The Evolution of Nadofaragene Firadenovec: A Review and the Path Forward.

BACKGROUND: The intravesical gene therapy nadofaragene firadenovec (rAd-IFNα/Syn3) was FDA approved in 2022 for non-muscle invasive bladder cancer (NMIBC) unresponsive to frontline treatment with BCG, and the first gene therapy developed for bladder cancer. This non-replicating recombinant adenovirus vector delivers a copy of the human interferon alpha-2b gene into urothelial and tumor cells, causing them to express this pleotropic cytokine with potent antitumor effects. OBJECTIVE: To provide a historical overview describing how several decades of preclinical and clinical studies investigating the role of interferon in the treatment of bladder cancer ultimately led to the development of gene therapy with nadofaragene for NMIBC. METHODS: We conducted a review of the literature using PubMed, Google Scholar, and ClinicalTrials.gov to summarize our knowledge of the evolution of interferon-based therapy in NMIBC. RESULTS: The FDA approval of this therapy represents an important landmark in urologic oncology and several decades of research dedicated to the study of interferon's direct and indirect antitumor properties in NMIBC. The data gathered from the phase 1, 2, and 3 clinical trials continue to provide additional insights into the precise mechanisms underlying both the efficacy of and resistance to nadofaragene. CONCLUSIONS: Nadofaragene leverages the cytotoxic, anti-angiogenic, and immune-modulatory roles of interferon to effectively treat NMIBC that is resistant to BCG. Ongoing studies of resistance mechanisms and prognostic biomarkers have been promising; these will ultimately improve patient selection and allow for the modulation of factors in the tumor or immune microenvironment to further increase therapeutic response.

Perspectives of US Medical Residency and Fellowship Applicants on No-Stakes Campus Visits.

Background Virtual interviews may limit an applicant's ability to ascertain the culture of a training program. No-stakes campus visits (NSCVs) have been offered but their value is unknown. Objective The purpose of our study was to determine factors that influence applicants' rank lists and determine barriers to and perceptions of NSCVs and their impact on applicants' final rank lists. Methods All interviewed applicants of graduate medical education (GME) programs who agreed to participate in the study were emailed a survey after the 2023 National Resident Matching Program Match. The survey contained sections on demographics, perspectives on factors affecting ranking decisions, and perceptions of NSCVs. Results Of 796 applicants, 183 (22.9%) who interviewed at 16 different Mayo Clinic GME programs responded to the survey. Of 131 respondents who answered whether they accepted an NSCV offer, 39 (29.8%) accepted. Of 35 respondents who answered whether they thought attending NSCVs impacted their rank, 19 (54.3%) were either uncertain or said yes. Of 34 respondents who answered whether the NSCV influenced their ranking of the program, 16 (47.1%) said their rank did not change, 12 (35.3%) said they ranked the program higher, and 5 (14.7%) said they ranked the program lower. For respondents who did not attend NSCVs, financial burden and lack of time were primary reasons. Conclusions NSCVs are perceived positively by most respondents. Many either believed they influenced their position on the program's rank list or were unsure. Most respondents said NSCVs either improved or did not change their ranking of the program.

Stenting versus medical treatment alone for symptomatic intracranial artery stenosis: a preplanned pooled individual patient data analysis.

