Thermodynamic and structural investigation of oily wastewater treatment using peach kernel and walnut shell based activated carbon.

Despite the many articles about activated carbon with different precursors in adsorption process, no in-depth research has been carried out to understand the causes of the difference in surface adsorption characteristics of activated carbon with different precursors and different activation processes. In this work, the ability of two active carbon adsorbents made of walnut shell and peach kernel by two chemical and physical methods (totally 4 different types of activated carbon) in treatment of oily wastewater including diesel, gasoline, used oil or engine lubricant has been compared. The results show that the chemical activated peach carbon active with 97% hardness has provided the highest hardness and physical activated walnut carbon active has obtained the lowest hardness value (87%). It is also found that peach activated carbon has a higher iodine number than walnut activated carbon, and this amount can be increased using chemical methods; Therefore, the highest amount of Iodine Number is related to Peach activated carbon that is made by chemical method (1230 mg/g), and the lowest amount of iodine number is seen in walnut activated carbon that is made by physical method (1020 mg/g). moreover, the pore diameter of physical activated carbon is lower than chemical activated carbon in all cases. So that the pore diameter of chemical activated peach carbon active is equal to 22.08 µm and the measured pore diameter of physical activated peach carbon active is equal to 20.42 µm. These values for walnut are obtained as 22.74 µm and 21.86 µm, respectively. Furthermore, the temperature and pH effects on the adsorption of different synthesized oily wastewater was studied and it was found that a decrease in adsorption can be seen with an increase in temperature or decreasing the pH value, which can be referred to this fact that the process of adsorption is an exothermic process. Finally, to analyze the compatibility of adsorption isotherms with experimental data and to predict the adsorption process, three different isotherms named Langmuir, Temkin, and Freundlich isotherms were applied and their parameters were correlated. The correlation results show that the Langmuir isotherm had the best correlation in all cases compared to the Freundlich and Temkin isotherms, based on the correlation coefficient, and the calculated R2 values which was greater than 0.99 in all the studied cases.

Evaluating Sex Differences in the Characteristics and Outcomes of Lupus Nephritis: A Systematic Review and Meta-Analysis.

Introduction: More frequent and severe lupus nephritis (LN) has been reported in men compared to women, but data are limited and inconsistent. We conducted a meta-analysis of the literature to compare the histopathologic findings and outcomes between men and women with biopsy-proven LN. Methods: A systematic search of MEDLINE, Embase, Cochrane, and Web of Science databases was conducted through February 2021. Clinical information was extracted and synthesized from 25 studies that met inclusion criteria (1,210 men and 6,635 women). Pooled odds ratios (OR) with corresponding 95% confidence intervals (CIs) were generated via meta-analysis, and meta-regression was performed to assess the impact of several covariates, both using random-effects models. Results: Twenty studies reported kidney histopathology, eleven reported kidney outcomes, and eight reported mortality rates. Men had greater odds of class IV ± V LN (OR 1.26, 95% CI: 1.01-1.56), and the composite of end-stage kidney disease, persistent eGFR <15 mL/min or doubling of serum creatinine (OR 2.20, 95% CI: 1.59-3.06), and lower odds of complete remission (OR 0.52, 95% CI: 0.39-0.68). Mortality was not statistically significantly different between sexes (OR 1.50, 95% CI: 0.92-2.46). Meta-regression did not reveal statistically significant study-level relationships between sex differences in any of the covariates that could account for the greater odds of worse kidney outcome in males. Conclusion: Our analysis confirms the association between male sex and increased severity of LN as well as worse kidney outcomes. Larger prospective studies are needed to validate this association and inform treatment strategies adapted to this population.

Recent trends and economic significance of modified/functionalized biochars for remediation of environmental pollutants.

The pollution of soil and aquatic systems by inorganic and organic chemicals has become a global concern. Economical, eco-friendly, and sustainable solutions are direly required to alleviate the deleterious effects of these chemicals to ensure human well-being and environmental sustainability. In recent decades, biochar has emerged as an efficient material encompassing huge potential to decontaminate a wide range of pollutants from soil and aquatic systems. However, the application of raw biochars for pollutant remediation is confronting a major challenge of not getting the desired decontamination results due to its specific properties. Thus, multiple functionalizing/modification techniques have been introduced to alter the physicochemical and molecular attributes of biochars to increase their efficacy in environmental remediation. This review provides a comprehensive overview of the latest advancements in developing multiple functionalized/modified biochars via biological and other physiochemical techniques. Related mechanisms and further applications of multiple modified biochar in soil and water systems remediation have been discussed and summarized. Furthermore, existing research gaps and challenges are discussed, as well as further study needs are suggested. This work epitomizes the scientific prospects for a complete understanding of employing modified biochar as an efficient candidate for the decontamination of polluted soil and water systems for regenerative development.

