Single-cell analysis of anti-BCMA CAR T cell therapy in patients with central nervous system autoimmunity.

Chimeric antigen receptor (CAR) T cell immunotherapy for the treatment of neurological autoimmune diseases is promising, but CAR T cell kinetics and immune alterations after treatment are poorly understood. Here, we performed single-cell multi-omics sequencing of paired cerebrospinal fluid (CSF) and blood samples from patients with neuromyelitis optica spectrum disorder (NMOSD) treated with anti-B cell maturation antigen (BCMA) CAR T cells. Proliferating cytotoxic-like CD8+ CAR T cell clones were identified as the main effectors in autoimmunity. Anti-BCMA CAR T cells with enhanced features of chemotaxis efficiently crossed the blood-CSF barrier, eliminated plasmablasts and plasma cells in the CSF, and suppressed neuroinflammation. The CD44-expressing early memory phenotype in infusion products was potentially associated with CAR T cell persistence in autoimmunity. Moreover, CAR T cells from patients with NMOSD displayed distinctive features of suppressed cytotoxicity compared with those from hematological malignancies. Thus, we provide mechanistic insights into CAR T cell function in patients with neurological autoimmune disease.

Performance of anterior segment OCT-based algorithms in the opportunistic screening for primary angle-closure disease.

Purpose: This study aimed to investigate the performance of deep learning algorithms in the opportunistic screening for primary angle-closure disease (PACD) using combined anterior segment parameters. Methods: This was an observational, cross-sectional hospital-based study. Patients with PACD and healthy controls who underwent comprehensive eye examinations, including gonioscopy and anterior segment optical coherence tomography (ASOCT) examinations under both light and dark conditions, were consecutively enrolled from the Department of Ophthalmology at the Beijing Tongren Hospital between November 2020 and June 2022. The anterior chamber, anterior chamber angle, iris, and lens parameters were assessed using ASOCT. To build the prediction models, backward logistic regression was utilized to select the variables to discriminate patients with PACD from normal participants, and the area under the receiver operating characteristic curve was used to evaluate the efficacy of the opportunistic screening. Results: The data from 199 patients (199 eyes) were included in the final analysis and divided into two groups: PACD (109 eyes) and controls (90 eyes). Angle opening distance at 500 µm, anterior chamber area, and iris curvature measured in the light condition were included in the final prediction models. The area under the receiver operating characteristic curve was 0.968, with a sensitivity of 91.74 % and a specificity of 91.11 %. Conclusion: ASOCT-based algorithms showed excellent diagnostic performance in the opportunistic screening for PACD. These results provide a promising basis for future research on the development of an angle-closure probability scoring system for PACD screening.

Cost-utility analysis of commonly used anti-glaucoma interventions for mild-to-moderate primary open-angle glaucoma patients in rural and urban China.

OBJECTIVE: An increasing number of studies have explored the clinical effects of antiglaucoma surgical procedures; however, economic evidence was scarce. We aimed to compare the cost-effectiveness between maximal medical treatment (MMT) and commonly used surgical procedures (trabeculectomy, Ahmed glaucoma valve implantation, gonioscopy-assisted transluminal trabeculotomy and ab interno canaloplasty). DESIGN AND SETTING: A Markov model study. PARTICIPANTS: A hypothetical cohort of 100 000 patients with mild-to-moderate primary open-angle glaucoma (POAG). OUTCOMES: Data were obtained from public sources. The main outcomes were incremental cost-utility ratios (ICURs) using quality-adjusted life-years (QALYs). Sensitivity analyses were conducted to verify the robustness and sensitivity of base-case results. MAIN RESULTS: Both cumulative costs and QALYs gained from surgical procedures (US$6045-US$13 598, 3.33-6.05 QALYs) were higher than those from MMT (US$3117-US$6458, 3.14-5.66 QALYs). Compared with MMT, all surgical procedures satisfied the cost-effectiveness threshold (lower than US$30 501 and US$41 568 per QALY gained in rural and urban settings, respectively). During the 5-year period, trabeculectomy produced the lowest ICUR (US$21 462 and US$15 242 per QALY gained in rural and urban settings, respectively). During the 10-year-follow-up, trabeculectomy still produced the lowest ICUR (US$13 379 per QALY gained) in urban setting; however, gonioscopy-assisted transluminal trabeculotomy (US$19 619 per QALY gained) and ab interno canaloplasty (US$18 003 per QALY gained) produced lower ICURs than trabeculectomy (US$19 675 per QALY gained) in rural areas. Base-case results were most sensitive to the utilities and costs of initial treatment and maintenance. CONCLUSIONS: The long-term cost-effectiveness of commonly used surgical procedures could be better than the short-term cost-effectiveness for mild-to-moderate POAG patients in China. Health economic studies, supported by more rigorous structured real-world data, are needed to assess their everyday cost-effectiveness.

