Targeting axonal guidance dependencies in glioblastoma with ROBO1 CAR T cells.

Resistance to genotoxic therapies and tumor recurrence are hallmarks of glioblastoma (GBM), an aggressive brain tumor. In this study, we investigated functional drivers of post-treatment recurrent GBM through integrative genomic analyses, genome-wide genetic perturbation screens in patient-derived GBM models and independent lines of validation. Specific genetic dependencies were found consistent across recurrent tumor models, accompanied by increased mutational burden and differential transcript and protein expression compared to its primary GBM predecessor. Our observations suggest a multi-layered genetic response to drive tumor recurrence and implicate PTP4A2 (protein tyrosine phosphatase 4A2) as a modulator of self-renewal, proliferation and tumorigenicity in recurrent GBM. Genetic perturbation or small-molecule inhibition of PTP4A2 acts through a dephosphorylation axis with roundabout guidance receptor 1 (ROBO1) and its downstream molecular players, exploiting a functional dependency on ROBO signaling. Because a pan-PTP4A inhibitor was limited by poor penetrance across the blood-brain barrier in vivo, we engineered a second-generation chimeric antigen receptor (CAR) T cell therapy against ROBO1, a cell surface receptor enriched across recurrent GBM specimens. A single dose of ROBO1-targeted CAR T cells doubled median survival in cell-line-derived xenograft (CDX) models of recurrent GBM. Moreover, in CDX models of adult lung-to-brain metastases and pediatric relapsed medulloblastoma, ROBO1 CAR T cells eradicated tumors in 50-100% of mice. Our study identifies a promising multi-targetable PTP4A-ROBO1 signaling axis that drives tumorigenicity in recurrent GBM, with potential in other malignant brain tumors.

Shared and unique 3D genomic features of substance use disorders across multiple cell types.

Recent genome-wide association studies (GWAS) have revealed shared genetic components among alcohol, opioid, tobacco and cannabis use disorders. However, the extent of the underlying shared causal variants and effector genes, along with their cellular context, remain unclear. We leveraged our existing 3D genomic datasets comprising high-resolution promoter-focused Capture-C/Hi-C, ATAC-seq and RNA-seq across >50 diverse human cell types to focus on genomic regions that coincide with GWAS loci. Using stratified LD regression, we determined the proportion of genomewide SNP heritability attributable to the features assayed across our cell types by integrating recent GWAS summary statistics for the relevant traits: alcohol use disorder (AUD), tobacco use disorder (TUD), opioid use disorder (OUD) and cannabis use disorder (CanUD). Statistically significant enrichments (P<0.05) were observed in 14 specific cell types, with heritability reaching 9.2-fold for iPSC-derived cortical neurons and neural progenitors, confirming that they are crucial cell types for further functional exploration. Additionally, several pancreatic cell types, notably pancreatic beta cells, showed enrichment for TUD, with heritability enrichments up to 4.8-fold, suggesting genomic overlap with metabolic processes. Further investigation revealed significant positive genetic correlations between T2D with both TUD and CanUD (FDR<0.05) and a significant negative genetic correlation with AUD. Interestingly, after partitioning the heritability for each cell type's cis-regulatory elements, the correlation between T2D and TUD for pancreatic beta cells was greater (r=0.2) than the global genetic correlation value. Our study provides new genomic insights into substance use disorders and implicates cell types where functional follow-up studies could reveal causal variant-gene mechanisms underpinning these disorders.

Epidemiology and clinical relevance of persistent bacteraemia in patients with Gram-negative bloodstream infection: a retrospective cohort study.

