Probing Short-Range Interactions in Isostructural Hydrate and Perhydrate of Dabrafenib by Magic-Angle Spinning Solid-State NMR.

Dabrafenib (DBF), an anticancer drug, exhibits isostructural properties in its hydrate (DBF⊃H2O) and perhydrate (DBF⊃H2O2) forms, as revealed by single-crystal X-ray diffraction. Despite the H2O and H2O2 solvent molecules occupying identical locations, the two polymorphs have different thermal behaviors. In general, determination of stoichiometry of H2O in the perhydrate crystals is difficult due to the presence of both H2O and H2O2 in the same crystal voids. This study utilizes magic-angle spinning (MAS) solid-state NMR (SSNMR) combined with gauge-included projector augmented wave calculations to characterize the influence of solvent molecules on the local environment in pseudopolymorphs. SSNMR experiments were employed to assign 1H, 13C, and 15N peaks and identify spectral differences in the isostructural pseudopolymorphs. Proton spectroscopy at fast MAS was used to identify and quantify H2O2/H2O in DBF⊃H2O2 (mixed hydrate/perhydrate). 1H-1H dipolar-coupling-based experiments were recruited to confirm the 3D molecular packing of solvent molecules in DBF⊃H2O and DBF⊃H2O2. Homonuclear (1H-1H) and heteronuclear (1H-14N) distance measurements, in conjunction with diffraction structures and optimized hydrogen atom positions by density functional theory, helped decipher local interactions of H2O2 with DBF and their geometry in DBF⊃H2O2. This integrated X-ray structure, quantum chemical calculations, and NMR study of pseudopolymorphs offer a practical approach to scrutinizing crystallized solvent interactions in the crystal lattice even without high-resolution crystal structures or artificial sample enrichment.

Filgotinib in Active Noninfectious Uveitis: The HUMBOLDT Randomized Clinical Trial.

Importance: Noninfectious uveitis is a leading cause of visual impairment with an unmet need for additional treatment options. Objective: To assess the efficacy and safety of filgotinib, a Janus kinase 1 (JAK1) preferential inhibitor, for the treatment of noninfectious uveitis. Design, Setting, and Participants: The HUMBOLDT trial was a double-masked, placebo-controlled, phase 2, randomized clinical trial conducted from July 2017 to April 2021 at 26 centers in 7 countries. Eligible participants (aged ≥18 years) had active noninfectious intermediate uveitis, posterior uveitis, or panuveitis despite at least 2 weeks of treatment with oral prednisone (10-60 mg per day). Interventions: Participants were randomly assigned 1:1 to receive filgotinib, 200 mg, or placebo orally once daily for up to 52 weeks. Main Outcomes and Measures: The primary end point was the proportion of participants experiencing treatment failure by week 24. Treatment failure was a composite end point represented by assessment of the presence of chorioretinal and/or retinal vascular lesions, best-corrected visual acuity, and anterior chamber cell and vitreous haze grades. Safety was assessed in participants who received at least 1 dose of study drug or placebo. Results: Between July 26, 2017, and April 22, 2021, 116 participants were screened, and 74 (mean [SD] age, 46 [16] years; 43 female [59.7%] of 72 participants, as 2 participants did not receive treatment doses) were randomly assigned to receive filgotinib (n = 38) or placebo (n = 36). Despite early termination of the trial for business reasons ahead of meeting enrollment targets, a significantly reduced proportion of participants who received filgotinib experienced treatment failure by week 24 vs placebo (12 of 32 participants [37.5%] vs 23 of 34 participants [67.6%]; difference vs placebo -30.1%; 95% CI, -56.2% to -4.1%; P = .006). Business reasons were unrelated to efficacy or safety. Adverse events were reported in 30 of 37 participants (81.1%) who received filgotinib and in 24 of 35 participants (68.6%) who received placebo. Serious adverse events were reported in 5 of 37 participants (13.5%) in the filgotinib group and in 2 of 35 participants (5.7%) in the placebo group. No deaths were reported during the trial. Conclusions and Relevance: Results of this randomized clinical trial show that filgotinib lowered the risk of treatment failure in participants with active noninfectious intermediate uveitis, posterior uveitis, or panuveitis vs placebo. Although the HUMBOLDT trial provided evidence supporting the efficacy of filgotinib in patients with active noninfectious uveitis, the premature termination of the trial prevented collection of additional safety or efficacy information of this JAK1 preferential inhibitor. Trial Registration: ClinicalTrials.gov Identifier: NCT03207815.

