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Investigation into the Roles of AAV Genetic Elements During Transduction
No full textUnpublished data under review titled "Analyses of circularized episomal rAAV genomes reveal high rates of truncated and deleted ITRs and transgene cassettes"The first inverted terminal repeat (ITR) elements were sequenced over 40 years ago and are the only obligatory sequences required in cis for therapeutic recombinant of adeno-associated virus (rAAV) production. Besides playing roles in replication and packaging AAV genomes, the ITRs and the ITR-proximal regions (IPRs) are known to have enhancer and/or promoter-like activities that vary by their associated AAV serotypes. ITRs also impact transduction through recombination and circularization of the genome into episomes, which persist within the cell and confer prolonged transgene expression. Episomes exist in different conformations, as monomers, dimers, and larger concatemers. However, the exact mechanism for how they are formed have not been extensively explored. We generated vectors with different ITRs at the 5’ and 3’ of the vector genome and with and without IPRs to test their impact on transgene expression and found that IPRs significantly increased transgene expression in the liver. Serendipitously, we were also able to identify the region within the IPR that is affiliated with increased expression, and a region that seems to repress expression. Circularized episomes were also characterized in its entirety for the first time through long-read sequencing. Nanopore and single molecule, real-time sequencing showed that contrary to the current dogma, only a small percentage of episomes contained intact ITRs post-entry and over 50% of the episomes did not retain any ITR sequences. This study has illuminated the potential for ITRs and IPRs in designing gene therapy vectors and has shed light on mechanisms behind episome formation for AAV.Interdisciplinary Graduate ProgramNo embarg
Echocardiography parameters and cardiac geometry in pregnancy by race and ethnicity
No full textObjectives: The objective of this study was to assess transthoracic echocardiography (TTE) parameters in pregnancy by race and ethnicity.
Methods: We performed a retrospective cohort study of pregnant individuals without cardiovascular disease who underwent a perinatal TTE between October 2017 and May 2022. Demographics and echocardiographic parameters were compared by race/ethnicity. Multivariate regression analysis was performed for TTE parameters after adjusting for age and hypertension.
Results: During the study period, 369 individuals had TTEs with a mean age of 31.8 ± 6.0 years old. Subjects were 55.3% White, 24.7% Hispanic, 14.1% Black, and 6.0% Asian. TTE parameters of left ventricular (LV) ejection fraction and LV mass index differed by race/ethnicity, though no difference was seen in cardiac geometry.
Conclusion: The differences in TTE parameters may not be clinically significant as most values fall within normal clinical ranges. Further prospective studies are needed to better evaluate cardiac outcomes by differences in echocardiographic parameters in pregnancy.No embarg
Randomised controlled trial of audit-and-feedback strategies to reduce imaging overutilisation in the emergency department
No full textBackground: Evaluation of neck trauma is a common reason for emergency department (ED) visits. There are several validated clinical decision rules, such as the National Emergency X-Radiography Utilization Study (NEXUS) Cervical Spine (C-spine) Rule, that can be used to risk stratify these patients and identify low-risk patients who do not require CT imaging. Overutilisation of CT imaging exposes patients to unnecessary radiation, impairs hospital throughput and increases healthcare costs. Various audit-and-feedback strategies have been described in other settings, but it is not known whether these strategies are effective for reducing imaging overutilisation in the ED. Additionally, the effectiveness of face-to-face feedback strategies as compared with digital feedback strategies for addressing this problem has not been previously evaluated. The aim of this study was to compare audit-and-feedback strategies to reduce CT overutilisation in the ED.
Methods: This was a prospective randomised controlled trial, in which emergency medicine clinicians were randomised into three arms to receive digital feedback, hybrid face-to-face/digital feedback or no feedback. Each clinician received three rounds of feedback on patient encounters in which they ordered a CT of the C-spine. Patient encounters were retrospectively reviewed to determine each clinician's overutilisation rate, defined as the percentage of patients who underwent CT of the C-spine despite being classified as low risk by NEXUS criteria.
Results: A total of 78 emergency medicine clinicians were randomised into three arms. Baseline overutilisation rates for each group were 46%-47% of CT of the C-spine studies. After three rounds of audit-and-feedback strategy, the clinicians in the digital feedback group had an overutilisation rate of 33%, compared with 44% in the control group (p=0.020). The hybrid feedback group had an overutilisation rate of 36% (p=0.055 vs control; p=0.577 vs digital feedback). Over the study period, the digital group saw a reduction of 1.26 CT of the C-spine studies per provider per month (p=0.049), and the hybrid feedback group saw a reduction of 1.43 CTs per provider per month (p=0.044).
