Dynamic encounters with red blood cells trigger splenic marginal zone B cell retention and function.

Spleen marginal zone (MZ) B cells are important for antibody responses against blood-borne antigens. The signals they use to detect exposure to blood are not well defined. Here, using intravital two-photon microscopy in mice, we observe transient contacts between MZ B cells and red blood cells that are in flow. We show that MZ B cells use adhesion G-protein-coupled receptor ADGRE5 (CD97) for retention in the spleen. CD97 function in MZ B cells depends on its ability to undergo autoproteolytic cleavage and signaling via Gα13 and ARHGEF1. Red blood cell expression of the CD97 ligand CD55 is required for MZ B cell homeostasis. Applying a pulling force on CD97-transfected cells using an optical C-trap and CD55+ beads leads to accumulation of active RhoA and membrane retraction. Finally, we show that CD97 deficiency leads to a reduced T cell-independent IgM response. Thus, our studies provide evidence that MZ B cells use mechanosensing to position in a manner that enhances antibody responses against blood-borne antigens.

Apoptotic contraction drives target cell release by cytotoxic T cells.

Cytotoxic T lymphocytes (CTLs) fight intracellular pathogens and cancer by identifying and destroying infected or transformed target cells1. To kill, CTLs form a specialized cytotoxic immune synapse (IS) with a target of interest and then release toxic perforin and granzymes into the interface to elicit programmed cell death2-5. The IS then dissolves, enabling CTLs to search for additional prey and professional phagocytes to clear the corpse6. While the mechanisms governing IS assembly have been studied extensively, far less is known about target cell release. Here, we applied time-lapse imaging to explore the basis for IS dissolution and found that it occurred concomitantly with the cytoskeletal contraction of apoptotic targets. Genetic and pharmacological perturbation of this contraction response indicated that it was both necessary and sufficient for CTL dissociation. We also found that mechanical amplification of apoptotic contractility promoted faster CTL detachment and serial killing. Collectively, these results establish a biophysical basis for IS dissolution and highlight the importance of mechanosensory feedback in the regulation of cell-cell interactions.

A tripartite view of the posterior cingulate cortex.

The posterior cingulate cortex (PCC) is one of the least understood regions of the cerebral cortex. By contrast, the anterior cingulate cortex has been the subject of intensive investigation in humans and model animal systems, leading to detailed behavioural and computational theoretical accounts of its function. The time is right for similar progress to be made in the PCC given its unique anatomical and physiological properties and demonstrably important contributions to higher cognitive functions and brain diseases. Here, we describe recent progress in understanding the PCC, with a focus on convergent findings across species and techniques that lay a foundation for establishing a formal theoretical account of its functions. Based on this converging evidence, we propose that the broader PCC region contains three major subregions - the dorsal PCC, ventral PCC and retrosplenial cortex - that respectively support the integration of executive, mnemonic and spatial processing systems. This tripartite subregional view reconciles inconsistencies in prior unitary theories of PCC function and offers promising new avenues for progress.

Development of 2nd generation aminomethyl spectinomycins that overcome native efflux in Mycobacterium abscessus.

Mycobacterium abscessus (Mab), a nontuberculous mycobacterial (NTM) species, is an emerging pathogen with high intrinsic drug resistance. Current standard-of-care therapy results in poor outcomes, demonstrating the urgent need to develop effective antimycobacterial regimens. Through synthetic modification of spectinomycin (SPC), we have identified a distinct structural subclass of N-ethylene linked aminomethyl SPCs (eAmSPCs) that are up to 64-fold more potent against Mab over the parent SPC. Mechanism of action and crystallography studies demonstrate that the eAmSPCs display a mode of ribosomal inhibition consistent with SPC. However, they exert their increased antimicrobial activity through enhanced accumulation, largely by circumventing efflux mechanisms. The N-ethylene linkage within this series plays a critical role in avoiding TetV-mediated efflux, as lead eAmSPC 2593 displays a mere fourfold susceptibility improvement against Mab ΔtetV, in contrast to the 64-fold increase for SPC. Even a minor shortening of the linkage by a single carbon, akin to 1st generation AmSPC 1950, results in a substantial increase in MICs and a 16-fold rise in susceptibility against Mab ΔtetV. These shifts suggest that longer linkages might modify the kinetics of drug expulsion by TetV, ultimately shifting the equilibrium towards heightened intracellular concentrations and enhanced antimicrobial efficacy. Furthermore, lead eAmSPCs were also shown to synergize with various classes of anti-Mab antibiotics and retain activity against clinical isolates and other mycobacterial strains. Encouraging pharmacokinetic profiles coupled with robust efficacy in Mab murine infection models suggest that eAmSPCs hold the potential to be developed into treatments for Mab and other NTM infections.