Long-Term Outcomes of Scleral-Sutured Fixated Secondary Intraocular Lenses in Patients With Uveitis.

OBJECTIVE: This study examined the long-term outcomes of scleral-sutured fixated intraocular lenses (SSIOLs) in patients with uveitis. PATIENTS AND METHODS: Retrospective, consecutive review of uveitis patients with SSIOL fixation from January 2017 to December 2020. SSIOL techniques included four-point fixation with the Akreos A060 (Bausch + Lomb) or enVista MX60 (Bausch + Lomb) lens, or Hoffman's pockets rescue. RESULTS: Thirteen eyes of 13 patients received an SSIOL (9 AO60, 2 MX60, 2 Hoffman's pockets). Diagnoses included pan- (9), anterior (2), and posterior uveitis (2). Average LogMAR best-corrected visual acuity pre- and postoperatively was 1.01 (Snellen ∼20/200) and 0.50 (Snellen ∼20/60), respectively (P = 0.003). No patients had postoperative SSIOL dislocation or conjunctival suture erosion. Six patients (46%) had uveitis flares postoperatively. Average follow-up was 50.2 months (range = 36.8 to 67.5). CONCLUSION: This series demonstrates a 0% dislocation and suture exposure rate. Risks of uveitis flares postoperatively are high despite aggressive perioperative control but are manageable with current treatments; therefore, patients must be continually monitored. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

Optical coherence tomography-derived texture-based radiomics features identify eyes with intraocular inflammation in the HAWK clinical trial.

Background and objective: Intravitreal injection of anti-VEGF agents is the first-line treatment for patients with neovascular-age related macular degeneration (nAMD). One unique serious adverse event that may be associated with these agents is intraocular inflammation (IOI). The main purpose of this analysis was to evaluate the potential presence of texture-based radiomics features characterizing heterogeneity within the vitreous compartment of spectral domain optical coherence tomography (SD-OCT) images that may precede or develop in association with IOI and might serve as OCT biomarkers for IOI. Methods: This is a post-hoc analysis of a subset of cases (N = 67) involving IOI, endophthalmitis, and/or retinal vascular occlusion in the phase 3 HAWK trial. These were investigator determined diagnoses that were also confirmed by the safety review committee. Intraocular inflammation was any signs of inflammation within the eye, endophthalmitis was inflammation associated with presumed infection, and retinal vascular occlusions consisted of intraocular inflammation with concurrent vascular occlusions/vasculitis. Out of 67 eyes, 34 belonged to the Safety group with an IOI event and 33 were propensity-matched Controls. A total of 481 texture-based radiomics features were extracted from the vitreous compartment of the SD-OCT scans at pre-IOI time point (i.e., much earlier than the actual event). Most discriminating five features, selected by the Wilcoxon Rank Sum feature selection were evaluated using Random Forest (RF) classifier on the training set ( S t r , N = 47) to differentiate between the two patient groups. Classifier performance was subsequently validated on the independent test set ( S t , N = 20). Additionally, the classifier performance in discriminating the Control and Safety group was also validated on S t at the IOI event timepoint. Results: The RF classifier yielded area under the Receiver Operating Characteristics curve (AUC) of 0.76 and 0.81 on S t using texture-based radiomics features at pre-IOI and event time-point, respectively. Conclusions: In this analysis, the presence of a pre-IOI safety signal was detected in the form of textural heterogeneity within the vitreous compartment even prior to the actual event being identified by the investigator. This finding may help the clinicians to assess for underlying posterior inflammation.

Addressing the Need for Universal Cognitive Assessment Among Older Adults With Congestive Heart Failure.

Congestive heart failure (CHF) and cognitive impairment (CI) are common in older age and often occur together. However, CI is often unrecognized leading to more hospitalizations and increased morbidity and mortality in patients with co-occurring CHF and CI. Universal screening can help identify these patients earlier and the use of the Institute of Healthcare Improvement's (IHI) 4Ms Framework (i.e. "What Matters, Medication, Mentation, and Mobility") can serve as a tool for providers to meet patients' needs surrounding goals of care, medication regimens, mental and emotional well-being, and mobility capabilities through a social determinants of health lens. Providers should engage in serious illness conversations early to honor patient preferences, reduce polypharmacy, use a validated instrument to assess cognition such as the Mini-Cog or Functional Activities Questionnaire, and assess the need for assistance completing activities of daily living (ADLs) and instrumental activities of daily living (IADLs). Consultation with social work is highly recommended given the complexity of the medical and social needs of newly discharged cognitively impaired CHF patients and the need to optimize the use of all available community resources.

