Citations

Abstract Lung diseases, including lung cancer, are rising causes of global mortality. Despite novel imaging technologies and the development of biomarker assays, the detection of lung cancer remains a significant challenge. However, the lung communicates directly with the external environment and releases aerosolized droplets during normal tidal respiration, which can be collected, stored and analzsed as exhaled breath condensate (EBC). A few studies have suggested that EBC contains extracellular vesicles (EVs) whose microRNA (miRNA) cargos may be useful for evaluating different lung conditions, but the cellular origin of these EVs remains unknown. In this study, we used nanoparticle tracking, transmission electron microscopy, Western blot analyses and super resolution nanoimaging (ONi) to detect and validate the identity of exhaled EVs (exh‐EVs). Using our customizable antibody‐purification assay, EV‐CATCHER, we initially determined that exh‐EVs can be selectively enriched from EBC using antibodies against three tetraspanins (CD9, CD63 and CD81). Using ONi we also revealed that some exh‐EVs harbour lung‐specific proteins expressed in bronchiolar Clara cells (Clara Cell Secretory Protein [CCSP]) and Alveolar Type II cells (Surfactant protein C [SFTPC]). When conducting miRNA next generation sequencing (NGS) of airway samples collected at five different anatomic levels (i.e., mouth rinse, mouth wash, bronchial brush, bronchoalveolar lavage [BAL] and EBC) from 18 subjects, we determined that miRNA profiles of exh‐EVs clustered closely to those of BAL EVs but not to those of other airway samples. When comparing the miRNA profiles of EVs purified from matched BAL and EBC samples with our three tetraspanins EV‐CATCHER assay, we captured significant miRNA expression differences associated with smoking, asthma and lung tumor status of our subjects, which were also reproducibly detected in EVs selectively purified with our anti‐CCSP/SFTPC EV‐CATCHER assay from the same samples, but that confirmed their lung tissue origin. Our findings underscore that enriching exh‐EV subpopulations from EBC allows non‐invasive sampling of EVs produced by lung tissues.

Background: Left atrial (LA) size increases in atrial fibrillation (AF). How changes in mitral annulus and atrial volume over time relate to severity of mitral regurgitation (MR) is unknown. Methods: This cohort study included 160 patients with a history of permanent AF who had at least 2 transthoracic echocardiograms (TTE) performed between 2005 and 2010 at Vancouver General Hospital (British Columbia, Canada). Patients with structural mitral valve disease, congenital heart disease, more than mild-moderate mitral/tricuspid regurgitation on their first TTE were excluded from analyses. LA volume was determined using biplane area-length method, averaged over 3 cardiac cycles. The mitral annulus diameter (MAD), defined as the distance between the hinge points of the anterior and posterior mitral leaflets from the apical 4-chamber view, was measured during end-systole and end-diastole. Linear mixed effects modeling was used in analyzing the above measurements for change over time. Mitral regurgitation was classified into 3 grades (mild, moderate, or severe) using standard color Doppler and PISA easurements where available. Results: Of the 160 subjects included in this analysis, 100 were men (62.5%). The mean age at study entry was 74±10 years. The median number of TTE performed was 3 (range 2 - 6). All 160 patients showed a progressive increase in MAD over time. There was a significant increase in MAD at end-systole and end-diastole over a mean follow-up of 3.2 ± 2.8 years; the increases were 0.48 mm/year (95% CI 0.124 -0.75, P=0.0037) and 0.45 mm/year (95% CI 0.102-0.716, P=0.0029) respectively. LA volume increased from a mean of 43 mL/m2 to 75 mL/m2 for the cohort, or 10 mL/m2 per year. Adjusting for age, sex, and left ventricular ejection fraction, an increase in MR severity by at least 1 grade was strongly and independently associated with an increase in MAD. A 15% increment in MAD was associated with an increase in MR severity by 1 grade. Conclusion: Permanent AF was associated with significant increases in MAD and LA volume over time. Severity of MR also significantly increased over time, and was independently related to the change in MAD. Further investigations as to whether this represents a mechanism for left heart failure in patients with permanent AF are warranted.

