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Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a major health concern worldwide and has evolved into different variants. SARS-CoV-2 possesses a spike glycoprotein on its envelope that binds to the angiotensin-converting enzyme 2 (ACE-2) receptor of the host cell via the receptor-binding domain (RBD) in the upper respiratory tract. Since the SARS-CoV-2 virus variants change the severity of the diesease and treatment scenarios, repurposing current medicines may provide a quick and appealing method with established safety features. The efficacy and safety of antiviral medicines against the coronavirus disease 2019 (COVID-19) have been investigated, and several of them are now undergoing clinical studies. Recently, it has been found that nitric oxide (NO) shows antiviral properties against SARS-CoV-2 and prevents the virus from binding to a host cell. In addition, NO is a well-known vasodilator and acts as an important coagulation mediator. With the fast-track development of COVID-19 treatments and vaccines, one avenue of research aimed at improving therapeutics is exploring different forms of drug delivery, including intranasal sprays and inhalation therapy. The nasal mucosa is more prone to be the site of infection as it is in more direct contact with the physical environment via air during inhalation and exhalation. Thus, the use of exogenous nasal NO therapy via the intranasal route displays a distinct advantage. Therefore, the objective of this review is to summarize the relevant actions of NO via the intranasal spray and inhalation delivery, its mechanism of action, and its use in the treatment of COVID-19.

Plant engineering technology has been working effectively since last 30 years. Commercialization of different product using plant engineering is encouraging us to develop effective treatment and this progress takes too much effort and time, but still many candidate vaccines for use in humans are in clinical trials. Virus-like particles (VLPs) are basically self-constructed structures departed from viral antigens which copy the organization of similar viruses but without viral genome. This technology offers several pros in terms of safety, immunogenicity and stability in production over vaccines derived from pathogen formulation. Now, many pharmaceutical companies are working in this technology to develop effective treatment against various diseases. This review discusses how plant engineering technology works for diseases and regulations relevant to the development of plant-based vaccines in the treatment of viruses like Hepatitis B, Ebola, Papilloma, Norwalk, Influenza, HIV and Covid-19. Keywords: Plant engineering technology, Virus-like Particles, Pathogens, Antibodies.

To analyze the sex-based differences in the prevalence of cardiovascular disease risk factors and outcomes in older patients with prediabetes using demographically matched national cohorts of hospitalized patients aged ≥65 years.We queried the 2007-2014 National Inpatient Database to identify older patients (65 years) admitted with prediabetes using ICD-9 Clinical Modification codes. The older patients were then subcategorized based on sex. Comparative analyses of their baseline characteristics, the prevalence of cardiovascular(CV) disease comorbidities, hospitalization outcomes, and mortality rates were performed on propensity-matched cohorts for demographics.A total of 1,197,978 older patients with prediabetes (599,223 males; mean age 75years and 598,755 females; mean age 76years) were identified. Higher admission rates were found commonly among older white males (84.1%) and females (81.7%). Prediabetic older males showed a higher frequency of cardiovascular comorbidities compared to females. Prediabetic older males had higher all-cause in-hospital mortality (4.2% vs. 3.6%, p0.001), acute myocardial infarction (7.0% vs. 4.7%, p0.001), arrhythmia (36.3% vs. 30.5%, p0.001), stroke (4.8% vs. 4.6%, p0.001), venous thromboembolism (3.3% vs. 3.0%, p0.001) and percutaneous coronary intervention (3.1% vs. 1.5%, p0.001) compared to females.Our analysis revealed that among older patients hospitalized with prediabetes, males suffered worse in-hospital CV outcomes and survival rates compared to females.

Autism is characterized by deficits in verbal and nonverbal communication and repetitive behaviors. There is a lack of data available regarding pharmacological treatment in autism spectrum disorders.\r\n A 2.8-year-old boy, diagnosed with autism spectrum disorder and CARS score 36, was given omega3 fatty acid supplementation. At the end of 4 weeks, he demonstrated significant improvement in eye contact, which is a marker of social competence and adjustment. After 4 months, CARS II score was found to be 34. We propose that the DHA in omega 3 aids in learning and cognition by enhancing synaptic plasticity. We may need controlled trials with high-dose omega 3 for proving this therapeutic benefit.\r\n Keywords: Autism, Eye Contact, Nutrition

Peptic ulcer disease (PUD) is more prevalent in cirrhotic patients and it has been associated with poor outcomes. However, there are no population-based studies from the United States (U.S.) that have investigated this association. Our study aims to estimate the incidence trends, predictors, and outcomes PUD patients with underlying cirrhosis.We analyzed Nationwide Inpatient Sample (NIS) and Healthcare Cost and Utilization Project (HCUP) data for years 2002-2014. Adult hospitalizations due to PUD were identified by previously validated ICD-9-CM codes as the primary diagnosis. Cirrhosis was also identified with presence of ICD-9-CM codes in secondary diagnosis fields. We analyzed trends and predictors of PUD in cirrhotic patients and utilized multivariate regression models to estimate the impact of cirrhosis on PUD outcomes.Between the years 2002-2014, there were 1,433,270 adult hospitalizations with a primary diagnosis of PUD, out of which 70,007 (4.88%) had cirrhosis as a concurrent diagnosis. There was a significant increase in the proportion of hospitalizations with a concurrent diagnosis of cirrhosis, from 3.9% in 2002 to 6.6% in 2014 (p 0.001). In an adjusted multivariable analysis, in-hospital mortality was significantly higher in hospitalizations of PUD with cirrhosis (odd ratio [OR] 1.78; 95% confidence interval [CI] 1.63-1.97; P 0.001), however, there was no difference in the discharge to facility (OR 1.00; 95%CI 0.94 - 1.07; P = 0.81). Moreover, length of stay (LOS) was also higher (6 days vs. 4 days, P 0.001) among PUD with cirrhosis. Increasing age and comorbidities were associated with higher odds of in-hospital mortality among PUD patients with cirrhosis.Our study shows that there is an increased hospital burden as well as poor outcomes in terms of higher in-hospital mortality among hospitalized PUD patients with cirrhosis. Further studies are warranted for better risk stratification and improvement of outcomes.

