Microscopic Small Airway Abnormalities Identified in Early Idiopathic Pulmonary Fibrosis In Vivo Using Endobronchial Optical Coherence Tomography.

Rationale: Idiopathic pulmonary fibrosis (IPF) affects the subpleural lung but is considered to spare small airways. Micro-computed tomography (micro-CT) studies demonstrated small airway reduction in end-stage IPF explanted lungs, raising questions about small airway involvement in early-stage disease. Endobronchial optical coherence tomography (EB-OCT) is a volumetric imaging modality that detects microscopic features from subpleural to proximal airways. Objectives: In this study, EB-OCT was used to evaluate small airways in early IPF and control subjects in vivo. Methods: EB-OCT was performed in 12 subjects with IPF and 5 control subjects (matched by age, sex, smoking history, height, and body mass index). Subjects with IPF had early disease with mild restriction (FVC: 83.5% predicted), which was diagnosed per current guidelines and confirmed by surgical biopsy. EB-OCT volumetric imaging was acquired bronchoscopically in multiple, distinct, bilateral lung locations (total: 97 sites). IPF imaging sites were classified by severity into affected (all criteria for usual interstitial pneumonia present) and less affected (some but not all criteria for usual interstitial pneumonia present). Bronchiole count and small airway stereology metrics were measured for each EB-OCT imaging site. Measurements and Main Results: Compared with the number of bronchioles in control subjects (mean = 11.2/cm3; SD = 6.2), there was significant bronchiole reduction in subjects with IPF (42% loss; mean = 6.5/cm3; SD = 3.4; P = 0.0039), including in IPF affected (48% loss; mean: 5.8/cm3; SD: 2.8; P < 0.00001) and IPF less affected (33% loss; mean: 7.5/cm3; SD: 4.1; P = 0.024) sites. Stereology metrics showed that IPF-affected small airways were significantly larger, more distorted, and more irregular than in IPF-less affected sites and control subjects. IPF less affected and control airways were statistically indistinguishable for all stereology parameters (P = 0.36-1.0). Conclusions: EB-OCT demonstrated marked bronchiolar loss in early IPF (between 30% and 50%), even in areas minimally affected by disease, compared with matched control subjects. These findings support small airway disease as a feature of early IPF, providing novel insight into pathogenesis and potential therapeutic targets.

Understanding Barriers and Facilitators of Primary Care Use Among Assertive Community Treatment Teams Via Qualitative Analysis of Clients and Clinicians.

Individuals with severe mental illness and substance use disorders face complex barriers to achieving physical health. This study aims to explore the barriers and facilitators of primary care access among an Assertive Community Treatment (ACT) team. Semi-structured qualitative interviews were conducted with 14 clients and 7 clinicians from an ACT team at a community mental health center in Connecticut. Data analysis followed a grounded theory approach, with codes and themes emerging iteratively during the interview process. The study identified multifaceted barriers to accessing primary care, including economic challenges, homelessness, and the prioritization of mental health and substance use symptoms over healthcare. The conceptual framework consists of nine dominant themes: clients' attitudes, knowledge, mental health, and motivations ("Client-Level Barriers and Facilitators"); ACT team-directed care coordination and relationship-building as well as primary care provider communication ("Provider-Level Barriers and Facilitators"); and clients' experiences with medical care and socioeconomic status ("Systemic-Level Barriers and Facilitators"). This research provides valuable insights into the various barriers faced by ACT clients in accessing primary care. Improving primary care access for individuals with severe mental illness and substance use disorders is crucial for reducing health disparities in this vulnerable population.

Therapeutic Targeting of DNA Repair Pathways in Pediatric Extracranial Solid Tumors: Current State and Implications for Immunotherapy.

DNA damage is fundamental to tumorigenesis, and the inability to repair DNA damage is a hallmark of many human cancers. DNA is repaired via the DNA damage repair (DDR) apparatus, which includes five major pathways. DDR deficiencies in cancers give rise to potential therapeutic targets, as cancers harboring DDR deficiencies become increasingly dependent on alternative DDR pathways for survival. In this review, we summarize the DDR apparatus, and examine the current state of research efforts focused on identifying vulnerabilities in DDR pathways that can be therapeutically exploited in pediatric extracranial solid tumors. We assess the potential for synergistic combinations of different DDR inhibitors as well as combinations of DDR inhibitors with chemotherapy. Lastly, we discuss the immunomodulatory implications of targeting DDR pathways and the potential for using DDR inhibitors to enhance tumor immunogenicity, with the goal of improving the response to immune checkpoint blockade in pediatric solid tumors. We review the ongoing and future research into DDR in pediatric tumors and the subsequent pediatric clinical trials that will be critical to further elucidate the efficacy of the approaches targeting DDR.

Inductive thematic analysis of healthcare qualitative interviews using open-source large language models: How does it compare to traditional methods?