Abstract Introduction Growing evidence suggests that there are sleep health disparities in the United States that disadvantage communities of color, and other socioeconomically marginalized groups in medical and mental health settings. Research in public policy indicates several points of intervention for increasing engagement with treatment services in communities of color at the primary care level, including individual beliefs about mental health/health issues, and perceptions of various points of treatment engagement, as well as community factors (e.g., neighbors and church; Davey & Watson, 2007). Accordingly, the current study implemented a community-level virtual intervention that targeted beliefs about sleep and perceptions of behavioral sleep treatment with the aim to increase willingness to engage with treatment at the primary care level. Methods We conducted 12 semi-structured qualitative focus groups with 35 individuals from communities of color about their awareness, perception of, and access to behavioral sleep treatment in healthcare settings. Transcripts were coded using the Rapid and Rigorous Qualitative Data Analysis method for themes relevant to the guiding question, 'What are people/persons of color experiences and perspectives of sleep, and specific areas of improvement to increase people/persons of color groups' utilization of behavioral sleep services?'. Results After a brief period of education (range = 15-20 minutes) about cognitive-behavioral therapy for insomnia (CBTi), participants perceived behavioral sleep treatment as a favorable option both over and in conjunction with pharmacological options. Medical mistrust was mentioned as the most significant barrier in each focus group, with participants highlighting that increased attention to collaborative care and comprehensive education about treatment options at the primary care level would be helpful for reducing mistrust. Pre- and post-group survey analysis indicated a significant increase in participants’ willingness to use primary care as an entry point to access/utilization of behavioral sleep treatment (pre-group willingness = 54.84%, post-group willingness = 91.42%, p<.001). Conclusion Findings suggest that intervention at the community level can be powerful for increasing the willingness of communities of color to engage in treatment at the primary care level. It is paramount that future research continues to examine ways to increase engagement with behavioral sleep treatment to help reduce sleep health disparities. Support (if any)

Evidence from medicine and other fields has shown that gender diversity results in better decision making and outcomes. The incoming workforce of congenital heart specialists (especially in pediatric cardiology) appears to be more gender balanced, but past studies have shown many inequities. Gender‐associated differences in leadership positions, opportunities presented for academic advancement, and recognition for academic contributions to the field persist. In addition, compensation packages remain disparate if evaluated based on gender with equivalent experience and expertise. This review explores these inequities and has suggested individual and institutional changes that could be made to recruit and retain women, monitor the climate of the institution, and identify and eliminate bias in areas like salary and promotions.

Abstract Background Customized and standard automated insulin delivery (AID) systems for use in pregnancies of women with preexisting type 1 diabetes (T1D) are being developed and tested to achieve pregnancy appropriate continuous glucose monitoring (CGM) targets. Guidance on the use of CGM for treatment decisions during pregnancy in the United States is limited. Methods Ten pregnant women with preexisting T1D participated in a trial evaluating at-home use of a pregnancy-specific AID system. Seven-point self-monitoring of blood glucose (SMBG) was compared to the closest sensor glucose (Dexcom G6 CGM) value biweekly to assess safety and reliability based on the 20%/20 mg/dL criteria. Results All participants completed the study with 7 participants satisfying the safety and reliability criteria with a mean absolute relative difference of 10.3%. Three participants did not fulfill the criteria, mainly because the frequency of SMBG did not meet the requirements. Conclusion Dexcom G6 CGM is safe and accurate in the real-world setting for use in pregnant women with preexisting T1D with reduced SMBG testing as part of a pregnancy-specific AID system.