Rehabilitation of endodontically treated molar stilla challenge. After endodontic management of extensively carious molars, theyhave decreased mechanical characteristics. They became fragile and that is in relation with the removal of pulp and adjacent dentin tissues. Endocrown which is a single partial restoration could be measured as a good alternative for restoring molars having large coronal destruction and presenting endodontic treatment complications. We discuss the indication and use of endocrown to substitute single crowns with intraradicular retention and to present a clinical case report of an endocrown-type restoration, made-up from lithium disilicate ceramic (IPS e.Max CAD) in a mandibular first molar with widespread coronal destruction. &nbsp

This paper, for the first time, analyses and presents the emission reduction potential of the Indian companies who have set science-based targets and highlight as to how it contributes to meeting the India’s NDC goals. The paper provides insights into the SBTs of 22 Indian companies who have adopted GHG emission reduction targets that are aligned with climate science.

Patterns of non-uniform usage of synonymous codons (codon bias) varies across genes in an organism and across species from all domains of life. The bias in codon usage is due to a combination of both non-adaptive (e.g. mutation biases) and adaptive (e.g. natural selection for translation efficiency/accuracy) evolutionary forces. Most population genetics models quantify the effects of mutation bias and selection on shaping codon usage patterns assuming a uniform mutation bias across the genome. However, mutation biases can vary both along and across chromosomes due to processes such as biased gene conversion, potentially obfuscating signals of translational selection. Moreover, estimates of variation in genomic mutation biases are often lacking for non-model organisms. Here, we combine an unsupervised learning method with a population genetics model of synonymous codon bias evolution to assess the impact of intragenomic variation in mutation bias on the strength and direction of natural selection on synonymous codon usage across 49 Saccharomycotina budding yeasts. We find that in the absence of a priori information, unsupervised learning approaches can be used to identify regions evolving under different mutation biases. We find that the impact of intragenomic variation in mutation bias varies widely, even among closely-related species. We show that the overall strength and direction of selection on codon usage can be underestimated by failing to account for intragenomic variation in mutation biases. Interestingly, genes falling into clusters identified by machine learning are also often physically clustered across chromosomes, consistent with processes such as biased gene conversion. Our results indicate the need for more nuanced models of sequence evolution that systematically incorporate the effects of variable mutation biases on codon frequencies.

MotivationRibosome profiling, or Ribo-seq, is the state of the art method for quantifying protein synthesis in living cells. Computational analysis of Ribo-seq data remains challenging due to the complexity of the procedure, as well as variations introduced for specific organisms or specialized analyses. Many bioinformatic pipelines have been developed, but these pipelines have key limitations in terms of functionality or usability.ResultsWe present riboviz 2, an updated riboviz package, for the comprehensive transcript-centric analysis and visualization of Ribo-seq data. riboviz 2 includes an analysis workflow built on the Nextflow workflow management system, combining freely available software with custom code. The package is extensively documented and provides example configuration files for organisms spanning the domains of life. riboviz 2 is distinguished by clear separation of concerns between annotation and analysis: prior to a run, the user chooses a transcriptome in FASTA format, paired with annotation for the CDS locations in GFF3 format. The user is empowered to choose the relevant transcriptome for their biological question, or to run alternative analyses that address distinct questions. riboviz 2 has been extensively tested on various library preparation strategies, including multiplexed samples. riboviz 2 is flexible and uses open, documented file formats, allowing users to integrate new analyses with the pipeline.Availabilityriboviz 2 is freely available at github.com/riboviz/riboviz.Supplementary information

Actively dividing cells, including some cancers, rely on aerobic glycolysis rather than oxidative phosphorylation to generate energy, a phenomenon termed “the Warburg effect1.” Constitutive activation of the Hypoxia Inducible Factor (HIF-1), a transcription factor known for mediating an adaptive response to oxygen deprivation (hypoxia), is a hallmark of the Warburg effect2. HIF-1 is thought to promote glycolysis and suppress oxidative phosphorylation. Here, we show instead that HIF-1 can promote gluconeogenesis. Using a multiomics approach, we determined the genomic, transcriptomic, and metabolomic landscapes regulated by constitutively active HIF-1 in C. elegans. We performed RNA-seq and ChIP-seq under aerobic conditions in mutants lacking EGL-9, a key negative regulator of HIF-1, and then integrated these approaches to identify over a hundred genes directly and functionally upregulated by HIF-1. We show that HIF-1 directly promotes the expression of PCK-1, a PEP carboxykinase that is a rate-limiting mediator of gluconeogenesis3. This activation of PCK-1 by HIF-1 promotes survival in response to both oxidative and hypoxic stress. Our work is the first to identify functional direct targets of HIF-1 in vivo, and it describes the first complete metabolome induced by constitutive HIF-1 activation in any organism.

