Pre-treatment with systemic agents for advanced NSCLC elicits changes in the phenotype of autologous T cell therapy products.

The antitumor activity of adoptive T cell therapies (ACT) is highly dependent on the expansion, persistence, and continued activity of adoptively transferred cells. Clinical studies using ACTs have revealed that products that possess and maintain less differentiated phenotypes, including memory and precursor T cells, show increased antitumor efficacy and superior patient outcomes owing to their increased expansion, persistence, and ability to differentiate into effector progeny that elicit antitumor responses. Strategies that drive the differentiation into memory or precursor-type T cell subsets with high potential for persistence and self-renewal will enhance adoptively transferred T cell maintenance and promote durable antitumor efficacy. Because of the high costs associated with ACT manufacturing, ACTs are often only offered to patients after multiple rounds of systemic therapy. An essential factor to consider in producing autologous ACT medicinal products is the impact of the patient's initial T cell fitness and subtype composition, which will likely differ with age, disease history, and treatment with prior anti-cancer therapies. This study evaluated the impact of systemic anti-cancer therapy for non-small cell lung cancer treatment on the T cell phenotype of the patient at baseline and the quality and characteristics of the genetically modified autologous T cell therapy product after manufacturing.

3D multicellular systems in disease modelling: From organoids to organ-on-chip.

Cell-cell interactions underlay organ formation and function during homeostasis. Changes in communication between cells and their surrounding microenvironment are a feature of numerous human diseases, including metabolic disease and neurological disorders. In the past decade, cross-disciplinary research has been conducted to engineer novel synthetic multicellular organ systems in 3D, including organoids, assembloids, and organ-on-chip models. These model systems, composed of distinct cell types, satisfy the need for a better understanding of complex biological interactions and mechanisms underpinning diseases. In this review, we discuss the emerging field of building 3D multicellular systems and their application for modelling the cellular interactions at play in diseases. We report recent experimental and computational approaches for capturing cell-cell interactions as well as progress in bioengineering approaches for recapitulating these complexities ex vivo. Finally, we explore the value of developing such multicellular systems for modelling metabolic, intestinal, and neurological disorders as major examples of multisystemic diseases, we discuss the advantages and disadvantages of the different approaches and provide some recommendations for further advancing the field.

Timing of Ocular Hypertension After Pediatric Closed-Globe Traumatic Hyphema: Implications for Surveillance.

PURPOSE: To evaluate the timing of ocular hypertension (OHT) after pediatric closed-globe injury (CGI) and traumatic hyphema. We hypothesize that OHT will occur at different times based on injury characteristics. DESIGN: Retrospective, cohort study. METHODS: Setting: Single-center, tertiary-care, pediatric hospital. PARTICIPANTS: Subjects included patients ≤18 years of age at the time of injury who suffered CGI and traumatic hyphema between 2002 and 2019. Observation Procedure(s): Intraocular pressure and injury demographics were abstracted for every visit after injury. OHT was defined as >21 mm Hg at presentation or after a reading of ≤21 mm Hg at a prior visit. MAIN OUTCOME MEASURES: The primary outcome measure was the timing of OHT categorized into 4 periods: presentation, acute (days 1-7), subacute (days 8-28), or late (day >28). Secondary outcome measures were identification of risks factors for OHT by multivariable logistic regression. RESULTS: OHT occurred in 119 of the 305 (39%) subject eyes. OHT occurred in 35 patients at presentation, 69 times acutely, 35 times subacutely, and 36 times late. Pupil damage predicted acute-period OHT (P = .004). OHT at presentation predicted subacute period OHT (P = .004). Iridodialysis and cataract predicted late-period OHT (P = .007 and P < .001, respectively). CONCLUSIONS: OHT after CGI and traumatic hyphema in pediatric patients is common. Injury demographics predict this complication. Integration of these risk factors with current literature allows proposal of a risk-stratification tool to guide efficient surveillance for OHT.

Drivers of Inflammation in Psoriatic Arthritis: the Old and the New.