Aluminum-Crosslinked Nanocellulose Scaffolds for Fluoride Removal.

Anionic carboxylated cellulose nanofibers (CNF) are effective media to remove cationic contaminants from water. In this study, sustainable cationic CNF-based adsorbents capable of removing anionic contaminants were demonstrated using a simple approach. Specifically, the zero-waste nitro-oxidization process was used to produce carboxylated CNF (NOCNF), which was subsequently converted into a cationic scaffold by crosslinking with aluminum ions. The system, termed Al-CNF, is found to be effective for the removal of fluoride ions from water. Using the Langmuir isotherm model, the fluoride adsorption study indicates that Al-CNF has a maximum adsorption capacity of 43.3 mg/g, which is significantly higher than that of alumina-based adsorbents such as activated alumina (16.3 mg/g). The selectivity of fluoride adsorption in the presence of other anionic species (nitrate or sulfate) by Al-CNF at different pH values was also evaluated. The results indicate that Al-CNF can maintain a relatively high selectivity towards the adsorption of fluoride. Finally, the sequential applicability of using spent Al-CNF after the fluoride adsorption to further remove cationic contaminant such as Basic Red 2 dye was demonstrated. The low cost and relatively high adsorption capacity of Al-CNF make it suitable for practical applications in fluoride removal from water.

Efficient synthesis of indole-chalcones based glycohybrids and their anticancer activity.

Indole based glycosides belong to the class of pharmacologically active molecules and found in diverse natural compounds. Herein, we report the synthesis of 1,2,3-triazole bridged chirally enriched diverse indole-chalcones based glycohybrids. Three series of glycohybrids were designed and efficiently synthesized using d-glucose, d-galactose and d-mannose derived 1-azido glycosides. The reactions sequence involved were, the synthesis of indole derived chalcones which were formed via Claisen-Schmidt condensation reaction and subsequently N-propargylation which leads to the production of N-propargylated indole-chalcones. The N-propargylated indole-chalcones get transformed into 1,2,3-triazole bridged indole-chalcone based glycohybrids by reacting with 1-azido sugar glycosides under click-chemistry reaction conditions. Further, the biological activity of synthesized glycohybrids (n = 27) was assessed in-vitro against MDA-MB231, MCF-7, MDA-MB453 cancer, and MCF-10A normal cell lines. The selected compounds showed potent anti-oncogenic properties against MCF-7 and MDA-MB231 breast cancer cell line with IC50 values of 1.05 µM and 11.40 µM respectively, with very good selectivity index (SI > 161). The active compounds show better binding affinity as compared to co-crystallized inhibitor 1-(tert-butyl)-3-(p-tolyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (PP1) with HCK (PTKs) proteins in molecular docking studies.

Lysophosphatidylcholine induces oxidative stress and calcium-mediated cell death in human blood platelets.

Platelets are essential component of circulation that plays a major role in hemostasis and thrombosis. During activation and its demise, platelets release platelet-derived microvesicles, with lysophosphatidylcholine (LPC) being a prominent component in their lipid composition. LPC, an oxidized low-density lipoprotein, is involved in cellular metabolism, but its higher level is implicated in pathologies like atherosclerosis, diabetes, and inflammatory disorders. Despite this, its impact on platelet function remains relatively unexplored. To address this, we studied LPC's effects on washed human platelets. A multimode plate reader was employed to measure reactive oxygen species and intracellular calcium using H2DCF-DA and Fluo-4-AM, respectively. Flow cytometry was utilized to measure phosphatidylserine expression, mitochondrial membrane potential (ΔΨm), and mitochondrial permeability transition pore (mPTP) formation using FITC-Annexin V, JC-1, and CoCl2/calcein-AM, respectively. Additionally, platelet morphology and its ultrastructure were observed via phase contrast and electron microscopy. Sonoclot and light transmission aggregometry were employed to examine fibrin formation and platelet aggregation, respectively. The findings demonstrate that LPC induced oxidative stress and increased intracellular calcium in platelets, resulting in increased phosphatidylserine expression and reduced ΔΨm. LPC triggered caspase-independent platelet death and mPTP opening via cytosolic and mitochondrial calcium, along with microvesiculation and reduced platelet counts. LPC increased the platelet's size, adopting a balloon-shaped morphology, causing membrane fragmentation and releasing its cellular contents, while inducing a pro-coagulant phenotype with increased fibrin formation and reduced integrin αIIbß3 activation. Conclusively, this study reveals LPC-induced oxidative stress and calcium-mediated platelet death, necrotic in nature with pro-coagulant properties, potentially impacting inflammation and repair mechanisms during vascular injury.