Hypermetabolism following severe burn injuries is associated with adipocyte dysfunction, elevated beige adipocyte formation, and increased energy expenditure. The resulting catabolism of adipose leads to detrimental sequelae such as fatty liver, increased risk of infections, sepsis, and even death. While the phenomenon of pathological white adipose tissue (WAT) browning is well‐documented in cachexia and burn models, the molecular mechanisms are essentially unknown. Here, we report that adipose triglyceride lipase (ATGL) plays a central role in burn‐induced WAT dysfunction and systemic outcomes. Targeting adipose‐specific ATGL in a murine (AKO) model resulted in diminished browning, decreased circulating fatty acids, and mitigation of burn‐induced hepatomegaly. To assess the clinical applicability of targeting ATGL, we demonstrate that the selective ATGL inhibitor atglistatin mimics the AKO results, suggesting a path forward for improving patient outcomes., A severe burn injury and its associated hypermetabolic response induces adipocyte dysfunction, fat catabolism, elevated fatty acids in the circulation and hepatic steatosis.Adipose triglyceride lipase (ATGL) plays a central role in adipose lipolysis and lipid metabolism.Targeting adipose‐specific ATGL post‐burn injury diminishes WAT browning, reduces fatty acids in the circulation and protects against liver dysfunction.

India’s per capita apparel consumption has been lower than other countries, however, it is steadily rising. India is poised to be the world’s sixth largest apparel market by 2022 (pre-COVID 19 estimate). The textile and apparel sector requires large amounts of non-renewable resource inputs causing social and environmental pressures.

Introduction: Ventricular tachycardia (VT) is a significant cause of morbidity and mortality in patients with heart failure with reduced ejection fraction (HFrEF). Hypothesis: Data on efficacy, safety, and outcomes of catheter ablation for VT in HFrEF have not been studied well. Methods: The 2002-2014 Nationwide Inpatient Sample (NIS) was used to identify all hospitalizations with a principle diagnosis of VT (International Classification of Diseases, Ninth Edition, Clinical Modification [ICD-9-CM] code 427.1) and a secondary diagnosis of HFrEF. Patients who underwent catheter ablation were identified using ICD-9-CM procedure code 37.34. Results: Of 228,557 patients with HFrEF & VT, 5845 (2.56%) underwent catheter ablation. The prevalence of Diabetes Mellitus (DM) and Chronic Kidney disease (CKD) was higher in the reference population contrary to a higher prevalence of prior myocardial infarction (MI), coronary bypass and AICD in those undergoing CA. The frequency of complications in the ablation group was 19.47%, the most common being post-operative hemorrhage (8.3%). This was followed by myocardial infarction (5.34%), pericardial complications (3.38%), and neurological complications (2.14%) (Figure 1.). The odds of in-hospital mortality were lower in the CA group compared to the reference group (5.08% vs 9.42%, p Conclusions: Compared to medical therapy, VT ablation in HFrEF is associated with lower mortality though with significant complication rate. This suggests a need for future studies identifying the safety measures in VT ablations and instituting appropriate interventions to improve overall VT ablation outcomes.

Objectives Cardiac transplant patients are at increased risk of Coronary Allograft Vasculopathy which requires percutaneous coronary intervention (PCI). Background We aim to determine national epidemiology describing trends, mortality, and morbidity risks in patients with heart transplant undergoing PCI. Methods We used Nationwide Inpatient Sample (NIS) data from 2002 to 2014 to identify adult hospitalizations with PCI using ICD 9 codes. Acute myocardial infarction (AMI), cardiac transplant status and complications were identified using validated ICD-9-CM diagnosis codes. Endpoints were in-hospital mortality and peri-procedural complications. Propensity match analysis was performed to compare the end-points between DES and BMS. Results Total 8,613,900 patients underwent PCI, of which 1,531(0.002%) patients had prior heart transplant status. Among these 1,531 PCIs, 311(20%) were due to AMI including 125(8%) due to STEMI. 74% of PCIs were done in males and 78% of the PCIs were performed in the 60-79 age group. Out of 1,380 stents placed, 1,090 were DES (79%) and 290 (21%) were BMS. Mortality was higher in the BMS versus DES (8.34% vs. 3.45%, p = .012), CONCLUSION: We concluded that majority of the population who underwent PCI were older males. DES was used more than BMS. The use of BMS is associated with increased mortality, cardiac complications and Acute Kidney Injury requiring dialysis compared with DES which likely is representative of preferential use of DES in these patient population.

Background The 30-day readmission rates are being used as a quality measure by Centers for Medicare and Medicaid Services (CMS) for specific medical and surgical conditions. Acute respiratory distress syndrome (ARDS) is one of the important causes of morbidity and mortality in the United States (US). The characteristics and predictors of 30-day readmission in ARDS patients in the US are not widely known, which we have depicted in our study. Objective The aim of this study is to identify 30-day readmission rates, characteristics, and predictors of ARDS patients using the largest publicly available nationwide database. Methods We used the National Readmission Database from the year 2013 to extract the patients with ARDS by primary discharge diagnosis with ICD9-CM codes. All-cause unplanned 30-day readmission rates were calculated for patients admitted between January and November 2013. The independent predictors for unplanned 30-day readmission were identified by survey logistic regression. Results After excluding elective readmission, the all-cause unplanned 30-day readmission rate for ARDS patients was 18%. Index admissions readmitted within 30-day had a significantly higher baseline burden of comorbidities with a Charlson Comorbidity Index (CCI) ≥1 as compared to those who were not readmitted within 30 days. In multivariate regression analysis, several predictors associated with 30-day readmission were self-pay/no charge/other (OR 1.19, 95%CI: 1.02-1.38; p = 0.02), higher-income class (OR 0.86, 95%CI:0.79-0.99; p = 0.03), private insurance (OR 0.81, 95%CI:0.67-0.94; p = 0.01), and teaching metropolitan hospital (OR 0.72, 95%CI:0.61-0.94; p = 0.01). Conclusion The unplanned 30-day readmission rates are higher in ARDS patients in the US. Several modifiable factors such as insurance, socioeconomic status, and hospital type are associated with 30-day readmission among ARDS patients.

