Impaired Visual Function in Posterior Vitreous Detachment Assessed With the Active-Learning Quantitative Contrast Sensitivity Function Test.

Introduction: To investigate whether there is visual function impairment in patients with posterior vitreous detachment (PVD) using the active-learning quantitative contrast sensitivity function test. Methods: In this cross-sectional study, contrast sensitivity was measured in eyes with PVD and eyes without PVD using the quantitative contrast sensitivity function algorithm on the Adaptive Sensory Technology platform. Outcomes included the area under the log contrast sensitivity function curve, contrast acuity, and contrast sensitivity thresholds at 1 to 18 cycles per degree (cpd). Snellen visual acuity (VA) was also measured. Mixed-effects multiple linear regression analyses were performed to evaluate the association between the presence of PVD and visual function, controlling for age and lens status. Results: The cohort comprised 232 healthy eyes of 205 participants; of these, 80 eyes of 69 patients had PVD. There was no significant association between VA and PVD presence. However, PVD was significantly associated with decreased contrast sensitivity thresholds at 1.5 cpd (ß, -0.058; P = .003) and 3 cpd (ß, -0.067; P = .004). Contrast sensitivity thresholds at lower (1 cpd) or higher (6, 12, 18 cpd) spatial frequencies did not significantly correlate with PVD presence. Even in the subgroup of symptomatic PVD eyes, VA was not significantly decreased, while quantitative contrast sensitivity function outcomes showed visual function deficits at low spatial frequencies (1.5 cpd and 3 cpd). Conclusions: Contrast sensitivity measured with the quantitative contrast sensitivity function test showed visual function deficits in eyes with PVD that would have been missed with VA testing alone. Incorporating this test in the retina clinic might offer a more comprehensive functional assessment of eyes with PVD, serving as an adjunct outcome metric in clinical decision-making.

Longitudinal Assessment of Intraretinal Microvascular Abnormalities in Diabetic Retinopathy Using Swept-Source Optical Coherence Tomography Angiography.

Purpose: To longitudinally investigate the changes in intraretinal microvascular abnormalities (IRMAs) over time, employing swept-source optical coherence tomography angiography in eyes with diabetic retinopathy. Methods: In this retrospective, longitudinal study, we evaluated 12 × 12-mm swept-source optical coherence tomography angiography centered on the macula at baseline and last available follow-up visit for (1) IRMA changes during follow-up, defined as (a) stable, (b) regressed, (c) obliterated, and (d) progressed; and the (2) development of new neovascularization (NV) and their origins. Competing-risk survival analysis was used to assess the factors associated with these changes. Results: In total, 195 eyes from 131 participants with diabetic retinopathy were included. Stable, regressed, obliterated, and progressed IRMA were observed in 65.1%, 12.8%, 11.3%, and 19% of eyes with diabetic retinopathy, respectively. Anti-VEGF injections during the follow-up periods and a slower increase of foveal avascular zone were associated with IRMA regression (P < 0.001 and P = 0.039). Obliterated IRMA were correlated with previous panretinal photocoagulation (P < 0.001) and a lower deep capillary plexus vessel density at baseline (P = 0.007), as well as with follow-up anti-VEGF injections (P = 0.025). A higher baseline ischemia index (ISI) and panretinal photocoagulation during the follow-up periods were associated with IRMA progression (P = 0.049 and P < 0.001). A faster increase in ISI predicted the development of NV elsewhere (NVE) from veins (P < 0.001). No significant factors were found to be associated with NVE originating from IRMA. Conclusions: Changes in IRMA closely correlated with the severity of retinal ischemia and treatment. Notably, our study confirmed the potential, yet relatively rare, development of NVE from IRMA in a large cohort; however, the risk factors associated with this transformation require further exploration.

Association of CD8+TILs co-expressing granzyme A and interferon-γ with colon cancer cells in the tumor microenvironment.