BACKGROUND: Whether the safety and efficacy of percutaneous transluminal angioplasty and stenting (PTAS) is significantly different from that of medical treatment alone for symptomatic intracranial arterial stenosis (ICAS) is debatable. A study was undertaken to determine the safety and efficacy of both treatments for symptomatic ICAS. METHODS: This preplanned pooled individual patient data analysis included 400 participants treated with PTAS and 409 treated with medical treatment alone in two large multicenter randomized clinical trials (SAMMPRIS and CASSISS). Patients were treated with PTAS using a self-expanding stent or medical treatment alone. The primary outcome was stroke or death within 30 days, or ischemic stroke in the territory of the qualifying artery more than 30 days after enrollment. RESULTS: Individual data were obtained for 809 patients, 451 from SAMMPRIS and 358 from CASSISS. 400 participants were randomly assigned to the PTAS group and 409 to the medical group. The risk of the primary outcome was not significant between the PTAS and medical groups (17.5% vs 13.2%; HR 1.37 (95% CI 0.96 to 1.95), P=0.08). However, the risk of stroke or death within 30 days was higher in the PTAS group (10.5% vs 4.2%; HR 2.62 (95% CI 1.49 to 4.61), P<0.001). Patients of white ethnicity (HR 1.97, 95% CI 1.17 to 3.31) and those with hyperlipidemia (HR 2.04, 95% CI 1.27 to 3.26) or a transient ischemic attack (TIA) (HR 2.19, 95% CI 1.08 to 4.45) were at higher risk for PTAS. CONCLUSIONS: PTAS poses an increased risk of short-term stroke/death and therefore is not advised as primary treatment for symptomatic ICAS. A balance exists between stroke risks and revascularization benefits. For patients with asymptomatic ICAS of white ethnicity and those with hyperlipidemia or a history of TIA, a thorough assessment is warranted before considering PTAS. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00576693, NCT01763320.

Carbon Dots in Photodynamic/Photothermal Antimicrobial Therapy.

Antimicrobial resistance (AMR) presents an escalating global challenge as conventional antibiotic treatments become less effective. In response, photodynamic therapy (PDT) and photothermal therapy (PTT) have emerged as promising alternatives. While rooted in ancient practices, these methods have evolved with modern innovations, particularly through the integration of lasers, refining their efficacy. PDT harnesses photosensitizers to generate reactive oxygen species (ROS), which are detrimental to microbial cells, whereas PTT relies on heat to induce cellular damage. The key to their effectiveness lies in the utilization of photosensitizers, especially when integrated into nano- or micron-scale supports, which amplify ROS production and enhance antimicrobial activity. Over the last decade, carbon dots (CDs) have emerged as a highly promising nanomaterial, attracting increasing attention owing to their distinctive properties and versatile applications, including PDT and PTT. They can not only function as photosensitizers, but also synergistically combine with other photosensitizers to enhance overall efficacy. This review explores the recent advancements in CDs, underscoring their significance and potential in reshaping advanced antimicrobial therapeutics.

Gill raker and pyloric caeca counts differ between Arctic char (Salvelinus alpinus) and Dolly Varden (S. malma) populations across their ranges.

Meristic characters are often used to differentiate between closely related forms, morphs, and species of fishes, and lend insight into ecology and post-glacial recolonization in taxa with complicated or contentious phylogenies, including the genus Salvelinus. Previous studies of meristics in Salvelinus have focused mostly on individual populations. We collated data from 456 populations/systems across the North American and Russian Arctic and sub-Arctic, and found that counts of pyloric caeca and gill rakers differed consistently between fish visually and/or genetically identified as Arctic char and Dolly Varden across their distributional ranges.

Utilizing connectome fingerprinting functional MRI models for motor activity prediction in presurgical planning: A feasibility study.

Presurgical planning prior to brain tumor resection is critical for the preservation of neurologic function post-operatively. Neurosurgeons increasingly use advanced brain mapping techniques pre- and intra-operatively to delineate brain regions which are "eloquent" and should be spared during resection. Functional MRI (fMRI) has emerged as a commonly used non-invasive modality for individual patient mapping of critical cortical regions such as motor, language, and visual cortices. To map motor function, patients are scanned using fMRI while they perform various motor tasks to identify brain networks critical for motor performance, but it may be difficult for some patients to perform tasks in the scanner due to pre-existing deficits. Connectome fingerprinting (CF) is a machine-learning approach that learns associations between resting-state functional networks of a brain region and the activations in the region for specific tasks; once a CF model is constructed, individualized predictions of task activation can be generated from resting-state data. Here we utilized CF to train models on high-quality data from 208 subjects in the Human Connectome Project (HCP) and used this to predict task activations in our cohort of healthy control subjects (n = 15) and presurgical patients (n = 16) using resting-state fMRI (rs-fMRI) data. The prediction quality was validated with task fMRI data in the healthy controls and patients. We found that the task predictions for motor areas are on par with actual task activations in most healthy subjects (model accuracy around 90%-100% of task stability) and some patients suggesting the CF models can be reliably substituted where task data is either not possible to collect or hard for subjects to perform. We were also able to make robust predictions in cases in which there were no task-related activations elicited. The findings demonstrate the utility of the CF approach for predicting activations in out-of-sample subjects, across sites and scanners, and in patient populations. This work supports the feasibility of the application of CF models to presurgical planning, while also revealing challenges to be addressed in future developments. PRACTITIONER POINTS: Precision motor network prediction using connectome fingerprinting. Carefully trained models' performance limited by stability of task-fMRI data. Successful cross-scanner predictions and motor network mapping in patients with tumor.

