Impact of Vision Impairment and Ocular Morbidity and Their Treatment on Quality of Life in Children: A Systematic Review.

TOPIC: This review summarizes existing evidence of the impact of vision impairment and ocular morbidity and their treatment on children's quality of life (QoL). CLINICAL RELEVANCE: Myopia and strabismus are associated with reduced QoL among children. Surgical treatment of strabismus significantly improves affected children's QoL. METHODS: We conducted a systematic review and meta-analysis by screening articles in any language in 9 databases published from inception through August 22, 2022, addressing the impact of vision impairment, ocular morbidity, and their treatment on QoL in children. We reported pooled standardized mean differences (SMDs) using random-effects meta-analysis models. Quality appraisal was performed using Joanna Briggs Institute and National Institutes of Health tools. This study was registered with the International Prospective Register of Systematic Reviews (identifier, CRD42021233323). RESULTS: Our search identified 29 118 articles, 44 studies (0.15%) of which were included for analysis that included 32 318 participants from 14 countries between 2005 and 2022. Seventeen observational and 4 interventional studies concerned vision impairment, whereas 10 observational and 13 interventional studies described strabismus and other ocular morbidities. Twenty-one studies were included in the meta-analysis. The QoL scores did not differ between children with and without vision impairment (SMD, -1.04; 95% confidence interval [CI], -2.11 to 0.03; P = 0.06; 9 studies). Myopic children demonstrated significantly lower QoL scores than those with normal vision (SMD, -0.60; 95% CI, -1.09 to -0.11; P = 0.02; 7 studies). Children with strabismus showed a significantly lower QoL score compared with those without (SMD, -1.19; 95% CI, -1.66 to -0.73; P < 0.001; 7 studies). Strabismus surgery significantly improved QoL in children (SMD, 1.36; 95% CI, 0.48-2.23; P < 0.001; 7 studies). No randomized controlled trials (RCTs) concerning refractive error and QoL were identified. Among all included studies, 35 (79.5%) were scored as low to moderate quality; the remaining met all quality appraisal tools criteria. DISCUSSION: Reduced QoL was identified in children with myopia and strabismus. Surgical correction of strabismus improves the QoL of affected children, which supports insurance coverage of strabismus surgery. Further studies, especially RCTs, investigating the impact of correction of myopia on QoL are needed. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Triglyceride-derived fatty acids reduce autophagy in a model of retinal angiomatous proliferation.

Dyslipidemia and autophagy have been implicated in the pathogenesis of blinding neovascular age-related macular degeneration (NV-AMD). VLDL receptor (VLDLR), expressed in photoreceptors with a high metabolic rate, facilitates the uptake of triglyceride-derived fatty acids. Since fatty acid uptake is reduced in Vldlr-/- tissues, more remain in circulation, and the retina is fuel deficient, driving the formation in mice of neovascular lesions reminiscent of retinal angiomatous proliferation (RAP), a subtype of NV-AMD. Nutrient scarcity and energy failure are classically mitigated by increasing autophagy. We found that excess circulating lipids restrained retinal autophagy, which contributed to pathological angiogenesis in the Vldlr-/- RAP model. Triglyceride-derived fatty acid sensed by free fatty acid receptor 1 (FFAR1) restricted autophagy and oxidative metabolism in photoreceptors. FFAR1 suppressed transcription factor EB (TFEB), a master regulator of autophagy and lipid metabolism. Reduced TFEB, in turn, decreased sirtuin-3 expression and mitochondrial respiration. Metabolomic signatures of mouse RAP-like retinas were consistent with a role in promoting angiogenesis. This signature was also found in human NV-AMD vitreous. Restoring photoreceptor autophagy in Vldlr-/- retinas, either pharmacologically or by deleting Ffar1, enhanced metabolic efficiency and suppressed pathological angiogenesis. Dysregulated autophagy by circulating lipids might therefore contribute to the energy failure of photoreceptors driving neovascular eye diseases, and FFAR1 may be a target for intervention.