CD8+T cells secreting granzyme A (GZMA) can induce pyroptosis in tumor cells by effectively cleaving gasdermin B (GSDMB), which is stimulated by interferon-γ (IFN-γ). However, the interaction between GZMA-expressing CD8+T cells and GSDMB-expressing tumor cells in colon cancer remains poorly understood. Our research employed multi-color immunohistochemistry (mIHC) staining and integrated clinical data to explore the spatial distribution and clinical relevance of GZMA- and IFN-γ-expressing CD8+ tumor-infiltrating lymphocytes (TILs), as well as GSDMB-expressing CK+ cells, within the tumor microenvironment (TME) of human colon cancer samples. Additionally, we utilizing single-cell RNA sequencing (scRNA-seq) data to examine the functional dynamics and interactions among these cell populations. scRNA-seq analysis of colorectal cancer (CRC) tissues revealed that CD8+TILs co-expressed GZMA and IFN-γ, but not other cell types. Our mIHC staining results indicated that a significant reduction in the infiltration of GZMA+IFN-γ+CD8+TILs in colon cancer patients (P < 0.01). Functional analysis results indicated that GZMA+IFN-γ+CD8+TILs demonstrated enhanced activation and effector functions compared to other CD8+TIL subsets. Furthermore, GSDMB-expressing CK+ cells exhibited augmented immunogenicity. Correlation analysis highlighted a positive association between GSDMB+CK+ cells and GZMA+IFN-γ+CD8+TILs (r = 0.221, P = 0.033). Analysis of cell-cell interactions further showed that these interactions were mediated by IFN-γ and transforming growth factor-ß (TGF-ß), the co-stimulatory molecule ICOS, and immune checkpoint molecules TIGIT and TIM-3. These findings suggested that GZMA+IFN-γ+CD8+TILs modulating GSDMB-expressing tumor cells, significantly impacted the immune microenvironment and patients' prognosis in colon cancer. By elucidating these mechanisms, our present study aims to provide novel insights for the advancement of immunotherapeutic strategies in colon cancer.

Progressive Choriocapillaris Changes on Optical Coherence Tomography Angiography Correlate With Stage Progression in AMD.

Purpose: We investigated the association between inner choroid flow deficit percentage (IC-FD%) using swept-source optical coherence tomography angiography (SS-OCTA) and progression of AMD. Methods: Retrospective, observational study including 64 eyes (42 participants) with early or intermediate AMD at baseline. Participants had two or more consecutive swept-source optical coherence tomography angiography covering a period of at least 18 months. Demographics, visual acuity, and AMD staging based on Beckman classification were reviewed. OCT was analyzed for hyperreflective foci, subretinal drusenoid deposits, hyporeflective drusen cores, and subfoveal choroidal thickness. IC-FD% was measured within the central 3- and 6-mm using a 16-µm slab, after compensation and binarization (Phansalkar method). Mixed-effects Cox regression models assessed the association between imaging biomarkers and AMD progression. Results: During follow-up (37 ± 9 months), 4 eyes with early AMD (31%) progressed to intermediate AMD and 30 (59%) eyes with intermediate AMD developed late AMD (19 geographic atrophy; 11 wet AMD). Baseline hyporeflective drusen core was associated with geographic atrophy development (P < 0.01), whereas greater IC-FD% (3-mm) was associated with wet AMD (P = 0.03). Time-varying analysis showed that faster subfoveal choroidal thickness reduction and IC-FD% (6-mm) increase were associated with geographic atrophy onset (P < 0.05), whereas IC-FD% (3-mm) increase was associated with wet AMD (P = 0.03). Notably, greater IC-FD% increases in the 3 mm (area under the curve = 0.72) and 6 mm (area under the curve = 0.89) were better predictive of wet AMD and geographic atrophy development, respectively. Conclusions: Our longitudinal IC-FD% assessment emphasizes the role of progressive choriocapillaris changes as a biomarker for AMD progression. Our findings support that widespread choriocapillaris alterations (6 mm) may precede progression to geographic atrophy, whereas more central choriocapillaris loss (3 mm) may provide an ischemic stimulus for wet AMD.