Conclusion: A digital audit-and-feedback strategy is effective for reducing overutilisation of CT imaging of the C-spine in the ED, while the effectiveness of a hybrid strategy requires further investigation.No embarg
Higher risk of recurrence in partially thrombosed cerebral aneurysms post-WEB (Woven EndoBridge) device treatment: insights from the WorldWideWEB Consortium registry
No full textBackground: The Woven EndoBridge (WEB) device is a prevalent treatment for intracranial aneurysms. While many studies have assessed the obliteration rate post-WEB embolization, few have focused on long-term outcomes in partially thrombosed aneurysms.
Objective: To assess whether partially thrombosed aneurysms are at higher risk of recurrence or retreatment following WEB embolization compared with non-thrombosed aneurysms.
Methods: We evaluated data from 22 academic institutions, focusing on previously untreated cerebral aneurysms treated with the WEB device. Logistic regression was utilized to analyze factors predicting long-term aneurysm obliteration and retreatment necessity.
Results: Among 1303 patients, 26 presented with a partially thrombosed aneurysm. In the partially thrombosed group, the mean aneurysm maximal diameter was 10.7±4 mm with a neck ratio of 1.99±1.19 mm, larger than in the control group where the mean aneurysm maximal diameter was 6.81±2.37 mm with a neck ratio of 1.64±0.51 mm (P<0.001 for both maximal diameter and neck ratio). At the final follow-up, partially thrombosed aneurysms treated by the WEB device had a 38.5% retreatment rate, compared with 7.0% for non-thrombosed aneurysms (P<0.001). Among partially thrombosed aneurysms, the Raymond-Roy type IIIa/b occlusion rate was higher (38.5% vs 9.9%, P<0.001). On multivariate analysis, partially thrombosed aneurysms compared with non-thrombosed aneurysms had an increased rate of retreatment (OR 3.64, 95% CI 1.28 to 10.1).
Conclusion: Partially thrombosed aneurysms are associated with a poorer occlusion rate and a higher rate of retreatment following WEB embolization. For partially thrombosed aneurysms, the WEB device appears suboptimal as a first-line treatment, and therefore alternative techniques should be prioritized.No embarg
Long-term safety and efficacy of the FRED X flow diverter for intracranial aneurysms: a multicenter study of 154 patients
No full textObjective: The Flow-Redirection Endoluminal Device X (FRED X) is a newer generation flow diverter with surface modifications aimed at minimizing thrombogenicity. At present, data on its long-term efficacy are limited. This multicenter study presents the largest series within the United States describing the device's efficacy, safety, and long-term outcomes in treating cerebral aneurysms of varying morphology.
Methods: Patients treated with the FRED X for a cerebral aneurysm between February 2022 and February 2024 at 6 high-volume centers across the United States were included. Data were collected regarding demographics, clinical presentation, and procedural efficacy. Angiographic and clinical follow-up outcomes were assessed at 6 and 12 months.
Results: A total of 154 patients with 162 aneurysms were treated with 164 FRED X devices over the study period. Overall, 81.8% of the cohort was female with a mean age of 56.8 years. The authors observed satisfactory rates (≥ 99.3%) of device deployment and good wall apposition and neck coverage. One hundred forty-seven (95.5%) patients were functionally independent at discharge (modified Rankin Scale scores 0-2). Rates of adequate occlusion (Raymond-Roy Occlusion Scale score I or II) increased from 84.2% at 6 months to 83.5% at the 12-month follow-up, while rates of in-stent stenosis decreased. All patients (100%) who underwent follow-up were functionally independent at 6 months, and 95.9% were functionally independent at 12 months.