Correlative Analysis of ATM, RB1, ERCC2, and FANCC Mutations and Pathologic Complete Response After Neoadjuvant Chemotherapy in Patients with Muscle-invasive Bladder Cancer: Results from the SWOG S1314 Trial.

We previously reported that tumors harboring any one of four gene mutations (ATM, RB1, FANCC, or ERCC2) were likely to respond to neoadjuvant cisplatin-based chemotherapy (NAC), resulting in cancer-free surgical specimens at the time of cystectomy (pT0). Here, we report our validation of this finding. Using the CARIS 592 Gene Panel (Caris Life Sciences, Phoenix, AZ, USA), we analyzed 105 pre-NAC tumor specimens from a large multicenter trial (S1314) of either neoadjuvant gemcitabine and cisplatin (GC), or dose-dense methotrexate, vinblastine, Adriamycin, and cisplatin (DDMVAC). We found that a mutation in any one of these four genes predicted for pT0 at surgery (odds ratio = 5.36; 95% confidence interval [CI] 2.05, 14.02; two-sided p = 0.0006). The biomarker was better at predicting the presence of disease (negative predictive value for pT0 86%; 95% CI 73%, 94%) than the absence of disease (positive predictive value for pT0 48%; 95% CI 35%, 62%). There was no evidence of an interaction between the treatment arm (DDMVAC vs GC) and the genetic variant in terms of pT0. When combined with clinical assessment, these findings help inform patient selection for bladder preservation after cisplatin-based chemotherapy. PATIENT SUMMARY: A common standard of care for patients with muscle-invasive bladder cancer is neoadjuvant chemotherapy (NAC) followed by cystectomy to achieve cure. We previously discovered that specific DNA mutations in tumor samples collected at initial biopsy (transurethral resection of a bladder tumor) were predictive of a complete response to NAC. In other words, patients with these mutations were more likely to have a bladder found to be cancer free after surgery. In this study, we analyzed a larger set of tumor samples from a national clinical trial of chemotherapy followed by cystectomy to validate these earlier findings. We conclude that this biomarker test, when combined with careful clinical assessment, can be used to allocate patients to careful bladder surveillance instead of surgery. This hypothesis has been tested in the RETAIN trial presented previously (NCT02710734).

Biomarkers of immunotherapy in glioblastoma.

Glioblastoma (GBM) is the most common primary brain cancer, comprising half of all malignant brain tumors. Patients with GBM have a poor prognosis, with a median survival of 14-15 months. Current therapies for GBM, including chemotherapy, radiotherapy, and surgical resection, remain inadequate. Novel therapies are required to extend patient survival. Although immunotherapy has shown promise in other cancers, including melanoma and non-small lung cancer, its efficacy in GBM has been limited to subsets of patients. Identifying biomarkers of immunotherapy response in GBM could help stratify patients, identify new therapeutic targets, and develop more effective treatments. This article reviews existing and emerging biomarkers of clinical response to immunotherapy in GBM. The scope of this review includes immune checkpoint inhibitor and antitumoral vaccination approaches, summarizing the variety of molecular, cellular, and computational methodologies that have been explored in the setting of anti-GBM immunotherapies.