BACKGROUND: Large language models (LLMs) are generative artificial intelligence that have ignited much interest and discussion about their utility in clinical and research settings. Despite this interest there is sparse analysis of their use in qualitative thematic analysis comparing their current ability to that of human coding and analysis. In addition, there has been no published analysis of their use in real-world, protected health information. OBJECTIVE: Here we fill that gap in the literature by comparing an LLM to standard human thematic analysis in real-world, semi-structured interviews of both patients and clinicians within a psychiatric setting. METHODS: Using a 70 billion parameter open-source LLM running on local hardware and advanced prompt engineering techniques, we produced themes that summarized a full corpus of interviews in minutes. Subsequently we used three different evaluation methods for quantifying similarity between themes produced by the LLM and those produced by humans. RESULTS: These revealed similarities ranging from moderate to substantial (Jaccard similarity coefficients 0.44-0.69), which are promising preliminary results. CONCLUSION: Our study demonstrates that open-source LLMs can effectively generate robust themes from qualitative data, achieving substantial similarity to human-generated themes. The validation of LLMs in thematic analysis, coupled with evaluation methodologies, highlights their potential to enhance and democratize qualitative research across diverse fields.

Venovenous Extracorporeal Membrane Oxygenation Candidacy Decision-Making: Lessons and Hypotheses From a Single-Center Observational Analysis.

BACKGROUND: Use of venovenous extracorporeal membrane oxygenation (ECMO) is increasing, but candidacy selection processes are variable and subject to bias. RESEARCH QUESTION: What are the reasons behind venovenous ECMO candidacy decisions, and are decisions made consistently across patients? STUDY DESIGN AND METHODS: Prospective observational study of all patients, admitted or outside hospital referrals, considered for venovenous ECMO at a tertiary referral center. Relevant clinical data and reasons for candidacy determination were cross-referenced with other noncandidates and candidates and were assessed qualitatively. RESULTS: Eighty-one consultations resulted in 44 noncandidates (54%), 29 candidates (36%; nine of whom subsequently underwent cannulation), and eight deferred decisions (10%). Fifteen unique contraindications were identified, variably present across all patients. Five contraindications were invoked as the sole reason to deny ECMO to a patient. In patients with three or more contraindications, additional contraindications were cited even if the severity was relatively minor. All but four contraindications invoked to deny ECMO to a patient were nonprohibitive for at least one other candidate. Contraindications documented in noncandidates were present but not mentioned in 21 other noncandidates (47%). Twenty-six candidates (90%) had at least one contraindication that was prohibitive in a noncandidate, including a contraindication that was the sole reason to deny ECMO. Contraindications were proposed as informing three prognostic domains, through which patterns of inconsistency could be understood better: (1) irreversible underlying pulmonary process, (2) unsurvivable critical illness, and (3) clinical condition too compromised for meaningful recovery. INTERPRETATION: ECMO candidacy decisions are inconsistent. We identified four patterns of inconsistency in our center and propose a three-domain model for understanding and categorizing contraindications, yielding five lessons that may improve candidacy decision processes until further research can guide practice more definitively.

Observational pilot study of multi-wavelength wearable light dosimetry for erythropoietic protoporphyria.

BACKGROUND: Erythropoietic protoporphyria (EPP) causes painful light sensitivity, limiting quality of life. Our objective was to develop and validate a wearable light exposure device and correlate measurements with light sensitivity in EPP to predict and prevent symptoms. METHODS: A wearable light dosimeter was developed to capture light doses of UVA, blue, and red wavelengths. A prospective observational pilot study was performed in which five EPP patients wore two light dosimeters for 3 weeks, one as a watch, and one as a shirt clip. RESULTS: Standard deviation (SD) increases from the mean in the daily blue light dose increased the odds ratio (OR) for symptom risk more than the self-reported outdoor time (OR 2.76 vs. 2.38) or other wavelengths, and a one SD increase from the mean in the daily blue light wristband device dose increased the OR for symptom risk more than the daily blue light shirt clip (OR 2.45 vs. 1.62). The area under the receiver operator curve for the blue light wristband dose was 0.78, suggesting 78% predictive accuracy. CONCLUSION: These data demonstrate that wearable blue light dosimetry worn as a wristband is a promising method for measuring light exposure and predicting and preventing symptoms in EPP.

Severe Hyponatremia Correction, Mortality, and Central Pontine Myelinolysis.

BACKGROUND: In clinical practice, sodium correction rates are frequently limited in patients with severe hyponatremia to prevent neurologic complications. The implications of correction rates on overall mortality and length of hospital stay are unclear. METHODS: In this multicenter observational study, we evaluated the association of sodium correction rates with mortality, length of stay, and central pontine myelinolysis (CPM) in patients hospitalized with severe hyponatremia (admission serum sodium level less than 120 mEq/l). RESULTS: The cohort included 3274 patients. A correction rate of less than 6 mEq/l/24 hours was observed in 38%, 6 to 10 mEq/l/24 hours was observed in 29%, and greater than 10 mEq/l/24 hours was observed in 33%. Compared with 6 to 10 mEq/l/24 hours, a correction rate of less than 6 mEq/l/24 hours exhibited higher in-hospital mortality in multivariable-adjusted and propensity score­weighted analyses. Compared with 6 to 10 mEq/l/24 hours, a correction rate of greater than 10 mEq/l/24 hours was associated with lower in-hospital mortality and shorter length of stay in multivariable analyses. Seven patients with CPM were identified, with five of seven developing CPM despite a sodium correction rate of less than or equal to 8 mEq/l/24 hours. Six of seven patients who developed CPM had alcohol use disorder, malnutrition, hypokalemia, or hypophosphatemia. CONCLUSIONS: Limiting the sodium correction rate was associated with higher mortality and longer length of stay. Whether the sodium correction rate influences neurologic complications needs further evaluation.