OBJECTIVES: The risk factors and outcomes associated with persistent bacteraemia in Gram-negative bloodstream infection (GN-BSI) are not well described. We conducted a follow-on analysis of a retrospective population-wide cohort to characterize persistent bacteraemia in patients with GN-BSI. METHODS: We included all hospitalized patients >18 years old with GN-BSI between April 2017 and December 2021 in Ontario who received follow-up blood culture (FUBC) 2-5 days after the index positive blood culture. Persistent bacteraemia was defined as having a positive FUBC with the same Gram-negative organism as the index blood culture. We identified variables independently associated with persistent bacteraemia in a multivariable logistic regression model. We evaluated whether persistent bacteraemia was associated with increased odds of 30- and 90-day all-cause mortality using multivariable logistic regression models adjusted for potential confounders. RESULTS: In this study, 8807 patients were included; 600 (6.8%) had persistent bacteraemia. Having a permanent catheter, antimicrobial resistance, nosocomial infection, ICU admission, respiratory or skin and soft tissue source of infection, and infection by a non-fermenter or non-Enterobacterales/anaerobic organism were associated with increased odds of having persistent bacteraemia. The 30-day mortality was 17.2% versus 9.6% in those with and without persistent bacteraemia (aOR 1.65, 95% CI 1.29-2.11), while 90-day mortality was 25.5% versus 16.9%, respectively (aOR 1.53, 95% CI 1.24-1.89). Prevalence and odds of developing persistent bacteraemia varied widely depending on causative organism. CONCLUSIONS: Persistent bacteraemia is uncommon in GN-BSI but is associated with poorer outcomes. A validated risk stratification tool may be useful to identify patients with persistent bacteraemia.

The TSC22D, WNK, and NRBP gene families exhibit functional buffering and evolved with Metazoa for cell volume regulation.

The ability to sense and respond to osmotic fluctuations is critical for the maintenance of cellular integrity. We used gene co-essentiality analysis to identify an unappreciated relationship between TSC22D2, WNK1, and NRBP1 in regulating cell volume homeostasis. All of these genes have paralogs and are functionally buffered for osmo-sensing and cell volume control. Within seconds of hyperosmotic stress, TSC22D, WNK, and NRBP family members physically associate into biomolecular condensates, a process that is dependent on intrinsically disordered regions (IDRs). A close examination of these protein families across metazoans revealed that TSC22D genes evolved alongside a domain in NRBPs that specifically binds to TSC22D proteins, which we have termed NbrT (NRBP binding region with TSC22D), and this co-evolution is accompanied by rapid IDR length expansion in WNK-family kinases. Our study reveals that TSC22D, WNK, and NRBP genes evolved in metazoans to co-regulate rapid cell volume changes in response to osmolarity.

Using network science to provide insights into the structure of event knowledge.

The structure of event knowledge plays a critical role in prediction, reconstruction of memory for personal events, construction of possible future events, action, language usage, and social interactions. Despite numerous theoretical proposals such as scripts, schemas, and stories, the highly variable and rich nature of events and event knowledge have been formidable barriers to characterizing the structure of event knowledge in memory. We used network science to provide insights into the temporal structure of common events. Based on participants' production and ordering of the activities that make up events, we established empirical profiles for 80 common events to characterize the temporal structure of activities. We used the event networks to investigate multiple issues regarding the variability in the richness and complexity of people's knowledge of common events, including: the temporal structure of events; event prototypes that might emerge from learning across many experiential instances and be expressed by people; the degree to which scenes (communities) are present in various events; the degree to which people believe certain activities are central to an event; how centrality might be distributed across an event's activities; and similarities among events in terms of their content and their temporal structure. Thus, we provide novel insights into human event knowledge, and describe 18 predictions for future human studies.

Mailed feedback to primary care physicians on antibiotic prescribing for patients aged 65 years and older: pragmatic, factorial randomised controlled trial.