The Effect of the Inner Engineering Online Program as a Positive Intervention on Subjective Well-Being and Positive Work Outcomes.

Objective: This study evaluates the effect of Inner Engineering Online (IEO) on subjective well-being and positive work outcomes. Design: The study uses a field quasi-experimental one group design with pre- and post-tests. Interventions: IEO is a multicomponent online self-paced program. The program consists of seven online sessions to be completed over a 4-week period. Results: The study finds that IEO has a positive effect on subjective well-being (mindfulness, joy, vitality, restfulness, and oneness) and positive work outcomes (meaningful work, psychological capital, and work engagement). Conclusion: The findings on IEO have important practical implications for improving subjective well-being and work experiences.

Patient-Reported Outcome and Clinical Scores Are Equally Accurate in Predicting Mucosal Healing in Ulcerative Colitis: A Prospective Study.

BACKGROUND: Optimal management of patients with ulcerative colitis (UC) requires the accurate, objective assessment of disease activity. AIMS: We aimed to determine how strong patient-reported outcomes, clinical scores and symptoms correlate with endoscopy and biomarkers for assessment of disease activity in patients with UC. METHODS: Consecutive patients with UC followed at the McGill University IBD Center and referred for endoscopy (surveillance or flare) were included prospectively between September 2018 and August 2020. Patient-reported outcome (PRO2), partial Mayo, Simple Clinical Colitis Activity Index (SCCAI), Mayo endoscopic subscore (MES) and Baron and Ulcerative Colitis Endoscopic Index of Severity (UCEIS) scores were calculated. C-reactive protein (CRP) and fecal calprotectin (FCAL) were collected. RESULTS: A total of 171 patients with UC [age: 49(IQR:38-61) years, female: 46.2%, 57.3% extensive disease, 42.7% on biologicals] were included prospectively. Rectal bleeding (RBS), stool frequency (SF) subscore of 0, or total PRO2 remission (RBS0 and SF ≤ 1), partial Mayo (≤ 2) and SCCAI (≤ 2.5) remission were similarly associated with mucosal healing defined by MES (0 or ≤ 1), Baron (0 or ≤ 1) or UCEIS (≤ 3) scores in ROC analysis (AUC:0.93-0.72). There was a moderate-to-strong agreement between MES Baron and UCEIS (K = 0.91-0.41). A UCEIS of ≤ 3 was identified as the best cutoff to clinical or endoscopic remission. Agreement between CRP and clinical remission or endoscopic healing (MES/Baron) was poor (K ~ 0.2), while agreement between FCAL and RBS-PRO2 or MES/Baron/UCEIS was moderate to strong (K = 0.44-0.70). CONCLUSIONS: Agreement between RBS, SF, PRO2, partial Mayo and SCCAI in predicting endoscopic healing was moderate to strong, while no clinically meaningful difference was found in accuracy across the scores and definitions. FCAL, but not CRP, was associated to clinical and endoscopic remission.

Author Correction: Antenatal IL-1-dependent inflammation persists postnatally and causes retinal and sub-retinal vasculopathy in progeny.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Immunometabolic modulation of retinal inflammation by CD36 ligand.

