an artificial intelligence-based chest CT and assess the association of AARs with exacerbations over time. Materials and Methods In a secondary analysis of ever-smokers from the prospective, observational, multicenter COPDGene study, AARs were quantified using an artificial intelligence tool. The percentage of airways with AAR greater than 1 (a measure of airway dilatation) in each participant on chest CT scans was determined. Pulmonary exacerbations were prospectively determined through biannual follow-up (from July 2009 to September 2021). Multivariable zero-inflated regression models were used to assess the association between the percentage of airways with AAR greater than 1 and the total number of pulmonary exacerbations over follow-up. Covariates included demographics, lung function, and conventional CT parameters. Results Among 4192 participants (median age, 59 years; IQR, 52-67 years; 1878 men [45%]), 1834 had chronic obstructive pulmonary disease (COPD). During a 10-year follow-up and in adjusted models, the percentage of airways with AARs greater than 1 (quartile 4 vs 1) was associated with a higher total number of exacerbations (risk ratio [RR], 1.08; 95% CI: 1.02, 1.15; P = .01). In participants meeting clinical and imaging criteria of bronchiectasis (ie, clinical manifestations with ≥3% of AARs >1) versus those who did not, the RR was 1.37 (95% CI: 1.31, 1.43; P < .001). Among participants with COPD, the corresponding RRs were 1.10 (95% CI: 1.02, 1.18; P = .02) and 1.32 (95% CI: 1.26, 1.39; P < .001), respectively. Conclusion In ever-smokers with chronic obstructive pulmonary disease, artificial intelligence-based CT measures of bronchiectasis were associated with more exacerbations over time. Clinical trial registration no. NCT00608764 © RSNA, 2022 Supplemental material is available for this article. See also the editorial by Schiebler and Seo in this issue.

Pulmonary arterial pruning is associated with CT-derived bronchiectasis progression in smokers.

Loss of small pulmonary arteries measured as the ratio of blood vessel volume in arteries <5 mm2 in cross-section to total arterial blood vessel volume (BV5a/TBVa), with lower values indicating more pruning, was associated with 5-yr progressing CT-derived bronchiectasis in smokers (Odds Ratio (OR) [95% Confidence interval], 1.28 [1.07-1.53] per 5% lower BV5a/TBVa, P = 0.007). Corresponding results in smokers with COPD were: OR 1.45 [1.11-1.89] per 5% lower BV5a/TBVa, P = 0.007. The results support a vascular factor for structural progression of bronchiectasis.

The Aging Human Lung Mucosa: A Proteomics Study.

The older adult population, estimated to double by 2050, is at increased risk of respiratory infections and other pulmonary diseases. Biochemical changes in the lung alveolar lining fluid (ALF) and in alveolar compartment cells can alter local immune responses as we age, generating opportunities for invading pathogens to establish successful infections. Indeed, the lung alveolar space of older adults is a pro-inflammatory, pro-oxidative, dysregulated environment that remains understudied. We performed an exploratory, quantitative proteomic profiling of the soluble proteins present in ALF, developing insight into molecular fingerprints, pathways, and regulatory networks that characterize the alveolar space in old age, comparing it to that of younger individuals. We identified 457 proteins that were significantly differentially expressed in older adult ALF, including increased production of matrix metalloproteinases, markers of cellular senescence, antimicrobials, and proteins of neutrophilic granule origin, among others, suggesting that neutrophils in the lungs of older adults could be potential contributors to the dysregulated alveolar environment with increasing age. Finally, we describe a hypothetical regulatory network mediated by the serum response factor that could explain the neutrophilic profile observed in the older adult population.

Stenotrophomonas maltophilia in patients with bronchiectasis: An analysis of the US bronchiectasis and NTM Research Registry.

INTRODUCTION: Little information is available about Stenotrophomonas maltophilia in patients with bronchiectasis. We analyzed data from the US Bronchiectasis and NTM Research Registry to determine its prevalence and association with patient characteristics and severity of disease. METHODS: Baseline and follow-up data were entered into a central web-based database. Patients were grouped into four cohorts based on their baseline cultures: 1) S. maltophilia, no Pseudomonas aeruginsosa, 2) P. aeruginosa, no S. maltophilia, 3) No pathogens, 4) Pathogens other than P. aeruginosa and S. maltophilia. The association between S. maltophilia, demographic characteristics, pulmonary function, exacerbations and hospitalizations was assessed at baseline and one year follow-up. RESULTS: Among 2659 patients, 134 (5.0%) had grown S. maltophilia at baseline. The prior exacerbation rate at baseline was similar in patients with S. maltophilia and P. aeruginosa, but significantly higher than the other two groups. Hospitalizations were more frequent in patients with S. maltophilia or P. aeruginosa. Pre-bronchodilator FEV1 among S. maltophilia patients was between that of Pseudomonas patients and patients without either organism, but was not significantly different from any of the other groups. For all risk-adjusted one-year outcomes, patients with S. maltophilia had a non-significant trend towards worse outcomes compared to patients without P. aeruginosa, but were more similar to patients with P aeruginosa. DISCUSSION: Bronchiectasis patients with S. maltophilia may have worse outcomes than patients without this organism or without P. aeruginosa; further study is needed to determine if the non-significant trends we note are clinically significant.