TCR-sequencing in cancer and autoimmunity: barcodes and beyond.

The T cell receptor (TCR) endows T cells with antigen specificity and is central to nearly all aspects of T cell function. Each naïve T cell has a unique TCR sequence that is stably maintained during cell division. In this way, the TCR serves as a molecular barcode that tracks processes such as migration, differentiation, and proliferation of T cells. Recent technological advances have enabled sequencing of the TCR from single cells alongside deep molecular phenotypes on an unprecedented scale. In this review, we discuss strengths and limitations of TCR sequences as molecular barcodes and their application to study immune responses following Programmed Death-1 (PD-1) blockade in cancer. Additionally, we consider applications of TCR data beyond use as a barcode.

Disentangling direct from indirect relationships in association networks.

Networks are vital tools for understanding and modeling interactions in complex systems in science and engineering, and direct and indirect interactions are pervasive in all types of networks. However, quantitatively disentangling direct and indirect relationships in networks remains a formidable task. Here, we present a framework, called iDIRECT (Inference of Direct and Indirect Relationships with Effective Copula-based Transitivity), for quantitatively inferring direct dependencies in association networks. Using copula-based transitivity, iDIRECT eliminates/ameliorates several challenging mathematical problems, including ill-conditioning, self-looping, and interaction strength overflow. With simulation data as benchmark examples, iDIRECT showed high prediction accuracies. Application of iDIRECT to reconstruct gene regulatory networks in Escherichia coli also revealed considerably higher prediction power than the best-performing approaches in the DREAM5 (Dialogue on Reverse Engineering Assessment and Methods project, #5) Network Inference Challenge. In addition, applying iDIRECT to highly diverse grassland soil microbial communities in response to climate warming showed that the iDIRECT-processed networks were significantly different from the original networks, with considerably fewer nodes, links, and connectivity, but higher relative modularity. Further analysis revealed that the iDIRECT-processed network was more complex under warming than the control and more robust to both random and target species removal (P < 0.001). As a general approach, iDIRECT has great advantages for network inference, and it should be widely applicable to infer direct relationships in association networks across diverse disciplines in science and engineering.

Abstract Value Encoding in Neural Populations But Not Single Neurons.

An important open question in neuroeconomics is how the brain represents the value of offers in a way that is both abstract (allowing for comparison) and concrete (preserving the details of the factors that influence value). Here, we examine neuronal responses to risky and safe options in five brain regions that putatively encode value in male macaques. Surprisingly, we find no detectable overlap in the neural codes used for risky and safe options, even when the options have identical subjective values (as revealed by preference) in any of the regions. Indeed, responses are weakly correlated and occupy distinct (semi-orthogonal) encoding subspaces. Notably, however, these subspaces are linked through a linear transform of their constituent encodings, a property that allows for comparison of dissimilar option types. This encoding scheme allows these regions to multiplex decision related processes: they can encode the detailed factors that influence offer value (here, risky and safety) but also directly compare dissimilar offer types. Together these results suggest a neuronal basis for the qualitatively different psychological properties of risky and safe options and highlight the power of population geometry to resolve outstanding problems in neural coding.SIGNIFICANCE STATEMENT To make economic choices, we must have some mechanism for comparing dissimilar offers. We propose that the brain uses distinct neural codes for risky and safe offers, but that these codes are linearly transformable. This encoding scheme has the dual advantage of allowing for comparison across offer types while preserving information about offer type, which in turn allows for flexibility in changing circumstances. We show that responses to risky and safe offers exhibit these predicted properties in five different reward-sensitive regions. Together, these results highlight the power of population coding principles for solving representation problems in economic choice.