Astrocyte-Derived Exosomes Contribute to Pathologies of Neuromyelitis Optica Spectrum Disorder in Rodent Model.

OBJECTIVE: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disease that leads to severe disability. A large proportion of NMOSD patients are seropositive for aquaporin-4 autoantibodies (AQP4-IgG, named as NMO-IgG) targeting AQP4, which is selectively expressed on astrocytes in the central nervous system. This study tests the hypothesis that in response to NMO-IgG, the pathogenic astrocyte-derived exosomes are released and injure the neighboring cells. METHODS: IgG purified from serum of either NMOSD patients or healthy controls was used to generate astrocyte-derived exosomes (AST-ExosNMO vs AST-ExosCON ) in cultured rat astrocytes. The exosomes were respectively delivered to cultured rat oligodendrocytes in vitro, tissue culture of rat optic nerve ex vivo, and rat optic nerve in vivo to evaluate the pathogenic roles of AST-ExosNMO . The microRNA (miRNA) sequencing of AST-Exos and verification were performed to identify the key pathogenic miRNA. The custom-designed adeno-associated virus (AAV) antagonizing the key miRNA was evaluated for its therapeutic effects in vivo. Moreover, the serum levels of the key exosomal miRNA were measured between NMOSD patients and healthy controls. RESULTS: AST-ExosNMO led to notable demyelination in both cultured oligodendrocytes and optic nerve tissue. Exosomal miR-129-2-3p was identified as the key miRNA mediating the demyelinating pathogenesis via downstream target gene SMAD3. AAV antagonizing miR-129-2-3p protected against demyelination in an NMOSD rodent model. The serum exosomal miR-129-2-3p level was significantly elevated in NMOSD patients and correlated with disease severity. INTERPRETATION: Astrocytes targeted by NMO-IgG release pathogenic exosomes that could potentially be used as therapeutic targets or disease monitoring biomarkers in NMOSD. ANN NEUROL 2023;94:163-181.

Economic evaluation of combined population-based screening for multiple blindness-causing eye diseases in China: a cost-effectiveness analysis.

BACKGROUND: More than 90% of vision impairment is avoidable. However, in China, a routine screening programme is currently unavailable in primary health care. With the dearth of economic evidence on screening programmes for multiple blindness-causing eye diseases, delivery options, and screening frequencies, we aimed to evaluate the costs and benefits of a population-based screening programme for multiple eye diseases in China. METHODS: We developed a decision-analytic Markov model for a cohort of individuals aged 50 years and older with a total of 30 1-year cycles. We calculated the cost-effectiveness and cost-utility of screening programmes for multiple major blindness-causing eye diseases in China, including age-related macular degeneration, glaucoma, diabetic retinopathy, cataracts, and pathological myopia, from a societal perspective (including direct and indirect costs). We analysed rural and urban settings separately by different screening delivery options (non-telemedicine [ie, face-to-face] screening, artificial intelligence [AI] telemedicine screening, and non-AI telemedicine screening) and frequencies. We calculated incremental cost-utility ratios (ICURs) using quality-adjusted life-years and incremental cost-effectiveness ratios (ICERs) in terms of the cost per blindness year avoided. One-way deterministic and simulated probabilistic sensitivity analyses were used to assess the robustness of the main outcomes. FINDINGS: Compared with no screening, non-telemedicine combined screening of multiple eye diseases satisfied the criterion for a highly cost-effective health intervention, with an ICUR of US$2494 (95% CI 1130 to 2716) and an ICER of $12 487 (8773 to 18 791) in rural settings. In urban areas, the ICUR was $624 (395 to 907), and the ICER was $7251 (4238 to 13 501). Non-AI telemedicine screening could result in fewer costs and greater gains in health benefits (ICUR $2326 [1064 to 2538] and ICER $11 766 [8200 to 18 000] in rural settings; ICUR $581 [368 to 864] and ICER $6920 [3926 to 13 231] in urban settings). AI telemedicine screening dominated no screening in rural settings, and in urban settings the ICUR was $244 (-315 to 1073) and the ICER was $2567 (-4111 to 15 389). Sensitivity analyses showed all results to be robust. By further comparison, annual AI telemedicine screening was the most cost-effective strategy in both rural and urban areas. INTERPRETATION: Combined screening of multiple eye diseases is cost-effective in both rural and urban China. AI coupled with teleophthalmology presents an opportunity to promote equity in eye health. FUNDING: National Natural Science Foundation of China.