Gingival health, plaque accumulation, and restoration outcomes in deciduous anterior teeth: evaluating zirconia crowns versus composite resin strip crowns.

BACKGROUND: Zirconia crowns, resembling crystals and with enamel-like aesthetics, are recent entrants in pediatric restorative dentistry. Despite growing use, their empirical efficacy remains under-explored. The aim of this study is to compare resin composite strip crowns and premanufactured zirconia crowns on primary maxillary incisors. METHODS: In the Pediatric Dental Clinics, 240 primary maxillary incisors (69 patients) were treated with either zirconia (120 teeth) or composite strip crowns (120 teeth). Evaluations of gingival health, plaque, secondary caries, restoration failure, and opposing teeth wear occurred at 3, 6, and 12-month intervals. RESULTS: At 3 months, zirconia crowns showed less gum bleeding (P=0.006) and plaque. Through 6 and 12 months, zirconia crowns exhibited fewer failures but higher opposing teeth wear. Strip crowns indicated greater tooth material loss. CONCLUSIONS: Zirconia crowns demonstrated superior gingival health and durability over composite resin strip crowns but caused increased wear on opposing teeth.

Development of Hsp90 inhibitor to regulate cytokine storms in excessive delayed- and acute inflammation.

BACKGROUND: The surplus cytokines remaining after use in the early stages of the inflammatory response stimulate immune cells even after the response is over, causing a secondary inflammatory response and ultimately damaging the host, which is called a cytokine storm. Inhibiting heat shock protein 90 (Hsp90), which has recently been shown to play an important role in regulating inflammation in various cell types, may help control excessive inflammatory responses and cytokine storms. METHODS: We discovered an anti-inflammatory compound by measuring the inhibitory effect of CD86 expression on spleen DCs (sDCs) using the chemical compounds library of Hsp90 inhibitors. Subsequently, to select the hit compound, the production of cytokines and expression of surface molecules were measured on the bone marrow-derived DCs (BMDCs) and peritoneal macrophages. Then, we analyzed the response of antigen-specific Th1 cells. Finally, we confirmed the effect of the compound using acute lung injury (ALI) and delayed-type hypersensitivity (DTH) models. RESULTS: We identified Be01 as the hit compound, which reduced CD86 expression the most in sDCs. Treatment with Be01 decreased the production of pro-inflammatory cytokines (IL-6, TNF-α, and IL-1ß) in BMDC and peritoneal macrophages stimulated by LPS. Under the DTH model, Be01 treatment reduced ear swelling and pro-inflammatory cytokines in the spleen. Similarly, Be01 treatment in the ALI model decreased neutrophil infiltration and lower levels of secreted cytokines (IL-6, TNF-α). CONCLUSIONS: Reduction of CD80 and CD86 expression on DCs by Be01 indicates reduced secondary inflammatory response by Th1 cells, and reduced release of pro-inflammatory cytokines by peritoneal macrophages may initially control the cytokine storm.

Histopathological Profile of Different Breast Lesions: A Single-Center Observational Study.