Fibronectin glomerulopathy in a kidney allograft biopsy.

BACKGROUND: Fibronectin glomerulopathy is a rare genetic nephropathy with only a few cases of post-transplant recurrence being reported previously. We highlight a case that was initially misdiagnosed and emphasize the importance of full immunofluorescence and electron microscopy evaluation in allograft biopsies. CASE PRESENTATION: A 36-year-old male with a history of end-stage kidney disease secondary to biopsy-proven type 1 membranoproliferative glomerulonephritis (MPGN) status-post living unrelated donor kidney transplant 12 years prior, presented with increasing creatinine and proteinuria. Biopsy was performed and was consistent with fibronectin glomerulopathy. Subsequent genetic testing revealed an FN1 mutation, the primary gene associated with this condition. CONCLUSIONS: Full histologic evaluation of the allograft biopsy corrected the diagnosis and additionally suggested that the patient's mother, who had expired in her 30s and had received a diagnosis of type 1 MPGN on autopsy, likely also had fibronectin glomerulopathy, enabling appropriate genetic counseling for the family.

Interactive Subspace Cluster Analysis Guided by Semantic Attribute Associations.

Multivariate datasets with many variables are increasingly common in many application areas. Most methods approach multivariate data from a singular perspective. Subspace analysis techniques, on the other hand. provide the user a set of subspaces which can be used to view the data from multiple perspectives. However, many subspace analysis methods produce a huge amount of subspaces, a number of which are usually redundant. The enormity of the number of subspaces can be overwhelming to analysts, making it difficult for them to find informative patterns in the data. In this paper, we propose a new paradigm that constructs semantically consistent subspaces. These subspaces can then be expanded into more general subspaces by ways of conventional techniques. Our framework uses the labels/meta-data of a dataset to learn the semantic meanings and associations of the attributes. We employ a neural network to learn a semantic word embedding of the attributes and then divide this attribute space into semantically consistent subspaces. The user is provided with a visual analytics interface that guides the analysis process. We show via various examples that these semantic subspaces can help organize the data and guide the user in finding interesting patterns in the dataset.

Ketamine Infusion for Sedation and Analgesia during Mechanical Ventilation in the ICU: A Multicenter Evaluation.

Methods: We reviewed the electronic medical record of critically ill adults who received a continuous infusion of ketamine for ≥24 hours during invasive mechanical ventilation in three hospitals over a two-year period. We captured data including ketamine indication, dose, unintended effects, and adjustments to coadministered sedatives or opioids. We analyzed these data to determine the incidence of reported unintended effects of ketamine infusion (primary outcome) and changes in exposure to coadministered sedatives or opioids during ketamine use (secondary outcome). Results: 95 mechanically ventilated adults received a ketamine infusion for a median duration of 75 hours (interquartile range [IQR] 44-115) at a mean ± standard deviation (SD) infusion rate of 1.3 ± 0.5 mg/kg/hour for the first 24 hours. At least one unintended effect attributed to ketamine was documented in 24% of cases, most frequently tachycardia (6%) and sialorrhea (6%). Other sedative or opioid infusions were administered with ketamine in 76% and 92% of cases, respectively. Comparing the total amount of sedative or opioid administered in the 24 hours prior to ketamine infusion with the total amount administered during the first 24 hours on ketamine, there were no significant differences in propofol, midazolam, or dexmedetomidine exposure, but the average fentanyl exposure was higher after ketamine (2740 ± 1812 mcg) than before (1975 ± 1860 mcg) (absolute difference 766 mcg, 95% confidence interval [CI] 442 to 1089 mcg). Conclusions: In this multicenter cohort of critically ill, mechanically ventilated adults, ketamine infusion was primarily used as an adjunct to conventional sedative and opioid infusions, with noticeable but unintended effects potentially related to ketamine in nearly one-quarter of cases.

