Discovery and Characterization of Selective, First-in-Class Inhibitors of Citron Kinase.

Citron kinase (CITK) is an AGC-family serine/threonine kinase that regulates cytokinesis. Despite knockdown experiments implicating CITK as an anticancer target, no selective CITK inhibitors exist. We transformed a previously reported kinase inhibitor with weak off-target CITK activity into a first-in-class CITK chemical probe, C3TD879. C3TD879 is a Type I kinase inhibitor which potently inhibits CITK catalytic activity (biochemical IC50 = 12 nM), binds directly to full-length human CITK in cells (NanoBRET Kd < 10 nM), and demonstrates favorable DMPK properties for in vivo evaluation. We engineered exquisite selectivity for CITK (>17-fold versus 373 other human kinases), making C3TD879 the first chemical probe suitable for interrogating the complex biology of CITK. Our small-molecule CITK inhibitors could not phenocopy the effects of CITK knockdown in cell proliferation, cell cycle progression, or cytokinesis assays, providing preliminary evidence that the structural roles of CITK may be more important than its kinase activity.

Neurologic Complications of Cancer Immunotherapy.

OBJECTIVE: Immunotherapeutic approaches have revolutionized cancer treatment with immune checkpoint inhibitors and adoptive T-cell therapy now approved to treat a variety of solid and hematologic malignancies. This article summarizes the distinctive neurologic side effects of these therapies as well as their management. LATEST DEVELOPMENTS: Neurologic immune-related adverse events are rare but potentially serious complications of immune checkpoint inhibitors. Both peripheral and central nervous system disorders have been described, often necessitating a pause or cessation of immunotherapy. Immune effector cell-associated neurotoxicity syndrome is a potentially serious complication of chimeric antigen receptor T-cell therapy. While symptoms may be mild and self-limited, delirium, encephalopathy, seizures, focal neurologic deficits, and fulminant cerebral edema can be seen. Close neurologic monitoring is imperative. The mainstay of treatment for neurologic complications includes high-dose corticosteroids, although other immunomodulatory strategies may be used in severe or refractory cases. ESSENTIAL POINTS: The spectrum of neurologic complications of cancer immunotherapy is broad, encompassing both central and peripheral nervous system disorders, indolent as well as fulminant clinical presentations, and wide-ranging severity with variable response to treatment. Early identification and multidisciplinary management are crucial to balance neurologic recovery and antitumor control.

An atopic dermatitis-like murine model by skin-brushed cockroach Per a 2 and oral tolerance induction by Lactococcus lactis-derived Per a 2.

Atopic dermatitis (AD) is a complex, chronic inflammatory skin disease. An estimated 57.5% of asthmatic patients and 50.7% of rhinitis patients are allergic to cockroaches in Taiwan. However, the role of cockroaches in the pathogenesis of AD is undetermined. Oral tolerance might be another strategy for protecting against AD and allergic inflammation by regulating T helper 2 (Th2) immune responses. Aim to examine the underlying immunologic mechanism, we developed an AD-like murine model by skin-brushing with cockroach Per a 2. We also investigated whether the systemic inflammation of AD in this murine model could be improved by specific tolerance to Lactococcus lactis-expressing Per a 2, which was administered orally. Repeated painting of Per a 2 without adjuvant to the skin of mice resulted in increased total IgE, Per a 2-specific IgE, and IgG1, but not IgG2a. In addition, epidermal thickening was significantly increased, there were more scratch episodes, and there were increases in total white blood cells (eosinophil, neutrophil, and lymphocyte) and Th2 cytokines (Interleukin (IL)-4, IL-5, IL-9, and IL-13) in a dose-dependent manner. The results revealed that oral administration of L. lactis-Per a 2 ameliorated Per a 2-induced scratch behavior and decreased the production of total IgE, Per a 2-specific IgE, and IgG1. Furthermore, L. lactis-Per a 2 treatment also suppressed inflammatory infiltration, expressions of thymic stromal lymphopoietin (TSLP) and IL-31 in skin lesions, and downregulated splenic IL-4 and IL-13 in Per a 2-induced AD mice. This study provides evidence supporting that repeated brushing of aeroallergens to the skin leads to atopic dermatitis phenotypes and oral allergen-specific immune tolerance can ameliorate AD-like symptoms and systemic inflammation and prevent progression of atopic march.

