Citations

Abstract Rationale Obstructive sleep apnea (OSA) is a highly prevalent disorder characterized by recurrent upper airway collapse during sleep, leading to intermittent hypoxemia, sleep fragmentation, and substantial cardiovascular and neurocognitive morbidity. Continuous positive airway pressure (CPAP) therapy remains the gold standard for management, yet adherence is suboptimal due to discomfort, noise, and device intolerance. This has generated growing interest in pharmacologic alternatives that target upper airway physiology. The combination of atomoxetine, a selective norepinephrine reuptake inhibitor, and oxybutynin, an antimuscarinic agent, has emerged as a promising non-device therapeutic option by enhancing pharyngeal muscle tone and stabilizing ventilatory control. This meta-analysis systematically evaluates the efficacy and safety of atomoxetine plus oxybutynin in adults with OSA who are intolerant to CPAP. Methods A comprehensive search was conducted across PubMed, Embase, Scopus, Web of Science, and Cochrane Central from inception through June 2025. Eligible studies were randomized controlled trials (RCTs) comparing atomoxetine plus oxybutynin with placebo or control therapy in adults diagnosed with OSA. Data were extracted and pooled using Stata version 18.0. Mean differences and relative risks (RR) were calculated for continuous and dichotomous outcomes, respectively. Methodologic quality and risk of bias were assessed using the Cochrane Risk of Bias 2.0 tool. Results Eleven RCTs encompassing 196 adults (141 males, 55 females) were included, with a mean treatment duration of 1.38 days. Compared with control, atomoxetine plus oxybutynin significantly reduced the apnea-hypopnea index (AHI) (mean difference −10.16 events/hour; 95% CI − 20.32 to − 0.01; p = 0.05). Improvements were also observed in oxygen desaturation index (ODI), arousal index, and loop gain, though these did not achieve statistical significance. The treatment group experienced fewer adverse events (RR = 0.66; 95% CI 0.37-0.90; p = 0.01) and no increase in sleep disturbances (RR = 0.87; 95% CI 0.83-1.31). Conclusions Combination therapy with atomoxetine and oxybutynin significantly improves AHI and demonstrates a favorable safety and tolerability profile in adults with OSA who are unable to tolerate CPAP. These findings highlight the therapeutic potential of targeting upper airway muscle tone pharmacologically. Larger, long-term RCTs are warranted to confirm sustained efficacy, determine optimal dosing strategies, and clarify the role of this regimen within the evolving landscape of OSA management. This abstract is funded by: None

Abstract Rationale The United States has the highest per capita incarceration rate of any developed democracy. As the incarcerated population ages, medically complex and frail patients are increasingly hospitalized in the community, often arriving without decisional capacity and with limited family involvement. This is the first analysis of state laws and policies governing decision-making for incapacitated incarcerated patients. Methods Two team members independently conducted Westlaw and Internet searches for statutes, regulations and department of corrections (DOC) policies from 50 states and the District of Columbia, identifying language about medical decision-making for incapacitated incarcerated patients. These parallel searches were merged into a single database and reviewed by the analytic team, who created a codebook of inductively and deductively derived themes, guided by principles of grounded theory. The codebook was then systematically applied to the database by 2 independent coders; all data were double-coded. Disputes were resolved by consensus with the entire analytic team, in consultation with a legal scholar. Results Thirty-four of 51 jurisdictions have language addressing decision-making for incapacitated incarcerated patients. Data collected include the definition and determination of incapacity, language affirming incarcerated persons’ right to autonomy in medical decision-making, approaches to decision-making for patients with and without surrogate decision-makers, and whether treatment over patient/surrogate objection is authorized. Assertions about the importance of advance care planning (n = 25) are often undercut by procedural hurdles (n = 20), such as complex witnessing requirements for advance directive completion. Many jurisdictions (n = 26) allow family or friends to serve as legally recognized decision-makers. Thirteen jurisdictions exclude an incarcerated person from serving as decision-maker for another incarcerated person. Fourteen jurisdictions have provisions allowing for treatment over the objection of a patient or their