The Impact of Empowering Leadership on Job Performance of Higher Education Institutions Employees: Mediating Role of Goal Clarity and Self-Efficacy.

Purpose: The main objective of existing research is to assess empowering leadership effects on employees' job performance at the academic level through mediating variables' goal clarity and self-efficacy. Methods: Data were congregated from 400 employees belonging to higher education institutions of Pakistan through research assistants, hired for data collection. Statistical procedures, such as factor analysis via statistical package for the social sciences (SPSS 23), structural equation modeling with bootstrapping via statistical tool analysis of moment structures (AMOS 24), were used to evaluate data and assess the relationship among the constructs. Results: The structural equation modeling analysis uncovered several results. For instance, it shows the positive influence of empowering leadership behaviors on goal clarity, self-efficacy, and employees' job performance. Moreover, the bootstrap investigation showed that goal clarity and self-efficacy mediate empowering leadership behaviors' influence on workers' job performance. Therefore, conferring to existing study results empowering leadership is significantly associated with employees' job performance in the presence of mediators goal clarity and self-efficacy at the academic level of higher education institutions of Sindh, Pakistan. Conclusion: The main research question of existing research is to assess empowering leadership effects on employees' job performance through mediating variables' goal clarity and self-efficacy. To investigate this research question, we have conducted this study and empirically established that empowering leadership can affect employees' job performance with and without mediation. We have also shown empowering leadership as collaborative effects produce advanced levels of self-efficacy, goal clarity, and employees' job performance than either leadership behavior could accomplish by itself.

Robot-assisted magnetic capsule endoscopy; navigating colorectal inclinations.

Purpose: To investigate the interaction of a robot assisted magnetically driven wireless capsule endoscope (WCE) with colonic tissue, as it traverses the colorectal bends in the dorsal and ventral directions, relying only on the feedback from a 3D accelerometer. We also investigate the impact of shell geometry and water insufflation on WCE locomotion.Methods: A 3D printed incline phantom, lined with porcine colon, was used as the experimental platform, for controlled and repeatable results. The tilt angle of WCE was controlled to observe its influence on WCE locomotion. The phantom was placed underwater to observe the effects of water insufflation. The experiments were repeated using the two capsule shell geometries to observe the effect of shell geometry on WCE locomotion.Results: Friction between WCE and intestinal tissue increased when the tilt angle of the WCE was lower than the angle of the incline of the phantom. Increasing the WCE tilt angle to match the angle of the incline reduced this friction. Water insufflation and elliptical capsule shell geometry reduced the friction further.Conclusion: Tilting of the WCE equal to, or more than the angle of the incline improved the WCE locomotion. WCE locomotion was also improved by using elliptical capsule shell geometry and water insufflation.Abbreviations: CRC: colorectal cancer; GI: gastrointestinal; MRI: magnetic resonance imaging; WCE: wireless capsule endoscope.

Incidence of giant cell arteritis after bisphosphonate exposure: A retrospective cohort study.

OBJECTIVES: Bisphosphonates may cause autoimmune reactions via a cytokine-mediated acute phase response. A case of giant cell arteritis (GCA) after zoledronate injection was recently reported. We aimed to evaluate this association by reviewing the incidence of GCA after bisphosphonate administration. METHODS: This was a retrospective study using the medical claims data of elderly patients in the 20% Medicare random sample from 2008-2014 who had received zoledronate or ibandronate. Patients who had a diagnosis claim of GCA within the past year before receiving either bisphosphonate were excluded. The development of GCA was assessed in 2 ways: GCA diagnosis claim within 28 days of bisphosphonate injection and another claim within 90 days of initial claim; and temporal artery biopsy claim within 28 days of bisphosphonate injection and GCA diagnosis claim within 90 days of biopsy. Due to the Centers for Medicare & Medicaid Services reporting requirements we excluded numbers less than 11 from analysis. RESULTS: The incidence of GCA was 0.010% and 0.013% after zoledronate and ibandronate injection respectively. In the zoledronate group incidence was highest in patients aged 75-85 years (0.011%), in Whites (0.011%), in the northeast census region (0.013%) and higher in females (0.011% vs 0.009%). All GCA cases noted in the ibandronate group involved White females. We are unable to report incidences by age and region due to the paucity of data. CONCLUSION: The incidence of GCA after bisphosphonate injection was not increased compared to the generally reported incidence in the USA.