Neurotoxicity and management of primary and secondary central nervous system lymphoma after adoptive immunotherapy with CD19-directed chimeric antigen receptor T-cells.

BACKGROUND: Chimeric antigen receptor (CAR) T-cells targeting CD19 have been established as a leading engineered T-cell therapy for B-cell lymphomas; however, data for patients with central nervous system (CNS) involvement are limited. METHODS: We retrospectively report on CNS-specific toxicities, management, and CNS response of 45 consecutive CAR T-cell transfusions for patients with active CNS lymphoma at the Massachusetts General Hospital over a 5-year period. RESULTS: Our cohort includes 17 patients with primary CNS lymphoma (PCNSL; 1 patient with 2 CAR T-cell transfusions) and 27 patients with secondary CNS lymphoma (SCNSL). Mild ICANS (grade 1-2) was observed after 19/45 transfusions (42.2%) and severe immune effector cell-associated neurotoxicity syndrome (ICANS) (grade 3-4) after 7/45 transfusions (15.6%). A larger increase in C-reactive protein (CRP) levels and higher rates of ICANS were detected in SCNSL. Early fever and baseline C-reactive protein levels were associated with ICANS occurrence. CNS response was seen in 31 cases (68.9%), including a complete response of CNS disease in 18 cases (40.0%) which lasted for a median of 11.4 ±â€…4.5 months. Dexamethasone dose at time of lymphodepletion (but not at or after CAR T-cell transfusion) was associated with an increased risk for CNS progression (hazard ratios [HR] per mg/d: 1.16, P = .031). If bridging therapy was warranted, the use of ibrutinib translated into favorable CNS-progression-free survival (5 vs. 1 month, HR 0.28, CI 0.1-0.7; P = .010). CONCLUSIONS: CAR T-cells exhibit promising antitumor effects and a favorable safety profile in CNS lymphoma. Further evaluation of the role of bridging regimens and corticosteroids is warranted.

Indoor aeroallergens from American cockroaches and mites initiate atopic march via cutaneous contact in a murine model.

The progression of allergic diseases from atopic dermatitis in childhood to other allergic conditions such as asthma in later life is often referred to as the atopic march. In order to study the relationship between cutaneous sensitization by aeroallergen and atopic march, we established a mouse model to test the hypothesis using American cockroaches and house dust mites as the model allergens. Mice were sensitized via skin with native cockroach extract (CraA) or recombinant Per a 2 and Der p 2 proteins without adjuvant. Each mouse was subjected to a total of three 1-week patching sensitizations with a 2-week interval in between each application. The resulting immunological variables in sera, scratching behavior, airway hyperresponsiveness (AHR), and pathology of skin lesions and nasal mucosa were evaluated. In mice, application of CraA, rPer a 2, and rDer p 2 aeroallergens through skin patching induced significantly high levels of both total IgE and specific IgEs. The epicutaneous sensitization after a subsequent allergen challenge showed a significant increase in scratch bouts, AHR, epidermal thickness, and eosinophil counts in the skin compared with the control mice. In addition, stimulation of murine splenocytes with allergens increased higher levels of Th2 cytokines, anti-inflammatory cytokines, and chemokines excretion. Our study provides evidence supporting that epicutaneous sensitization to aeroallergens also led to nasal and airway symptoms comparable to atopic march as described in humans. We hope this new allergy model will be useful in the development of new preventive and therapeutic strategies aimed at stopping the atopic march.

Targeting lung cancer brain metastases: a narrative review of emerging insights for anaplastic lymphoma kinase (ALK)-positive disease.