surrogate. While approaches to unrepresented patients differ widely (Figure), 5 jurisdictions grant narrow decisional authority to treating physicians and 4 jurisdictions authorize correctional employees to make medical decisions. Conclusion A heterogeneous assortment of laws, policies and regulations govern the care of incapacitated incarcerated patients, with wide variation observed from jurisdiction to jurisdiction. One-third of jurisdictions lack policies or language regarding decision-making processes for incapacitated incarcerated patients. Even more troubling, 14 jurisdictions allow treatment over a patient or surrogate’s objection and 4 jurisdictions delegate authority over decisions for unrepresented patients to correctional employees, such as the prison medical director or the warden. These findings raise serious concerns about autonomy, beneficence and justice. National reform is needed to align correctional policies with established ethical standards for surrogate decision-making. This abstract is funded by: National Institute on Aging

Abstract Introduction The COVID-19 pandemic exposed underrecognized structural deficiencies in pandemic preparedness across the US, particularly impacting marginalized and medically vulnerable populations. State leaders who were developing policies to allocate critical care resources, often called crisis standards of care (CSC), confronted challenges such as whether and how to incorporate age and chronic conditions into triage protocols, how to contend with imperfect illness acuity scores such as the sequential organ failure assessment (SOFA), and whether essential worker status or area deprivation index (ADI) ought to confer an advantage during triage. To our knowledge, this is the first analysis to highlight CSC writers’ approach to ethical challenges, including from states whose policies provoked corrective action from the Office of Civil Rights (OCR). This study explores how state leaders navigated ethical controversies underlying states’ CSC policies, including whether those controversies were satisfactorily resolved. Methods Between February-September 2022 we conducted semi-structured interviews of public health leaders tasked with developing their states’ (CSC) policies. Interviews were transcribed verbatim and a codebook was developed iteratively, using inductively and deductively derived themes based on principles of grounded theory. The codebook was systematically applied to transcripts; disputes were resolved by consensus discussion among analytic team members. Results Leaders from 34 states were interviewed. Participants described how their states’ CSC policy writing committees considered the role of age in triage, some proposing age as a tiebreaker, or considering age only if coupled with measures of frailty or chronic illness, with others proposing age as an “exclusion criterion.” Many leaders acknowledged a controversial approach to disability in early versions of their policies, some describing how they responded to civil rights complaints. Participants described debates over whether pandemic triage decisions should advantage patients from underserved populations or affirmatively consider essential worker status or pregnancy. While most leaders regretted that early iterations of their policies stood to exacerbate health disparities, others described a less conciliatory response to civil rights complaints. In particular, triage exclusion criteria, whereby certain patients would be excluded outright from certain resources, provoked intense debate. Conclusion We describe ethical controversies that stymied CSC policy writing committees during the COVID-19 pandemic. Leaders described spirited debate around how age, disability, and justice ought to factor into triage; few described satisfactory resolution to those debates. Improved community engagement and adherence to civil rights protections in CSC are imperative to protect marginalized populations as we prepare for future calamites, whether global or local. This abstract is funded by: R03 AG73987; K76 AG88403