The Imaging Characteristics of Lens Subluxation on the Ultrasound Biomicroscopy.

Background: To evaluate the imaging characteristics of the lens subluxation with the use of ultrasound biomicroscopy. Methods: From October 2018 to September 2019, 55 eyes diagnosed with lens subluxation were enrolled in the group. All patients underwent detailed eye examination and panoramic ultrasound biomicroscopy. Results: The most common sites of lens suspensory ligament injury were superior temporal side (32.73%) and superior nasal side (23.63%). The most common range of subluxation in all patients was 30°. Comparing the measurement indicators of all patients, ciliary body thickness (CBT) in affected eyes was smaller than that in healthy eyes (0.79 ± 0.21, 1.04 ± 0.16), the distance between ciliary process and crystal equator increased (1.91 ± 0.70, 1.17 ± 0.32), and iris-ciliary processes distance (ICPD) increased (1.04 ± 0.51, 0.80 ± 0.17) (P < 0.05). The range of subluxation in patients with lens subluxation was positively correlated with the distance between ciliary processes and the crystal equator. Conclusions: The ultrasound biological microscope has a good application significance in the diagnosis of lens subluxation. From this study, we suggest that the three indexes of CBT, ICPD, and the distance between the ciliary process and crystal equator are of high reference value in ultrasound biomicroscopy among patients with lens subluxation.

Progression rate to primary angle closure following laser peripheral iridotomy in primary angle-closure suspects: a randomised study.

AIM: To report the progression rate (PR) to primary angle closure (PAC) following laser peripheral iridotomy (LPI) in PAC suspects (PACS). METHODS: Prospective, randomized controlled interventional clinical trial conducted at the Handan Eye Hospital, China. Totally 134 bilateral PACS, defined as non-visibility of the posterior trabecular meshwork for ≥180 degrees on gonioscopy were randomly assigned to undergo LPI in one eye. Gonioscopy and Goldmann applanation tonometry were performed prior to, on day 7 and 12mo post LPI. RESULTS: Eighty of 134 patients (59.7%) could be followed up at one year. The mean intraocular pressure (IOP) in treated eyes was 15.9±2.6 mm Hg at baseline, 15.4±3.0 mm Hg on day 7; 16.5±2.9 mm Hg at one month, and 15.5±2.9 mm Hg at 12mo; the IOP in untreated eyes was similar (P=0.834). One or more quadrants of the angle opened in 93.7% of the LPI treated eyes, but 67.0% (53/79) remained closed in two or more quadrants. The PR to PAC in untreated eyes was 3.75% and one developed acute angle-closure glaucoma (AACG); the PR to PAC in treated eyes was 2.5% and none had developed peripheral anterior synechia (PAS) or AACG. CONCLUSION: LPI can open some of the occludable angle in the majority of eyes with PACS, but 67% continue to have non-visibility of the trabecular meshwork for over 180 degrees.

Clinical features and relapse risks of IgG4-related ophthalmic disease: a single-center experience in China.