PURPOSE OF REVIEW: The recognition that IL-17 is produced by many lymphoid-like cells other than CD4+ T helper (Th17) cells raises the potential for new pathogenic pathways in IBD/psoriasis/SpA. We review recent knowledge concerning the role of unconventional and conventional lymphocytes expressing IL-17 in human PsA and axSpA. RECENT FINDINGS: Innate-like lymphoid cells, namely gamma delta (γδ) T-cells, invariant natural killer T (iNKT) cells and mucosal-associated invariant T (MAIT) cells, together with innate lymphoid cells (ILCs) are found at sites of disease in PsA/SpA. These cells are often skewed to Type-17 profiles and may significantly contribute to IL-17 production. Non-IL-23 dependent IL-17 production pathways, utilising cytokines such as IL-7 and IL-9, also characterise these cells. Both conventional CD4 and CD8 lymphocytes show pathogenic phenotypes at sites of disease. A variety of innate-like lymphoid cells and conventional lymphocytes contribute towards IL-17-mediated pathology in PsA/SpA. The responses of these cells to non-conventional immune and non-immune stimuli may explain characteristic clinical features of these diseases and potential therapeutic mechanisms of therapies such as Jak inhibitors.

Safety and immunogenicity of one versus two doses of the COVID-19 vaccine BNT162b2 for patients with cancer: interim analysis of a prospective observational study.

BACKGROUND: The efficacy and safety profiles of vaccines against SARS-CoV-2 in patients with cancer is unknown. We aimed to assess the safety and immunogenicity of the BNT162b2 (Pfizer-BioNTech) vaccine in patients with cancer. METHODS: For this prospective observational study, we recruited patients with cancer and healthy controls (mostly health-care workers) from three London hospitals between Dec 8, 2020, and Feb 18, 2021. Participants who were vaccinated between Dec 8 and Dec 29, 2020, received two 30 µg doses of BNT162b2 administered intramuscularly 21 days apart; patients vaccinated after this date received only one 30 µg dose with a planned follow-up boost at 12 weeks. Blood samples were taken before vaccination and at 3 weeks and 5 weeks after the first vaccination. Where possible, serial nasopharyngeal real-time RT-PCR (rRT-PCR) swab tests were done every 10 days or in cases of symptomatic COVID-19. The coprimary endpoints were seroconversion to SARS-CoV-2 spike (S) protein in patients with cancer following the first vaccination with the BNT162b2 vaccine and the effect of vaccine boosting after 21 days on seroconversion. All participants with available data were included in the safety and immunogenicity analyses. Ongoing follow-up is underway for further blood sampling after the delayed (12-week) vaccine boost. This study is registered with the NHS Health Research Authority and Health and Care Research Wales (REC ID 20/HRA/2031). FINDINGS: 151 patients with cancer (95 patients with solid cancer and 56 patients with haematological cancer) and 54 healthy controls were enrolled. For this interim data analysis of the safety and immunogenicity of vaccinated patients with cancer, samples and data obtained up to March 19, 2021, were analysed. After exclusion of 17 patients who had been exposed to SARS-CoV-2 (detected by either antibody seroconversion or a positive rRT-PCR COVID-19 swab test) from the immunogenicity analysis, the proportion of positive anti-S IgG titres at approximately 21 days following a single vaccine inoculum across the three cohorts were 32 (94%; 95% CI 81-98) of 34 healthy controls; 21 (38%; 26-51) of 56 patients with solid cancer, and eight (18%; 10-32) of 44 patients with haematological cancer. 16 healthy controls, 25 patients with solid cancer, and six patients with haematological cancer received a second dose on day 21. Of the patients with available blood samples 2 weeks following a 21-day vaccine boost, and excluding 17 participants with evidence of previous natural SARS-CoV-2 exposure, 18 (95%; 95% CI 75-99) of 19 patients with solid cancer, 12 (100%; 76-100) of 12 healthy controls, and three (60%; 23-88) of five patients with haematological cancers were seropositive, compared with ten (30%; 17-47) of 33, 18 (86%; 65-95) of 21, and four (11%; 4-25) of 36, respectively, who did not receive a boost. The vaccine was well tolerated; no toxicities were reported in 75 (54%) of 140 patients with cancer following the first dose of BNT162b2, and in 22 (71%) of 31 patients with cancer following the second dose. Similarly, no toxicities were reported in 15 (38%) of 40 healthy controls after the first dose and in five (31%) of 16 after the second dose. Injection-site pain within 7 days following the first dose was the most commonly reported local reaction (23 [35%] of 65 patients with cancer; 12 [48%] of 25 healthy controls). No vaccine-related deaths were reported. INTERPRETATION: In patients with cancer, one dose of the BNT162b2 vaccine yields poor efficacy. Immunogenicity increased significantly in patients with solid cancer within 2 weeks of a vaccine boost at day 21 after the first dose. These data support prioritisation of patients with cancer for an early (day 21) second dose of the BNT162b2 vaccine. FUNDING: King's College London, Cancer Research UK, Wellcome Trust, Rosetrees Trust, and Francis Crick Institute.