Dorsal Anterior Cingulate Cortex: A Bottom-Up View.

The dorsal anterior cingulate cortex (dACC) has attracted great interest from neuroscientists because it is associated with so many important cognitive functions. Despite, or perhaps because of, its rich functional repertoire, we lack a single comprehensive view of its function. Most research has approached this puzzle from the top down, using aggregate measures such as neuroimaging. We provide a view from the bottom up, with a focus on single-unit responses and anatomy. We summarize the strengths and weaknesses of the three major approaches to characterizing the dACC: as a monitor, as a controller, and as an economic structure. We argue that neurons in the dACC are specialized for representing contexts, or task-state variables relevant for behavior, and strategies, or aspects of future plans. We propose that dACC neurons link contexts with strategies by integrating diverse task-relevant information to create a rich representation of task space and exert high-level and abstract control over decision and action.

Assessment of Thrombectomy versus Combined Thrombolysis and Thrombectomy in Patients with Acute Ischemic Stroke and Medium Vessel Occlusion.

Background The combination of intravenous thrombolysis (IVT) with mechanical thrombectomy (MT) may have clinical benefits for patients with medium vessel occlusion. Purpose To examine whether MT combined with IVT is associated with different outcomes than MT alone in patients with acute ischemic stroke (AIS) and medium vessel occlusion. Materials and Methods This retrospective study included consecutive adult patients with AIS and medium vessel occlusion treated with MT or MT with IVT at 37 academic centers in North America, Asia, and Europe. Data were collected from September 2017 to July 2021. Propensity score matching was performed to reduce confounding. Univariable and multivariable logistic regression analyses were performed to test the association between the addition of IVT treatment and different functional and safety outcomes. Results After propensity score matching, 670 patients (median age, 75 years [IQR, 64-82 years]; 356 female) were included in the analysis; 335 underwent MT alone and 335 underwent MT with IVT. Median onset to puncture (350 vs 210 minutes, P < .001) and onset to recanalization (397 vs 273 minutes, P < .001) times were higher in the MT group than the MT with IVT group, respectively. In the univariable regression analysis, the addition of IVT was associated with higher odds of a modified Rankin Scale (mRS) score 0-2 (odds ratio [OR], 1.44; 95% CI: 1.06, 1.96; P = .019); however, this association was not observed in the multivariable analysis (OR, 1.37; 95% CI: 0.99, 1.89; P = .054). In the multivariable analysis, the addition of IVT also showed no evidence of an association with the odds of first-pass effect (OR, 1.27; 95% CI: 0.9, 1.79; P = .17), Thrombolysis in Cerebral Infarction grades 2b-3 (OR, 1.64; 95% CI: 0.99, 2.73; P = .055), mRS scores 0-1 (OR, 1.27; 95% CI: 0.91, 1.76; P = .16), mortality (OR, 0.78; 95% CI: 0.49, 1.24; P = .29), or intracranial hemorrhage (OR, 1.25; 95% CI: 0.88, 1.76; P = .21). Conclusion Adjunctive IVT may not provide benefit to MT in patients with AIS caused by distal and medium vessel occlusion. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Wojak in this issue.

White-tailed deer population dynamics in a multipredator landscape shaped by humans.