Background and Objective: Lung cancer is commonly associated with brain metastasis formation, and certain subtypes, such as anaplastic lymphoma kinase (ALK) rearranged disease, have an especially high propensity for early and frequent central nervous system (CNS) involvement for which treatment can be challenging. Historical management has centered on surgery and radiation therapy (RT), which persist as mainstays of treatment for large, symptomatic lesions and widespread CNS disease. To date, sustained disease control remains elusive, and the role for effective systemic adjunctive therapies is clear. Here we discuss the epidemiology, genomics, pathophysiology, identification, and management of lung cancer brain metastases with a particular emphasis on systemic treatment of ALK-positive disease according to the best available evidence. Methods: Review of PubMed and Google Scholar databases as well as ClinicalTrials.gov provided background and seminal trials for the local and systemic management of ALK rearranged lung cancer brain metastases. Key Content and Findings: The development of effective, CNS-penetrant systemic agents-including alectinib, brigatinib, ceritinib, and lorlatinib-has dramatically changed the management and prevention of ALK rearranged brain metastases. Most notably, there is a burgeoning role for upfront systemic therapy for both symptomatic and incidentally discovered lesions. Conclusions: Novel targeted therapies offer patients a pathway to delay, obviate, or supplement traditional local therapies while minimizing neurologic sequelae of treatment and may reduce the risk of brain metastasis formation. However, the selection of patients to whom local and targeted treatments is offered is not trivial, and the risks and benefits of both must be weighed carefully. More work is needed to establish treatment regimens that yield durable intra- and extracranial disease control.

Therapeutic Role of Tamoxifen for Triple-Negative Breast Cancer: Leveraging the Interaction Between ERß and Mutant p53.

The absence of effective therapeutic targets and aggressive nature of triple-negative breast cancer (TNBC) renders this disease subset difficult to treat. Although estrogen receptor beta (ERß) is expressed in TNBC, studies on its functional role have yielded inconsistent results. However, recently, our preclinical studies, along with other observations, have shown the potential therapeutic utility of ERß in the context of mutant p53 expression. The current case study examines the efficacy of the selective estrogen receptor modulator tamoxifen in p53-mutant TNBC with brain metastases. Significant increase in ERß protein expression and anti-proliferative interaction between mutant p53 and ERß were observed after cessation of tamoxifen therapy, with significant regression of brain metastases. This case study provides supporting evidence for the use of tamoxifen in p53-mutant, ERß+TNBC, especially in the setting of brain metastasis.

Comprehensive Geriatric Assessment for younger outpatients with severe mental illness: protocol for a feasibility study.

INTRODUCTION: Individuals with severe mental illness are at risk of becoming prematurely frail. There is a critical unmet need for an intervention that reduces the risk of frailty and minimises the associated negative outcomes in this population. This study aims to provide novel evidence on the feasibility, acceptability and preliminary effectiveness of Comprehensive Geriatric Assessment (CGA) to improve health outcomes among people with co-occurring frailty and severe mental illness. METHODS AND ANALYSIS: Twenty-five participants with frailty and severe mental illness, aged 18-64 years, will be recruited from Metro South Addiction and Mental Health Service outpatient clinics and provided with the CGA. Primary outcome measures will include the feasibility and acceptability of the CGA embedded in routine healthcare. Other variables of interest will include frailty status, quality of life, polypharmacy, and a range of mental and physical health factors. ETHICS AND DISSEMINATION: All procedures involving human subjects/patients were approved by Metro South Human Research Ethics Committee (HREC/2022/QMS/82272). Study findings will be disseminated through peer-reviewed publications and conference presentations.

Computed tomography rates in pediatric trauma patients among emergency medicine and pediatric emergency medicine physicians.