Polymyalgia rheumatica: An updated review.

Polymyalgia rheumatica should be suspected in older patients with bilateral shoulder and hip stiffness that is worse in the morning and improves with use. An array of nonspecific musculoskeletal complaints, constitutional symptoms, and elevated serum inflammatory markers may be present, so other conditions should also be considered. Prolonged glucocorticoids with patient-tailored dosing and duration are the mainstay of treatment. Corticosteroid-sparing therapy with adjunctive methotrexate may benefit select patients.

Taxonomizer: Interactive Construction of Fully Labeled Hierarchical Groupings from Attributes of Multivariate Data.

Organizing multivariate data spaces by their dimensions or attributes can be a rather difficult task. Most of the work in this area focuses on the statistical aspects such as correlation clustering, dimension reduction, and the like. These methods typically produce hierarchies in which the leaf nodes are labeled by the attribute names while the inner nodes are often represented by just a statistical measure and criterion, such as a threshold. This makes them difficult to understand for mainstream users. Taxonomies in science, biology, engineering, etc. on the other hand, are easy to comprehend since they provide meaningful labels at the inner nodes as well. Labeling inner nodes of taxonomies automatically requires the identification of hypernyms. Our proposed framework, called Taxonomizer, takes a visual analytics approach to meet this challenge. It appeals to the wisdom of humans to liaise with state of the art data analytics, neural word embeddings, and lexical databases. It consists of a set of visual tools that starts out with an automatically computed hierarchy where the leaf nodes are the original data attributes, and it then allows users to sculpt high-quality taxonomies for any multivariate dataset.

Food fortification with multiple micronutrients: impact on health outcomes in general population.