Importance Factors associated with clinical heterogeneity in Alzheimer disease (AD) lay along a continuum hypothesized to associate with tangle distribution and are relevant for understanding glial activation considerations in therapeutic advancement. Objectives To examine clinicopathologic and neuroimaging characteristics of disease heterogeneity in AD along a quantitative continuum using the corticolimbic index (CLix) to account for individuality of spatially distributed tangles found at autopsy. Design, Setting, and Participants This cross-sectional study was a retrospective medical record review performed on the Florida Autopsied Multiethnic (FLAME) cohort accessioned from 1991 to 2020. Data were analyzed from December 2022 to December 2023. Structural magnetic resonance imaging (MRI) and tau positron emission tomography (PET) were evaluated in an independent neuroimaging group. The FLAME cohort includes 2809 autopsied individuals; included in this study were neuropathologically diagnosed AD cases (FLAME-AD). A digital pathology subgroup of FLAME-AD cases was derived for glial activation analyses. Main Outcomes and Measures Clinicopathologic factors of heterogeneity that inform patient history and neuropathologic evaluation of AD; CLix score (lower, relative cortical predominance/hippocampal sparing vs higher, relative cortical sparing/limbic predominant cases); neuroimaging measures (ie, structural MRI and tau-PET). Results Of the 2809 autopsied individuals in the FLAME cohort, 1361 neuropathologically diagnosed AD cases were evaluated. A digital pathology subgroup included 60 FLAME-AD cases. The independent neuroimaging group included 93 cases. Among the 1361 FLAME-AD cases, 633 were male (47%; median [range] age at death, 81 [54-96] years) and 728 were female (53%; median [range] age at death, 81 [53-102] years). A younger symptomatic onset (Spearman ρ = 0.39, P < .001) and faster decline on the Mini-Mental State Examination (Spearman ρ = 0.27; P < .001) correlated with a lower CLix score in FLAME-AD series. Cases with a nonamnestic syndrome had lower CLix scores (median [IQR], 13 [9-18]) vs not (median [IQR], 21 [15-27]; P < .001). Hippocampal MRI volume (Spearman ρ = −0.45; P < .001) and flortaucipir tau-PET uptake in posterior cingulate and precuneus cortex (Spearman ρ = −0.74; P < .001) inversely correlated with CLix score. Although AD cases with a CLix score less than 10 had higher cortical tangle count, we found lower percentage of CD68-activated microglia/macrophage burden (median [IQR], 0.46% [0.32%-0.75%]) compared with cases with a CLix score of 10 to 30 (median [IQR], 0.75% [0.51%-0.98%]) and on par with a CLix score of 30 or greater (median [IQR], 0.40% [0.32%-0.57%]; P = .02). Conclusions and Relevance Findings show that AD heterogeneity exists along a continuum of corticolimbic tangle distribution. Reduced CD68 burden may signify an underappreciated association between tau accumulation and microglia/macrophages activation that should be considered in personalized therapy for immune dysregulation.

Objectives Compare the risk of extended major adverse cardiovascular (CV) event (MACE) composite outcomes and component events in patients with rheumatoid arthritis (RA) treated with tofacitinib versus tumour necrosis factor inhibitors (TNFi) in Oral Rheumatoid Arthritis Trial (ORAL) Surveillance. Methods Patients with RA aged ≥50 years and with ≥1 additional CV risk factor received tofacitinib 5 mg or 10 mg two times per day or TNFi. MACE (non-fatal myocardial infarction (MI), non-fatal stroke or CV death (MACE-3)) was extended by sequential addition of CV events (hospitalisation for unstable angina (MACE-4), coronary revascularisation (MACE-5), transient ischaemic attack (MACE-6), peripheral vascular disease (MACE-7)), heart failure (HF) hospitalisation (MACE-8) and venous thromboembolism (VTE; (MACE-8 plus VTE)). HRs (tofacitinib vs TNFi) were evaluated for MACE and individual components. Results HRs for MACE-4 to MACE-8 with combined and individual tofacitinib doses versus TNFi were similar. Risk of MACE-8 plus VTE appeared similar with tofacitinib 5 mg two times per day versus TNFi (HR 1.12 (0.82 to 1.52)), but higher with tofacitinib 10 mg two times per day versus TNFi (HR 1.38 (1.02 to 1.85)). Risk of MI was higher with tofacitinib versus TNFi, but difference in risk of other individual CV events was not suggested. Across extended MACE definitions, risk appeared higher with tofacitinib versus TNFi in those with atherosclerotic CV disease or age ≥65 years. Conclusion In ORAL Surveillance, risk of composite CV endpoints combining all ischaemic CV events and HF did not appear different with tofacitinib versus TNFi. The totality of CV risk was higher with tofacitinib 10 mg two times per day versus TNFi, driven by an increase in VTE. Trial registration number NCT02092467.