Abstract Purpose This study aimed to analyze mortality trends among patients with pneumonia and chronic kidney disease in the United States from 1999 to 2020. By examining patterns across urbanization levels, racial and ethnic groups, geographic regions, and sex, the study sought to identify significant changes over time and potential disparities in mortality outcomes. Methods Mortality data were extracted from the CDC WONDER database for patients diagnosed with pneumonia (ICD-10: J09-J18) and chronic kidney disease (ICD-10: N18). Trends were analyzed using Annual Percent Change (APC) with 95% confidence intervals (CI). Joinpoint regression was utilized to identify significant shifts in mortality trends over time. The analysis was stratified by urbanization level (Large Central Metro, Large Fringe Metro, Medium Metro, Small Metro, Micropolitan), ethnicity (American Indian or Alaska Native, Asian or Pacific Islander, Black or African American, White), census region (Northeast, Midwest, South, West), Hispanic origin (Hispanic or Latino, Not Hispanic or Latino), and sex (Female, Male). Results From 2018 to 2020, significant increases in mortality were observed across all demographic and geographic categories. Urban areas, particularly Large Central Metro (APC = 39.4026%, p = 0.0008) and Small Metro (APC = 37.0284%, p = 0.0004), experienced the most pronounced rises. Ethnic disparities were evident, with Black or African American (APC = 49.9199%, p < 0.000001) and Hispanic or Latino (APC = 61.5742%, p < 0.000001) populations showing the highest mortality increases. By census region, the Midwest (APC = 35.7843%, p = 0.0004) and South (APC = 34.7972%, p = 0.0016) had the most significant spikes. Both females (APC = 36.0664%, p = 0.0004) and males (APC = 35.1504%, p < 0.000001) experienced substantial mortality increases, with females showing slightly higher rates. Conclusion The findings reveal significant increases in mortality from 2018 to 2020 across all analyzed categories, with notable disparities among racial, ethnic, and geographic groups. These trends highlight the need for further investigation into underlying causes and targeted interventions to address inequities. Clinical implications The results underscore the importance of addressing disparities in healthcare access and outcomes, particularly for Black or African American and Hispanic or Latino populations. Clinicians should focus on early diagnosis, effective management of comorbidities, and equitable resource distribution to mitigate mortality risks in high-risk groups. This abstract is funded by: None

Abstract Introduction Hydralazine is a common arterial vasodilator used in the treatment of hypertension and heart failure. Rarely, hydralazine can cause an overlapping syndrome of drug-induced lupus and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The clinical spectrum of this disease process includes features of systemic lupus erythematous and AAV Case Presentation A 62-year-old male previous smoker with 50 pack-year history and hypertension presented with an eight-month history of exertional dyspnea and pleuritic chest pain. Prior to his presentation, he was treated for pneumonia with antibiotics without improvement. His subsequent chest imaging showed a right sided pleural effusion, evaluated by thoracentesis which was exudative and lymphocytic with negative cultures. He then developed progressive ground glass opacities, anemia, lymphopenia, splenomegaly, and acute kidney injury. With concern for underlying malignancy, he underwent a PET/CT and bone marrow biopsy which were not suggestive of malignancy. Serology revealed strongly a myeloperoxidase (MP) antibody (>8 U) with low titer proteinase-3 (PR3) antibody (1.2 U) and p-ANCA by immunofluorescence. Additional serology were notable for positive anti-double stranded DNA (dsDNA), positive ANA by hep2A, normal C3/C4, and creatinine peaking at 1.78 mg/dL, subnephrotic range proteinuria, and hematuria without RBC casts. Bronchoscopy noted progressively bloody return and 99% hemosiderin laden macrophages consistent with diffuse alveolar hemorrhage. Hydralazine was promptly discontinued with a clinical presentation consistent hydralazine-associated AAV and overlapping drug-induced lupus. They received remission induction therapy with IV methylprednisolone followed by tapering course of prednisone, rituximab, and avacopan. He was managed and monitored closely in the outpatient setting. With gradually improvement in renal function, a renal biopsy was deferred. Discussion Drug-induced lupus and drug-associated AAV can overlap in patients exposed to hydralazine, which can present up to several years after drug initiation. Renal and pulmonary involvement in hydralazine-induced lupus is uncommon and should prompt concern for drug-associated AAV. Compared with primary AAV, features suggestive of hydralazine-associated AAV include an adequate history of drug exposure and frequently a unique ANCA profile, hypocomplementemia, cytopenias, and additional seropositivity-including anti-histone and anti-dsDNA antibodies. Conclusion The cornerstone of management in hydralazine-induced lupus and hydralazine-associated AAV is early recognition and discontinuation of the offending medication. Induction of remission with standard immunosuppression is generally warranted, with specific therapies dictated by organ manifestations at diagnosis, similar to patients with primary AAV. Long-term outcomes in hydralazine-associated AAV appear comparable to those in primary AAV. The need for and duration of maintenance immunosuppression should be individualized based on patient presentation. This abstract is funded by: None