Revolutionizing tumor immunotherapy: unleashing the power of progenitor exhausted T cells.

In exploring persistent infections and malignancies, a distinctive subgroup of CD8+ T cells, progenitor exhausted CD8+ T (Tpex) cells, has been identified. These Tpex cells are notable for their remarkable self-renewal and rapid proliferation abilities. Recent strides in immunotherapy have demonstrated that Tpex cells expand and differentiate into responsive exhausted CD8+ T cells, thus underscoring their critical role in the immunotherapeutic retort. Clinical examinations have further clarified a robust positive correlation between the proportional abundance of Tpex cells and enhanced clinical prognosis. Tpex cells have found noteworthy applications in the formulation of inventive immunotherapeutic approaches against tumors. This review describes the functions of Tpex cells in the tumor milieu, particularly their potential utility in tumor immunotherapy. Precisely directing Tpex cells may be essential to achieving successful outcomes in immunotherapy against tumors.

Decreased Macular Choriocapillaris Perfusion Correlates with Contrast Sensitivity Function in Dry Age-Related Macular Degeneration.

PURPOSE: To investigate the relationships between contrast sensitivity (CS), choriocapillaris perfusion, and other structural OCT biomarkers in dry age-related macular degeneration (AMD). DESIGN: Cross-sectional, observational study. PARTICIPANTS: One hundred AMD eyes (22 early, 52 intermediate, and 26 late) from 74 patients and 45 control eyes from 37 age-similar subjects. METHODS: All participants had visual acuity (VA) assessment, quantitative CS function (qCSF) testing, macular OCT, and 6 × 6-mm swept-source OCT angiography scans on the same day. OCT volumes were analyzed for subretinal drusenoid deposits and hyporeflective drusen cores, and to measure thickness of the outer nuclear layer. OCT angiography scans were utilized to calculate drusen volume and inner choroid flow deficit percentage (IC-FD%), and to measure the area of choroidal hypertransmission defects (HTDs). Inner choroid flow deficit percentage was measured from a 16-µm thick choriocapillaris slab after compensation and binarization with Phansalkar's method. Generalized linear mixed-effects models were used to evaluate the associations between functional and structural variables. MAIN OUTCOME MEASURES: To explore the associations between qCSF-measured CS, IC-FD%, and various AMD imaging biomarkers. RESULTS: Age-related macular degeneration exhibited significantly reduced qCSF metrics eyes across all stages compared with controls. Univariate analysis revealed significant associations between various imaging biomarkers, reduced qCSF metrics, and VA in both groups. Multivariate analysis confirmed that higher IC-FD% in the central 5 mm was significantly associated with decreases in all qCSF metrics in AMD eyes (ß = -0.74 to -0.25, all P < 0.05), but not with VA (P > 0.05). Outer nuclear layer thickness in the central 3 mm correlated with both VA (ß = 2.85, P < 0.001) and several qCSF metrics (ß = 0.01-0.90, all P < 0.05), especially in AMD eyes. Further, larger HTD areas were associated with decreased VA (ß = -0.89, P < 0.001) and reduced CS at low-intermediate frequencies across AMD stages (ß = -0.30 to -0.29, P < 0.001). CONCLUSIONS: The significant association between IC-FD% in the central 5 mm and qCSF-measured CS reinforces the hypothesis that decreased macular choriocapillaris perfusion contributes to visual function changes in AMD, which are more pronounced in CS than in VA. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Targeting PAX8 sensitizes ovarian cancer cells to ferroptosis by inhibiting glutathione synthesis.