BACKGROUND: Pediatric trauma patients undergo fewer computed tomography (CT) scans when evaluated at pediatric trauma centers (PTC) versus adult trauma centers (ATC) with no change in clinical outcome. Factors contributing to this difference are unclear. We sought to identify whether the training background of physicians, specifically emergency medicine (EM) versus pediatric emergency medicine (PEM), affected the CT rate of pediatric trauma patients within one institution. METHODS: A single-center retrospective study of CT utilization based on attending physicians' training in trauma patients <18 years between November 2018 and November 2020. Attendings were categorized into two groups: EM residency with no PEM fellowship, or pediatrics/EM residency with PEM fellowship. Primary outcomes measured were the proportion of patients receiving a CT and CT positivity rate. RESULTS: Of 463 study patients, CTs were obtained in 145/228 (64%) patients by EM, and 130/235 (55%) by PEM (p=.07). CT positivity rate was 21% and 19% in EM and PEM, respectively (p=.46). The mean number of CTs per patient in EM was 2.8 compared to 2.1 in PEM (p<.01), and for patients with an injury severity score (ISS) >15, mean number of CTs per patient increased to 4.9 in EM versus 2.4 in PEM (p=.01). CONCLUSIONS: The mean number of CTs ordered per patient was statistically higher for EM attendings. The differences between CT rates highlight future opportunities for ongoing development of pediatric trauma imaging guidelines and radiation exposure reduction. LEVELS OF EVIDENCE: Retrospective Study, Level III.

Clinical characteristics and differential cytokine expression in hospitalized Taiwanese children with respiratory syncytial virus and rhinovirus bronchiolitis.

BACKGROUND: Viral bronchiolitis presents a heterogeneous spectrum. In this study, we investigated the clinical characteristics and the cytokines/chemokines profiles among respiratory syncytial virus (RSV), rhinovirus (RV), and their dual infection in Taiwanese children with viral bronchiolitis. METHOD: This study was conducted between October 2014 and June 2017. Viral etiology was identified using a Luminex respiratory virus panel and blood cytokines were evaluated using a MILLIPLEX MAP Human Cytokine/Chemokine Panel. Cytokine/Chemokine expressions were compared by clinical severity, steroid treatment, and viral entities. RESULTS: A total of 184 patients were evaluated; at least one respiratory virus was identified in 163 (88.6%) patients. RSV and RV were the two leading viral etiologies, with 25.5% and 17.3%, respectively. RV bronchiolitis has a comparable severity to RSV but is more common in children of an older age with a history of recurrent wheezing and blood eosinophilia. Decreased tumor necrosis factor-alpha (TNF-α) and interferon gamma (INF-γ) levels were correlated with clinical severity. Patients infected with RV exhibited higher levels of Interleukin (IL)-22, IL-23, IL-25, IL-31, and IL-33 (p < 0.05), whereas those with RSV had higher levels of TNF-α, INF-γ, and IL-10 (p < 0.05). Systemic steroid treatment was associated with higher expressions of IL-4, IL-8, IL-13, and MIP-1α levels (p < 0.05). Cluster analysis revealed a high correlation of IL-33 and IL-31(R2 = 0.9731, p < 0.0001). CONCLUSION: Different viral infections elicited the characteristic clinical presentation and immune profiles in bronchiolitis. Our findings also highlight the role of the IL-33/IL-31 axis in the immunopathogenesis of bronchiolitis.

Ethnic differences on long term outcomes of polypoidal choroidal vasculopathy after predominantly bevacizumab monotherapy.

BACKGROUND: A 3-year single-centre, retrospective, comparative, non-randomized cohort study to describe the long-term outcomes of treatment-naïve, Caucasian and non-Caucasian eyes with polypoidal choroidal vasculopathy (PCV) after treatment with predominantly Bevacizumab monotherapy or in combination with rescue photodynamic therapy (PDT). METHODS: Demographics, visual outcomes, optical coherence tomography (OCT) and treatment data were collected up to 3 years after the first visit. Stratified analysis according to ethnicity and baseline vision was performed to identify factors predictive of long-term visual improvement and maintenance. RESULTS: A total of 89 eyes with PCV were identified, of which 14 received rescue verteporfin PDT. There was an equal distribution between Caucasian and non-Caucasian individuals. Non-Caucasians present at a younger age (67.3 vs. 76.0 years, p = 0.002), have a higher proportion of foveal involvement (80.9%, vs.54.2% p = 0.007), choroidal hyperpermeability (50% vs 25.8%, p = 0.013) and lower baseline visual acuity (53.1 vs. 63.3 letters, p = 0.008). Mean visual acuity (VA) gain was + 8.9 letters and + 5.0 letters at 1 and 3 years of follow-up, respectively. Non-Caucasian individuals had a lower mean final visual acuity (VA) (54.7 vs. 70.5, respectively; P < 0.001) and net gain in VA (+ 2.0 vs. + 7.6 letters, p = 0.581) compared to Caucasian individuals. The mean total number of injections given over 3 years was 14. CONCLUSIONS: Most patients treated with predominantly Bevacizumab anti-vascular endothelial growth factor (VEGF) monotherapy achieved sustained visual acuity gains out to 3 years. Due to ethnic-specific differences in presenting PCV phenotypes, non-Caucasians presented with lower baseline VA and had poorer long-term visual outcomes.