Abstract Background Spinal cord ischemia (SCI) is an uncommon but devastating complication of Veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Peripheral femoral cannulation, while rapidly deployable, may compromise spinal cord perfusion. We report a case of thoracolumbar spinal cord ischemia presenting as paraplegia with cauda equina enhancement in a patient on femoral VA-ECMO. Case Presentation A 57-year-old man with nonischemic cardiomyopathy (EF 30%), atrial fibrillation on apixaban, and ICD (2023) suffered a witnessed out-of-hospital cardiac arrest requiring 45 minutes of CPR before return of spontaneous circulation. Peripheral femoral-femoral VA-ECMO was initiated, complicated by left femoral artery injury requiring repair. He was supported with the right axillary Impella 5.5 and listed UNOS Status 1 for heart transplantation. On ECMO day 5, the patient developed acute bilateral lower extremity weakness with preserved sensation and allodynia of the soles. Neurologic exam demonstrated flaccid paralysis below the quadriceps, consistent with a T12 motor level (ASIA C). Given his prolonged low-flow state and ECMO configuration, spinal cord ischemia was suspected. Hemodynamic augmentation and conversion of ECMO drainage from femoral to left subclavian were performed, along with corticosteroids. Following orthotopic heart transplantation on 8/8/2025, MRI of the thoracic and lumbar spine showed thickening, clumping, and enhancement of the cauda equina nerve roots without cord infarction. CSF analysis was negative for infection or inflammation, supporting an ischemic etiology. Despite rehabilitation and neuropathic pain management with pregabalin, lower extremity weakness persisted. He was discharged to inpatient rehabilitation with residual paraplegia. Discussion SCI is a rare neurological complication of femoral VA-ECMO, likely resulting from compromised spinal perfusion due to retrograde aortic flow, vascular injury, or systemic hypoperfusion during cardiac arrest. Post-ischemic cauda equina enhancement may reflect reperfusion-related breakdown of the blood-nerve barrier. Conclusion This case underscores the need for early recognition of spinal cord ischemia in ECMO-supported patients with new-onset paraplegia. Maintaining adequate mean arterial pressure, minimizing femoral arterial compromise, and early reevaluation of cannulation strategy may mitigate irreversible neurologic injury. This abstract is funded by: None

Abstract Introduction Critical aortic stenosis causing cardiogenic shock has very high mortality, particularly in patients with end-stage renal disease (ESRD) and multivalvular involvement. options for surgical aortic valve replacement (SAVR) are often limited by prohibitive perioperative risk. Transcatheter aortic valve replacement (TAVR) has emerged as a lifesaving alternative in select high-risk populations. We describe a patient with ESRD who presented in cardiogenic shock due to critical aortic stenosis (AS) and experienced dramatic reversal of left ventricular (LV) dysfunction following TAVR. Case A 62-year-old male with ESRD on peritoneal dialysis and hypertension presented with acute chest pain and dyspnea. Laboratory findings revealed elevated Troponin T (353ng/L) and Pro-BNP (70,000 pg/mL). He was admitted for non-ST elevation myocardial infarction; however, coronary angiography demonstrated no coronary artery disease. Transthoracic echocardiogram (TTE) revealed a left ventricular ejection fraction (LVEF) of 15-20%, sever global akinesis, eccentric left ventricular hypertrophy, and severe aortic stenosis (mean gradient 34 mmHg, valve area 0.53 cm²). Additional findings included severe aortic regurgitation and severe mitral regurgitation. Overnight, he developed altered mentation, cold extremities and lactic acidosis (14.5 mmol/L), Pulmonary artery catheter readings were consistent with cardiogenic shock. Repeat TTE redemonstrated critical aortic stenosis (peak velocity 5.3 m/s, mean gradient 71 mmHg, valve area 0.73 cm²). An urgent TAVR was performed with deployment of a 26 mm Edwards Sapien 3 pericardial prosthesis. A post-procedure TTE demonstrated LVEF improvement to 50-55%, with only mild residual LV hypokinesis. The patient showed rapid clinical recovery and was weaned off inotropes. Discussion Severe aortic stenosis imposes a fixed obstruction to left ventricular outflow, leading to excessive afterload and secondary systolic dysfunction. The rapid