OBJECTIVE: To describe the histopathological pattern of different breast lesions among tissue specimens sent to our laboratory. METHOD: A record-based study using a retrospective review of 255 histologically diagnosed breast biopsy reports in the histopathology department of authors from December 2016 to November 2021 was conducted. The specimens were collected from core biopsy, lumpectomy, and mastectomy. All data obtained were analyzed using the Statistical Package for the Social Sciences (SPSS) version 28 (IBM SPSS Statistics, Armonk, NY). Then, the findings were presented using text, tables, and charts. RESULT: A total of 255 breast lesions were analyzed in this study. Most of the cases were benign (58.8%), followed by inflammatory lesions (21.6%), and malignant (19.6%). Fibroadenoma was the most prevalent benign lesion (36.7%), and most of the patients (70.9%) were in the age group of 20-39 years old. The most common inflammatory lesion was granulomatous mastitis (56.4%), and most of the cases were diagnosed in the age group of 30-39 years old. Invasive ductal carcinoma (IDC) was the most encountered histological type of carcinoma (62%). Of the malignant cases, 52% were diagnosed before the age of 50 years. Among these 50 cases, grade 2 was the most prevalent one (46%). CONCLUSION: Benign breast lesions are more common than malignant breast lesions, and fibroadenoma is the most common benign subtype. Granulomatous mastitis is the most prevalent inflammatory breast lesion. About two-thirds of malignant cases are non-Arab. Invasive ductal carcinoma with no special type (NST) is the most common malignant subtype.

QbD-Based Development and Evaluation of Pazopanib Hydrochloride Extrudates Prepared by Hot-Melt Extrusion Technique: In Vitro and In Vivo Evaluation.

BACKGROUND: Pazopanib hydrochloride (PZB) is a protein kinase inhibitor approved by the United States Food and Drug Administration and European agencies for the treatment of renal cell carcinoma and other renal malignancies. However, it exhibits poor aqueous solubility and inconsistent oral drug absorption. In this regard, the current research work entails the development and evaluation of the extrudates of pazopanib hydrochloride by the hot-melt extrusion (HME) technique for solubility enhancement and augmenting oral bioavailability. RESULTS: Solid dispersion of the drug was prepared using polymers such as Kollidon VA64, hydroxypropylmethylcellulose (HPMC), Eudragit EPO, and Affinisol 15LV in a 1:2 ratio by the HME process through a lab-scale 18 mm extruder. Systematic optimization of the formulation variables was carried out with the help of custom screening design (JMP Software by SAS, Version 14.0) to study the impact of polymer type and plasticizer level on the quality of extrudate processability by measuring the torque value, appearance, and disintegration time as the responses. The polymer blends containing Kollidon VA64 and Affinisol 15LV resulted in respective clear transparent extrudates, while Eudragit EPO and HPMC extrudates were found to be opaque white and brownish, respectively. Furthermore, evaluation of the impact of process parameters such as screw rpm and barrel temperature was measured using a definitive screening design on the extrude appearance, torque, disintegration time, and dissolution profile. Based on the statistical outcomes, it can be concluded that barrel temperature has a significant impact on torque, disintegration time, and dissolution at 30 min, while screw speed has an insignificant impact on the response variables. Affinisol extrudates showed less moisture uptake and faster dissolution in comparison to Kollidon VA64 extrudates. Affinisol extrudates were evaluated for polymorphic stability up to a 3-month accelerated condition and found no recrystallization. PZB-Extrudates using the Affinisol polymer (Test formulation A) revealed significantly higher bioavailability (AUC) in comparison to the free Pazopanib drug and marketed formulation.

Tenecteplase versus alteplase for thrombolysis in patients selected by use of perfusion imaging within 4·5 h of onset of ischaemic stroke (TASTE): a multicentre, randomised, controlled, phase 3 non-inferiority trial.