The frequency with which people interact with technology means that users may develop interface habits, i.e. fast, automatic responses to stable interface cues. Design guidelines often assume that interface habits are beneficial. However, we lack quantitative evidence of how the development of habits actually affect user performance and an understanding of how changes in the interface design may affect habit development. Our work quantifies the effect of habit formation and disruption on user performance in interaction. Through a forced choice lab study task (n=19) and in the wild deployment (n=18) of a notificationdialog experiment on smartphones, we show that people become more accurate and faster at option selection as they develop an interface habit. Crucially this performance gain is entirely eliminated once the habit is disrupted. We discuss reasons for this performance shift and analyse some disadvantages of interface habits, outlining general design patterns on how to both support and disrupt them.Keywords: Interface habits, user behaviour, breaking habit, interaction science, quantitative research., 32 pages, 8 figures, to be published in the International Journal of Human Computer Interaction

PurposeTo investigate the effects of Ripasudil (K-115), a Rho-kinase inhibitor, in a porcine model of pigmentary glaucoma.MethodsHallmark features of trabecular meshwork (TM), the principle structure of the outflow system affected in this model, were analyzed. In vitro TM cells and ex vivo perfused eyes were subjected to pigment dispersion followed by K-115 treatment (PK115). PK115 was compared to sham-treated controls (C) and pigment (P). Cytoskeletal alterations were assessed by F-actin labeling. TM cell phagocytosis of fluorescent targets was evaluated by flow cytometry. Cell migration was studied with a wound-healing assay. Intraocular pressure was continuously monitored and compared to after the establishment of the pigmentary glaucoma model and after treatment with K-115.ResultsIn vitro, the percentage of cells with stress fibers increased in response to pigment but declined sharply after treatment with K-115 (P: 32.8 +/- 2.9%; PK115: 11.6 +/- 3.3%, P < 0.001). Phagocytosis first declined but recovered after K-115 (P: 25.7+/-2.1%, PK115: 33.4+/-0.8%, P ConclusionIn vitro, K-115 reduced TM stress fibers, restored phagocytosis, and restored migration of TM cells. Ex vivo, K-115 normalized intraocular pressure.

Objective Our aim is to describe characteristics of liver transplant patients undergoing percutaneous coronary interventions (PCI) as well as in-hospital outcomes including the mortality and peri-procedural complications from the largest publicly available inpatient database in the United States from 2002 to 2014. Background Outcomes of PCI are well studied in patients with end-stage liver disease but not well studied in patients who receive liver transplant (LT). Methods Data derived from Nationwide Inpatient Sample (NIS) were analyzed for years 2002-2014. Adult Hospitalizations with PCI were identified using ICD-9-CM procedure codes. LT status and various complications were identified by using previously validated ICD-9-CM diagnosis codes. Endpoints were in-hospital mortality and peri-procedural complications. Propensity match analysis was performed to compare the endpoints between two groups. Results During the study period, 8,595,836 patients underwent PCI; 4,080 (0.04%) patients had prior LT status. 93% of patients were above age 59 years, 79% were males and 69% were nonwhites. Out of the total patients with LT status, 73% had hypertension, 57% had diabetes mellitus, and 47% had renal failure. Post-PCI complications were studied further in both liver and non-LT patients after 1:1 propensity match which showed the incidence of acute kidney injury (AKI) was higher in LT group (12.3 vs 10.7%, p = .024) but dialysis requiring AKI was similar. Conclusion Among the LT recipients undergoing PCI, majority were nonwhite males. Almost more than half of the recipients had diabetes mellitus and renal failure. Incidence of AKI was higher in LT group, but other peri-procedural complications were comparable.

PURPOSE: To analyze the 5-year results of trabectome ab interno trabeculectomy of a single glaucoma center. METHOD: In this retrospective interventional single-center case series, data of 93 patients undergoing ab interno trabeculotomy between September 2010, and December 2012 were included. Kaplan-Meier analysis was performed using success criteria defined as postoperative intraocular pressure (IOP) ≤ 21 mmHg, and > 20% reduction from preoperative IOP, and no need for further glaucoma surgery. Risk factors for failure were identified using Cox proportional hazards ratio (HR). RESULTS: The retention rate for 5-year follow-up was 66%. The cumulative probability of success at 1, 2, 3, 4, and 5 years was 82.6%, 76.7%, 73.9%, 72.3%, and 67.5%. Risk factors for failure were lower baseline IOP (HR = 0.27, P = 0.001), younger age (HR = 0.25, P = 0.02), and higher central corneal thickness (HR = 0.18, P = 0.01). Exfoliative glaucoma was associated with a higher success rate (HR = 0.39, P = 0.02). IOP was decreased significantly from 20.0 ± 5.6 mmHg at baseline to 15.6 ± 4.6 mmHg at 5-year follow-up (P = 0.001). The baseline number of glaucoma medications was 1.8 ± 1.2, which decreased to 1.0 ± 1.2 medications at 5 years. CONCLUSION: Trabectome surgery was associated with a good long-term efficacy and safety profile in this single-center case series with a high retention rate.