In subretinal inflammation, activated mononuclear phagocytes (MP) play a key role in the progression of retinopathies. Little is known about the mechanism involved in the loss of photoreceptors leading to vision impairment. Studying retinal damage induced by photo-oxidative stress, we observed that cluster of differentiation 36 (CD36)-deficient mice featured less subretinal MP accumulation and attenuated photoreceptor degeneration. Moreover, treatment with a CD36-selective azapeptide ligand (MPE-001) reduced subretinal activated MP accumulation in wild type mice and preserved photoreceptor layers and function as assessed by electroretinography in a CD36-dependent manner. The azapeptide modulated the transcriptome of subretinal activated MP by reducing pro-inflammatory markers. In isolated MP, MPE-001 induced dissociation of the CD36-Toll-like receptor 2 (TLR2) oligomeric complex, decreasing nuclear factor-kappa B (NF-κB) and NLR family pyrin domain containing 3 (NLRP3) inflammasome activation. In addition, MPE-001 caused an aerobic metabolic shift in activated MP, involving peroxisome proliferator-activated receptor-γ (PPAR-γ) activation, which in turn mitigated inflammation. Accordingly, PPAR-γ inhibition blocked the cytoprotective effect of MPE-001 on photoreceptor apoptosis elicited by activated MP. By altering activated MP metabolism, MPE-001 decreased immune responses to alleviate subsequent inflammation-dependent neuronal injury characteristic of various vision-threatening retinal disorders.

Müller Cell-Localized G-Protein-Coupled Receptor 81 (Hydroxycarboxylic Acid Receptor 1) Regulates Inner Retinal Vasculature via Norrin/Wnt Pathways.

Ischemic retinopathies are characterized by a progressive microvascular degeneration followed by a postischemic aberrant neovascularization. To reinstate vascular supply and metabolic equilibrium to the ischemic tissue during ischemic retinopathies, a dysregulated production of growth factors and metabolic intermediates occurs, promoting retinal angiogenesis. Glycolysis-derived lactate, highly produced during ischemic conditions, has been associated with tumor angiogenesis and wound healing. Lactate exerts its biological effects via G-protein-coupled receptor 81 (GPR81) in several tissues; however, its physiological functions and mechanisms of action in the retina remain poorly understood. Herein, we show that GPR81, localized predominantly in Müller cells, governs deep vascular complex formation during development and in ischemic retinopathy. Lactate-stimulated GPR81 Müller cells produce numerous angiogenic factors, including Wnt ligands and particularly Norrin, which contributes significantly in triggering inner retinal blood vessel formation. Conversely, GPR81-null mice retina shows reduced inner vascular network formation associated with low levels of Norrin (and Wnt ligands). Lactate accumulation during ischemic retinopathy selectively activates GPR81-extracellular signal-regulated kinase 1/2-Norrin signaling to accelerate inner retinal vascularization in wild-type animals, but not in the retina of GPR81-null mice. Altogether, we reveal that lactate via GPR81-Norrin participates in inner vascular network development and in restoration of the vasculature in response to injury. These findings suggest a new potential therapeutic target to alleviate ischemic diseases.

Examination of novel 4-aminoquinoline derivatives designed and synthesized by a hybrid pharmacophore approach to enhance their anticancer activities.

In an attempt to develop effective and potentially safe anticancer agents, thirty-six 4-aminoquinoline derived sulfonyl analogs were designed and synthesized using a hybrid pharmacophore approach. The cytotoxicity of these compounds was determined using three breast tumor cell lines (MDA-MB231, MDA-MB468 and MCF7) and two matching non-cancer breast epithelial cell lines (184B5 and MCF10A). Although most of the compounds were quite effective on the breast cancer cells, the compound 7-chloro-4-(4-(2,4-dinitrophenylsulfonyl)piperazin-1-yl)quinoline (13; VR23) emerged as potentially the most desirable one in this series of compounds. Data from the NCI-60 cancer panel screening show that compound 13 is effective on a wide range of different cancers. Importantly, compound 13 is needed up to 17.6-fold less doses to achieve the same IC50 against cancer than non-cancer cells (MDA-MB468 vs MCF10A), suggesting that it can potentially be less toxic to normal cells. Cancer cells formed multiple centrosomes in the presence of compound 13, resulting in the cell cycle arrest at prometa-meta phase. This abnormality leads to eventual cell demise with sub-G1 DNA content typically shown with apoptotic cells. In addition, compound 13 also causes an increase in lysosomal volume in cancer but not in non-cancer cells, which may contribute at least in part to its preferential cancer cell-killing. The cancer cell-killing effect of compound 13 is highly potentiated when combined with either bortezomib or monastrol.

