Citations

Abstract Extracellular vesicles (EVs) are key mediators of cell–cell communication and are involved in transferring specific biomolecular cargo to recipient cells to regulate their physiological functions. A major challenge in the understanding of EV function in vivo is the difficulty ascertaining the origin of the EV particles. The recent development of the “Snorkel-tag,” which includes EV-membrane-targeted CD81 fused to a series of extra-vesicular protein tags, can be used to mark EVs originating from a specific source for subsequent isolation and characterization. We developed an in vivo mouse model, termed “CAGS-Snorkel,” which expresses the Snorkel-tag under the control of the Cre-lox system, and crossed this mouse with either Prx1-Cre (mesenchymal progenitors) or Ocn-Cre (osteoblasts/osteocytes) and isolated Snorkel-tagged EVs from the mouse bone marrow plasma using a magnetic bead affinity column. miRNA-sequencing was performed on the isolated EVs, and although similar profiles were observed, a few key miRNAs involved in bone metabolism (miR-106b-5p, miRs-19b-3p, and miRs-219a-5p) were enriched in the Ocn-derived relative to the Prx1-derived EV subpopulations. To characterize the effects of these small EVs on a bone cell target, cultured mouse bone marrow stromal cells were treated with Prx1 or Ocn EVs, and mRNA-sequencing was performed. Pathways involved in ossification, bone development, and extracellular matrix interactions were regulated by both EV subpopulations, whereas a few pathways including advanced glycation end-products signaling were uniquely regulated in the Ocn EV subpopulation, underlying important biological effects of specific EV subpopulations within the bone marrow microenvironment. These data demonstrate that EV isolation in vivo using the CAGS-Snorkel mouse model is a useful tool in characterizing the cargo and understanding the biology of tissue-specific EVs. Moreover, while bone mesenchymal cell populations share a common EV secretory profile, we uncover key differences based on the stage of osteoblastic differentiation that may have important biological consequences.

Abstract Introduction Despite direct access to clinicians through the electronic health record, patients are increasingly turning to the internet for information related to their health, especially with sensitive urologic conditions such as Peyronie’s disease (PD). Large language model (LLM) chatbots are a form of artificial intelligence that rely on user prompts to mimic conversation, and they have shown remarkable capabilities. The conversational nature of these chatbots has the potential to answer patient questions related to PD; however, the accuracy, comprehensiveness, and readability of these LLMs related to PD remain unknown. Aims To assess the quality and readability of information generated from 4 LLMs with searches related to PD; to see if users could improve responses; and to assess the accuracy, completeness, and readability of responses to artificial preoperative patient questions sent through the electronic health record prior to undergoing PD surgery. Methods The National Institutes of Health’s frequently asked questions related to PD were entered into 4 LLMs, unprompted and prompted. The responses were evaluated for overall quality by the previously validated DISCERN questionnaire. Accuracy and completeness of LLM responses to 11 presurgical patient messages were evaluated with previously accepted Likert scales. All evaluations were performed by 3 independent reviewers in October 2023, and all reviews were repeated in April 2024. Descriptive statistics and analysis were performed. Results Without prompting, the quality of information was moderate across all LLMs but improved to high quality with prompting. LLMs were accurate and complete, with an average score of 5.5 of 6.0 (SD, 0.8) and 2.8 of 3.0 (SD, 0.4), respectively. The average Flesch-Kincaid reading level was grade 12.9 (SD, 2.1). Chatbots were unable to communicate at a grade 8 reading level when prompted, and their citations were appropriate only 42.5% of the time. Conclusion LLMs may become a valuable tool for patient education for PD, but they currently rely on clinical context and appropriate prompting by humans to be useful. Unfortunately, their prerequisite reading level remains higher than that of the average patient, and their citations cannot be trusted. However, given their increasing uptake and accessibility, patients and physicians should be educated on how to interact with these LLMs to elicit the most appropriate responses. In the future, LLMs may reduce burnout by helping physicians respond to patient messages.