OBJECTIVES: To evaluate whether providing family physicians with feedback on their antibiotic prescribing compared with that of their peers reduces antibiotic prescriptions. To also identify effects on antibiotic prescribing from case-mix adjusted feedback reports and messages emphasising antibiotic associated harms. DESIGN: Pragmatic, factorial randomised controlled trial. SETTING: Primary care physicians in Ontario, Canada PARTICIPANTS: All primary care physicians were randomly assigned a group if they were eligible and actively prescribing antibiotics to patients 65 years or older. Physicians were excluded if had already volunteered to receive antibiotic prescribing feedback from another agency, or had opted out of the trial. INTERVENTION: A letter was mailed in January 2022 to physicians with peer comparison antibiotic prescribing feedback compared with the control group who did not receive a letter (4:1 allocation). The intervention group was further randomised in a 2x2 factorial trial to evaluate case-mix adjusted versus unadjusted comparators, and emphasis, or not, on harms of antibiotics. MAIN OUTCOME MEASURES: Antibiotic prescribing rate per 1000 patient visits for patients 65 years or older six months after intervention. Analysis was in the modified intention-to-treat population using Poisson regression. RESULTS: 5046 physicians were included and analysed: 1005 in control group and 4041 in intervention group (1016 case-mix adjusted data and harms messaging, 1006 with case-mix adjusted data and no harms messaging, 1006 unadjusted data and harms messaging, and 1013 unadjusted data and no harms messaging). At six months, mean antibiotic prescribing rate was 59.4 (standard deviation 42.0) in the control group and 56.0 (39.2) in the intervention group (relative rate 0.95 (95% confidence interval 0.94 to 0.96). Unnecessary antibiotic prescribing (0.89 (0.86 to 0.92)), prolonged duration prescriptions defined as more than seven days (0.85 (0.83 to 0.87)), and broad spectrum prescribing (0.94 (0.92 to 0.95)) were also significantly lower in the intervention group compared with the control group. Results were consistent at 12 months post intervention. No significant effect was seen for including emphasis on harms messaging. A small increase in antibiotic prescribing with case-mix adjusted reports was noted (1.01 (1.00 to 1.03)). CONCLUSIONS: Peer comparison audit and feedback letters significantly reduced overall antibiotic prescribing with no benefit of case-mix adjustment or harms messaging. Antibiotic prescribing audit and feedback is a scalable and effective intervention and should be a routine quality improvement initiative in primary care. TRIAL REGISTRATION: ClinicalTrials.gov NCT04594200.

Management of Cochlear Implant Electrode Arrays Misplaced in the Internal Auditory Canal: A Systematic Review.

OBJECTIVE: Misplacement of electrode arrays in the internal auditory canal (IAC) presents a unique clinical challenge. Speech recognition is limited for cochlear implant (CI) users with misplaced arrays, and there are risks with revision surgery including facial and/or cochlear nerve injury. DATABASES REVIEWED: PubMed, Embase, and Scopus. METHODS: A literature search was performed from inception to September 2023. The search terms were designed to capture articles on misplaced arrays and the management options. Articles written in English that described cases of array misplacement into the IAC for children and adults were included. The level of evidence was assessed using Oxford Center for Evidence Based Medicine guidelines. Descriptive statistical analyses were performed. RESULTS: Twenty-eight cases of arrays misplaced in the IAC were identified. Thirteen (46%) were patients with incomplete partition type 3 (IP3), and 7 (25%) were patients with common cavity (CC) malformations. Most misplaced arrays were identified postoperatively (19 cases; 68%). Of these cases, 11 (58%) were managed with array removal. No facial nerve injuries were reported with revision surgery. Eight cases (42%) were left in place. Several underwent mapping procedures in an attempt improve the sound quality with the CI. CONCLUSION: Electrode array misplacement in the IAC is a rare complication that reportedly occurs predominately in cases with IP3 and CC malformations. Removal of misplaced arrays from the IAC reportedly has not been associated with facial nerve injuries. Cases identified with IAC misplacement postoperatively can potentially be managed with modified mapping techniques before proceeding with revision surgery.

Public transit mobility as a leading indicator of COVID-19 transmission in 40 cities during the first wave of the pandemic.