Impact of a Participatory Wellness Continuing Medical Education Program on Physician Burnout and Well-Being.

OBJECTIVE: Examine the impact of a participatory wellness continuing medical education (CME) program on physician burnout, wellness, and well-being. METHODS: Physicians attending a three-day wellness CME program. Self-reported questionnaires at baseline with paired analyses at 26-week follow-up. RESULTS: Compared to baseline, at 26 weeks there were decreases in burnout (P < .001, ES -0.68), red meat consumption (P = .02, ES -0.29), and current stress levels (P < .001, ES -0.50). There were increases in fruit/vegetable consumption (P < .001, ES 0.55), energy levels at work (P < .001, ES 0.60) and at home (P < .001, ES 0.66), quality of life (P < .001, ES 0.53), and confidence (P < .001, ES 0.89) and frequency (P = .01, ES 0.32) of counseling patients on wellness. CONCLUSION: Attendance at this participatory wellness CME program was associated with improved physician burnout, health behaviors in diet, stress, energy, quality of life, and wellness counseling.

Stomatal dynamics in Alloteropsis semialata arise from the evolving interplay between photosynthetic physiology, stomatal size and biochemistry.

C4 plants are expected to have faster stomatal movements than C3 species because they tend to have smaller guard cells. However, little is known about how the evolution of C4 photosynthesis influences stomatal dynamics in relation to guard cell size and environmental factors. We studied photosynthetically diverse populations of the grass Alloteropsis semialata, showing that the origin of C4 photosynthesis in this species was associated with a shortening of stomatal guard and subsidiary cells. However, for a given cell size, C4 and C3-C4 intermediate individuals had similar or slower light-induced stomatal opening speeds than C3 individuals. Conversely, when exposed to decreasing light, stomata in C4 plants closed as fast as those in non-C4 plants. Polyploid formation in some C4 plants led to larger stomatal cells and was associated with slower stomatal opening. Conversely, diversification of C4 diploid plants into wetter environments was associated with an acceleration of stomatal opening. Overall, there was significant relationship between light-saturated photosynthesis and stomatal opening speed in the C4 plants, implying that photosynthetic energy production was limiting for stomatal opening. Stomatal dynamics in this wild grass therefore arise from the evolving interplay between photosynthetic physiology and the size and biochemical function of stomatal complexes.

Multimodal Analysis of the Retinal Manifestations of Tuberous Sclerosis Complex: A Case Series.

BACKGROUND AND OBJECTIVE: We used a multi-modal imaging approach including fundus fluorescein angiography (FFA) to assess the retinal lesions in tuberous sclerosis complex (TSC) and evaluate their correlation with intracranial tuber burden on magnetic resonance imaging (MRI). PATIENTS AND METHODS: Participants with TSC underwent bilateral fundus photography, optical coherence tomography (OCT), infrared (IR) imaging, and FFA. Participants' most recent MRI brain scans were analyzed to determine intracranial tuber load. RESULTS: Nine participants were included. OCT identified all retinal astrocytic hamartoma (RAH) lesions, IR identified 75%, fundus photography identified 63%, and FFA detected just 57%. On FFA, 20% of flat-type hamartomas and all multi-nodular and transitional types were hyperfluorescent. There were significant positive correlations between the quantities of intracranial tubers and all TSC-retinal lesions (r = 0.8, P < 0.01) and all RAH lesions (r = 0.8, P = 0.01). CONCLUSIONS: A multimodal imaging-based approach with fundal photography, IR imaging, and OCT should be used to assess the retina in TSC as it may indicate the intracranial tuber burden. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

Identifying genomic regions associated with C4 photosynthetic activity and leaf anatomy in Alloteropsis semialata.