BACKGROUND: IgG4-related ophthalmic disease (IgG4-ROD) is one of the phenotypes of IgG4-related disease (IgG4-RD), and its lesions are mainly located in the ocular. Currently, there are few studies on IgG4-ROD and no study has compared the phenotypic differences between IgG4-ROD and non IgG4-ROD (nIgG4-ROD). Thus, it is difficult to establish the optimal treatment strategy for IgG4-ROD. The aim of this study was to identify the disparities between the two groups and to clarify the risk factors for IgG4-ROD relapse. METHODS: 434 IgG4-RD patients met comprehensive diagnostic criteria and diagnosed at Peking University People's Hospital between January 2009 and January 2020 were recruited in this study. Patients were divided into IgG4-ROD and nIgG4-ROD group according to the ophthalmic involvement. Demographic, clinical, and laboratory data of two groups were collected and compared. Cox regression analysis was used to identify the independent risk factors for IgG4-ROD relapse. RESULTS: 255 IgG4-ROD patients were identified in this study. IgG4-ROD group had almost equal sex ratio, younger age of disease onset and diagnosis comparing with nIgG4-ROD patients. As compared to nIgG4-ROD group, higher percentage of IgG4-ROD patients met the 2019 American College of Rheumatology/European League Against Rheumatism classification criteria (AECC) for IgG4-RD; moreover, IgG4-ROD patients had higher AECC scores and IgG4-RD responder index (RI). Allergic diseases and multiorgan involvement were more common in IgG4-ROD group. IgG4-ROD was frequently associated with salivary gland, paranasal sinus, lung, and lymph node involvement, while retroperitoneal fibrosis and biliary system lesions were more common in nIgG4-ROD. IgG4-ROD patients had higher serum IgG4 levels, IgG4/IgG ratio, IgE levels, and lower CRP levels. The initial glucocorticoid plus immunosuppressant was a protective factor for IgG4-ROD relapse. IgG4-ROD patients treated with initial glucocorticoid plus immunosuppressant had longer relapse-free survival time than patients treated with initial glucocorticoid monotherapy. CONCLUSIONS: IgG4-ROD patients had distinctive clinical features compared with nIgG4-ROD patients. The initial glucocorticoid plus immunosuppressant was a protective factor for IgG4-ROD relapse, which could prolong the relapse-free survival time of IgG4-ROD patients. These findings may have important implications for understanding and management of IgG4-ROD.

Development and Validation of a Deep Learning System to Detect Glaucomatous Optic Neuropathy Using Fundus Photographs.

Importance: A deep learning system (DLS) that could automatically detect glaucomatous optic neuropathy (GON) with high sensitivity and specificity could expedite screening for GON. Objective: To establish a DLS for detection of GON using retinal fundus images and glaucoma diagnosis with convoluted neural networks (GD-CNN) that has the ability to be generalized across populations. Design, Setting, and Participants: In this cross-sectional study, a DLS for the classification of GON was developed for automated classification of GON using retinal fundus images obtained from the Chinese Glaucoma Study Alliance, the Handan Eye Study, and online databases. The researchers selected 241 032 images were selected as the training data set. The images were entered into the databases on June 9, 2009, obtained on July 11, 2018, and analyses were performed on December 15, 2018. The generalization of the DLS was tested in several validation data sets, which allowed assessment of the DLS in a clinical setting without exclusions, testing against variable image quality based on fundus photographs obtained from websites, evaluation in a population-based study that reflects a natural distribution of patients with glaucoma within the cohort and an additive data set that has a diverse ethnic distribution. An online learning system was established to transfer the trained and validated DLS to generalize the results with fundus images from new sources. To better understand the DLS decision-making process, a prediction visualization test was performed that identified regions of the fundus images utilized by the DLS for diagnosis. Exposures: Use of a deep learning system. Main Outcomes and Measures: Area under the receiver operating characteristics curve (AUC), sensitivity and specificity for DLS with reference to professional graders. Results: From a total of 274 413 fundus images initially obtained from CGSA, 269 601 images passed initial image quality review and were graded for GON. A total of 241 032 images (definite GON 29 865 [12.4%], probable GON 11 046 [4.6%], unlikely GON 200 121 [83%]) from 68 013 patients were selected using random sampling to train the GD-CNN model. Validation and evaluation of the GD-CNN model was assessed using the remaining 28 569 images from CGSA. The AUC of the GD-CNN model in primary local validation data sets was 0.996 (95% CI, 0.995-0.998), with sensitivity of 96.2% and specificity of 97.7%. The most common reason for both false-negative and false-positive grading by GD-CNN (51 of 119 [46.3%] and 191 of 588 [32.3%]) and manual grading (50 of 113 [44.2%] and 183 of 538 [34.0%]) was pathologic or high myopia. Conclusions and Relevance: Application of GD-CNN to fundus images from different settings and varying image quality demonstrated a high sensitivity, specificity, and generalizability for detecting GON. These findings suggest that automated DLS could enhance current screening programs in a cost-effective and time-efficient manner.

Long-term Efficacy of Trabeculectomy on Chinese Patients with Pigmentary Glaucoma: A Prospective Case Series Observational Study.