BACKGROUND: Intravenous tenecteplase increases reperfusion in patients with salvageable brain tissue on perfusion imaging and might have advantages over alteplase as a thrombolytic for ischaemic stroke. We aimed to assess the non-inferiority of tenecteplase versus alteplase on clinical outcomes in patients selected by use of perfusion imaging. METHODS: This international, multicentre, open-label, parallel-group, randomised, clinical non-inferiority trial enrolled patients from 35 hospitals in eight countries. Participants were aged 18 years or older, within 4·5 h of ischaemic stroke onset or last known well, were not being considered for endovascular thrombectomy, and met target mismatch criteria on brain perfusion imaging. Patients were randomly assigned (1:1) by use of a centralised web server with randomly permuted blocks to intravenous tenecteplase (0·25 mg/kg) or alteplase (0·90 mg/kg). The primary outcome was the proportion of patients without disability (modified Rankin Scale 0-1) at 3 months, assessed via masked review in both the intention-to-treat and per-protocol populations. We aimed to recruit 832 participants to yield 90% power (one-sided alpha=0·025) to detect a risk difference of 0·08, with an absolute non-inferiority margin of -0·03. The trial was registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000243718, and the European Union Clinical Trials Register, EudraCT Number 2015-002657-36, and it is completed. FINDINGS: Recruitment ceased early following the announcement of other trial results showing non-inferiority of tenecteplase versus alteplase. Between March 21, 2014, and Oct 20, 2023, 680 patients were enrolled and randomly assigned to tenecteplase (n=339) and alteplase (n=341), all of whom were included in the intention-to-treat analysis (multiple imputation was used to account for missing primary outcome data for five patients). Protocol violations occurred in 74 participants, thus the per-protocol population comprised 601 people (295 in the tenecteplase group and 306 in the alteplase group). Participants had a median age of 74 years (IQR 63-82), baseline National Institutes of Health Stroke Scale score of 7 (4-11), and 260 (38%) were female. In the intention-to-treat analysis, the primary outcome occurred in 191 (57%) of 335 participants allocated to tenecteplase and 188 (55%) of 340 participants allocated to alteplase (standardised risk difference [SRD]=0·03 [95% CI -0·033 to 0·10], one-tailed pnon-inferiority=0·031). In the per-protocol analysis, the primary outcome occurred in 173 (59%) of 295 participants allocated to tenecteplase and 171 (56%) of 306 participants allocated to alteplase (SRD 0·05 [-0·02 to 0·12], one-tailed pnon-inferiority=0·01). Nine (3%) of 337 patients in the tenecteplase group and six (2%) of 340 in the alteplase group had symptomatic intracranial haemorrhage (unadjusted risk difference=0·01 [95% CI -0·01 to 0·03]) and 23 (7%) of 335 and 15 (4%) of 340 died within 90 days of starting treatment (SRD 0·02 [95% CI -0·02 to 0·05]). INTERPRETATION: The findings in our study provide further evidence to strengthen the assertion of the non-inferiority of tenecteplase to alteplase, specifically when perfusion imaging has been used to identify reperfusion-eligible stroke patients. Although non-inferiority was achieved in the per-protocol population, it was not reached in the intention-to-treat analysis, possibly due to sample size limtations. Nonetheless, large-scale implementation of perfusion CT to assist in patient selection for intravenous thrombolysis in the early time window was shown to be feasible. FUNDING: Australian National Health Medical Research Council; Boehringer Ingelheim.

Identification of WNK1 as a therapeutic target to suppress IgH/MYC expression in multiple myeloma.

Multiple myeloma (MM) remains an incurable hematological malignancy demanding innovative therapeutic strategies. Targeting MYC, the notorious yet traditionally undruggable oncogene, presents an appealing avenue. Here, using a genome-scale CRISPR-Cas9 screen, we identify the WNK lysine-deficient protein kinase 1 (WNK1) as a regulator of MYC expression in MM cells. Genetic and pharmacological inhibition of WNK1 reduces MYC expression and, further, disrupts the MYC-dependent transcriptional program. Mechanistically, WNK1 inhibition attenuates the activity of the immunoglobulin heavy chain (IgH) enhancer, thus reducing MYC transcription when this locus is translocated near the MYC locus. WNK1 inhibition profoundly impacts MM cell behaviors, leading to growth inhibition, cell-cycle arrest, senescence, and apoptosis. Importantly, the WNK inhibitor WNK463 inhibits MM growth in primary patient samples as well as xenograft mouse models and exhibits synergistic effects with various anti-MM compounds. Collectively, our study uncovers WNK1 as a potential therapeutic target in MM.

Imaging Characteristics and Clinical Utility of Half-Dose versus Full-Dose Ultrawidefield Fundus Fluorescein Angiography.