BACKGROUND AND OBJECTIVES: Stereotactic radiosurgery (SRS) with neoadjuvant embolization is a treatment strategy for brain arteriovenous malformations (AVMs), especially for those with large nidal volume or concomitant aneurysms. The aim of this study was to assess the effects of pre-SRS embolization in AVMs with an associated intracranial aneurysm (IA). METHODS: The International Radiosurgery Research Foundation AVM database from 1987 to 2018 was retrospectively reviewed. SRS-treated AVMs with IAs were included. Patients were categorized into those treated with upfront embolization (E + SRS) vs stand-alone SRS (SRS). Primary end point was a favorable outcome (AVM obliteration + no permanent radiation-induced changes or post-SRS hemorrhage). Secondary outcomes included AVM obliteration, mortality, follow-up modified Rankin Scale, post-SRS hemorrhage, and radiation-induced changes. RESULTS: Forty four AVM patients with associated IAs were included, of which 23 (52.3%) underwent pre-SRS embolization and 21 (47.7%) SRS only. Significant differences between the E + SRS vs SRS groups were found for AVM maximum diameter (1.5 ± 0.5 vs 1.1 ± 0.4 cm 3 , P = .019) and SRS treatment volume (9.3 ± 8.3 vs 4.3 ± 3.3 cm 3 , P = .025). A favorable outcome was achieved in 45.4% of patients in the E + SRS group and 38.1% in the SRS group ( P = .625). Obliteration rates were comparable (56.5% for E + SRS vs 47.6% for SRS, P = .555), whereas a higher mortality rate was found in the SRS group (19.1% vs 0%, P = .048). After adjusting for AVM maximum diameter, SRS treatment volume, and maximum radiation dose, the likelihood of achieving favorable outcome and AVM obliteration did not differ between groups ( P = .475 and P = .820, respectively). CONCLUSION: The likelihood of a favorable outcome and AVM obliteration after SRS with neoadjuvant embolization in AVMs with concomitant IA seems to be comparable with stand-alone SRS, even after adjusting for AVM volume and SRS maximum dose. However, the increased mortality among the stand-alone SRS group and relatively low risk of embolization-related complications suggest that these patients may benefit from a combined treatment approach.

ObjectiveTo evaluate the impact of age on disease recurrence in idiopathic subglottic stenosis (iSGS) patients.MethodsThis was a retrospective chart review of iSGS patients treated with laser wedge excision. Patients did not have prior surgery. Survival rates free of recurrence were estimated using the Kaplan–Meier methods, and associations were evaluated using Cox Proportional Hazards models.ResultsEighty‐five female patients were included in the study. Most patients (68%) were postmenopausal, had first period at or before 13 years of age, had at least one full‐term pregnancy (82%), were not undergoing hormone replacement therapy (93%), were not using hormonal birth control (88%), and were either partially or completely compliant with triple therapy regime (80%). There was a statistically significant average reduction in risk of recurrence of 5% for every additional year of age (p < 0.0001). When compared to patients older than 65 years of age, patients less than 35 were nearly 10 times more likely to recur (p = 0.002), and patients 55–65 and 45–55 years of age were 8 and 5 times more likely to recur, respectively (p = 0.003 and 0.009). Additionally, females on birth control showed decreased risk of recurrence of 74% compared with their counterparts (p = 0.04).ConclusionThis is the first study to demonstrate an inverse relationship between age and disease recurrence in patients with iSGS following surgery. Using age as a surrogate for menopausal status, these results suggest that increased age and/or birth control provide a protective effect through decreased recurrence rates, possibly mediated by decreased estrogen levels.Level of Evidence4 Laryngoscope, 2024