BACKGROUND: Though trabeculectomy is often performed on patients with medically refractive pigmentary glaucoma (PG), the clinical outcomes of surgical treatment on PG remain unknown. The aim of this study was to summarize the long-term efficacy and safety of trabeculectomy on PG. METHODS: This was a prospective case series observational study. Eighteen consecutive PG patients were followed up for 8 years after trabeculectomy from May 2006 to April 2007. Visual acuity (VA), best-corrected visual acuity (BCVA), slit lamp biomicroscopy, intraocular pressure (IOP) measurement, Humphrey visual field analysis (VFA), and stereoscopic funduscopy were performed on admission and every 6 months after the surgery. Postoperative IOP, VA, BCVA, VFA, adjunctive anti-glaucoma medication, treatment-related side-effects, changes in blebs, and main clinical findings in the anterior segment of PG were recorded and compared with the baseline. RESULTS: Eighteen PG eyes from 18 patients, with average preoperative IOP of 34.5 ± 4.7 mmHg (range: 21-47 mmHg, 1 mmHg=0.133 kPa) were enrolled in this study. All enrolled patients completed the follow-up visits and required examinations. Eight years after trabeculectomy, all surgical eyes (18/18) had satisfactory IOP control with an average of 13.7 ± 2.5 mmHg (range: 9-19 mmHg), which was significantly lower than baseline (P = 0.001). Majority (15/18) of the PG eyes had stable VA, BCVA, VFA, and optic disc cupping parameters. Functional blebs still existed in 12/18 of the PG eyes at the last follow-up visit. Unanimously, pigmentation in the anterior segment attenuated with time after surgical treatment. No severe side-effects were recorded in any of the surgical eyes. CONCLUSIONS: All surgical PG eyes in this study had satisfactory IOP control 8 years after the surgery with well-preserved visual function. The long-term efficacy and safety of trabeculectomy are promising in PG patients.

Peripheral anterior synechia reduce extent of angle widening after laser peripheral iridotomy in eyes with primary angle closure.

PURPOSE: To quantify the effect of laser peripheral iridotomy (LPI) on angle widening in primary angle closure with and without peripheral anterior synechia (PAS). PATIENTS AND METHODS: Prospective hospital-based study of 44 consecutive patients (69 eyes) with primary angle closure. Comprehensive ophthalmic examination and ultrasound biomicroscopy were performed at enrollment and 2 weeks following LPI. The following angle parameters: angle opening distance, trabecular-iris angle, and angle recess area were obtained. On the basis of the presence of PAS, angle quadrants were divided into 3 groups: group A comprised quadrants in PAS-negative eyes; group B, the unaffected quadrants in PAS-positive eyes; and group C, the quadrants with PAS in PAS-positive eyes. Correlation between PAS and angle width was determined and changes in angle parameters following LPI were compared between groups. RESULTS: Sixty-six eyes of 42 patients (31 eyes with PAS) were available for analysis. Groups A, B, and C provided 140, 66, and 58 quadrants, respectively, for analysis. There was a moderate negative correlation between angle width changes (angle opening distance, trabecular-iris angle, angle recess area) after LPI and PAS extent at baseline (r=-0.46 to -0.39; P<0.01). The change in angle width was significantly different between groups A and B compared to group C (P<0.01); there was no difference between groups A and B. CONCLUSIONS: Changes in anterior chamber angle following LPI were inversely correlated with presence of PAS. Quadrants unaffected by PAS can be expected to widen as much as in eyes with only appositional closure. In quadrants with PAS the ultrasound biomicroscopy parameters did not change following LPI.

Narrow- and open-angle measurements with anterior-segment optical coherence tomography and Pentacam™.

BACKGROUND AND OBJECTIVE: To assess the agreement of the Pentacam (Oculus, Wetzlar, Germany) and anterior-segment optical coherence tomography (AS-OCT) in measuring open and narrow angles. PATIENTS AND METHODS: Prospective observational case series in which 39 healthy normal subjects (39 eyes) and 25 patients with narrow angles (37 eyes) were enrolled between May and September 2008. The anterior chamber measurements were performed by AS-OCT and the Pentacam. RESULTS: There was no significant difference in the open-angle measurements between the Pentacam and AS-OCT (P > .05). However, in patients with narrow angles, the average values of nasal and temporal anterior chamber angles taken by the Pentacam were larger than those of AS-OCT (25.5° ± 5.66° and 25.77° ± 5.15° vs 13.40° ± 6.81° and 12.13° ± 6.47°; P < .001). CONCLUSION: Both AS-OCT and the Pentacam can reliably measure anterior chamber angles in healthy normal subjects. The difference in measuring narrow angles by the two instruments was due to inability to view the angle recess or the scleral spur with the Pentacam.