CLINICAL AND MORPHOLOGIC FEATURES OF POSTERIOR STAPHYLOMA EDGES BY ULTRA-WIDEFIELD IMAGING IN PATHOLOGIC MYOPIA.

PURPOSE: To investigate morphologic features along posterior staphyloma edges in eyes with pathologic myopia using ultra-widefield optical coherence tomography imaging. METHODS: Highly myopic patients (refractive error < -8 diopters or axial length ≥26.5 mm) were consecutively examined by prototype ultra-widefield optical coherence tomography with a scan width of 23 mm and depth of 5 mm. Staphyloma edges were assessed for scleral, choroidal, and retinal status, as well as measurements of angle size. Findings were correlated with pigmentary changes observed on Optos fundus photography, and multivariate logistic regression analyses were performed. RESULTS: In 164 eyes diagnosed with posterior staphyloma by ultra-widefield optical coherence tomography, choroidal thinning and scleral protrusion were hallmark features of staphyloma edges, observed simultaneously in more than 95% of staphylomatous eyes. Outer neural retinal thinning was observed in 80 eyes (48.8%), whereas 15 eyes (9.1%) showed retinal pigment epithelium damage. The mean angle at the staphyloma edge was 23° ± 12.4° (range 8° to 77°). Larger angles were significant predictors of retinal thinning (adjusted odds ratio: 1.17, confidence interval: 1.09-1.25), and the staphyloma was detected by Optos pseudocolor fundus photography (adjusted odds ratio: 1.08, confidence interval: 1.02-1.15). CONCLUSION: These morphologic findings may provide a basis for exploring the natural evolution of posterior staphyloma as part of the development of pathologic myopia.

Transformation of valence signaling in a striatopallidal circuit.

The ways in which sensory stimuli acquire motivational valence through association with other stimuli is one of the simplest forms of learning. Though we have identified many brain nuclei that play various roles in reward processing, a significant gap remains in understanding how valence encoding transforms through the layers of sensory processing. To address this gap, we carried out a comparative investigation of the olfactory tubercle (OT), and the ventral pallidum (VP) - 2 connected nuclei of the basal ganglia which have both been implicated in reward processing. First, using anterograde and retrograde tracing, we show that both D1 and D2 neurons of the OT project primarily to the VP and minimally elsewhere. Using 2-photon calcium imaging, we then investigated how the identity of the odor and reward contingency of the odor are differently encoded by neurons in either structure during a classical conditioning paradigm. We find that VP neurons robustly encode reward contingency, but not identity, in low-dimensional space. In contrast, OT neurons primarily encode odor identity in high-dimensional space. Though D1 OT neurons showed larger response vectors to rewarded odors than other odors, we propose this is better interpreted as identity encoding with enhanced contrast rather than as valence encoding. Finally, using a novel conditioning paradigm that decouples reward contingency and licking vigor, we show that both features are encoded by non-overlapping VP neurons. These results provide a novel framework for the striatopallidal circuit in which a high-dimensional encoding of stimulus identity is collapsed onto a low-dimensional encoding of motivational valence.

Rationally targeted anti-VISTA antibody that blockades the C-C' loop region can reverse VISTA immune suppression and remodel the immune microenvironment to potently inhibit tumor growth in an Fc independent manner.

BACKGROUND: Despite significant progress in cancer immunotherapy in recent years, resistance to existing immune checkpoint therapies (ICT) is common. V-domain Ig suppressor of T cell activation (VISTA), a predominantly myeloid immune checkpoint regulator, represents a promising therapeutic target due to its role in suppressing proinflammatory antitumor responses in myeloid-enriched tumor microenvironments. However, uncertainty around the cognate VISTA ligand has made the development of effective anti-VISTA antibodies challenging. The expression of VISTA on normal immune cell subtypes argues for a neutralizing non-depleting antibody, however, previous reported anti-VISTA antibodies use IgG1 Fc isotypes that deplete VISTA+ cells by antibody dependent cellular cytotoxicity/complement dependent cytotoxicity and these antibodies have shown fast serum clearance and immune toxicities. METHOD: Here we used a rational antibody discovery approach to develop the first Fc-independent anti-VISTA antibody, HMBD-002, that binds a computationally predicted functional epitope within the C-C-loop, distinct from other known anti-VISTA antibodies. This epitope is species-conserved allowing robust in vitro and in vivo testing of HMBD-002 in human and murine models of immune activation and cancer including humanized mouse models. RESULTS: We demonstrate here that blockade by HMBD-002 inhibits VISTA binding to potential partners, including V-Set and Immunoglobulin domain containing 3, to reduce myeloid-derived suppression of T cell activity and prevent neutrophil migration. Analysis of immune cell milieu suggests that HMBD-002 treatment stimulates a proinflammatory phenotype characterized by a Th1/Th17 response, recapitulating a phenotype previously noted in VISTA knockout models. This mechanism of action is further supported by immune-competent syngenic and humanized mouse models of colorectal, breast and lung cancer where neutralizing VISTA, without depleting VISTA expressing cells, significantly inhibited tumor growth while decreasing infiltration of suppressive myeloid cells and increasing T cell activity. Finally, we did not observe either the fast serum clearance or immune toxicities that have been reported for IgG1 antibodies. CONCLUSION: In conclusion, we have shown that VISTA-induced immune suppression can be reversed by blockade of the functional C-C' loop region of VISTA with a first-in-class rationally targeted and non-depleting IgG4 isotype anti-VISTA antibody, HMBD-002. This antibody represents a highly promising novel therapy in the VISTA-suppressed ICT non-responder population.