Background: The rapid global emergence of the COVID-19 pandemic in early 2020 created urgent demand for leading indicators to track the spread of the virus and assess the consequences of public health measures designed to limit transmission. Public transit mobility, which has been shown to be responsive to previous societal disruptions such as disease outbreaks and terrorist attacks, emerged as an early candidate. Methods: We conducted a longitudinal ecological study of the association between public transit mobility reductions and COVID-19 transmission using publicly available data from a public transit app in 40 global cities from March 16 to April 12, 2020. Multilevel linear regression models were used to estimate the association between COVID-19 transmission and the value of the mobility index 2 weeks prior using two different outcome measures: weekly case ratio and effective reproduction number. Results: Over the course of March 2020, median public transit mobility, measured by the volume of trips planned in the app, dropped from 100% (first quartile (Q1)-third quartile (Q3) = 94-108%) of typical usage to 10% (Q1-Q3 = 6-15%). Mobility was strongly associated with COVID-19 transmission 2 weeks later: a 10% decline in mobility was associated with a 12.3% decrease in the weekly case ratio (exp(ß) = 0.877; 95% confidence interval (CI): [0.859-0.896]) and a decrease in the effective reproduction number (ß = -0.058; 95% CI: [-0.068 to -0.048]). The mobility-only models explained nearly 60% of variance in the data for both outcomes. The adjustment for epidemic timing attenuated the associations between mobility and subsequent COVID-19 transmission but only slightly increased the variance explained by the models. Discussion: Our analysis demonstrated the value of public transit mobility as a leading indicator of COVID-19 transmission during the first wave of the pandemic in 40 global cities, at a time when few such indicators were available. Factors such as persistently depressed demand for public transit since the onset of the pandemic limit the ongoing utility of a mobility index based on public transit usage. This study illustrates an innovative use of "big data" from industry to inform the response to a global pandemic, providing support for future collaborations aimed at important public health challenges.

Factors associated with transition to a nursing home in older adults living in naturally occurring retirement communities.

BACKGROUND: Naturally occurring retirement communities (NORCs) are geographic areas (generally high-rise buildings or neighborhoods) that have a high concentration of individuals 65 years and older. Supportive service programs in NORCs can address resident needs and delay nursing home (NH) admission but understanding what factors are associated with NORC residents requiring NH admission is needed to tailor such programs. Our aim was to examine individual- and neighborhood-level factors associated with NH wait-list status in NORC residents in Ontario. METHODS: We conducted a population-based, cross-sectional study of Ontario adults 65 years of age or older living in a NORC building as of January 1, 2020, by linking a provincial registry of NORC high-rise buildings with health administrative data. Older adults were classified as being on the NH wait-list if they had an open application for a NH on the index date. We conducted a multilevel logistic regression analysis using generalized estimating equations to determine individual- and neighborhood-level factors associated with NH wait-list status, including sociodemographic, clinical, healthcare use, and building factors. We explored the role of sex and age through stratification by sex (male, female) and age (65-80 and 80+ years). RESULTS: Among 220,864 NORC residents, 4710 individuals (2.1%) were on the NH wait-list. Female sex, older age, immigrant status, dementia diagnosis, receiving homecare, multimorbidity, and polypharmacy (five or more unique drug names) were associated with an increased odds of wait-list status. Several neighborhood-level variables were associated with a significantly increased likelihood of wait-list status, including low income, high dependency, high ethnic diversity, and living in a building with supports. CONCLUSION: NORC supportive service programs can be tailored to account for the factors associated with NH wait-list status, allowing NORC residents who are living in the community to age in their desired place and achieve optimal health outcomes.

Proteomic approaches for protein kinase substrate identification in Apicomplexa.

Apicomplexa is a phylum of protist parasites, notable for causing life-threatening diseases including malaria, toxoplasmosis, cryptosporidiosis, and babesiosis. Apicomplexan pathogenesis is generally a function of lytic replication, dissemination, persistence, host cell modification, and immune subversion. Decades of research have revealed essential roles for apicomplexan protein kinases in establishing infections and promoting pathogenesis. Protein kinases modify their substrates by phosphorylating serine, threonine, tyrosine, or other residues, resulting in rapid functional changes in the target protein. Post-translational modification by phosphorylation can activate or inhibit a substrate, alter its localization, or promote interactions with other proteins or ligands. Deciphering direct kinase substrates is crucial to understand mechanisms of kinase signaling, yet can be challenging due to the transient nature of kinase phosphorylation and potential for downstream indirect phosphorylation events. However, with recent advances in proteomic approaches, our understanding of kinase function in Apicomplexa has improved dramatically. Here, we discuss methods that have been used to identify kinase substrates in apicomplexan parasites, classifying them into three main categories: i) kinase interactome, ii) indirect phosphoproteomics and iii) direct labeling. We briefly discuss each approach, including their advantages and limitations, and highlight representative examples from the Apicomplexa literature. Finally, we conclude each main category by introducing prospective approaches from other fields that would benefit kinase substrate identification in Apicomplexa.