Self-grading effect of inferior oblique myectomy and recession.

PURPOSE: To evaluate the outcomes of inferior oblique (IO) weakening surgery, whether recession or myectomy, and to assess the dose-response relationship and correlation with angle of preoperative hypertropia. METHODS: The medical records of all patients with vertical deviation in primary gaze who underwent unilateral IO-weakening surgery, either recession or myectomy, at Boston Children's Hospital over an 8-year period with a minimum postoperative follow-up of 1 month were reviewed retrospectively. Outcome measures were effect of IO weakening surgery on vertical deviation in primary gaze and its correlation with the preoperative angle of hyperdeviation. Secondary outcomes included resolution of abnormal head posture, reduction of ocular torsion, and postoperative under- and overcorrection. RESULTS: A total of 94 patients were identified (mean age at surgery, 29.3 ± 19.8 years; range, 1-69). The mean postoperative follow-up period was 17.2 ± 15 months. IO recession was performed in 30 patients; IO myectomy, in 64. Surgical success in primary position was achieved in 72 patients (77%), with resolution of anomalous preoperative head posture in 93%. The mean effect on alignment in primary position was 11.3Δ ± 6.8Δ. The response to IO-weakening surgery was strongly correlated with the preoperative hyperdeviation for both recession (R2 = 0.53) and myectomy (R2 = 0.87). CONCLUSIONS: As with other types of strabismus surgery, IO weakening has a "self-grading" contribution, in which the surgical effect strongly correlates with the magnitude of preoperative deviation. A large range of vertical misalignment can be corrected with the same surgical approach.

Myectomy of the four horizontal rectus muscles with pulley fixation for the treatment of horizontal nystagmus in 10 adults: a pilot study.

PURPOSE: Myectomy and release of the four horizontal rectus muscles can ameliorate nystagmus, but may result in adduction limitation, convergence insufficiency, or exotropia. We developed a modified four-muscle myectomy with pulley fixation, in which the myectomized muscles are attached to the pulley rather than released. The purpose of this study was to present a prospective review of the clinical, nystagmographic, and quality-of-life data in a cohort of adults. METHODS: Ten adults with horizontal infantile nystagmus syndrome were recruited between July 2018 and October 2018. Subjects were grouped according to presence or absence of foveal hypoplasia (FH). Following myectomy, all four horizontal rectus muscles were sutured within the pulley or encircling fascia. All participants completed a comprehensive sensorimotor examination, videonystagmography, and a nystagmus-specific quality-of-life questionnaire. RESULTS: Of the 10 subjects, 5 were in the FH group and 5 in the no-FH group. Postoperatively, all 10 subjects experienced an improved quality of life, with median increases of 73% (FH) and 104% (No-FH). Nystagmus amplitude and slow-phase velocity were reduced, and binocular best-corrected visual acuity improved in both groups. Foveation time increased, but inconsistently, within subjects and between groups. Horizontal ocular rotations were reduced by up to 58%. Five subjects required transposition surgery for symptomatic exotropia (4) or hypertropia (1). CONCLUSIONS: In this small study cohort, four-muscle myectomy with pulley fixation reduced the amplitude and velocity of nystagmus and improved quality of life and visual acuity, notwithstanding reduced ocular rotation and reoperation. Fixation of the muscle to the pulley did not reduce the risk of exotropia.

Using a Macro Lens for Anterior Segment Imaging in Rural Panama.

Background: Visual impairment, specifically anterior segment pathology, presents a significant burden of disease in the world. Introduction: Inexpensive tools are necessary to improve eye health of residents in developing countries where care is difficult to access. Our study aimed at determining whether a $5 macro lens attached to a smartphone camera is an effective anterior segment imaging method for screening diseases. Materials and Methods: Fifty four (n = 54) patients had anterior segment imaging performed by using an Easy Macro lens and an iPhone. Imaging was performed at the Floating Doctors' mobile clinic sites in Panama. Images were sent back and graded by two board-certified ophthalmologists using a modified version of the FOTO-ED scale. Statistical analysis was performed by using a Wilcoxon signed-rank test to compare grades between the two imaging modalities. Results: There was no significant difference in overall clinical utility of images obtained by the iPhone versus Easy Macro lens. The iPhone was significantly superior in imaging of the lens and conjunctiva, whereas the Easy Macro lens was superior in regards to the anterior chamber, iris, and lens. Discussion: The imaging modality that best captures pathology is dependent on what part of the anterior segment is being examined. An imaging protocol with a pair of images, one from a smartphone and one from a macro lens, would have significant clinical utility. Conclusion: Our study demonstrates how minimally trained users can deliver effective eye screening via a telemedicine-based approach in a resource-deprived setting. Future directions would be to develop a telemedicine protocol and determine whether it improves clinically measurable outcomes in patients.