Whose voices should shape global health education? Curriculum codesign and codelivery by people with direct expertise and lived experience.

There are contrasting opinions of what global health (GH) curricula should contain and limited discussion on whose voices should shape it. In GH education, those with first-hand expertise of living and working in the contexts discussed in GH classrooms are often absent when designing curricula. To address this, we developed a new model of curriculum codesign called Virtual Roundtable for Collaborative Education Design (ViRCoED). This paper describes the rationale and outputs of the ViRCoED approach in designing a new section of the Global Health Bachelor of Science (BSc) curriculum at Imperial College London, with a focus on healthcare in the Syrian conflict. The team, importantly, involved partners with lived and/or professional experience of the conflict as well as alumni of the course and educators in all stages of design and delivery through to marking and project evaluation. The project experimented with disrupting power dynamics and extending ownership of the curriculum beyond traditional faculty by codesigning and codelivering module contents together with colleagues with direct expertise and experience of the Syrian context. An authentic approach was applied to assessment design using real-time syndromic healthcare data from the Aleppo and Idlib Governorates. We discuss the challenges involved in our collaborative partnership and describe how it may have enhanced the validity of our curriculum with students engaging in a richer representation of key health issues in the conflict. We observed an enhanced self-reflexivity in the students' approach to quantitative data and its complex interpretation. The dialogic nature of this collaborative design was also a formative process for partners and an opportunity for GH educators to reflect on their own positionality. The project aims to challenge current standards and structures in GH curriculum development and gesture towards a GH education sector eventually led by those with lived experience and expertise to significantly enhance the validity of GH education.

A comprehensive CHO SWATH-MS spectral library for robust quantitative profiling of 10,000 proteins.

Sequential window acquisition of all theoretical fragment-ion spectra (SWATH) is a data-independent acquisition (DIA) strategy that requires a specific spectral library to generate unbiased and consistent quantitative data matrices of all peptides. SWATH-MS is a promising approach for in-depth proteomic profiling of Chinese hamster Ovary (CHO) cell lines, improving mechanistic understanding of process optimization, and real-time monitoring of process parameters in biologics R&D and manufacturing. However, no spectral library for CHO cells is publicly available. Here we present a comprehensive CHO global spectral library to measure the abundance of more than 10,000 proteins consisting of 199,102 identified peptides from a CHO-K1 cell proteome. The robustness, accuracy and consistency of the spectral library were validated for high confidence in protein identification and reproducible quantification in different CHO-derived cell lines, instrumental setups and downstream processing samples. The availability of a comprehensive SWATH CHO global spectral library will facilitate detailed characterization of upstream and downstream processes, as well as quality by design (QbD) in biomanufacturing. The data have been deposited to ProteomeXchange (PXD016047).

Medication education for patients with epilepsy in Taiwan.

The aim of this study is to evaluate the medication knowledge achieved by conventional verbal education and the influence of drug information leaflets in patients with epilepsy. Drug compliance and sources of information of the patients were also examined. Fifty-one adults in an epilepsy outpatient clinic participated this survey. These patients were asked to complete a questionnaire and to specify sources of drug information. Serum drug levels were checked and compared with the self-reported compliance. Then, drug information leaflets were given to patients. In the next follow-up visit, patients were asked to fill out the same questionnaire again. In the baseline assessment, 36 patients (70.6%) could accurately list their medications. However, half of patients were not knowledgeable about side effects and did not keep a seizure diary. After provision of drug leaflets, the epilepsy medication assessment score increased from 3.9 +/- 1.9 to 5.1 +/- 1.7 (P<0.001). In addition, patients reported being compliant most of the time and this matched drug levels. On average, each patient had 2.8 sources of information and 5 patients used Internet as a tool. Despite achieving good compliance, conventional verbal education did not sufficiently cover drug-related issues. Providing patients with written information apparently increase their medication knowledge and probably enhance seizure control.