Five steps to high quality antimicrobial stewardship research.

The escalating threat of antimicrobial resistance (AMR) necessitates impactful, reproducible, and scalable antimicrobial stewardship strategies. This review addresses the critical need to enhance the quality of antimicrobial stewardship intervention research. We propose five considerations for authors planning and evaluating antimicrobial stewardship initiatives. Antimicrobial stewards should consider the following mnemonic ABCDE: (A) plan Ahead using implementation science; (B) Be clear and thoroughly describe the intervention by using the TidIER checklist; (C) Use a Checklist to comprehensively report study components; (D) Select a study Design carefully; and (E) Assess Effectiveness and implementation by selecting meaningful outcomes. Incorporating these recommendations will help strengthen the evidence base of antimicrobial stewardship literature and support optimal implementation of strategies to mitigate AMR.

The Effect of COVID-19 Vaccination on Outpatient Antibiotic Prescribing in Older Adults: A Self-Controlled Risk-Interval Study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) vaccination has been associated with reduced outpatient antibiotic prescribing among older adults with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We assessed the impact of COVID-19 vaccination on outpatient antibiotic prescribing in the broader population of older adults, regardless of SARS-CoV-2 infection status. METHODS: We included adults aged ≥65 years who received their first, second, and/or third COVID-19 vaccine dose from December 2020 to December 2022. We used a self-controlled risk-interval design and included cases who received an antibiotic prescription 2-6 weeks before vaccination (pre-vaccination or control interval) or after vaccination (post-vaccination or risk interval). We used conditional logistic regression to estimate the odds of being prescribed (1) any antibiotic, (2) a typical "respiratory" infection antibiotic, or (3) a typical "urinary tract" infection antibiotic (negative control) in the post-vaccination interval versus the pre-vaccination interval. We accounted for temporal changes in antibiotic prescribing using background monthly antibiotic prescribing counts. RESULTS: 469 923 vaccine doses met inclusion criteria. The odds of receiving any antibiotic or a respiratory antibiotic prescription were lower in the post-vaccination versus pre-vaccination interval (aOR, .973; 95% CI, .968-.978; aOR, .961; 95% CI, .953-.968, respectively). There was no association between vaccination and urinary antibiotic prescriptions (aOR, .996; 95% CI, .987-1.006). Periods with high (>10%) versus low (<5%) SARS-CoV-2 test positivity demonstrated greater reductions in antibiotic prescribing (aOR, .875; 95% CI, .845-.905; aOR, .996; 95% CI, .989-1.003, respectively). CONCLUSIONS: COVID-19 vaccination was associated with reduced outpatient antibiotic prescribing in older adults, especially during periods of high SARS-CoV-2 circulation.

Association between infectious diseases consultation and mortality in hospitalized patients with Gram-negative bloodstream infection: a retrospective population-wide cohort study.

OBJECTIVES: Data supporting routine infectious diseases (ID) consultation in Gram-negative bloodstream infection (GN-BSI) are limited. We evaluated the association between ID consultation and mortality in patients with GN-BSI in a retrospective population-wide cohort study in Ontario using linked health administrative databases. METHODS: Hospitalized adult patients with GN-BSI between April 2017 and December 2021 were included. The primary outcome was time to all-cause mortality censored at 30 days, analyzed using a mixed effects Cox proportional hazards model with hospital as a random effect. ID consultation 1-10 days after the first positive blood culture was treated as a time-varying exposure. RESULTS: Of 30,159 patients with GN-BSI across 53 hospitals, 11,013 (36.5%) received ID consultation. Median prevalence of ID consultation for patients with GN-BSI across hospitals was 35.0% with wide variability (range 2.7-76.1%, interquartile range 19.6-41.1%). 1041 (9.5%) patients who received ID consultation died within 30 days, compared to 1797 (9.4%) patients without ID consultation. In the fully-adjusted multivariable model, ID consultation was associated with mortality benefit (adjusted HR 0.82, 95% CI 0.77-0.88, p < 0.0001; translating to absolute risk reduction of -3.8% or NNT of 27). Exploratory subgroup analyses of the primary outcome showed that ID consultation could have greater benefit in patients with high-risk features (nosocomial infection, polymicrobial or non-Enterobacterales infection, antimicrobial resistance, or non-urinary tract source). CONCLUSIONS: Early ID consultation was associated with reduced mortality in patients with GN-BSI. If resources permit, routine ID consultation for this patient population should be considered to improve patient outcomes.