One-year real-world outcomes of bevacizumab for the treatment of macular oedema secondary to retinal vein occlusion.

BACKGROUND: Bevacizumab is the only agent that many people can afford, yet there are only limited data on whether it improves macular oedema (MO) secondary to retinal vein occlusion (RVO) in real-world clinical practice. Here we studied 12-month real-world treatment outcomes of bevacizumab for RVO-related MO. METHODS: This was a multicentre, observational study analysing 12-month data from the Fight Retinal Blindness! (FRB) database. We studied treatment-naïve eyes with MO secondary to RVO commencing bevacizumab therapy between June 2009 and June 2019. Visual acuity (VA) and central subfield thickness (CST) were measured at baseline, 6 and 12 months. The primary outcome was a change in VA from baseline to 12 months. RESULTS: Two hundred and twenty treatment naive eyes were analyzed. The baseline VA for BRVO was better than CRVO (55.8 vs. 42.6 LogMAR letters) and this gap widened over the 12-month period, with a 12-month VA change of +14.0 (95% CI 11.1, 16.8) letters for BRVO and + 11.9 (95% CI 6.4, 17.4) for CRVO. The mean CST at baseline was 511 µm for BRVO and 627 µm for CRVO, falling at 12 months by -155 µm (-190, -121) in BRVO and -198 µm (-252, -145) in CRVO. The median number of injections for BRVO and CRVO completers was 7 (5, 9). CONCLUSIONS: Bevacizumab can be an effective treatment of RVO-MO in a real-world setting with outcomes approaching those reported by the seminal clinical trials. The functional and anatomical outcomes of intravitreal therapy were better for BRVO than CRVO.

Microenvironmental Landscape of Human Melanoma Brain Metastases in Response to Immune Checkpoint Inhibition.

Melanoma-derived brain metastases (MBM) represent an unmet clinical need because central nervous system progression is frequently an end stage of the disease. Immune checkpoint inhibitors (ICI) provide a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique elements of the MBM TME and correlates of MBM response to ICI, we collected 32 fresh MBM and performed single-cell RNA sequencing of the MBM TME and T-cell receptor clonotyping on T cells from MBM and matched blood and extracranial lesions. We observed myeloid phenotypic heterogeneity in the MBM TME, most notably multiple distinct neutrophil states, including an IL8-expressing population that correlated with malignant cell epithelial-to-mesenchymal transition. In addition, we observed significant relationships between intracranial T-cell phenotypes and the distribution of T-cell clonotypes intracranially and peripherally. We found that the phenotype, clonotype, and overall number of MBM-infiltrating T cells were associated with response to ICI, suggesting that ICI-responsive MBMs interact with peripheral blood in a manner similar to extracranial lesions. These data identify unique features of the MBM TME that may represent potential targets to improve clinical outcomes for patients with MBM.

Patient-reported quality of life and eligibility for cataract surgery: assessing the relationship between ethnicity and 'Impact on Life' questionnaire scores in New Zealand.