Ovarian cancer is a malignant tumor originating from the ovary, characterized by its high mortality rate and propensity for recurrence. In some patients, especially those with recurrent cancer, conventional treatments such as surgical resection or standard chemotherapy yield suboptimal results. Consequently, there is an urgent need for novel anti-cancer therapeutic strategies. Ferroptosis is a distinct form of cell death separate from apoptosis. Ferroptosis inducers have demonstrated promising potential in the treatment of ovarian cancer, with evidence indicating their ability to enhance ovarian cancer cell sensitivity to cisplatin. However, resistance of cancer cells to ferroptosis still remains an inevitable challenge. Here, we analyzed genome-scale CRISPR-Cas9 loss-of function screens and identified PAX8 as a ferroptosis resistance protein in ovarian cancer. We identified PAX8 as a susceptibility gene in GPX4-dependent ovarian cancer. Depletion of PAX8 rendered GPX4-dependent ovarian cancer cells significantly more sensitive to GPX4 inhibitors. Additionally, we found that PAX8 inhibited ferroptosis in ovarian cancer cells. Combined treatment with a PAX8 inhibitor and RSL3 suppressed ovarian cancer cell growth, induced ferroptosis, and was validated in a xenograft mouse model. Further exploration of the molecular mechanisms underlying PAX8 inhibition of ferroptosis mutations revealed upregulation of glutamate-cysteine ligase catalytic subunit (GCLC) expression. GCLC mediated the ferroptosis resistance induced by PAX8 in ovarian cancer. In conclusion, our study underscores the pivotal role of PAX8 as a therapeutic target in GPX4-dependent ovarian cancer. The combination of PAX8 inhibitors such as losartan and captopril with ferroptosis inducers represents a promising new approach for ovarian cancer therapy.

A Pilot Randomized Controlled Trial of Augmented Reality Just-in-Time Guidance for the Performance of Rugged Field Procedures.

INTRODUCTION: Medical resuscitations in rugged prehospital settings require emergency personnel to perform high-risk procedures in low-resource conditions. Just-in-Time Guidance (JITG) utilizing augmented reality (AR) guidance may be a solution. There is little literature on the utility of AR-mediated JITG tools for facilitating the performance of emergent field care. STUDY OBJECTIVE: The objective of this study was to investigate the feasibility and efficacy of a novel AR-mediated JITG tool for emergency field procedures. METHODS: Emergency medical technician-basic (EMT-B) and paramedic cohorts were randomized to either video training (control) or JITG-AR guidance (intervention) groups for performing bag-valve-mask (BVM) ventilation, intraosseous (IO) line placement, and needle-decompression (Needle-d) in a medium-fidelity simulation environment. For the interventional condition, subjects used an AR technology platform to perform the tasks. The primary outcome was participant task performance; the secondary outcomes were participant-reported acceptability. Participant task score, task time, and acceptability ratings were reported descriptively and compared between the control and intervention groups using chi-square analysis for binary variables and unpaired t-testing for continuous variables. RESULTS: Sixty participants were enrolled (mean age 34.8 years; 72% male). In the EMT-B cohort, there was no difference in average task performance score between the control and JITG groups for the BVM and IO tasks; however, the control group had higher performance scores for the Needle-d task (mean score difference 22%; P = .01). In the paramedic cohort, there was no difference in performance scores between the control and JITG group for the BVM and Needle-d tasks, but the control group had higher task scores for the IO task (mean score difference 23%; P = .01). For all task and participant types, the control group performed tasks more quickly than in the JITG group. There was no difference in participant usability or usefulness ratings between the JITG or control conditions for any of the tasks, although paramedics reported they were less likely to use the JITG equipment again (mean difference 1.96 rating points; P = .02). CONCLUSIONS: This study demonstrated preliminary evidence that AR-mediated guidance for emergency medical procedures is feasible and acceptable. These observations, coupled with AR's promise for real-time interaction and on-going technological advancements, suggest the potential for this modality in training and practice that justifies future investigation.