Objective: To evaluate three different microincisional ab interno trabeculectomy procedures in a porcine eye perfusion model. Methods: In perfused porcine anterior segments, 90 degrees of trabecular meshwork (TM) were ablated using the Trabectome (T; n = 8), Goniotome (G; n = 8), or Kahook device (K; n = 8). After 24 hours, additional 90 degrees of TM were removed. Intraocular pressure (IOP) and outflow facility were measured at 5 µL/min and 10 µL/min perfusion to simulate an elevated IOP. Structure and function were assessed with canalograms and histology. Results: At 5 µL/min infusion rate, T resulted in a greater IOP reduction than G or K from baseline (76.12% decrease versus 48.19% and 47.96%, P = 0.013). IOP reduction between G and K was similar (P = 0.420). Removing another 90 degrees of TM caused an additional IOP reduction only in T and G but not in K. Similarly, T resulted in the largest increase in outflow facility at 5 µL/min compared with G and K (first ablation: 3.41 times increase versus 1.95 and 1.87; second ablation: 4.60 versus 2.50 and 1.74) with similar results at 10 µL/min (first ablation: 3.28 versus 2.29 and 1.90 (P = 0.001); second ablation: 4.10 versus 3.01 and 2.01 (P = 0.001)). Canalograms indicated circumferential flow beyond the ablation endpoints. Conclusions: T, G and K significantly increased the outflow facility. In this model, T had a larger effect than G and K.

Purpose To correlate outflow function and outflow tract vessel diameter changes induced by nitric oxide (NO). Methods In a porcine anterior segment perfusion model, the effects of a nitric oxide donor (100 μM DETA-NO) on outflow facility were compared with controls (n = 8 per group) with trabecular meshwork (TM) and after circumferential ab interno trabeculectomy (AIT). Outflow structures were assessed with spectral-domain optical coherence tomography (SD-OCT) before and after NO, or an NO synthase inhibitor (100 μM L-NAME) and the vasoconstrictor, endothelin-1 (100 pg/mL ET-1). Scans were processed with a custom macroscript and aligned for automated reslicing and quantification of cross-sectional outflow tract areas (CSA). Results The facility increased after DETA-NO (Δ of 0.189 ± 0.081 μL/min·mm Hg, P = 0.034) and AIT (Δ of 0.251 ± 0.094 μL/min·mm Hg, P = 0.009), respectively. Even after AIT, DETA-NO increased the facility by 61.5% (Δ of 0.190 ± 0.074 μL/min·mm Hg, P = 0.023) and CSA by 13.9% (P < 0.001). L-NAME + ET-1 decreased CSA by -8.6% (P < 0.001). NO increased the diameter of focal constrictions 5.0 ± 3.8-fold. Conclusions NO can dilate vessels of the distal outflow tract and increase outflow facility in a TM-independent fashion. There are short, focally constricting vessel sections that display large diameter changes and may have a substantial impact on outflow.

Purpose: To investigate whether microsurgical excision of trabecular meshwork (TM) in an ex vivo pigmentary glaucoma model can normalize the hypertensive phenotype. Methods: Eight eyes of a porcine pigmentary glaucoma model underwent 90° of microsurgical TM excision with an aspirating dual-blade (Goniotome (G)). 24 hours later, an additional 90° of TM were removed. Anterior segments with sham surgeries served as the control (C). Outflow facility and intraocular pressure (IOP) were analyzed. Histology with hematoxylin and eosin (H&E) was obtained. Results: After the first 90° TM excision, IOP was significantly lower in G (10.23±2.39 mmHg, n=7) than C (20.04±1.97mmHg, n=8, P

Purpose: To create a highly balanced comparison of ab interno trabeculectomy (Trabectome, AIT) and trabecular bypass stenting (iStent, TBS).Setting: Eye and Ear Institute, Pittsburgh, Ross Eye Institute, Buffalo, and Glaucoma Associates of Texas, Dallas, USA.Design: Retrospective Exact Matching analysis.Methods: AIT and TBS patients were included from three large glaucoma practices. The primary outcome measure was the unmedicated IOP ≤ 21 mmHg at 2-year follow-up visit. A secondary measure was unmedicated IOP reduction ≥ 20% at 2 years. Patients were matched by baseline IOP, the number of glaucoma medications and glaucoma type using Exact Matching and by age using Nearest Neighbor matching. Patients without a close match were excluded. All surgeries were combined with phacoemulsification. Results: 154 AIT and 110 TBS eyes were analyzed. 48 AIT patients were exactly matched to 48 TBS patients. Both groups had a baseline IOP of 15.3±3.1 mmHg. At 24 months, the mean IOP was 13.9±3.3 for AIT versus 16.8±2.8 mmHg for TBS (p=0.04), while the number of medications was 0.7±1.0 for AIT versus 1.7±1.2 for TBS (p=0.04). The proportion of subjects achieving IOP ≤ 21 mmHg without medications at 24 months was 53% in AIT versus 16.6% in TBS (P < 0.05). At 24-month follow up 17.6% of patients in AIT had ≥ 20% IOP reduction without medication versus no patient in TBS. Conclusions: An Exact Matching comparison of AIT and TBS demonstrated greater IOP reduction with fewer medications in AIT.

Purpose: To investigate the extent of anterior chamber angle circumference needed to maintain a physiological outflow facility (C). Methods: Twenty anterior segments of porcine eyes were assigned to 5 groups, each with a different degree of cyanoacrylate-mediated angle closure: 90° (n = 4), 180° (n = 4), 270° (n = 4), 360° (n = 4) and four unoccluded control eyes. The outflow facility was measured at baseline, 3, 12, 24, and 36 hours after angle closure. Outflow patterns were evaluated with canalograms and the histomorphology was compared. Results: Baseline outflow facilities of the five groups were similar (F = 0.922, P = 0.477). Complete, circumferential occlusion over 360° induced a significant decrease in facility from baseline at all time-points (P ≤ 0.023 at 3, 12, 24 and 36 hours). However, no difference from baseline was found in any of the partially-occluded (0–270°) groups (F ≥ 0.067, P ≥ 0.296 at 3, 12, 24 and 36 hours). The canalograms confirmed the extent of occlusion with flow through the unblocked regions. Histology revealed no adverse effects of blockage on the TM or aqueous plexus in the unoccluded angle portions. The unoccluded TM appeared normal. Conclusion: Cyanoacrylate-mediated angle occlusion created a reproducible angle closure model. 90° of unoccluded anterior chamber angle circumference was sufficient to maintain physiological outflow. This model may help understand how outflow can be regulated in healthy, nonglaucomatous TM.