Regional variations in antimicrobial susceptibility of community-acquired uropathogenic Escherichia coli in India: Findings of a multicentric study highlighting the importance of local antibiograms.

Objectives: Evidence-based prescribing is essential to optimize patient outcomes in cystitis. This requires knowledge of local antibiotic resistance rates. Diagnostic and Antimicrobial Stewardship (DASH) to Protect Antibiotics (https://dashuti.com/) is a multicentric mentorship program guiding centers in preparing, analyzing and disseminating local antibiograms to promote antimicrobial stewardship in community urinary tract infection. Here, we mapped the susceptibility profile of Escherichia coli from 22 Indian centers. Methods: These centers spanned 10 Indian states and three union territories. Antibiograms for urinary E. coli from the outpatient departments were collated. Standardization was achieved by regional online training; anomalies were resolved via consultation with study experts. Data were collated and analyzed. Results: Nationally, fosfomycin, with 94% susceptibility (inter-center range 83-97%), and nitrofurantoin, with 85% susceptibility (61-97%), retained the widest activity. The susceptibility rates were lower for co-trimoxazole (49%), fluoroquinolones (31%), and oral cephalosporins (26%). The rates for third- and fourth-generation cephalosporins were 46% and 52%, respectively, with 54% (33-58%) extended-spectrum ß-lactamase prevalence. Piperacillin-tazobactam (81%), amikacin (88%), and meropenem (88%) retained better activity; however, one center in Delhi recorded only 42% meropenem susceptibility. Susceptibility rates were mostly higher in South, West, and Northeast India; centers in the heavily populated Gangetic plains, across north and northwest India, had greater resistance. These findings highlight the importance of local antibiograms in guiding appropriate antimicrobial choices. Conclusions: Fosfomycin and nitrofurantoin are the preferred oral empirical choices for uncomplicated E. coli cystitis in India, although elevated resistance in some areas is concerning. Empiric use of fluoroquinolones and third-generation cephalosporins is discouraged, whereas piperacillin/tazobactam and aminoglycosides remain carbapenem-sparing parenteral agents.

Hybrid spectral CT system with clinical rapid kVp-switching x-ray tube and dual-layer detector for improved iodine quantification.

Spectral computed tomography (CT) is a powerful diagnostic tool offering quantitative material decomposition results that enhance clinical imaging by providing physiologic and functional insights. Iodine, a widely used contrast agent, improves visualization in various clinical contexts. However, accurately detecting low-concentration iodine presents challenges in spectral CT systems, particularly crucial for conditions like pancreatic cancer assessment. In this study, we present preliminary results from our hybrid spectral CT instrumentation which includes clinical-grade hardware (rapid kVp-switching x-ray tube, dual-layer detector). This combination expands spectral datasets from two to four channels, wherein we hypothesize improved quantification accuracy for low-dose and low-iodine concentration cases. We modulate the system duty cycle to evaluate its impact on quantification noise and bias. We evaluate iodine quantification performance by comparing two hybrid weighting strategies alongside rapid kVp-switching. This evaluation is performed with a polyamide phantom containing seven iodine inserts ranging from 0.5 to 20 mg/mL. In comparison to alternative methodologies, the maximum separation configuration, incorporating data from both the 80 kVp, low photon energy detector layer and the 140 kVp, high photon energy detector layer produces spectral images containing low quantitative noise and bias. This study presents initial evaluations on a hybrid spectral CT system, leveraging clinical hardware to demonstrate the potential for enhanced precision and sensitivity in spectral imaging. This research holds promise for advancing spectral CT imaging performance across diverse clinical scenarios.

Demographic Representation in Clinical Research Relative to a Cochlear Implant Patient Population.