Abstract Background Transcatheter closure of patent ductus arteriosus (PDA) in small, premature infants is increasingly performed in the contemporary practice. Data regarding optimal timing of PDA closure are scarce. We therefore decided to compare morbidity and mortality of early and late device closure in preterm infants. Methods Hospitalizations of 166,583 newborn infants diagnosed with PDA were identified from the Kids’ Inpatient Database (KID) in 2009, 2012, 2016, and 2019. Of these, 299 preterm infants (gestational age (GA) ≤32 weeks, birth weight <1500 grams) underwent percutaneous PDA closure. Characteristics and peri-procedural outcomes were compared between early (≤ 30 days) (n=120) and late PDA closure (>30 days) (n=179). Results Mean age (±standard deviation) for early PDA closure was 18.6 days ± 7 and 67.3 days ± 36.5 in late PDA closure. Co-morbidities including respiratory distress syndrome/bronchopulmonary dysplasia, heart failure and pulmonary hypertension were comparable between the two groups. There was no difference in mortality or referral for surgical ligation between early and late closure. Post-procedural vascular complications were low, but higher in patients with early PDA closure (3.3% vs 0%; p=0.025). Length of hospital stay was longer in late PDA closure group (121.1 days ± 51.7 vs 81.5 days ± 48.8; p=<0.01). Conclusion Preterm or very low birth weight infants may benefit from early percutaneous PDA closure as it is associated with a shorter hospital LOS. There was no difference in in-hospital mortality or major periprocedural complications between early and late PDA closure, except vascular complications that were higher with early PDA closure.

Background and Aims: Metabolic dysfunction–associated steatotic liver disease management guidelines have been published worldwide; we aimed to summarize, categorize, and compare their lifestyle intervention recommendations. Approach and Results: We searched metabolic dysfunction–associated steatotic liver disease/NAFLD management guidelines published between January 1, 2013, and June 31, 2024, through databases including PubMed/MEDLINE, Cochrane, and CINAHL. In total, 35 qualifying guidelines were included in the final analysis. Guideline recommendations were categorized into 5 domains (ie, weight reduction goals, physical activity, nutrition, alcohol, and tobacco smoking) and were ranked based on how frequently they appeared. A recommendation was defined as widely adopted if recommended in ≥24 (≥66.6%) of the guidelines. These included increasing physical activity; reducing body weight by 7%–10% to improve steatohepatitis and/or fibrosis; restricting caloric intake; undertaking 150–300 or 75–150 minutes/week of moderate or vigorous-intensity physical activity, respectively; and decreasing consumption of commercially produced fructose. The least mentioned topics, in ≤9 of the guidelines, evaluated environmental determinants of health, mental health, referring patients for psychological or cognitive behavioral therapy, using digital health interventions, and assessing patients’ social determinants of health. Conclusions: Most guidelines recommend weight reduction through physical activity and improving nutrition, as these have proven positive effects on health outcomes when sustained. However, gaps regarding mental health and the social and environmental determinants of metabolic dysfunction–associated steatotic liver disease were found. To optimize behavioral modifications and treatment, we recommend carrying out studies that will provide further evidence on social support, environmental factors, and mental health, as well as further exploring digital health interventions.

PURPOSE The study assesses the current state of global oncology (GO)/hematology training opportunities in US fellowship programs. METHODS We developed a comprehensive survey of 64-Likert multiple-choice and open-ended questions. The survey was electronically distributed to fellowship program leaders at Accreditation Council for Graduate Medical Education-accredited adult hematology/oncology fellowships. Program directors received three reminders after which survey was sent to assistant program directors or division heads for programs not represented. RESULTS A total of 171 programs were eligible for the survey. We received 42 (24.6%) responses; 40 were included in the analysis, and two were excluded for declined consent and incomplete responses. The programs include large academic (81.6%) and community hospitals (10.5%). Of the respondents, 18 (48.6%) reported offering some opportunities for global health training, and half reported interest among current fellows. Most programs (29, 82.9%) had three or fewer faculty engaged in GO research. Institutional training grants were available in 15 (39.5%) programs, of which six (40%) allowed for global health research. Of the 18 programs offering global health training activities, most (15, 83.3%) report less than a quarter of their trainees currently participate in GO experiences. The most commonly perceived barriers to GO opportunities include competing priorities (85.3%) and lack of faculty mentors with GO-related experience (82.4%). Conversely, the most commonly perceived facilitators include established partnerships outside the United States (97.0%) and dedicated institutional funding (93.9%). CONCLUSION Our survey demonstrates that although there is significant interest among fellowship trainees, a minority of the fellowship programs offer GO opportunities. Providing GO opportunities would require programs to establish partnerships with institutions outside the United States and to have systematic approaches of addressing other barriers, including enhancing funding and mentorship.