AIMS: The 'Impact on Life' (IoL) questionnaire is a patient reported quality-of-life assessment tool used to prioritise cataract surgery in New Zealand (NZ). This study evaluated the association between ethnicity and IoL questionnaire responses. METHODS: This is a retrospective cohort study of patients prioritised for public-funded cataract surgery between November 2014 and March 2019 in New Zealand. Data were extracted from the New Zealand Ministry of Health National Prioritisation Web Service database. Ethnic, demographic and IoL data for all patients who were prioritised for surgery were analysed after controlling for age, gender, visual acuity and cataract type. RESULTS: Of the 58,648 prioritisation events, over the four-and-a-half-year period, 46,352 prioritisation events had documented scores for the IoL questionnaire. The study population had a mean age of 74.4 years and had a female preponderance (74%). The average IoL score was 22.5/36 (SD 7.8). After controlling for age, gender, visual acuity (VA) and cataract type, there was only a marginal difference between Maori and non-Maori IoL scores (22.8/36 vs 22.4/36) despite statistical significance for the difference (p=0.001). Maori and Pacific people presented at a younger age (68.5 years and 66.7 years, respectively) with worse visual acuity than other ethnic groups (mean range 70.1-76.7 years). Mean IoL scores were 23.0/36 for Maori and Pacific people and 22.4/36 for other ethnic groups. CONCLUSIONS: Maori and Pacific people present younger with worse VA and more advanced cataracts at time of surgical prioritisation when compared with other ethnic groups. Despite these differences, after controlling for confounding factors, the mean IoL score did not differ to a level that was clinically significant between different ethnic groups in New Zealand at time of prioritisation for cataract surgery. These results suggest that there are no meaningful ethnic specific differences in patient reported quality of life for patients with cataract in New Zealand after controlling for other factors. Alternatively, the IoL tool may lack the sensitivity to detect meaningful ethnic disparities that may exist for quality of life in this cohort of patients.

Phase 2 study of pembrolizumab in patients with recurrent and residual high-grade meningiomas.

High-grade meningiomas are associated with neuro-cognitive morbidity and have limited treatments. High-grade meningiomas harbor an immunosuppressive tumor microenvironment (TME) and programmed death-ligand 1 (PD-L1) expression may contribute to their aggressive phenotype. Here, we present the results of a single-arm, open-label phase 2 trial (NCT03279692) evaluating the efficacy of pembrolizumab, a PD-1 inhibitor, in a cohort of 25 evaluable patients with recurrent and progressive grade 2 and 3 meningiomas. The primary endpoint is the proportion of patients alive and progression-free at 6 months (PFS-6). Secondary endpoints include progression-free and overall survival, best intracranial response, and toxicity. Our study has met its primary endpoint and achieved a PFS-6 rate of 0.48 (90% exact CI: 0.31-0.66) and a median PFS of 7.6 months (90% CI: 3.4-12.9 months). Twenty percent of patients have experienced one (or more) grade-3 or higher treatment-related adverse events. These results suggest that pembrolizumab exerts promising efficacy on a subset of these tumors. Further studies are needed to identify the biological facets within the meningioma TME that may drive response to immune-based therapies.

Nonparametric estimation of the survival distribution under covariate-induced dependent truncation.

There is often delayed entry into observational studies, which results in left truncation. In the estimation of the distribution of time-to-event from left-truncated data, standard survival analysis methods require quasi-independence between the truncation time and event time. Incorrectly assuming quasi-independence may lead to biased estimation. We address the problem of estimation of the survival distribution when dependence between the event time and its left truncation time is induced by shared covariates. We introduce propensity scores for truncated data and propose two inverse probability weighting methods that adjust for both truncation and dependence, if all of the shared covariates are measured. The proposed methods additionally allow for right censoring. We evaluate the proposed methods in simulations, conduct sensitivity analyses, and provide guidelines for use in practice. We illustrate our approach in application to data from a central nervous system lymphoma study. The proposed methods are implemented in the R package, depLT.

Structure-Based Optimization of ML300-Derived, Noncovalent Inhibitors Targeting the Severe Acute Respiratory Syndrome Coronavirus 3CL Protease (SARS-CoV-2 3CLpro).