improvement in ejection fraction following TAVR supports the concept of afterload-induced myocardial stunning rather than irreversible cardiomyopathy. Although TAVR was traditionally avoided in unstable or shock patients, particularly those with ESRD, growing evidence supports its use as a rescue therapy in carefully selected cases. By reducing afterload, TAVR restores forward cardiac output, enhances coronary perfusion, and can reverse shock. Emerging registry data demonstrates that patients with severe AS and cardiogenic shock can achieve meaningful recovery following TAVR when performed expeditiously. This case underscores the expanding role of TAVR in managing cardiogenic shock due to severe valvular disease. The magnitude of left ventricular recovery in this case underscores the reversibility of left ventricular dysfunction once the mechanical obstruction is relieved, it highlights the importance of early recognition and intervention before irreversible myocardial remodeling occurs. This abstract is funded by: NA

Abstract Introduction Burkholderia, Achromobacter, and Stenotrophomonas species are associated with worse clinical outcomes in cystic fibrosis (CF),1 though little is known about their prevalence or pathogenicity in non-CF bronchiectasis (pwBE). Herein we describe the prevalence and clinical characteristics of pwBE who isolated each of these three organisms. Methods We conducted a retrospective cross-sectional analysis of baseline data from the US Bronchiectasis and Nontuberculous Mycobacteria (NTM) Research Registry (BRR). Adult bronchiectasis patients with known Achromobacter, Burkholderia cepacia complex (BCC), or Stenotrphomonas maltophilia culture results were included. Patients were stratified according to the presence of at least one positive culture among the gram-negative species. Demographics, clinical characteristics, and first annual follow-up culture results were summarized descriptively for the overall study population and between groups. No inferential analyses or hypothesis testing was performed. Results 5003 pwBE met the inclusion criteria, of which 39 (0.78%) isolated Achromobacter species, 11 isolated Burkholderia (0.22%), and 288 isolated Stenotrophomonas maltophilia (5.8%). Patients with Achromobacter were older, with a median age (interquartile range) of 76 (73.0-79.0) years, compared to the overall bronchiectasis cohort (69.0 years). Those with Burkholderia or Stenotrophomonas were younger, at 69.0 (53.0-75.0) and 71.0 (63.0-77.0) years, respectively. A high proportion of those with Achromobacter were male (31%) versus those with Burkholderia (9%) and Stenotrophomonas (24%), were current or former smokers (46%), were more likely to have had one or more exacerbations in the 2 years prior to enrollment (87%) than the overall BE cohort (57%), and were more likely to have had pulmonary-related hospitalization than those with either Burkholderia or Stenotrophomonas (46% vs. 27% and 19%, respectively). PwBE who isolated Burkholderia were less likely to have co-colonization with Pseudomonas aeruginosa or NTM species (9% each). At first annual follow-up, no patients with baseline Burkholderia isolated them at follow-up, and only 31% with baseline Stenotrophomonas isolated it at follow-up. Conclusion Overall prevalence of Achromobacter, Burkholderia, and Stenotrophomonas species in the BE cohort was low. Patients who isolated Achromobacter species were older, more likely to be current or former smokers, and more likely to experience pulmonary exacerbation and hospitalization. 15 patients who had not previously isolated Achromobacter, and 3 patients who had not previously isolated Burkholderia did so at annual follow-up. Interestingly, no patients with baseline Burkholderia isolates went on to isolate it at annual follow-up, which contradicts earlier studies in pwCF.2 The number of patients isolating Burkholderia in the U.S. BRR is very low, thereby limiting interpretation. This abstract is funded by: None

Abstract Introduction Aminoglycoside antibiotics are well known to cause cochlear and vestibular toxicity when used systemically. Inhaled tobramycin was developed to reduce systemic exposure and is considered safer with only rare reports of ototoxicity have been reported in patients with renal dysfunction. We describe a case of bilateral sensorineural hearing loss (SNHL) and tinnitus associated with inhaled tobramycin in a patient without renal impairment, emphasizing that even inhaled formulations can induce significant auditory toxicity in susceptible individuals. Case A 85 year old woman with Sjogren’s related interstitial lung disease and bronchiectasis who was chronically colonized by Pseudomonas aeruginosa was treated with inhaled tobramycin