BACKGROUND: Vitamins and minerals are essential for growth and maintenance of a healthy body, and have a role in the functioning of almost every organ. Multiple interventions have been designed to improve micronutrient deficiency, and food fortification is one of them. OBJECTIVES: To assess the impact of food fortification with multiple micronutrients on health outcomes in the general population, including men, women and children. SEARCH METHODS: We searched electronic databases up to 29 August 2018, including the Cochrane Central Register of Controlled Trial (CENTRAL), the Cochrane Effective Practice and Organisation of Care (EPOC) Group Specialised Register and Cochrane Public Health Specialised Register; MEDLINE; Embase, and 20 other databases, including clinical trial registries. There were no date or language restrictions. We checked reference lists of included studies and relevant systematic reviews for additional papers to be considered for inclusion. SELECTION CRITERIA: We included randomised controlled trials (RCTs), cluster-RCTs, quasi-randomised trials, controlled before-after (CBA) studies and interrupted time series (ITS) studies that assessed the impact of food fortification with multiple micronutrients (MMNs). Primary outcomes included anaemia, micronutrient deficiencies, anthropometric measures, morbidity, all-cause mortality and cause-specific mortality. Secondary outcomes included potential adverse outcomes, serum concentration of specific micronutrients, serum haemoglobin levels and neurodevelopmental and cognitive outcomes. We included food fortification studies from both high-income and low- and middle-income countries (LMICs). DATA COLLECTION AND ANALYSIS: Two review authors independently screened, extracted and quality-appraised the data from eligible studies. We carried out statistical analysis using Review Manager 5 software. We used random-effects meta-analysis for combining data, as the characteristics of study participants and interventions differed significantly. We set out the main findings of the review in 'Summary of findings' tables, using the GRADE approach. MAIN RESULTS: We identified 127 studies as relevant through title/abstract screening, and included 43 studies (48 papers) with 19,585 participants (17,878 children) in the review. All the included studies except three compared MMN fortification with placebo/no intervention. Two studies compared MMN fortification versus iodised salt and one study compared MMN fortification versus calcium fortification alone. Thirty-six studies targeted children; 20 studies were conducted in LMICs. Food vehicles used included staple foods, such as rice and flour; dairy products, including milk and yogurt; non-dairy beverages; biscuits; spreads; and salt. Fourteen of the studies were fully commercially funded, 13 had partial-commercial funding, 14 had non-commercial funding and two studies did not specify the source of funding. We rated all the evidence as of low to very low quality due to study limitations, imprecision, high heterogeneity and small sample size. When compared with placebo/no intervention, MMN fortification may reduce anaemia by 32% (risk ratio (RR) 0.68, 95% confidence interval (CI) 0.56 to 0.84; 11 studies, 3746 participants; low-quality evidence), iron deficiency anaemia by 72% (RR 0.28, 95% CI 0.19 to 0.39; 6 studies, 2189 participants; low-quality evidence), iron deficiency by 56% (RR 0.44, 95% CI 0.32 to 0.60; 11 studies, 3289 participants; low-quality evidence); vitamin A deficiency by 58% (RR 0.42, 95% CI 0.28 to 0.62; 6 studies, 1482 participants; low-quality evidence), vitamin B2 deficiency by 64% (RR 0.36, 95% CI 0.19 to 0.68; 1 study, 296 participants; low-quality evidence), vitamin B6 deficiency by 91% (RR 0.09, 95% CI 0.02 to 0.38; 2 studies, 301 participants; low-quality evidence), vitamin B12 deficiency by 58% (RR 0.42, 95% CI 0.25 to 0.71; 3 studies, 728 participants; low-quality evidence), weight-for-age z-scores (WAZ) (mean difference (MD) 0.1, 95% CI 0.02 to 0.17; 8 studies, 2889 participants; low-quality evidence) and weight-for-height/length z-score (WHZ/WLZ) (MD 0.1, 95% CI 0.02 to 0.18; 6 studies, 1758 participants; low-quality evidence). We are uncertain about the effect of MMN fortification on zinc deficiency (RR 0.84, 95% CI 0.65 to 1.08; 5 studies, 1490 participants; low-quality evidence) and height/length-for-age z-score (HAZ/LAZ) (MD 0.09, 95% CI 0.01 to 0.18; 8 studies, 2889 participants; low-quality evidence). Most of the studies in this comparison were conducted in children. Subgroup analyses of funding sources (commercial versus non-commercial) and duration of intervention did not demonstrate any difference in effects, although this was a relatively small number of studies and the possible association between commercial funding and increased effect estimates has been demonstrated in the wider health literature. We could not conduct subgroup analysis by food vehicle and funding; since there were too few studies in each subgroup to draw any meaningful conclusions. When we compared MMNs versus iodised salt, we are uncertain about the effect of MMN fortification on anaemia (R 0.86, 95% CI 0.37 to 2.01; 1 study, 88 participants; very low-quality evidence), iron deficiency anaemia (RR 0.40, 95% CI 0.09 to 1.83; 2 studies, 245 participants; very low-quality evidence), iron deficiency (RR 0.98, 95% CI 0.82 to 1.17; 1 study, 88 participants; very low-quality evidence) and vitamin A deficiency (RR 0.19, 95% CI 0.07 to 0.55; 2 studies, 363 participants; very low-quality evidence). Both of the studies were conducted in children. Only one study conducted in children compared MMN fortification versus calcium fortification. None of the primary outcomes were reported in the study. None of the included studies reported on morbidity, adverse events, all-cause or cause-specific mortality. AUTHORS' CONCLUSIONS: The evidence from this review suggests that MMN fortification when compared to placebo/no intervention may reduce anaemia, iron deficiency anaemia and micronutrient deficiencies (iron, vitamin A, vitamin B2 and vitamin B6). We are uncertain of the effect of MMN fortification on anthropometric measures (HAZ/LAZ, WAZ and WHZ/WLZ). There are no data to suggest possible adverse effects of MMN fortification, and we could not draw reliable conclusions from various subgroup analyses due to a limited number of studies in each subgroup. We remain cautious about the level of commercial funding in this field, and the possibility that this may be associated with higher effect estimates, although subgroup analysis in this review did not demonstrate any impact of commercial funding. These findings are subject to study limitations, imprecision, high heterogeneity and small sample sizes, and we rated most of the evidence low to very low quality. and hence no concrete conclusions could be drawn from the findings of this review.

Predictive Tilt Compensation for Robot Assisted Magnetic Capsule Endoscope.

Wireless capsule endoscopes provide a painless and non-invasive alternative to the flexible endoscope in various applications of the gastrointestinal tract diagnosis. Operating a wireless capsule endoscope in the colon may benefit from an active position control as the large colon diameter can lead to uncontrollable and unpredictable capsule trajectory. Robot assisted magnetic steering is an attractive technique that is being explored by researchers worldwide. This paper presents the implications of a novel capsule geometry to markedly improve capsule stabilization and locomotion compared to the cylinder-based capsule geometry that is commonly used.