Starting from the MLPCN probe compound ML300, a structure-based optimization campaign was initiated against the recent severe acute respiratory syndrome coronavirus (SARS-CoV-2) main protease (3CLpro). X-ray structures of SARS-CoV-1 and SARS-CoV-2 3CLpro enzymes in complex with multiple ML300-based inhibitors, including the original probe ML300, were obtained and proved instrumental in guiding chemistry toward probe compound 41 (CCF0058981). The disclosed inhibitors utilize a noncovalent mode of action and complex in a noncanonical binding mode not observed by peptidic 3CLpro inhibitors. In vitro DMPK profiling highlights key areas where further optimization in the series is required to obtain useful in vivo probes. Antiviral activity was established using a SARS-CoV-2-infected Vero E6 cell viability assay and a plaque formation assay. Compound 41 demonstrates nanomolar activity in these respective assays, comparable in potency to remdesivir. These findings have implications for antiviral development to combat current and future SARS-like zoonotic coronavirus outbreaks.

Better visual outcome associated with early vitrectomy in the management of endophthalmitis.

AIMS: To examine the role of early vitrectomy in the management of endophthalmitis from all causes. METHODS: Retrospective study of 290 consecutive subjects diagnosed with endophthalmitis at Auckland District Health Board between 1 January 2006 and 31 July 2019. Main outcome measure was visual acuity at 9-month follow-up and proportion of subjects with severe vision loss (≤20/200). RESULTS: Median age at presentation was 70.4 years and 151 subjects (52.1%) were women. Cataract surgery was the most common cause of endophthalmitis in 92 subjects (31.7%) followed by intravitreal injection in 57 (19.7%), endogenous endophthalmitis in 48 subjects (16.6%), non-surgical trauma in 42 subjects (14.5%), glaucoma surgery in 24 subjects (8.3%), vitrectomy in 22 subjects (7.6%) and corneal in 5 subjects (1.7%). Culture was positive in 136 (46.9%) with gram-positive organisms most common (76.5%). Early vitrectomy was performed in 82 subjects (28.3%). Median visual acuity at 9 months was 20/100 (IQR 20/30 to light perception), and severe vision loss occurred in 100 (43.5%). Retinal detachment occurred in 35 eyes (12.1%) and 26 eyes were enucleated. On multivariate analysis, younger age, poor presenting visual acuity and culture-positive endophthalmitis were associated with worse outcomes, and early vitrectomy was associated with better outcomes. CONCLUSIONS: Early vitrectomy (within 24 hours) is associated with better visual outcomes at 9 months, while younger age, poor presenting visual acuity and culture-positive endophthalmitis are associated with poorer visual acuity outcomes.

Bevacizumab for diabetic macular oedema: one-year treatment outcomes from the Fight Retinal Blindness! Registry.

OBJECTIVES: This study evaluated the 1-year treatment outcomes of bevacizumab for diabetic macular oedema (DMO) in routine clinical practice. METHODS: A retrospective analysis was performed on 298 eyes of 220 patients with DMO that received intra-vitreal bevacizumab between 1 September 2013 and 31 August 2018 that were tracked by a prospectively designed, web-based observational registry-the Fight Retinal Blindness! Registry. RESULTS: The mean visual acuity (95% confidence interval [CI]) at 1-year was 3 (2, 5) letters better than a mean (SD) of 68 (15) letters at study entry. Nearly a quarter of eyes achieved ≥20/40. Eyes presenting with better vision (≥20/40) tended to maintain that vision during the period of observation, whereas those presenting with worse vision (<20/40) gained a mean (95% CI) of 9 (5, 13) letters. A mean reduction in the macular thickness was observed over the study period with the central subfield improving by 29 µm (95% CI 17, 40) from a mean (SD) of 402 (109) µm at study entry. Eyes that completed 1 year of follow-up received a median (Q1, Q3) of 7 (4, 9) bevacizumab injections. Sixty-two eyes, ~20%, that started with bevacizumab changed to either another VEGF inhibitor or steroid (triamcinolone) during the period of observation. This did not lead to functional improvement for eyes changed to either ranibizumab or aflibercept despite a further reduction in macular thickness. An improvement in vision and reduction in macular thickness was noted in the 13 eyes that subsequently received triamcinolone. Approximately 10% of eyes dropped out over 12 months, even though their mean visual acuity had improved by seven letters from the initial visit. CONCLUSIONS: Bevacizumab is an effective treatment for DMO in unselected populations.