for recurrent infections. She had normal renal function and no prior aminoglycoside exposure. After approximately three months of inhaled therapy, she noted progressive bilateral hearing decline and high pitched tinnitus without vertigo or otalgia. Physical examination revealed clear ear canals and intact tympanic membranes. Baseline audiometry one year ago had demonstrated mild to moderately-severe bilateral SNHL. Repeat testing after tobramycin exposure showed worsening thresholds and reduced word recognition bilaterally. MRI of the brain and internal auditory canals was unremarkable. Serum creatinine remained normal throughout treatment. Inhaled tobramycin was discontinued, after which hearing loss stabilized. No further progression was observed on follow-up audiometry. Discussion Although systemic absorption from inhaled tobramycin is typically low, elderly and low-body-weight patients may accumulate sufficient serum levels to cause cochlear injury. Mechanisms include reactive oxygen species mediated hair cell toxicity and possible genetic susceptibility involving the mitochondrial 12S rRNA mutation. Prior reports of vestibulotoxicity and cochleotoxicity from inhaled tobramycin primarily involved patients with renal dysfunction, however, this case report demonstrates that toxicity can occur despite preserved renal function. Clinicians should maintain vigilance for otologic symptoms in patients receiving inhaled aminoglycosides. Baseline and periodic audiometric monitoring should be incorporated into chronic treatment protocols. This abstract is funded by: None

Abstract Primary Ciliary Dyskinesia (PCD) is a rare, genetically heterogenous disorder of motile cilia, leading to impaired mucociliary clearance and chronic respiratory disease. Its clinical presentation often overlaps with common conditions, including obstructive pulmonary diseases, contributing to diagnostic delays. Mutations in the DNAH11 gene are associated with PCD, but patients frequently lack the classic ultrastructural ciliary defects. We present a case which highlights the importance of considering rare ciliopathies in patients with refractory respiratory symptoms and the evolving role of genetic testing in diagnosis. A 44-year-old woman with early onset asthma was referred for evaluation of recurrent pneumonias, occurring biannually in recent years. She had been affected by respiratory disease since childhood. Despite aggressive asthma management, including long-term mepolizumab, she reported frequent pneumonias and persistent respiratory symptoms. Pulmonary function tests demonstrated obstructive physiology with bronchodilator responsiveness. Chest CT revealed diffuse cylindrical bronchiectasis, small airway disease, and a tree-in-bud pattern. Initial genetic testing identified heterozygous variants in DNAH11 and AP3D1. Whole genome sequencing later revealed a maternally inherited, likely pathogenic, DNAH11 variant and a paternally inherited variant of uncertain significance (VUS), suggesting a compound heterozygous state. Although not definitively diagnostic, this genetic profile, combined with lifelong respiratory symptoms, and imaging findings, raised strong clinical suspicion for PCD. She was treated targeting both asthma and PCD. Her regimen included a combination inhaler of fluticasone, umeclidinium, and vilanterol, as-needed albuterol, mepolizumab, and the addition of airway clearance focused techniques, including nebulized hypertonic saline, flutter valves, and chest physiotherapy. She demonstrated significant symptomatic improvement and a dramatic reduction in pneumonias or exacerbations. This case underscores the diagnostic complexity of chronic respiratory disease in young adults. PCD should be considered in patients with early-onset, persistent respiratory symptoms and recurrent infections, particularly when standard asthma therapies fail. DNAH11 mutations are known to cause PCD, often without detectable ciliary ultrastructural abnormalities, making diagnosis reliant on clinical features, nasal nitric oxide levels, high-speed video microscopy, and genetic testing. Compound heterozygosity involving a pathogenic variant and a VUS, as seen in this case, is not definitively diagnostic per current ATS/ERS guidelines, but may support a clinical diagnosis when aligned with phenotype and imaging findings. This case illustrates the importance of a multidisciplinary approach, including pulmonology, allergy, genetics, and immunology, in evaluating complex respiratory presentations. Early recognition and tailored therapy, including airway clearance and infection prevention, are critical to improving patient outcomes and quality of life in patients with suspected PCD. This abstract is funded by: None