OBJECTIVES: Research samples that are representative of patient populations are needed to ensure the generalizability of study findings. The primary aim was to assess the efficacy of a study design and recruitment strategy in obtaining a participant sample that was representative of the broader cochlear implant (CI) patient population at the CI center. A secondary aim was to review whether the CI recipient population was representative of the state population. METHODS: Demographic variables were compared for a research participant sample (n = 79) and the CI patient population (n = 338). The participant sample was recruited from the CI patient population. The study design included visits that were at the same location and frequency as the recommended clinical follow-up intervals. The demographics for the combined group (participant sample and patient population) were then compared to the reported demographics for the population in North Carolina. RESULTS: There were no significant differences between the participant sample and patient population for biological sex, age at implantation, racial distribution, socioeconomic position, degree of urbanization, or drive time to the CI center (p ≥ 0.086). The combined CI recipient population was significantly different from the North Carolina population for the distributions of race, ethnicity, and degree of urbanization (p < 0.001). CONCLUSION: The study design and recruitment strategy allowed for recruitment of a participant sample that was representative of the CI patient population. Disparities in access to cochlear implantation persist, as supported by the significant differences in the combined CI recipient population and the population for our state. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:4101-4110, 2024.

Progressive Pulmonary Fibrosis and Interstitial Lung Abnormalities: AJR Expert Panel Narrative Review.

Progressive pulmonary fibrosis (PPF) and interstitial lung abnormalities (ILA) are relatively new concepts in interstitial lung disease (ILD) imaging and clinical management. Recognition of signs of PPF, as well as identification and classification of ILA, are important tasks during chest high-resolution CT interpretation, to optimize management of patients with ILD and those at risk of developing ILD. However, following professional society guidance, the role of imaging surveillance remains unclear in stable patients with ILD, asymptomatic patients with ILA who are at risk of progression, and asymptomatic patients at risk of developing ILD without imaging abnormalities. In this AJR Expert Panel Narrative Review, we summarize the current knowledge regarding PPF and ILA and describe the range of clinical practice with respect to imaging patients with ILD, those with ILA, and those at risk of developing ILD. In addition, we offer suggestions to help guide surveillance imaging in areas with an absence of published guidelines, where such decisions are currently driven primarily by local pulmonologists' preference.

Computational Deconvolution of Cell Type-Specific Gene Expression in COPD and IPF Lungs Reveals Disease Severity Associations.

RATIONALE: Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are debilitating diseases associated with divergent histopathological changes in the lungs. At present, due to cost and technical limitations, profiling cell types is not practical in large epidemiology cohorts (n>1000). Here, we used computational deconvolution to identify cell types in COPD and IPF lungs whose abundances and cell type-specific gene expression are associated with disease diagnosis and severity. METHODS: We analyzed lung tissue RNA-seq data from 1026 subjects (COPD, n=465; IPF, n=213; control, n=348) from the Lung Tissue Research Consortium. We performed RNA-seq deconvolution, querying thirty-eight discrete cell-type varieties in the lungs. We tested whether deconvoluted cell-type abundance and cell type-specific gene expression were associated with disease severity. RESULTS: The abundance score of twenty cell types significantly differed between IPF and control lungs. In IPF subjects, eleven and nine cell types were significantly associated with forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO), respectively. Aberrant basaloid cells, a rare cells found in fibrotic lungs, were associated with worse FVC and DLCO in IPF subjects, indicating that this aberrant epithelial population increased with disease severity. Alveolar type 1 and vascular endothelial (VE) capillary A were decreased in COPD lungs compared to controls. An increase in macrophages and classical monocytes was associated with lower DLCO in IPF and COPD subjects. In both diseases, lower non-classical monocytes and VE capillary A cells were associated with increased disease severity. Alveolar type 2 cells and alveolar macrophages had the highest number of genes with cell type-specific differential expression by disease severity in COPD and IPF. In IPF, genes implicated in the pathogenesis of IPF, such as matrix metallopeptidase 7, growth differentiation factor 15, and eph receptor B2, were associated with disease severity in a cell type-specific manner. CONCLUSION: Utilization of RNA-seq deconvolution enabled us to pinpoint cell types present in the lungs that are associated with the severity of COPD and IPF. This knowledge offers valuable insight into the alterations within tissues in more advanced illness, ultimately providing a better understanding of the underlying pathological processes that drive disease progression.