Large terrestrial mammals increasingly rely on human-modified landscapes as anthropogenic footprints expand. Land management activities such as timber harvest, agriculture, and roads can influence prey population dynamics by altering forage resources and predation risk via changes in habitat, but these effects are not well understood in regions with diverse and changing predator guilds. In northeastern Washington state, USA, white-tailed deer (Odocoileus virginianus) are vulnerable to multiple carnivores, including recently returned gray wolves (Canis lupus), within a highly human-modified landscape. To understand the factors governing predator-prey dynamics in a human context, we radio-collared 280 white-tailed deer, 33 bobcats (Lynx rufus), 50 cougars (Puma concolor), 28 coyotes (C. latrans), and 14 wolves between 2016 and 2021. We first estimated deer vital rates and used a stage-structured matrix model to estimate their population growth rate. During the study, we observed a stable to declining deer population (lambda = 0.97, 95% confidence interval: 0.88, 1.05), with 74% of Monte Carlo simulations indicating population decrease and 26% of simulations indicating population increase. We then fit Cox proportional hazard models to evaluate how predator exposure, use of human-modified landscapes, and winter severity influenced deer survival and used these relationships to evaluate impacts on overall population growth. We found that the population growth rate was dually influenced by a negative direct effect of apex predators and a positive effect of timber harvest and agricultural areas. Cougars had a stronger effect on deer population dynamics than wolves, and mesopredators had little influence on the deer population growth rate. Areas of recent timber harvest had 55% more forage biomass than older forests, but horizontal visibility did not differ, suggesting that timber harvest did not influence predation risk. Although proximity to roads did not affect the overall population growth rate, vehicle collisions caused a substantial proportion of deer mortalities, and reducing these collisions could be a win-win for deer and humans. The influence of apex predators and forage indicates a dual limitation by top-down and bottom-up factors in this highly human-modified system, suggesting that a reduction in apex predators would intensify density-dependent regulation of the deer population owing to limited forage availability.

Use of the pRESET LITE thrombectomy device in combined approach for medium vessel occlusions: A multicenter evaluation.

PURPOSE: Our purpose was to assess the efficacy and safety of the pRESET LITE stent retriever (Phenox, Bochum, Germany), designed for medium vessel occlusion (MeVO) in acute ischemic stroke (AIS) patients with a primary MeVO. METHODS: We performed a retrospective analysis of the MAD MT Consortium, an integration of prospectively maintained databases at 37 academic institutions in Europe, North America, and Asia, of AIS patients who underwent mechanical thrombectomy with the pRESET LITE stent retriever for a primary MeVO. We subcategorized occlusions into proximal MeVOs (segments A1, M2, and P1) vs. distal MeVOs/DMVO (segments A2, M3-M4, and P2). We reviewed patient and procedural characteristics, as well as angiographic and clinical outcomes. RESULTS: Between September 2016 and December 2021, 227 patients were included (50% female, median age 78 [65-84] years), of whom 161 (71%) suffered proximal MeVO and 66 (29%) distal MeVO. Using a combined approach in 96% of cases, successful reperfusion of the target vessel (mTICI 2b/2c/3) was attained in 85% of proximal MeVO and 97% of DMVO, with a median of 2 passes (IQR: 1-3) overall. Periprocedural complications rate was 7%. Control CT at day 1 post-MT revealed a hemorrhagic transformation in 63 (39%) patients with proximal MeVO and 24 (36%) patients with DMVO, with ECASS-PH type hemorrhagic transformations occurring in 3 (1%) patients. After 3 months, 58% of all MeVO and 63% of DMVO patients demonstrated a favorable outcome (mRS 0-2). CONCLUSION: Mechanical thrombectomy using the pRESET LITE in a combined approach with an aspiration catheter appears effective for primary medium vessel occlusions across several centers and physicians.

Surgical prioritization based on decision model outcomes is not sensitive to differences between the health-related quality of life values estimates of physicians and citizens.