PURPOSE: To establish the extent of anterior chamber angle circumference needed to maintain a physiological outflow facility (C). This could create a model to investigate focal outflow regulation. METHODS: Twenty anterior segments of porcine eyes were assigned to five groups, each with a different degree of cyanoacrylate-mediated angle closure: 90° (n = 4), 180° (n = 4), 270° (n = 4), 360° (n = 4), and four unoccluded control eyes. The outflow facility was measured at baseline, 3, 12, 24, and 36 h after angle closure. Outflow patterns were evaluated with canalograms and the histomorphology was compared. RESULTS: Baseline outflow facilities of the five groups were similar (F = 0.922, p = 0.477). Occlusion of 360° induced a significant decrease in facility from baseline at all time-points (p ≤ 0.023 at 3, 12, 24, and 36 h). However, no difference from baseline was found in any of the partially occluded (0–270°) groups (F ≥ 0.067, p ≥ 0.296 at 3, 12, 24, and 36 h). The canalograms confirmed the extent of occlusion with flow through the unblocked regions. Histology revealed no adverse effects of blockage on the TM or aqueous plexus in the unoccluded angle portions. The unoccluded TM appeared normal. CONCLUSION: Cyanoacrylate-mediated angle occlusion created a reproducible angle closure model. Ninety degrees of unoccluded anterior chamber angle circumference was sufficient to maintain physiological outflow. This model may help understand how outflow can be regulated in healthy, nonglaucomatous TM.

RNA binding proteins, such as IMP1, are emerging as essential regulators of intestinal development and cancer. IMP1 hypomorphic mice exhibit severe intestinal growth defects, yet it’s role in adult intestinal epithelium is unclear. We employed ribosome profiling to test the effect of IMP1 loss on the “translatome” in colon cancer cell lines. In parallel, we evaluated mice with intestinal epithelial-specific Imp1 deletion (Imp1ΔIEC) following irradiation or colitis models. Ribosome-profiling revealed translation efficiency changes for multiple pathways important for intestinal homeostasis, including autophagy, in IMP1 knockout cells. We found increased autophagy flux in Imp1ΔIEC mice, reinforced through in silico and biochemical analyses revealing direct binding of IMP1 to autophagy transcripts MAP1LC3B and ATG3. We found that Imp1ΔIEC mice exhibit enhanced recovery following irradiation, which is attenuated with genetic deletion of autophagy gene Atg7. Finally, we demonstrated that IMP1 is upregulated in Crohn’s disease patients and Imp1 loss lessened colitis severity in mice. These studies demonstrate that IMP1 acts as a posttranscriptional regulator of gut epithelial repair post-irradiation and colitis, in part through modulation of autophagy.

Purpose: This study investigated the hypotensive effect of RKI-1447, a Rho kinase inhibitor, in a porcine ex vivo pigmentary glaucoma model. Methods: Twenty-eight porcine anterior chambers were perfused with medium supplemented with 1.67 × 107 pigment particles/mL for 48 hours before treatment with RKI-1447 (n = 16) or vehicle control (n = 12). Intraocular pressure (IOP) was recorded and outflow facility was calculated. Primary trabecular meshwork cells were exposed to RKI-1447 or vehicle control; effects on the cytoskeleton, motility, and phagocytosis were evaluated. Result: Compared to baseline, the perfusion of pigment caused a significant increase in IOP in the RKI-1447 group (P = 0.003) at 48 hours. Subsequent treatment with RKI-1447 significantly reduced IOP from 20.14 ± 2.59 mmHg to 13.38 ± 0.91 mmHg (P = 0.02). Pigment perfusion reduced the outflow facility from 0.27 ± 0.03 at baseline to 0.18 ± 0.02 at 48 hours (P < 0.001). This was partially reversed with RKI-1447. RKI-1447 caused no apparent histological changes in the micro- or macroscopic TM appearance. RKI-1447-treated primary TM cells showed significant disruption of the actin cytoskeleton both in the presence and absence of pigment (P < 0.001) but no effect on TM migration was observed. Pigment-treated TM cells exhibited a reduction in TM phagocytosis, which RKI-1447 reversed. Conclusion: RKI-1447 significantly reduces IOP by disrupting TM stress fibers and increasing TM phagocytosis. These features may make it useful for the treatment of secondary glaucomas with an increased phagocytic load.