Design and synthesis of 4-piperazinyl quinoline derived urea/thioureas for anti-breast cancer activity by a hybrid pharmacophore approach.

In an attempt to improve anti-breast cancer activity, a new series of 4-piperazinylquinoline derivatives based on the urea/thiourea scaffold were designed and synthesised by a pharmacophore hybrid approach. We then examined for their antiproliferative effects on three human breast tumor cell lines, MDA-MB231, MDA-MB468 and MCF7, and two non-cancer breast epithelial cell lines, 184B5 and MCF10A. Among those 26 novel compounds examined, 5, 9, 17, 18, 21, 23 and 29 showed significantly improved antiproliferative activity on breast cancer cells. Compound 23 (4-(7-chloro-quinolin-4-yl)-piperazine-1-carbothioic acid (2-morpholin-4-yl-ethyl)-amide) (RL-15) is especially desirable, since its antigrowth/cell-killing activity is 7-11 fold higher on cancer than non-cancer cells. Data from cell biological studies demonstrated that cancer cells compromised plasma membrane integrity in the presence of compound 23. The cancer cell-specific property of compound 23 shown in cell culture stands in vivo test, this compound can be an excellent lead for effective and safe anticancer drug.

Antenatal IL-1-dependent inflammation persists postnatally and causes retinal and sub-retinal vasculopathy in progeny.

Antenatal inflammation as seen with chorioamnionitis is harmful to foetal/neonatal organ development including to eyes. Although the major pro-inflammatory cytokine IL-1ß participates in retinopathy induced by hyperoxia (a predisposing factor to retinopathy of prematurity), the specific role of antenatal IL-1ß associated with preterm birth (PTB) in retinal vasculopathy (independent of hyperoxia) is unknown. Using a murine model of PTB induced with IL-1ß injection in utero, we studied consequent retinal and choroidal vascular development; in this process we evaluated the efficacy of IL-1R antagonists. Eyes of foetuses exposed only to IL-1ß displayed high levels of pro-inflammatory genes, and a persistent postnatal infiltration of inflammatory cells. This prolonged inflammatory response was associated with: (1) a marked delay in retinal vessel growth; (2) long-lasting thinning of the choroid; and (3) long-term morphological and functional alterations of the retina. Antenatal administration of IL-1R antagonists - 101.10 (a modulator of IL-1R) more so than Kineret (competitive IL-1R antagonist) - prevented all deleterious effects of inflammation. This study unveils a key role for IL-1ß, a major mediator of chorioamnionitis, in causing sustained ocular inflammation and perinatal vascular eye injury, and highlights the efficacy of antenatal 101.10 to suppress deleterious inflammation.

Design and synthesis of novel quinacrine-[1,3]-thiazinan-4-one hybrids for their anti-breast cancer activity.

In an attempt to develop effective and safe anticancer agents, we designed, synthesized and examined 23 novel quinacrine (QC) derivatives by combining the 9-aminoacridine scaffold and the [1,3]thiazinan-4-ones group. Most of these hybrids showed strong anticancer activities, among which 3-(3-(6-chloro-2-methoxyacridin-9-ylamino)propyl)-2-(thiophen-2-yl)-1,3-thiazinan-4-one (25; VR151) effectively killed many different cancer cell types, including eight breast cancer cell lines with different genetic background, two prostate cancer and two lung cancer cell lines. In contrast, compound 25 is less effective against non-cancer cells, suggesting it may be less toxic to humans. Our data showed that cancer cells are arrested in S phase for a prolonged period due to the down-regulation of DNA replication, leading to eventual cell death. We have also shown that the S phase arrest may be resulted by the down-regulation of cyclin A coupled with the continued up-regulation of cyclin E, which coincide with the down-regulation of mTor-S6K and mTor-4EBP1 pathways.