Constrictive Pericarditis Presenting as Bilateral Pleural Effusion: A Report of Two Cases.

Constrictive pericarditis is a rare presentation. We need a very high index of clinical suspicion to diagnose the disease. It most commonly presents secondary to tuberculosis (TB) in the developing world and post-radiation therapy in the developed world. Classically, it presents with symptoms of heart failure and as pericardial thickening or calcification on imaging studies. In hospital settings, constrictive pericarditis is not usually considered as a differential in patients presenting with pleural effusion. According to the literature, associated pleural effusions in cases of constrictive pericarditis could be left-sided. Herein, we present two unusual presentations of cases with bilateral pleural effusions. One of our cases developed constrictive pericarditis with concurrent active tuberculosis. This is a rare presentation because, normally, constrictive pericarditis is a late complication of tuberculosis. We suggest that when dealing with cases of bilateral pleural effusion, the etiology of constrictive pericarditis should be considered.

Lower red cell transfusion rates with use of tranexamic acid in single-stage bilateral total knee arthroplasty: A retrospective audit.

Bilateral total knee arthroplasty (BTKA) patients may require blood transfusion which has its risks. Anti-fibrinolytic drugs such as aprotinin, aminocaproic acid and tranexamic acid (TXA) have reduced transfusion requirements in major surgery. This retrospective audit was performed to assess effectiveness of TXA in reducing blood transfusion rate in single-stage sequential BTKA cases operated by a single surgeon. Records of 91 patients given TXA and 80 controls who were operated before 2012 and not given TXA were reviewed. TXA was given 15mg/kg intravenously (IV) before tourniquet deflation and 3 hours postoperatively.Blood transfusion was done in 9(10%) patients in the TXA group compared to 20(25%)in the control group (p<0.01). One (1.25%) patient in the control group had non-fatal pulmonary embolism.TXA appeared to be effective in decreasing post-operative blood loss and requirement for blood transfusion after single-stage BTKA.

Aganirsen antisense oligonucleotide eye drops inhibit keratitis-induced corneal neovascularization and reduce need for transplantation: the I-CAN study.

OBJECTIVE: Eye drops of aganirsen, an antisense oligonucleotide preventing insulin receptor substrate-1 expression, inhibited corneal neovascularization in a previous dose-finding phase II study. We aimed to confirm these results in a phase III study and investigated a potential clinical benefit on visual acuity (VA), quality of life (QoL), and need for transplantation. DESIGN: Multicenter, double-masked, randomized, placebo-controlled phase III study. PARTICIPANTS: Analysis of 69 patients with keratitis-related progressive corneal neovascularization randomized to aganirsen (34 patients) or placebo (35 patients). Patients applied aganirsen eye drops (86 µg/day/eye) or placebo twice daily for 90 days and were followed up to day 180. MAIN OUTCOME MEASURES: The primary end point was VA. Secondary end points included area of pathologic corneal neovascularization, need for transplantation, risk of graft rejection, and QoL. RESULTS: Although no significant differences in VA scores between groups were observed, aganirsen significantly reduced the relative corneal neovascularization area after 90 days by 26.20% (P = 0.014). This improvement persisted after 180 days (26.67%, P = 0.012). Aganirsen tended to lower the transplantation need in the intent-to-treat (ITT) population at day 180 (P = 0.087). In patients with viral keratitis and central neovascularization, a significant reduction in transplantation need was achieved (P = 0.048). No significant differences between groups were observed in the risk of graft rejection. However, aganirsen tended to decrease this risk in patients with traumatic/viral keratitis (P = 0.162) at day 90. The QoL analyses revealed a significant improvement with aganirsen in composite and near activity subscores (P = 0.039 and 0.026, respectively) at day 90 in the per protocol population. Ocular and treatment-related treatment-emergent adverse events (TEAEs) were reported in a lower percentage with aganirsen compared with placebo. Only 3 serious TEAEs (2 with aganirsen and 1 with placebo) were considered treatment-related. CONCLUSIONS: This first phase III study on a topical inhibitor of corneal angiogenesis showed that aganirsen eye drops significantly inhibited corneal neovascularization in patients with keratitis. The need for transplantation was significantly reduced in patients with viral keratitis and central neovascularization. Topical application of aganirsen was safe and well tolerated.