Purpose: To correlate outflow function and outflow tract vessel diameter changes induced by nitric oxide (NO). Methods: In a porcine anterior segment perfusion model, the effects of a nitric oxide donor (100 µM DETA-NO) on outflow facility were compared to controls (n=8 per group) with trabecular meshwork (TM) and after circumferential ab interno trabeculectomy (AIT). Outflow structures were assessed with spectral domain optical coherence tomography (SD-OCT) before and after NO, or an NO synthase inhibitor (100 µM L-NAME) and the vasoconstrictor, endothelin-1 (100 pg/mL ET-1). Scans were processed with a custom macro script and aligned for automated reslicing and quantification of cross-sectional outflow tract areas (CSA). Results: The facility increased after DETA-NO (0.189±0.081 μL/min·mmHg, p=0.034) and AIT (0.251±0.094 μL/min·mmHg, p=0.009), respectively. Even after AIT, DETA-NO increased the facility by 61.5% (0.190±0.074 μL/min·mmHg, p=0.023) and CSA by 13.9% (p

Purpose: To analyze the five-year results of Trabectome ab interno trabeculectomy of a single glaucoma center. Method: In this retrospective interventional single-center case series, data of 93 patients undergoing ab interno trabeculotomy between September 2010, and December 2012 were included. Kaplan-Meier analysis was performed using success criteria defined as postoperative intraocular pressure (IOP) ≤21 mm Hg, or >20% reduction from preoperative IOP, and no need for further glaucoma surgery. Risk factors for failure were identified using Cox proportional hazards ratio (HR). Results: The retention rate for five years follow-up was 66%. The cumulative probability of success at 1, 2, 3, 4 and 5 years was 82.6%, 76.7%, 73.9%, 72.3%, and 67.5%. Risk factors for failure were lower baseline IOP (HR=0.27, P=0.001), younger age (HR=0.25, P=0.02), and higher central corneal thickness (HR=0.18, P= 0.01). Pseudoexfoliation was associated with a higher success rate (HR= 0.39, P=0.02). IOP was decreased significantly from 20.0±5.6 mmHg at baseline to 15.6±4.6 mmHg at 5-year follow-up (P=0.001). The baseline number of glaucoma medications was 1.8±1.2, which decreased to 1.0±1.2 medications at 5 years. Conclusion: Trabectome surgery was associated with a good long-term efficacy and safety profile in this single-center case series with a high retention rate. A higher baseline IOP, older age, thinner cornea, and pseudoexfoliation glaucoma were associated with a higher success rate.

Background: Outflow regulation and phagocytosis are key functions of the trabecular meshwork (TM), but it is not clear how the two are related in secondary open angle glaucomas characterized by an increased particle load. We hypothesized that diminished TM phagocytosis is not the primary cause of early ocular hypertension and recreated pigment dispersion in a porcine ex vivo model. Methods: Sixteen porcine anterior chamber cultures received a continuous infusion of pigment granules (Pg), while 16 additional anterior chambers served as controls (C). Pressure transducers recorded the intraocular pressure (IOP). The phagocytic capacity of the trabecular meshwork was determined by fluorescent microspheres. Results: The baseline IOPs in Pg and C were similar (P=0.82). A significant IOP elevation occurred in Pg at 48, 120, and 180 hours (all P0.05). Conclusions: In this porcine model of pigmentary glaucoma, an IOP elevation occurs much earlier than when phagocytosis fails, suggesting that two separate mechanisms might be at work.

Purpose: To evaluate the efficacy and survival rates of same session ab interno trabeculectomy with the trabectome and Ahmed glaucoma valve implant (AT) in comparison to the Ahmed glaucoma valve alone (A). Method: A total of 107 eyes undergoing primary glaucoma surgery were enrolled in this retrospective comparative case series, including 48 eyes which underwent AT and 59 eyes which received A alone. Participants were identified using the procedural terminology codes, and their medical records were reviewed. The primary outcome measure was surgical success, defined as intraocular pressure (IOP) > 5 mmHg, ≤ 21 mmHg, and IOP reduction ≥ 20% from baseline at two consecutive visits after three months, no reoperation for glaucoma. Secondary outcome measures were IOP, the number of glaucoma medications, incidence of a hypertensive phase, and best corrected visual acuity (BCVA). Results: The cumulative probability of success at one year was 70% in AT, and 65% in A (p=0.85). IOP decreased significantly from 26.6 ± 10.1 mmHg at baseline to 14.7 ± 3.3 mmHg at the final follow-up in AT (p= 0.001). The corresponding numbers for A were 28.8 ± 10.2 and 16.7 ± 4.9, respectively (p= 0.001). The final IOP was significantly lower in AT (p= 0.022). The number of medications at baseline was comparable in both groups (2.6 ± 1.2 in AT and 2.5 ± 1.3 in A, p=0.851). Corresponding number at 1 year visit was 1.2±2 in AT and 2.8±1.8 in A (p=0.001). The incidence of a hypertensive phase was 18.7% in AT and 35.5% in A (p=0.05). HP resolved in only 30% of eyes. The criteria for HP resolution were fulfilled in 9 eyes (30%). There was no difference in the rate of resolution of the hypertensive phase between AT and A (33.3% and 28.5%, respectively, p=0.67). Conclusion: Ahmed glaucoma valve implant with same session trabectome surgery significantly decreased the rate of the hypertensive phase and postoperative IOP as well as the number of glaucoma medications.

Objective: The Rho GTPase/Rho kinase pathway is an important target in glaucoma treatment. This study investigated the hypotensive effect of RKI-1447, a Rho kinase inhibitor developed for cancer treatment, in a porcine ex vivo pigmentary glaucoma model. Materials and Methods: Twenty-eight fresh porcine anterior chambers were perfused with pigment medium (1.67 × 107 pigment particles/mL) for 48 hours before being subjected to the RKI-1447 (n = 16) or the vehicle control (n = 12). Another twelve eyes with normal medium perfusion served as the control. The intraocular pressure (IOP) was recorded at two-minute intervals and the outflow facility was calculated. To investigate the intracellular mechanism of the IOP reduction, primary trabecular meshwork cells were exposed to RKI-1447 or the vehicle control and then analyzed for changes in cytoskeleton, motility, and phagocytosis. Results: Compared to the baseline, the perfusion of pigment caused a significant increase in IOP in the RKI-1447 group (P = 0.003) at 48 hours. Subsequent treatment with RKI-1447 significantly reduced IOP from 20.14 ± 2.59 mmHg to 13.38 ± 0.91 mmHg (P = 0.02). Pigment perfusion reduced the outflow facility from 0.27 ± 0.03 at baseline to 0.18 ± 0.02 at 48 hours (P < 0.001). This was partially reversed with RKI-1447. RKI-1447 exhibited no apparent changes in the micro- or macroscopic appearance, including histology. Primary TM cells exposed to RKI-1447 showed a significant disruption of the actin cytoskeleton both in the presence and absence of pigment exposure (P < 0.001) but no effect on TM migration was observed. Pigment-treated TM cells exhibited a reduction in TM phagocytosis, which RKI reversed. Conclusions: RKI-1447 is a novel ROCK inhibitor that significantly reduces IOP by disrupting TM stress fibers and increasing TM phagocytosis. These features may make it especially useful for the treatment of secondary glaucomas with an increased phagocytosis load but also for other open angle glaucomas.