C4 photosynthesis is a complex trait requiring multiple developmental and metabolic alterations. Despite this complexity, it has independently evolved over 60 times. However, our understanding of the transition to C4 is complicated by the fact that variation in photosynthetic type is usually segregated between species that diverged a long time ago. Here, we perform a genome-wide association study (GWAS) using the grass Alloteropsis semialata, the only known species to have C3, intermediate, and C4 accessions that recently diverged. We aimed to identify genomic regions associated with the strength of the C4 cycle (measured using δ13C), and the development of C4 leaf anatomy. Genomic regions correlated with δ13C include regulators of C4 decarboxylation enzymes (RIPK), nonphotochemical quenching (SOQ1), and the development of Kranz anatomy (SCARECROW-LIKE). Regions associated with the development of C4 leaf anatomy in the intermediate individuals contain additional leaf anatomy regulators, including those responsible for vein patterning (GSL8) and meristem determinacy (GIF1). The parallel recruitment of paralogous leaf anatomy regulators between A. semialata and other C4 lineages implies the co-option of these genes is context-dependent, which likely has implications for the engineering of the C4 trait into C3 species.

Multi-generational benefits of genetic rescue.

Genetic rescue-an increase in population fitness following the introduction of new alleles-has been proven to ameliorate inbreeding depression in small, isolated populations, yet is rarely applied as a conservation tool. A lingering question regarding genetic rescue in wildlife conservation is how long beneficial effects persist in admixed populations. Using data collected over 40 years from 1192 endangered Florida panthers (Puma concolor coryi) across nine generations, we show that the experimental genetic rescue implemented in 1995-via the release of eight female pumas from Texas-alleviated morphological, genetic, and demographic correlates of inbreeding depression, subsequently preventing extirpation of the population. We present unequivocal evidence, for the first time in any terrestrial vertebrate, that genetic and phenotypic benefits of genetic rescue remain in this population after five generations of admixture, which helped increase panther abundance (> fivefold) and genetic effective population size (> 20-fold). Additionally, even with extensive admixture, microsatellite allele frequencies in the population continue to support the distinctness of Florida panthers from other North American puma populations, including Texas. Although threats including habitat loss, human-wildlife conflict, and infectious diseases are challenges to many imperiled populations, our results suggest genetic rescue can serve as an effective, multi-generational tool for conservation of small, isolated populations facing extinction from inbreeding.

A Pragmatic Approach to Assessing Supervisor Leadership Capability to Support Healthcare Worker Well-Being.

GOAL: We sought to build upon previous studies that have demonstrated how healthcare workers' ratings of their immediate supervisor's leadership capabilities relate to their well-being and job satisfaction. METHODS: In 2022, we analyzed cross-sectional data from 1,780 physicians and 39,896 allied health professionals (collected in 2017) and 729 residents (collected in 2019), as well as longitudinal data from 1,632 physicians (collected from 2015 to 2017), to identify a psychometrically strong, broadly applicable, actionable, and low-burden approach to assessing supervisor leadership capability to support healthcare worker well-being. PRINCIPAL FINDINGS: The magnitude of association between our 1-, 2-, 3-, and 9-item leadership indexes and burnout, and between our 1-, 2-, 3-, and 9-item leadership indexes and satisfaction with the organization were similar to each other in the cross-sectional and longitudinal cohorts and across diverse groups of healthcare workers, including physicians, residents, and allied health professionals. The likelihood ratio for a high leadership score increased with an increasing score for each leadership measure. The area under the receiver operating characteristic curve for the 1-, 2-, and 3-item measures for a high leadership score was 0.9349, 0.9672, and 0.9819, respectively. PRACTICAL APPLICATIONS: A single item assessing perceptions of leadership capability efficiently provides useful information about leadership qualities of healthcare workers' immediate supervisors. The inclusion of this item in healthcare worker surveys may be useful for evaluating interventions and galvanizing organizational action to support healthcare worker well-being.

Engineering a nanoscale liposome-in-liposome for in situ biochemical synthesis and multi-stage release.