PURPOSE: Decision models can be used to support allocation of scarce surgical resources. These models incorporate health-related quality of life (HRQoL) values that can be determined using physician panels. The predominant opinion is that one should use values obtained from citizens. We investigated whether physicians give different HRQoL values to citizens and evaluate whether such differences impact decision model outcomes. METHODS: A two-round Delphi study was conducted. Citizens estimated HRQoL of pre- and post-operative health states for ten surgeries using a visual analogue scale. These values were compared using Bland-Altman analysis with HRQoL values previously obtained from physicians. Impact on decision model outcomes was evaluated by calculating the correlation between the rankings of surgeries established using the physicians' and the citizens' values. RESULTS: A total of 71 citizens estimated HRQoL. Citizens' values on the VAS scale were - 0.07 points (95% CI - 0.12 to - 0.01) lower than the physicians' values. The correlation between the rankings of surgeries based on citizens' and physicians' values was 0.96 (p < 0.001). CONCLUSION: Physicians put higher values on health states than citizens. However, these differences only result in switches between adjacent entries in the ranking. It would seem that HRQoL values obtained from physicians are adequate to inform decision models during crises.

The Association of Guideline-Directed Prophylaxis With Postoperative Nausea and Vomiting in Adult Patients: A Single-Center, Retrospective Cohort Study.

BACKGROUND: Consensus guidelines for postoperative nausea and vomiting (PONV) prophylaxis recommend a risk-based approach in which the number of antiemetics administered is based on a preoperative estimate of PONV risk. These guidelines have been adapted by the Multicenter Perioperative Outcomes Group (MPOG) to serve as measures of clinician and hospital compliance with guideline-recommended care. However, the impact of this approach on clinical outcomes is not known. METHODS: We performed a single-center, retrospective study of adult patients undergoing general anesthesia from 2018 to 2021. Risk factors for PONV were defined using MPOG definitions: female sex, history of PONV or motion sickness, nonsmoker, inhaled anesthesia >60 minutes, high-risk procedure (cholecystectomy, laparoscopic, gynecologic), and age <50 years. Adequate prophylaxis was defined using the MPOG PONV-05 metric: at least 2 agents for patients with 1 to 2 risk factors and at least 3 agents for patients with 3+ risk factors. PONV was defined as documented PONV or receipt of rescue antiemetics. To estimate the association between adequate prophylaxis and PONV, we used Bayesian binomial models with overlap propensity score weighting. RESULTS: We included 76,703 cases (43% receiving adequate prophylaxis) with PONV occurring in 19%. In unadjusted and unweighted comparison, adequate prophylaxis was associated with increased incidence of PONV: median odds ratio 1.21 (95% credible interval [1.16-1.25]). However, after propensity score weighting and multivariable adjustment, adequate prophylaxis was associated with reduced relative and absolute risk for PONV: weighted marginal median odds ratio 0.90 [0.84-0.98] and absolute risk reduction (ARR) 1.6% [0.6%-2.6%]. There was evidence for a differential effect of adequate prophylaxis across the guideline-defined risk spectrum, with benefit seen in patients with 1 to 5 risk factors (conditional probabilities of benefit >0.81), but not in those at high predicted risk. Patient-specific, covariate-adjusted ARR was heterogeneous, with a median patient-specific conditional probability of benefit of 0.84 (95% credible interval, 0.73-0.90). CONCLUSIONS: Guideline-directed PONV prophylaxis is associated with a modest reduction in PONV, although this effect is small and heterogeneous on the absolute scale. We found evidence for a differential association between adequate prophylaxis and PONV across the guideline-defined risk spectrum, with diminution in patients at very high predicted preoperative risk. While patient-specific benefit was heterogenous, most patients had reasonably high predicted probabilities of absolute benefit from a guideline-directed strategy. Further assessment of these associations in a multicenter setting, with more robust investigation of risk prediction methods will allow for better understanding of the optimal approach to PONV prophylaxis.

Effects of down-regulated carbonic anhydrase 8 on cell survival and glucose metabolism in human colorectal cancer cell lines.