The antiangiogenic insulin receptor substrate-1 antisense oligonucleotide aganirsen impairs AU-rich mRNA stability by reducing 14-3-3ß-tristetraprolin protein complex, reducing inflammation and psoriatic lesion size in patients.

Increased inflammation and aberrant angiogenesis underlie psoriasis. Here, we report that the inhibition of insulin receptor substrate-1 (IRS-1) expression with aganirsen resulted in a dose-dependent reduction (P < 0.0001) in IRS-1 protein in the cytoplasm, while IRS-1 protein remained quantitatively unchanged in the perinuclear environment. Aganirsen induced a dose-dependent increase in serine-phosphorylated IRS-1 in the soluble perinuclear-nuclear fraction, inducing IRS-1-14-3-3ß protein association (P < 0.001), thereby impairing 14-3-3ß-tristetraprolin protein complex and AU-rich mRNA's stability (P < 0.001). Accordingly, aganirsen inhibited (P < 0.001) in vitro the expression of interleukin-8 (IL-8), IL-12, IL-22, and tumor necrosis factor alpha (TNFα), four inflammatory mediators containing mRNA with AU-rich regions. To demonstrate the clinical relevance of this pathway, we tested the efficacy of aganirsen by topical application in a pilot, double-blind, randomized, dose-ranging study in 12 psoriatic human patients. After 6 weeks of treatment, least square mean differences with placebo were -38.9% (95% confidence interval, -75.8 to -2.0%) and -37.4% (-74.3 to -0.5%) at the doses of 0.86 and 1.72 mg/g, respectively. Lesion size reduction was associated with reduced expression of IRS-1 (P < 0.01), TNFα (P < 0.0001), and vascular endothelial growth factor (P < 0.01); reduced keratinocyte proliferation (P < 0.01); and the restoration (P < 0.02) of normal levels of infiltrating CD4(+) and CD3(+) lymphocytes in psoriatic skin lesions. These results suggest that aganirsen is a first-in-class of a new generation of antiangiogenic medicines combining anti-inflammatory activities. Aganirsen-induced downregulation of inflammatory mediators characterized by AU-rich mRNA likely underlies its beneficial clinical outcome in psoriasis. These results justify further large-scale clinical studies to establish the dose of aganirsen and its long-term efficacy in psoriasis.

Antiangiogenic activity of aganirsen in nonhuman primate and rodent models of retinal neovascular disease after topical administration.

PURPOSE: Aganirsen, an antisense oligonucleotide inhibiting insulin receptor substrate (IRS)-1 expression, has been shown to promote the regression of pathologic corneal neovascularization in patients. In this study, the authors aimed to demonstrate the antiangiogenic activity of aganirsen in animal models of retinal neovascularization. METHODS: Eyedrops of aganirsen were applied daily in nonhuman primates after laser-induced choroidal neovascularization (CNV; model of wet age-related macular degeneration [AMD]) and in newborn rats after oxygen-induced retinopathy (OIR; model of ischemic retinopathy). Retinal aganirsen concentrations were assessed in rabbits and monkeys after topical delivery (21.5, 43, or 86 µg). Clinical significance was further evaluated by determination of IRS-1 expression in monkey and human retinal biopsy specimens. RESULTS: Topical corneal application of aganirsen attenuated neovascular lesion development dose dependently in African green monkeys. The incidence of high-grade CNV lesions (grade IV) decreased from 20.5% in vehicle-treated animals to 1.7% (P < 0.05) at the 86-µg dose. Topical aganirsen inhibited retinal neovascularization after OIR in rats (P < 0.05); furthermore, a single intravitreal injection of aganirsen reduced OIR as effectively as ranibizumab, and their effects were additive. Significantly, topical applications of aganirsen did not interfere with physiological retinal vessel development in newborn rats. Retinal delivery after topical administration was confirmed, and retinal expression of IRS-1 was demonstrated to be elevated in patients with subretinal neovascularization and AMD. CONCLUSIONS: Topical application of aganirsen offers a safe and effective therapy for both choroidal and retinal neovascularization without preventing its normal vascularization. Together, these findings support the clinical testing of aganirsen for human retinal neovascular diseases.