Soft-matter nanoscale assemblies such as liposomes and lipid nanoparticles have the potential to deliver and release multiple cargos in an externally stimulated and site-specific manner. Such assemblies are currently structurally simplistic, comprising spherical capsules or lipid clusters. Given that form and function are intertwined, this lack of architectural complexity restricts the development of more sophisticated properties. To address this, we have devised an engineering strategy combining microfluidics and conjugation chemistry to synthesize nanosized liposomes with two discrete compartments, one within another, which we term concentrisomes. We can control the composition of each bilayer and tune both particle size and the dimensions between inner and outer membranes. We can specify the identity of encapsulated cargo within each compartment, and the biophysical features of inner and outer bilayers, allowing us to imbue each bilayer with different stimuli-responsive properties. We use these particles for multi-stage release of two payloads at defined time points, and as attolitre reactors for triggered in situ biochemical synthesis.

Measuring Documentation Burden in Healthcare.

BACKGROUND: The enactment of the Health Information Technology for Economic and Clinical Health Act and the wide adoption of electronic health record (EHR) systems have ushered in increasing documentation burden, frequently cited as a key factor affecting the work experience of healthcare professionals and a contributor to burnout. This systematic review aims to identify and characterize measures of documentation burden. METHODS: We integrated discussions with Key Informants and a comprehensive search of the literature, including MEDLINE, Embase, Scopus, and gray literature published between 2010 and 2023. Data were narratively and thematically synthesized. RESULTS: We identified 135 articles about measuring documentation burden. We classified measures into 11 categories: overall time spent in EHR, activities related to clinical documentation, inbox management, time spent in clinical review, time spent in orders, work outside work/after hours, administrative tasks (billing and insurance related), fragmentation of workflow, measures of efficiency, EHR activity rate, and usability. The most common source of data for most measures was EHR usage logs. Direct tracking such as through time-motion analysis was fairly uncommon. Measures were developed and applied across various settings and populations, with physicians and nurses in the USA being the most frequently represented healthcare professionals. Evidence of validity of these measures was limited and incomplete. Data on the appropriateness of measures in terms of scalability, feasibility, or equity across various contexts were limited. The physician perspective was the most robustly captured and prominently focused on increased stress and burnout. DISCUSSION: Numerous measures for documentation burden are available and have been tested in a variety of settings and contexts. However, most are one-dimensional, do not capture various domains of this construct, and lack robust validity evidence. This report serves as a call to action highlighting an urgent need for measure development that represents diverse clinical contexts and support future interventions.

Addressing the Evidence Gap in Aneurysmal Subarachnoid Hemorrhage: The Need for a Pragmatic Randomized Trial Platform.

Aneurysmal subarachnoid hemorrhage (aSAH) occurs less often than other stroke types but affects younger patients, imposing a disproportionately high burden of long-term disability. Although management advances have improved outcomes over time, relatively few aSAH treatments have been tested in randomized clinical trials (RCTs). One lesson learned from COVID-19 is that trial platforms can facilitate the efficient execution of multicenter RCTs even in complex diseases during challenging conditions. An aSAH trial platform with standardized eligibility criteria, randomization procedures, and end point definitions would enable the study of multiple targeted interventions in a perpetual manner, with treatments entering and leaving the platform based on predefined decision algorithms. An umbrella institutional review board protocol and clinical trial agreement would allow individual arms to be efficiently added as amendments rather than stand-alone protocols. Standardized case report forms using the National Institutes of Health/National Institute of Neurological Disorders and Stroke common data elements and general protocol standardization across arms would create synergies for data management and monitoring. A Bayesian analysis framework would emphasize frequent interim looks to enable early termination of trial arms for futility, common controls, borrowing of information across arms, and adaptive designs. A protocol development committee would assist investigators and encourage pragmatic designs to maximize generalizability, reduce site burden, and execute trials efficiently and cost-effectively. Despite decades of steady clinical progress in the management of aSAH, poor patient outcomes remain common, and despite the increasing availability of RCT data in other fields, it remains difficult to perform RCTs to guide more effective care for aSAH. The development of a platform for pragmatic RCTs in aSAH would help close the evidence gap between aSAH and other stroke types and improve outcomes for this important disease with its disproportionate public health burden.