Conclusions: This multicenter cohort study demonstrates the ease of FRED X deployment with an adequate safety profile, with low rates of procedural complications and favorable outcomes on follow-up. Rates of aneurysm occlusion increased over time, with a subsequent decrease in stent-associated complications.No embarg
Deep cervical lymph node volume decreases following B-cell depletion therapy
Get PDFThe deep cervical lymph nodes (dCLNs) are sites of immune presentation and B-cell maturation from the brain, and potentially involved in mechanisms of neuroinflammation. We hypothesized a reduction in dCLN volume following B-cell depletion therapy. In a retrospective cohort, we segmented bilateral dCLN from T2-FLAIR MRI at "prebaseline," "baseline," and "post-B-cell depletion" timepoints. Using a multivariable mixed-effect regression model, we find no changes in dCLN volumes between prebaseline and baseline timepoints ( > 0.05), but a significant decrease of 158 mm following ocrelizumab infusion ( = -3.3, = 0.005). Baseline use of a disease-modifying therapy was also significantly associated with a smaller dCLN volume and attenuated the effects of B-cell depletion. These results are congruent with therapeutic mechanisms, although other alternative explanations for reductions in dCLN volumes cannot be ruled out based on this data. Deep CLN represent potential imaging biomarkers of pharmacological or clinical utility and warrant further investigation.No embarg
"It's within your own power": shared decision-making to support transitions to buprenorphine
No full textIntroduction: Buprenorphine is an effective first-line treatment for opioid use disorder (OUD) that substantially reduces morbidity and mortality. For patients using illicitly-manufactured fentanyl (IMF), however, transitioning to buprenorphine can be challenging. Evidence is lacking for how best to make this transition in the outpatient setting. A shared decision-making (SDM) approach has been found to benefit patients with OUD but has not been studied for buprenorphine initiation. We sought to explore participants' experiences with a SDM approach to buprenorphine initiation.
Methods: Participants were seeking care at a low barrier, telehealth buprenorphine clinic. Clinicians implemented a standardized SDM approach whereby they offered patients using IMF three options for buprenorphine initiation (traditional, low-dose, and QuickStart). They elicited patient goals and preferences and discussed the pros and cons of each method to come to a shared decision. Patients meeting study criteria were invited to participate in semi-structured qualitative interviews 1-2 weeks after the initial visit. Interviews focused on experiences with the clinical visit, suggestions for enhancing the treatment experience, and patient factors affecting the method they chose. Interviews were coded and analyzed using reflexive thematic analysis.
Results: Twenty participants completed interviews. Participants' mean age was 33, they were 50% female, predominantly white (16 [80%]), and most had Medicaid insurance (19 [95%]). We identified three important themes. First, participants found SDM acceptable and a positive addition to their OUD treatment. They felt their opinion mattered and reported that SDM gave them important control over their care plan. Second, patient goals, preferences, and past experiences with buprenorphine-associated withdrawal impacted what type of buprenorphine initiation method they chose. Finally, participants had advice for clinicians to improve SDM counseling. Participant recommendations included ensuring patients are informed that withdrawal (or "feeling sick") can occur with any initiation method, that buprenorphine will eventually "block" fentanyl effects once at a high enough dose, and that clinicians provide specific advice for tapering off fentanyl during a low dose initiation.
Conclusions: For patients with OUD using IMF, shared decision-making is an acceptable approach to buprenorphine initiation in the outpatient setting. It can enhance patient autonomy and lead to an individualized approach to OUD care.No embarg
The Other Option: Examining Write-in Responses to Sexual Orientation and Gender Identity Surveys
No full textBackground: When asked to affiliate with listed gender identity and/or sexual orientation options in large population surveys, increasing proportions of respondents indicate “other” and write in their identities that are not captured by the traditional multiple-choice options. These “other” responses often receive little inquiry and are often categorized as incomplete data or as though respondents identify with a sexual and/or gender minority identity.
Objective: The purpose of this qualitative study is to identify categories that are left out of sexual orientation and gender identity (SOGI) questionnaires using survey items from the Healthy Minds Study, a survey of over 935,000 undergraduate and graduate college and university students in the United States.
Methods: A diverse panel of seven reviewers differing in terms of age, SOGI status, and race and ethnicity was established to examine verbatim “Other” responses to SOGI survey items from the Healthy Minds Study. Panelists were prompted to develop their own taxonomies to describe and categorize the responses they encountered. After convening to discuss their findings, panelists established a shared taxonomy and re-categorized the survey responses into the shared taxonomy, with inter-rater reliability estimated as a qualitative parameter. Finally, quantitative descriptions of the response-category distributions and associated survey respondents’ demographic descriptors were generated.