Colorado retinopathy of prematurity model: a multi-institutional validation study.

PURPOSE: The Colorado retinopathy of prematurity (ROP) prediction model (CO-ROP), developed using a cohort of infants from Colorado, calls for ROP examination of infants meeting all of the following criteria: gestational age of ≤30 weeks, birth weight of ≤1500 g, and a net weight gain of ≤650 g between birth and 4 weeks of age. The purpose of this study was to perform an external validation to assess the sensitivity and specificity of the CO-ROP model in a larger cohort of babies screened for ROP from four academic institutions in the United States. METHODS: The medical records of neonates screened for ROP according current national guidelines was conducted at 4 US academic centers were retrospectively reviewed. Sensitivity, specificity, and respective 95% confidence intervals in detecting ROP using CO-ROP were calculated for type 1, type 2, and any grade of ROP. RESULTS: A total of 858 cases were included. The CO-ROP algorithm had a sensitivity of 98.1% (95% CI, 93.3%-99.8%) for type 1 ROP, 95.6% (95% CI 78.0-99.9%) for type 2 ROP, and 95.0% (95% CI, 93.1-97.4%) for all grades of ROP. The CO-ROP model would have reduced the total number of infants screened by 23.9% compared to current 2013 screening guidelines. CONCLUSIONS: CO-ROP demonstrated high sensitivity in predicting ROP and would have greatly reduced the number of infants needing examination.

Medical Therapies of Amblyopia: Translational Research to Expand Our Treatment Armamentarium.

Amblyopia is a developmental brain disorder in which vision is lost due to asymmetric or inadequate visual stimulation early in life. Although amblyopia is responsive to treatment if therapy is initiated early, treatment of older children and adults is usually unsuccessful due to closure of a window of cortical brain plasticity. Extensive basic research has been devoted to understanding modulators in shaping the visual cortex during the critical period of plasticity, and to providing potential clinical applications of neurotransmitters in the treatment of amblyopia. Current pharmacological treatments are reviewed from basic science research extending into clinical use, focusing on the acetylcholinesterase inhibitor donezepil, serotonin receptor inhibitor fluoxetine, dopamine precursors carbidopa-levodopa, and catecholamine modulator citicoline.

Comparison of corneal biomechanical properties between healthy blacks and whites using the Ocular Response Analyzer.

PURPOSE: To analyze and compare corneal biomechanical properties in healthy black and white subjects using the Ocular Response Analyzer (ORA) and to evaluate their relationship with other ocular parameters. DESIGN: Observational cross-sectional study. METHODS: One hundred eighty one eyes (46 in blacks, 135 in whites) of 119 patients (37 blacks, 82 whites) were recruited from the longitudinal Diagnostic Innovations in Glaucoma Study (DIGS) and from the African Descent and Glaucoma Evaluation Study (ADAGES) at the University of California, San Diego. Corneal curvature, axial length, central corneal thickness (CCT), corneal hysteresis (CH), and corneal resistance factor (CRF) were obtained from all participants. Univariable and multivariable regression analyses were used to evaluate the associations between ORA measurements and age, CCT, axial length, corneal curvature, and race. RESULTS: Black subjects had significantly lower values of CH (9.7 mm Hg vs 10.4 mm Hg; P = .033), CRF (9.84 mm Hg vs 10.70 mm Hg; P = .028), and CCT (534 mum vs 562 mum; P = .001) compared to white subjects. A significant relationship was found between CH and CCT (R(2) = 0.25; P < .001) and between CRF and CCT (R(2) = 0.42; P < .001). After adjusting for CCT, age, axial length, and corneal curvature, the difference between blacks and whites in CH (P = .077) and CRF (P = .621) measurements lost statistical significance. CONCLUSION: Black subjects tended to have lower measurements of corneal hysteresis compared to white subjects; however, this was largely explained by differences in corneal thickness. Therefore, it is unlikely that CH would have an independent effect in explaining differences in susceptibility of disease between these 2 racial groups.