PURPOSE: In early 2022, a fluorescein shortage occurred in the United States. To meet the standard of care for patients who required ultrawidefield fundus fluorescein angiography (UWFFA), a regimen of half-dose (250 mg) sodium fluorescein (10%) was adopted instead of the full dose (500 mg) at the Cole Eye Institute (CEI). In this paper, we compare the image quality, clinical utility, and the side-effect profile of half-dose versus full-dose fluorescein in UWFFA for a cohort of stable patients. DESIGN: Retrospective chart review. PARTICIPANTS: Patients with retinal vascular disease were included if they received half-dose and full-dose UWFFA (Optos California) within 6 months at the CEI. Eyes were excluded if they received intraocular injections, laser procedures, new immunosuppression, and worsened or improved inflammation on clinical examination. METHODS: Quantitative assessment of vascular leakage was performed using a machine learning-enhanced automated segmentation platform. Leakage from late-phase UWFFA images was compared between half-dose and full-dose images. Qualitative assessment of image quality and relative vascular leakage was performed by 2 masked independent reviewers. Side effects after fluorescein administration were recorded for each patient. MAIN OUTCOME MEASURES: Masked leakage grading and automated leakage scores. RESULTS: There were 52 eyes of 35 patients, 42 (81%) uveitic, 5 (9%) diabetic, and 4 (8%) normal controls. Patients had no change to their visual acuity (logarithm of the minimum angle of resolution mean, 0.3 ± 0.6), anterior chamber and vitreous cell between UFFWA's. UWFFA images were deemed of equal quality and leakage by both masked reviewers (78%-87% agreement; κ, 0.642). Automated leakage analysis showed mildly increased leakage in half-dose images overall (3.8% vs. 2.8%; P = 0.01) and in the macula (1.5% vs. 0.6%; P = 0.01). Side effects included nausea (half [n = 3, 9%] vs. full [n = 2, 6%]; P = 0.69) and urticaria (n = 0, 0% vs. n = 1, 2%; P = 0.99) and were not different between doses. CONCLUSIONS: In this cohort, half-dose UWFFA produced images that were of similar quality, clinical utility and with a similar side effect profile compared with full dose. Half-dose UWFFA can be used to accurately assess the retinal vasculature and could be used primarily as a method to save cost and prevent waste. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Mesenchymal stromal cells protect tissues from Th1 immune responses via IL-11 secretion.

Mesenchymal stromal cells (MSCs) have been shown to modulate the function of various subsets of T cells such as naïve CD4+ T cells and IFNγ+CD4+ Th1 cells; however, mechanisms underlying this regulation have not been fully deciphered. Our in vitro culture assays demonstrate that MSCs suppress the activation and function of CD4+ T cells by secreting interleukin 11, and neutralization of IL11 abrogates MSC-mediated suppression of CD4+ T cell function. Moreover, delayed-type, exogenous supplementation of IL11 significantly suppressed IFNγ+ expression by Th1 cells. Th1 and CD8+ cells play central roles in T cell-mediated tissue damage. Using a murine model of hypersensitivity response to study T cell-mediated tissue damage, we show that silencing IL11 in MSCs significantly abates the capacity of MSCs to suppress the generation of IFNγ-secreting CD4+ and CD8+ cells, failing to prevent T cell-mediated tissue inflammation and tissue damage.

Correlation Between Blue Fundus Autofluorescence and SD-OCT Measurements of Geographic Atrophy in Dry Age-Related Macular Degeneration.

PURPOSE: To compare fundus autofluorescence (FAF) and spectral domain optical coherence tomography (OCT) measurements of geographic atrophy (GA) area and to analyze lesion area changes measured by spectral domain OCT in GATHER1. DESIGN: An assessment reliability analysis using prospective, randomized, double-masked phase 2/3 clinical trial data. METHODS: GATHER1 examined the efficacy and safety of avacincaptad pegol (ACP) for GA treatment. A post hoc analysis was performed to identify correlations between FAF- and OCT-based measurements of GA. GA area was measured on blue-light FAF images using semiautomatic segmentation software with support from OCT and near-infrared imaging. Machine-learning enhanced, multilayer segmentation of OCT scans were reviewed by human readers, and segmentation errors were corrected as needed. GA area was defined as total RPE loss on cross-sectional B scans. Time points included Months 0, 6, 12, and 18. Additionally, OCT-based GA-area changes between ACP and sham were analyzed. RESULTS: There was a strong correlation (r = 0.93) between FAF and OCT GA area measurements that persisted through 18 months. Mean (SD) differences between OCT and FAF GA measurements were negligible: 0.11 mm2 (1.42) at Month 0, 0.03 mm2 (1.62) at Month 6, -0.17 mm2 (1.81) at Month 12, and -0.07 mm2 (1.78) at Month 18. OCT assessments of GA growth revealed a 30% and 27% reduction at Months 12 and 18, respectively, between ACP and sham, replicating FAF measurements from GATHER1. CONCLUSIONS: The strong correlation between blue FAF and OCT measurements of GA area supports OCT as a reliable method to measure GA lesion area in clinical trials.