Results: Preliminary results show several large categories routinely left out of SOGI answer choices. These often include individual descriptions of attraction that do not depend on the identity of partners, such as asexuality and polyamory, as well as many different descriptions for individuals attracted to partners of multiple genders, such as queer or pansexual. Additionally, there are a large number of respondents using the write-in option to express political opinions, transphobia, or a desire to see changes in the way the questions are worded.
Conclusions: Developing a qualitative understanding of the identities that are currently being left out and largely unexamined can inform future survey development, increase dataset accuracy, and improve participants’ subjective experience. This study presents the opportunity to more accurately capture the broad spectrum of sexual orientation and gender identities on surveys which will both help researchers to better understand the experiences of all respondents, and allow participants the opportunity to correctly and concisely share their identities, ultimately leading to a more affirming and accurate process for everyone involved.NoneBiochemistry and Molecular BiotechnologyNo embarg
Silk Vista Baby for the treatment of distal anterior cerebral artery aneurysms
No full textPurpose: Treating small-caliber vessel aneurysms with flow diverters poses challenges due to narrow luminal diameters and tortuous vasculature, which complicate the navigation and deployment of conventional devices using standard microcatheters. The Silk Vista Baby (SVB, Balt, Montmorency, France) flow diverter was developed to treat intracranial aneurysms located in smaller vessels or more distal segments and is compatible with 0.017″ microcatheters. We present the largest multicenter analysis to date evaluating the outcomes of SVB use in unruptured distal anterior cerebral artery (DACA) aneurysms.
Methods: Retrospective data from 20 centers were reviewed for patients with unruptured DACA aneurysms treated with the SVB. Demographic information, clinical presentation, radiographic characteristics, complications, and outcomes were recorded.
Results: Seventy-nine patients (79 DACA aneurysms) were treated between January 2018 and December 2022; 59 were female (74.7%), and the median age was 61 years (IQR 53-67). Most aneurysms were saccular (89.9%), and 65.8% involved a branch. The median parent vessel diameter was 1.9 mm (IQR 1.7-2.1). A single stent was implanted in 97.5% of cases; 2.5% required two stents. The median imaging follow-up duration was 12 months (IQR 9.5-24). At the last follow-up, 76% of aneurysms showed complete or near-complete occlusion (O'Kelly-Marotta scale C or D, Raymond-Roy 1 or 2). Overall, thromboembolic or hemorrhagic complications occurred in 14% of patients, with two cases being symptomatic. The mortality rate was 0%, and the retreatment rate was 1.3%.
Conclusion: In this multicenter series, the SVB flow diverter represented a valuable treatment option for distal anterior cerebral artery (DACA) aneurysms.No embarg
Image-Guided Thermal Ablation of Upper Pole Renal Lesions ≤4 cm: Safety and Effectiveness
No full textPURPOSE: To compare the safety and effectiveness of image-guided thermal ablation (IGTA) for upper pole versus nonupper pole renal lesions ≤4 cm given the technical challenges of the former.
MATERIALS AND METHODS: This retrospective single-center study (2017-2024) included 115 patients (116 lesions, 41 upper pole and 75 nonupper pole) undergoing IGTA for suspected or confirmed renal cell carcinoma (RCC) ≤4 cm. Overall, 67 lesions were biopsy-confirmed RCCs (22 upper pole and 45 nonupper pole). Lesion characteristics, adverse events (AEs), and oncologic outcomes were analyzed.
RESULTS: Primary effectiveness was 100% (41/41) for upper pole lesions versus 97.3% (73/75) for nonupper pole lesions (P = .54). Grade 3 (severe) AEs occurred in 2.4% (1/41) versus 1.3% (1/75) (P > .99). Median follow-up times were 27.0 months for all patients and 24.4 months for those with biopsy-confirmed RCC. For biopsy-confirmed RCC, local tumor progression rates were 9.1% (2/22) for upper pole lesions versus 0% (0/45) for nonupper pole lesions (P = .10), and distant progression rates were 0% for both groups (P > .99). Median overall survival (OS) was 808 days versus 709 days with 3-year OS rates of 92.9% versus 87.0% (P = .22). Nephrometry scores and polar location showed no association with local progression or AEs. Lesion size was correlated with local progression (P < .01) and Grade 2 or higher AEs (P < .01).
CONCLUSIONS: IGTA for upper pole renal lesions ≤4 cm demonstrated safety and effectiveness comparable to nonupper pole lesions with similar AE rates and oncologic outcomes in this single-center cohort.No embarg