ABSTRACT Although severe coronavirus disease 2019 (COVID-19) and hospitalization associated with COVID-19 are generally preventable among healthy vaccine recipients, patients with immunosuppression have poor immunogenic responses to COVID-19 vaccines and remain at high risk of infection with SARS-CoV-2 and hospitalization. In addition, monoclonal antibody therapy is limited by the emergence of novel SARS-CoV-2 variants that have serially escaped neutralization. In this context, there is interest in understanding the clinical benefit associated with COVID-19 convalescent plasma collected from persons who have been both naturally infected with SARS-CoV-2 and vaccinated against SARS-CoV-2 (“vax-plasma”). Thus, we report the clinical outcome of 386 immunocompromised outpatients who were diagnosed with COVID-19 and who received contemporary COVID-19-specific therapeutics (standard-of-care group) and a subgroup who also received concomitant treatment with very high titer COVID-19 convalescent plasma (vax-plasma group) with a specific focus on hospitalization rates. The overall hospitalization rate was 2.2% (5 of 225 patients) in the vax-plasma group and 6.2% (10 of 161 patients) in the standard-of-care group, which corresponded to a relative risk reduction of 65% ( P = 0.046). Evidence of efficacy in nonvaccinated patients cannot be inferred from these data because 94% (361 of 386 patients) of patients were vaccinated. In vaccinated patients with immunosuppression and COVID-19, the addition of vax-plasma or very high titer COVID-19 convalescent plasma to COVID-19-specific therapies reduced the risk of disease progression leading to hospitalization. IMPORTANCE As SARS-CoV-2 evolves, new variants of concern (VOCs) have emerged that evade available anti-spike monoclonal antibodies, particularly among immunosuppressed patients. However, high-titer COVID-19 convalescent plasma continues to be effective against VOCs because of its broad-spectrum immunomodulatory properties. Thus, we report clinical outcomes of 386 immunocompromised outpatients who were treated with COVID-19-specific therapeutics and a subgroup also treated with vaccine-boosted convalescent plasma. We found that the administration of vaccine-boosted convalescent plasma was associated with a significantly decreased incidence of hospitalization among immunocompromised COVID-19 outpatients. Our data add to the contemporary data providing evidence to support the clinical utility of high-titer convalescent plasma as antibody replacement therapy in immunocompromised patients.

Background: The implications of delaying surgical intervention for patients with adolescent idiopathic scoliosis (AIS) wishing to undergo vertebral body tethering (VBT) have not yet been explored. It is important to understand how these delays can impact surgical planning and patient outcomes. Methods: This was a retrospective review that analyzed all AIS patients treated between 2015 and 2021 at a single tertiary center. Time to surgery from initial surgical consultation and ultimate surgical plan were assessed. Patient characteristics, potential risk factors associated with increased curve progression, and reasons for delay were also analyzed. Results: 174 patients were evaluated and 95 were scheduled for VBT. Four patients later required a change to posterior spinal fusion (PSF) due to excessive curve progression. Patients requiring PSF were shown to have significantly longer delays than those who received VBT. Additionally, longer delays, younger age, greater curve progression, and lower skeletal maturity were correlated with significant curve progression (≥5 degrees). Conclusions: Surgical delays for AIS patients awaiting VBT may lead to significant curve progression and necessitate more invasive procedures. Patients with longer delays experienced an increased risk of needing PSF instead of VBT. Of those requiring PSF, the majority were due to insurance denials. Optimizing surgical timing and shared decision-making among patients, families, and healthcare providers are essential for achieving the best outcomes.