Carbonic anhydrase 8 (CA8) is a member of the α-carbonic anhydrase family but does not catalyze the reversible hydration of carbon dioxide. In the present study, we examined the effects of CA8 on two human colon cancer cell lines, SW480 and SW620, by suppressing CA8 expression through shRNA knockdown. Our results showed that knockdown of CA8 decreased cell growth and cell mobility in SW620 cells, but not in SW480 cells. In addition, downregulated CA8 resulted in a significant decrease of glucose uptake in both SW480 and SW620 cells. Interestingly, stable downregulation of CA8 decreased phosphofructokinase-1 expression but increased glucose transporter 3 (GLUT3) levels in SW620 cells. However, transient downregulation of CA8 fails to up-regulate GLUT3 expression, indicating that the increased GLUT3 observed in SW620-shCA8 cells is a compensatory effect. In addition, the interaction between CA8 and GLUT3 was evidenced by pull-down and IP assays. On the other hand, we showed that metformin, a first-line drug for type II diabetes patients, significantly inhibited cell migration of SW620 cells, depending on the expressions of CA8 and focal adhesion kinase. Taken together, our data demonstrate that when compared to primary colon cancer SW480 cells, metastatic colon cancer SW620 cells respond differently to downregulated CA8, indicating that CA8 in more aggressive cancer cells may play a more important role in controlling cell survival and metformin response. CA8 may affect glucose metabolism- and cell invasion-related molecules in colon cancer, suggesting that CA8 may be a potential target in future cancer therapy.

Lurbinectedin in small cell lung cancer: real-world experience of a multicentre national early access programme.

BACKGROUND AND AIMS: Lurbinectedin is a novel oncogenic transcription inhibitor active in several cancers, including small cell lung cancer (SCLC). We aimed to describe the first Australian experience of the clinical efficacy and tolerability of lurbinectedin for the treatment of SCLC after progression on platinum-containing therapy. METHODS: Multicentre real-world study of individuals with SCLC initiating lurbinectedin monotherapy (3.2 mg/m2 three-weekly) on an early access programme between May 2020 and December 2021. Key outcomes were clinical utilisation, efficacy and tolerability. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Outcome data were collected within the AUstralian Registry and biObank of thoRacic cAncers (AURORA). RESULTS: Data were analysed for 46 individuals across seven sites. Lurbinectedin was given as second- (83%, 38/46) or subsequent- (17%, 8/46) line therapy, mostly with prior chemoimmunotherapy (87%, 40/46). We report dose modifications (17%, 8/46), interruptions/delays (24%, 11/46), high-grade toxicities (28%, 13/46) and hospitalisations (54%, 25/46) during active treatment. The overall response rate was 33% and the disease control rate was 50%. Six-month OS was 44% (95% confidence interval (CI): 29.0-57.1). Twelve-month OS was 15% (95% CI: 6.5-26.8). From lurbinectedin first dose, the median PFS was 2.5 months (95% CI: 1.8-2.9) and OS was 4.5 months (95% CI: 3.5-7.2). From SCLC diagnosis, the median OS was 12.9 months (95% CI: 11.0-17.2). Individuals with a longer chemotherapy-free interval prior to lurbinectedin had longer PFS and OS. CONCLUSION: This real-world national experience of lurbinectedin post-platinum chemotherapy and immunotherapy for individuals with SCLC was similar to that reported in clinical trials.

Urologic surveillance of persons with spinal cord injuries - a scoping review.

