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E-learning is the best platform for distance learning as it is a cost-efficient technology. Distance learning through an E-Learning platform offers enormous opportunity for Sri Lanka, because it can open doors to everybody without hassle. Distance learning with E-Learning focuses on delivering education to students without a traditional classroom. Educational institutes in Sri Lanka may use distance learning with students who are unable to follow regular courses. E-Learning runs with web technologies which make interactions for both teachers and students easy. It also makes it easy to exchange relevant educational tools and interactive exercises.

Many regions in the world have recently experienced more frequent and intensive disasters such as flash floods and persistent droughts. The Sultanate of Oman is no exception to this. We analyzed two-decade long daily precipitation records in three major cities, namely, Sohar, Muscat and Salalah, mainly focusing on extremes. A set of climate indices defined in the RClimDex software package was used. Moreover, annual maximum 1-day precipitations in three study areas were analyzed using the Generalized Extreme Value (GEV) distribution function. Results showed significant changes in the precipitation regime in recent years. The annual total precipitation in Sohar and Salalah decreased, while that in Muscat shows statistically week increasing trend. However, all indices analyzed indicate enhanced extreme precipitation toward 2010 in Muscat and Salalah. As a result, the contribution from extreme events to the annual total rainfall steadily increases in both study areas. A clear conclusion could not be made based on selected indices for Sohar due to consistent drier years occurred from 1999 to 2005. Frequency analysis indicates that the annual the maximum 1-day rainfall estimated in Sohar and Muscat for 5 and 10 year return periods are approximately same (70 mm/day and 108 mm/day, respectively) but about two-fold greater than that in Salalah (29 mm/day and 60 mm/day, respectively). [ABSTRACT FROM AUTHOR]

Abstract Background Rhinovirus (RV) is a major cause of chronic obstructive pulmonary disease (COPD) exacerbations, and primarily infects bronchial epithelial cells. Immune responses from BECs to RV infection are critical in limiting viral replication, and remain unclear in COPD. The objective of this study is to investigate innate immune responses to RV infection in COPD primary BECs (pBECs) in comparison to healthy controls. Methods Primary bronchial epithelial cells (pBECs) from subjects with COPD and healthy controls were infected with RV-1B. Cells and cell supernatant were collected and analysed using gene expression microarray, qPCR, ELISA, flow cytometry and titration assay for viral replication. Results COPD pBECs responded to RV-1B infection with an increased expression of antiviral and pro-inflammatory genes compared to healthy pBECs, including cytokines, chemokines, RNA helicases, and interferons (IFNs). Similar levels of viral replication were observed in both disease groups; however COPD pBECs were highly susceptible to apoptosis. COPD pBECs differed at baseline in the expression of 9 genes, including calgranulins S100A8/A9, and 22 genes after RV-1B infection including the signalling proteins pellino-1 and interleukin-1 receptor associated kinase 2. In COPD, IFN-β/λ1 pre-treatment did not change MDA-5/RIG-I and IFN-β expression, but resulted in higher levels IFN-λ1, CXCL-10 and CCL-5. This led to reduced viral replication, but did not increase pro-inflammatory cytokines. Conclusions COPD pBECs elicit an exaggerated pro-inflammatory and antiviral response to RV-1B infection, without changing viral replication. IFN pre-treatment reduced viral replication. This study identified novel genes and pathways involved in potentiating the inflammatory response to RV in COPD.

Abstract Background Plasminogen activator inhibitor type-2 (PAI-2, SERPINB2) is an irreversible, specific inhibitor of the urokinase plasminogen activator (uPA). Since overexpression of uPA at the surface of cancer cells is linked to malignancy, targeting of uPA by exogenous recombinant PAI-2 has been proposed as the basis of potential cancer therapies. To this end, reproducible yields of high purity protein that maintains this targeting ability is required. Herein we validate the use in vitro of recombinant 6 × His-tagged-PAI-2 lacking the intrahelical loop between C and D alpha-helices (PAI-2 ΔCD-loop) for these purposes. Results We show that PAI-2 ΔCD-loop expressed and purified from the pQE9 vector system presents an easier purification target than the previously used pET15b system. Additionally, PAI-2 ΔCD-loop gave both higher yield and purity than wild-type PAI-2 expressed and purified under identical conditions. Importantly, absence of the CD-loop had no impact on the inhibition of both solution phase and cell surface uPA or on the clearance of receptor bound uPA from the cell surface. Furthermore, uPA:PAI-2 ΔCD-loop complexes had similar binding kinetics (KD ~5 nM) with the endocytosis receptor Very Low Density Lipoprotein Receptor (VLDLR) to that previously published for uPA:PAI-2 complexes. Conclusion We demonstrate that the CD-loop is redundant for the purposes of cellular uPA inhibition and cell surface clearance (endocytosis) and is thus suitable for the development of anti-uPA targeted cancer therapeutics.