Purpose: The purpose of this study was to investigate the relationship between perceptual ratings of hypernasality made during connected speech and velopharyngeal (VP) gap size measured in millimeters in the sagittal plane during sustained vowel production using magnetic resonance imaging (MRI). Method: A retrospective cross-sectional analysis was completed. A subgroup of 110 participants from another study with an M age of 10.1 years presenting for management of VP insufficiency was included. Perceptual ratings of hypernasality during connected speech and measurement of gap size during sustained /i/ production on MRI were performed by raters blinded to the participants' medical and surgical history. Results: There was a moderate-to-strong, positive correlation ( r = .61; p < .001) between hypernasality ratings and VP gap size measured on MRI using sustained /i/. The odds of a higher hypernasality rating increased as the gap size increased (odds ratio = 1.34; 95% CI [1.20, 1.49]; p < .001). The predicted probability for hypernasality ratings of none/minimal/mild steadily decreased as the gap size increased indicating that lower ratings of hypernasality were associated with smaller gap sizes. For the rating of “moderate” hypernasality, the predicted probability of the rating steadily increased up to 8 mm and then decreased as the gap size continued to increase. The predicted probability for a hypernasality rating of “severe” consistently increased as the gap size increased. Conclusions: Hypernasality ratings made at the connected speech level were significantly associated with VP gap size as measured during sustained vowel production. These findings suggest sustained vowel production elicited on MRI may adequately characterize VP gap size in the evaluation of VP insufficiency.

Abstract Background and Aims: Recent systematic reviews and meta-analyses (SRMAs) have shown inconsistent effectiveness of FMT among IBD patients. This study aimed to appraise the evidence for clinically relevant outcomes with FMT in IBD patients using published SRMAs. Methods: We searched major databases from inception through Nov 2023 to identify SRMAs assessing the effectiveness of FMT in IBD patients. Primary outcomes included clinical remission, clinical response, endoscopic remission/response, a composite endpoint, and adverse effects. We included SRMAs investigating FMT's effect in IBD patients using RCTs and observational studies data. Methodological quality and evidence certainty were assessed using AMSTAR 2 and GRADE. Results: Out of 106 citations, 16 SRMAs were included with varying study sizes (2 to 60 primary studies) and participants (112 to 1169 per SRMA). Five SRMAs assessed FMT in IBD, while 11 focused on Ulcerative Colitis (UC). Seven SRMAs included RCTs only, and nine included both RCTs and observational studies. Methodological quality was critically low in 9 SRMAs (56%) and low in 7 studies (44%). FMT showed clinical remission benefit in all 16 SRMAs, with varying certainty: 3 high, 4 moderate, 4 low, and 5 very low. Endoscopic remission/response was reported in 5 meta-analyses on UC, with 1 high, 3 moderate, and 1 very low certainty. Combined clinical remission and endoscopic response were reported in 3 SRMAs on UC, with 1 low and 2 moderate certainty. Adverse events were reported in 6 SRMAs, with 1 high, 3 moderate, 1 low, and 1 very low certainty. Conclusion: Current evidence shows potential benefits of FMT in IBD, particularly UC, supported by significant associations in 16 meta-analyses. However, poor methodological quality and variability in evidence certainty call for high-quality RCTs to strengthen the evidence.