Antenatal Suppression of IL-1 Protects against Inflammation-Induced Fetal Injury and Improves Neonatal and Developmental Outcomes in Mice.

Preterm birth (PTB) is commonly accompanied by in utero fetal inflammation, and existing tocolytic drugs do not target fetal inflammatory injury. Of the candidate proinflammatory mediators, IL-1 appears central and is sufficient to trigger fetal loss. Therefore, we elucidated the effects of antenatal IL-1 exposure on postnatal development and investigated two IL-1 receptor antagonists, the competitive inhibitor anakinra (Kineret) and a potent noncompetitive inhibitor 101.10, for efficacy in blocking IL-1 actions. Antenatal exposure to IL-1ß induced Tnfa, Il6, Ccl2, Pghs2, and Mpges1 expression in placenta and fetal membranes, and it elevated amniotic fluid IL-1ß, IL-6, IL-8, and PGF2α, resulting in PTB and marked neonatal mortality. Surviving neonates had increased Il1b, Il6, Il8, Il10, Pghs2, Tnfa, and Crp expression in WBCs, elevated plasma levels of IL-1ß, IL-6, and IL-8, increased IL-1ß, IL-6, and IL-8 in fetal lung, intestine, and brain, and morphological abnormalities: e.g., disrupted lung alveolarization, atrophy of intestinal villus and colon-resident lymphoid follicle, and degeneration and atrophy of brain microvasculature with visual evoked potential anomalies. Late gestation treatment with 101.10 abolished these adverse outcomes, whereas Kineret exerted only modest effects and no benefit for gestation length, neonatal mortality, or placental inflammation. In a LPS-induced model of infection-associated PTB, 101.10 prevented PTB, neonatal mortality, and fetal brain inflammation. There was no substantive deviation in postnatal growth trajectory or adult body morphometry after antenatal 101.10 treatment. The results implicate IL-1 as an important driver of neonatal morbidity in PTB and identify 101.10 as a safe and effective candidate therapeutic.

VR23: A Quinoline-Sulfonyl Hybrid Proteasome Inhibitor That Selectively Kills Cancer via Cyclin E-Mediated Centrosome Amplification.

The proteasome is clinically validated as a target for cancer therapeutics. However, proteasome-inhibitory agents that are cancer selective have yet to be developed. In this study, we report the identification of a safe and effective proteasome inhibitor with selective anticancer properties. We screened a chemical library constructed using a hybrid approach that incorporated a 4-piperazinylquinoline scaffold and a sulfonyl phamarcophore. From this library, we identified 7-chloro-4-(4-(2,4-dinitrophenylsulfonyl)piperazin-1-yl)quinoline (VR23) as a small molecule that potently inhibited the activities of trypsin-like proteasomes (IC50 = 1 nmol/L), chymotrypsin-like proteasomes (IC50 = 50-100 nmol/L), and caspase-like proteasomes (IC50 = 3 µmol/L). Data from molecular docking and substrate competition assays established that the primary molecular target of VR23 was ß2 of the 20S proteasome catalytic subunit. Notably, VR23 was structurally distinct from other known proteasome inhibitors and selectively killed cancer cells by apoptosis, with little effect on noncancerous cells. Mechanistic investigations showed that cancer cells exposed to VR23 underwent an abnormal centrosome amplification cycle caused by the accumulation of ubiquitinated cyclin E. In combinations with the clinically approved chymotrypsin-like proteasome inhibitor bortezomib, VR23 produced a synergistic effect in killing multiple myeloma cells, including those that were resistant to bortezomib. VR23 was effective in vivo in controlling multiple myelomas and metastatic breast cancer cells, in the latter case also enhancing the antitumor activity of paclitaxel while reducing its side effects. Overall, our results identify VR23 as a structurally novel proteasome inhibitor with desirable properties as an anticancer agent.