STUDY DESIGN: Scoping review - standardized according to the Equator-network and the Prisma-Statement guidelines with PRISMA-ScR. OBJECTIVES: Review the literature concerning surveillance of the urinary- and renal systems in persons with spinal cord injuries (SCI). Specifically, to assess: #1 the usability of non-invasive and non-ultrasound methods, #2 the usage of systematic ultrasound surveillance #3 patient characteristics which predispose to urinary tract abnormalities (UTA) or renal function deterioration. METHODS: The literature assessed was collected from PubMed by creating a search string comprised of three main phrases: #1 persons with SCI, #2 kidney function and #3 surveillance program. The final search resulted in 685 studies. Eligibility criteria were defined prior to the search to assess the studies systematically. RESULTS: Four studies found serum cystatin C (s-cysC) to be accurate in estimating the glomerular filtration rate in persons with SCI. One study found no difference in UTA between surveillance adherent and surveillance non-adherent persons up to 30 years post injury. UTA and especially renal function deterioration seems rare the first 15 years post-injury. Non-traumatic SCI, time since injury, high detrusor pressure, upper urinary tract dilation, vesicourethral reflux, trabeculated bladder, history of calculi removal are significant risk factors for developing UTA or renal function deterioration. CONCLUSION: Measurements of S-cysC should be considered to replace serum creatinine in most cases. Surveillance non-adherent persons are not at higher risk of developing UTA. A selective surveillance based on a baseline risk profile may be beneficial for patients and caretakers.

Findings From a National Survey of Older US Adults on Patient Willingness to Use Telehealth Services: Cross-Sectional Survey.

BACKGROUND: Telehealth (telemedicine and telepharmacy) services increase access to patient services and ensure continuity of care. However, few studies have assessed factors that influence patients' willingness to use telehealth services, and we sought to investigate this. OBJECTIVE: This study aims to examine respondents' (aged between 45 and 75 years) willingness to use telehealth services (telepharmacy and telemedicine) and the correlates of the willingness to use telehealth services. METHODS: We administered a cross-sectional national survey of 1045 noninstitutionalized US adults aged between 45 and 75 years in March and April 2021. Multiple logistic regression analyses were used to identify demographic and health service use correlates of self-reported willingness to use telehealth services. RESULTS: Overall willingness to use telemedicine was high (674/1045, 64.5%). Adults aged 55 years and older were less willing to use telemedicine (aged between 55 and 64 years: odds ratio [OR] 0.61, 95% CI 0.42-0.86; aged 65 years or older: OR 0.33, 95% CI 0.22-0.49) than those younger than 55 years. Those with a regular provider (OR 1.01, 95% CI 1-1.02) and long travel times (OR 1.75, 95% CI 1.03-2.98) were more willing to use telemedicine compared to those without a regular provider and had shorter travel times, respectively. Willingness to use telemedicine services increased from 64.5% (674/1045) to 83% (867/1045) if the service was low-cost or insurance-covered, was with their existing health care provider, or was easy-to-use. Overall willingness to use telepharmacy was 76.7% (801/1045). Adults aged older than 55 years were less willing to use telepharmacy (aged between 55 and 64 years: OR 0.57, 95% CI 0.38-0.86; aged 65 years or older: OR 0.24, 95% CI 0.15-0.37) than those younger than 55 years. Those who rated pharmacy service quality higher were more willing to use telepharmacy (OR 1.06, 95% CI 1.03-1.09) than those who did not. CONCLUSIONS: Respondents were generally willing to use telehealth (telemedicine and telepharmacy) services, but the likelihood of their being willing to use telehealth decreased as they were older. For those initially unwilling (aged 55 years or older) to use telemedicine services, inexpensive or insurance-covered services were acceptable.

Comparative Single Vesicle Analysis of Aqueous Humor Extracellular Vesicles before and after Radiation in Uveal Melanoma Eyes.