As the population of the United States undergoes significant qualitative and quantitative changes the healthcare needs of the population changes accordingly. Since the “old-old” ≥85 years sector of the population is growing fast we embarked on studying how spine surgery profile changes across age groups. Methods: A database of 6147 spine surgery patients operated in a tertiary care center in Middle Georgia between 2003 and 2009 was divided to four age groups. The threshold for old-old age was set at 75. The percentage of old-old patients was calculated and their spine surgery profile for the whole period was studied. Changes in spine surgery profile were evaluated in relation to age group and gender. Type of surgery was determined by ICD-9 code. Results: For the whole study period, the percentage of old-old spine surgery patients was 6.7%. The percentage of old-old spine surgery patients increased from 4.7% in 2003 to 7.3% in 2009. Females were preponderant in the later three age groups (53.8%, 53.2% and 55.0%) while males were more in the 2 = 1446.958, P = 0.000). The spine surgery profile for the whole study period was characterized by shifts in the ≥75 age group toward less primary fusions of the cervical and lumbar spine and more refusions of the lumbar spine, more intervertebral disk excisions and more canal exploratory operations in older-old patients. In addition to the age factor, the gender factor had an impact on the spine surgery profile. Statistically significant differences (P < 0.5) were noted between males and females in each age group. Conclusions: Spine surgery profile shows a tendency toward less invasive procedures in the older-old population unless indicated by previous surgery failures, upper neck injuries or osteoporosis-induced fractures.

Background: Outflow regulation and phagocytosis are key functions of the trabecular meshwork (TM), but it is not clear how the two are related in secondary open angle glaucomas characterized by an increased particle load. We hypothesized that diminished TM phagocytosis is not the primary cause of early ocular hypertension and recreated pigment dispersion in a porcine ex vivo model. Methods: Sixteen porcine anterior chamber cultures received a continuous infusion of pigment granules (Pg), while 16 additional anterior chambers served as controls (C). Pressure transducers recorded the intraocular pressure (IOP). The phagocytic capacity of the trabecular meshwork was determined by fluorescent microspheres. Results: The baseline IOPs in Pg and C were similar (P=0.82). A significant IOP elevation occurred in Pg at 48, 120, and 180 hours (all PP=0.001 compared to C). This reduction did not result in an additional IOP increase at 120 or 180 hours compared to the first IOP elevation at 48 hours (P>0.05). Conclusions: In this porcine model of pigmentary glaucoma, an IOP elevation occurs much earlier than when phagocytosis fails, suggesting that two separate mechanisms might be at work.

Whereas condensation of 2-methyl-3-nitrobenzoate esters with dimethylformamide dimethyl acetal gives 5-nitroisocoumarin, analogous condensation with dimethylacetamide dimethyl acetal proceeds via a different route, affording 1-methoxy-3-dimethylamino-5-nitronaphthalene in good yield. Extension of the reaction to other naphthalenes with this novel ‘push–pull’ substitution motif has been explored. A deuterium labelling study revealed that equilibration of the alkoxy groups in the reaction mixture took place before the final carbocyclisation.

All the closed loop control system requires the controller for improvement of transient response of the error signal. Though the tuning of PID controller in real time is bit difficult and moreover it lacks the disturbance rejection capability. In order to compensate these internal design problems, internal model control (IMC) based tuning approach has been developed. The analytical method based on IMC principle for the design of PID controller is also developed. The IMC has a single tuning parameter to adjust the performance and robustness of the controller. The tuning method is very efficient in controlling the overshoot, stability and the dynamics of the speed-control system of the DC motor. The resulting structure of the control system is capable of controlling a fast dynamic process by integral control, which results in a striking improvement in performance.

Cervical cancer is the third most commonly diagnosed cancer and the fourth leading cause of cancer death in womenworldwide. The highest incidence rates are in Africa, as well as South-Central Asia and South America. According to the National Institute of Cancer (INCA) at the last year, it was estimated 15,590 new cases of cervical cancer in Brazil. About 90% of cervical cancers originate in the evolution of cervical intraepithelial neoplasia (CIN) which is classified on the basis of cyto-histological characteristics (low and high grade lesions). The equipment (CerCa 150 System, MMOptics Ltda., Trubios LLC, Brazil-USA) and the medication (20% MAL cream, PDTPharma, Brazil) are produced in Brazil with relative low cost. The Photodynamic Therapy is a promising procedure and it is even known as safe to normal tissue. The device includes two components specifically adapted to detect and treat abnormal cervical tissue, enabling proper lighting of the cervix. It is portable and does not require special infrastructure or installation. More than 60 patients between the ages of 14-57 years and with CIN 1 were treated and presented 100% of cure. Based on these results a larger randomized study with patients with CIN 2, placebo and follow-up only is ongoing.