Small extracellular vesicles (sEVs) have been shown to promote tumorigenesis, treatment resistance, and metastasis in multiple cancer types; however, sEVs in the aqueous humor (AH) of uveal melanoma (UM) patients have never previously been profiled. In this study, we used single particle analysis to characterize sEV subpopulations in the AH of UM patients by quantifying their size, concentration, and phenotypes based on cell surface markers, specifically the tetraspanin co-expression patterns of CD9, CD63, and CD81. sEVs were analyzed from paired pre- and post-treatment (brachytherapy, a form of radiation) AH samples collected from 19 UM patients. In post-brachytherapy samples, two subpopulations, CD63/81+ and CD9/63/81+ sEVs, were significantly increased. These trends existed even when stratified by tumor location and GEP class 1 and class 2 (albeit not significant for GEP class 2). In this initial report of single vesicle profiling of sEVs in the AH of UM patients, we demonstrated that sEVs can be detected in the AH. We further identified two subpopulations that were increased post-brachytherapy, which may suggest radiation-induced release of these particles, potentially from tumor cells. Further study of the cargo carried by these sEV subpopulations may uncover important biomarkers and insights into tumorigenesis for UM.

Providing 0.1 Full-Time Equivalent (FTE) Support to Fellowship Core Faculty Improves Faculty Involvement in Fellowship Education and Recruitment.

In 2022, the American Council for Graduate Medical Education (ACGME) recommended that core faculty (CF) in medical subspecialty fellowships receive at least 0.1 full-time equivalent (FTE) salary support, with plans to enforce compliance in July 2023. After early feedback raised concerns about potential unintended consequences, ACGME deferred enforcement to July 2024. Hence, there is an urgent need to understand the ramifications of providing FTE support for CF. In 2020, the Yale hematology and medical oncology (HO) fellowship program began providing 0.1 FTE support to all CF. Perceptions regarding this were assessed via surveys distributed to all CF in 2021 and 2022 and to all HO fellows in 2021. The vast majority (83.3%) of CF survey respondents reported improved job satisfaction and an increased sense of involvement in the fellowship program as a result of the new 0.1 FTE-supported CF program. Most CF increased attendance at fellowship conferences, devoted more time to mentorship, and increased participation in recruitment. In free text comments, CF respondents described that providing 0.1 FTE support made them "feel rewarded," gave them "a sense of commitment" to the fellowship, and helped "offset clinical requirements." HO fellows reported "a positive impact" of the new program with faculty being "more present at lectures." The median number of times faculty were available to interview fellowship applicants rose markedly after introduction of the program. The FTE-supported CF program was viewed enthusiastically by fellows and faculty, resulting in increased CF involvement in fellowship education and recruitment.

Tubular-specific expression of HIV protein Vpr leads to severe tubulointerstitial damage accompanied by progressive fibrosis and cystic development.

Chronic kidney disease (CKD) is a common cause of morbidity in human immunodeficiency virus (HIV)-positive individuals. HIV infection leads to a wide spectrum of kidney cell damage, including tubular epithelial cell (TEC) injury. Among the HIV-1 proteins, the pathologic effects of viral protein R (Vpr) are well established and include DNA damage response, cell cycle arrest, and cell death. Several in vitro studies have unraveled the molecular pathways driving the cytopathic effects of Vpr in tubular epithelial cells. However, the in vivo effects of Vpr on tubular injury and CKD pathogenesis have not been thoroughly investigated. Here, we use a novel inducible tubular epithelial cell-specific Vpr transgenic mouse model to show that Vpr expression leads to progressive tubulointerstitial damage, interstitial inflammation and fibrosis, and tubular cyst development. Importantly, Vpr-expressing tubular epithelial cells displayed significant hypertrophy, aberrant cell division, and atrophy; all reminiscent of tubular injuries observed in human HIV-associated nephropathy (HIVAN). Single-cell RNA sequencing analysis revealed the Vpr-mediated transcriptomic responses in specific tubular subsets and highlighted the potential multifaceted role of p53 in the regulation of cell metabolism, proliferation, and death pathways in Vpr-expressing tubular epithelial cells. Thus, our study demonstrates that HIV Vpr expression in tubular cells is sufficient to induce HIVAN-like tubulointerstitial damage and fibrosis, independent of glomerulosclerosis and proteinuria. Additionally, as this new mouse model develops progressive CKD with diffuse fibrosis and kidney failure, it can serve as a useful tool to examine the mechanisms of kidney disease progression and fibrosis in vivo.