Expansion microscopy (ExM) enables sub-diffraction imaging by physically expanding labeled tissue samples. This increases the tissue volume relative to the instrument point spread function (PSF), thereby improving the effective resolution by reported factors of 4 - 20X [1, 2]. However, this volume increase dilutes the fluorescence signal, reducing both signal-to noise ratio (SNR) and acquisition speed. This paper proposes and validates a method for mitigating these challenges. We overcame the limitations of ExM by developing a fast photo-stable protocol to enable scalable widefield three-dimensional imaging with ExM. We combined widefield imaging with quantum dots (QDots). Widefield imaging provides a significantly faster acquisition of a single field-of-view (FOV). However, the uncontrolled incoherent illumination induces photobleaching. We mitigated this challenge using QDots, which exhibit a long fluorescence lifetime and improved photostability. First, we developed a protocol for QDot labeling. Next, we utilized widefield imaging to obtain 3D image stacks and applied deconvolution, which is feasible due to reduced scattering in ExM samples. We show that tissue clearing, which is a side-effect of ExM, enables widefield deconvolution, dramatically reducing the acquisition time for three-dimensional images compared to laser scanning microscopy. The proposed QDot labeling protocol is compatible with ExM and provides enhanced photostability compared to traditional fluorescent dyes. Widefield imaging significantly improves SNR and acquisition speed compared to conventional confocal microscopy. Combining widefield imaging with QDot labeling and deconvolution has the potential to be applied to ExM for faster imaging of large three-dimensional samples with improved SNR.

Background: Increased airway NLRP3 inflammasome-mediated IL-1β responses may underpin severe neutrophilic asthma. However, whether increased inflammasome activation is unique to severe asthma, is a common feature of immune cells in all inflammatory types of severe asthma, and whether inflammasome activation can be therapeutically targeted in patients, remains unknown., Objective: To investigate the activation and inhibition of inflammasome-mediated IL-1β responses in immune cells from patients with asthma., Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from patients with non-severe (n = 59) and severe (n = 36 stable, n = 17 exacerbating) asthma and healthy subjects (n = 39). PBMCs were stimulated with nigericin or lipopolysaccharide (LPS) alone, or in combination (LPS + nigericin), with or without the NLRP3 inhibitor MCC950, and the effects on IL-1β release were assessed., Results: PBMCs from patients with non-severe or severe asthma produced more IL-1β in response to nigericin than those from healthy subjects. PBMCs from patients with severe asthma released more IL-1β in response to LPS + nigericin than those from non-severe asthma. Inflammasome-induced IL-1β release from PBMCs from patients with severe asthma was not increased during exacerbation compared to when stable. Inflammasome-induced IL-1β release was not different between male and female, or obese and non-obese patients and correlated with eosinophil and neutrophil numbers in the airways. MCC950 effectively suppressed LPS-, nigericin-, and LPS + nigericin-induced IL-1β release from PBMCs from all groups., Conclusion: An increased ability for inflammasome priming and/or activation is a common feature of systemic immune cells in both severe and non-severe asthma, highlighting inflammasome inhibition as a universal therapy for different subtypes of disease., (© 2023. The Author(s).)

Introduction: This drug utilization study evaluated the impact of 2019 label changes on real-world febuxostat utilization among patients with gout. We describe the numbers and proportions of patients initiating febuxostat as new users (allopurinol-naïve) or prevalent new users (prior allopurinol use) and data on febuxostat users with established cardiovascular disease (CVD) morbidities before, during, and after the 2019 label changes., Methods: This descriptive, non-interventional, cross-sectional study used data from two large administrative claims databases in the United States, the IQVIA PharMetrics Plus database and the Optum Research Database (ORD). The study population included patients with gout initiating febuxostat on or after June 1, 2016. Data were collected on febuxostat and allopurinol use, established CVD morbidities, comorbidities of interest, concomitant medications, and patient demographics., Results: In both databases, the total number of febuxostat users and proportion of patients who initiated febuxostat as new users both decreased during the study period. Of 13,848 patients in the PharMetrics Plus cohort, 42.7% were new users of febuxostat and 57.3% were prevalent new users. In the ORD cohort, 40.5% of the 10,198 patients were new users and 59.5% were prevalent new users. The most common established CVD morbidities in the 12 months prior to initiation of febuxostat were diabetes mellitus, ischemic heart disease, and heart failure/cardiomyopathy., Conclusions: Although the benefit-risk profile for febuxostat is considered favorable for the treatment of hyperuricemia in certain patients with gout, real-world febuxostat utilization decreased during the study period, presumably in response to the label change., (© 2023. The Author(s).)

Objective: To investigate whether serum urate levels, number of gout flares, and tophi burden are related to death from cardiovascular (CV) causes after treatment with febuxostat or allopurinol in patients with gout from the Cardiovascular Safety of Febuxostat or Allopurinol in Patients With Gout and Cardiovascular Comorbidities (CARES) trial., Methods: Patients were randomly assigned to receive febuxostat (40 mg or 80 mg once daily, according to serum urate levels at week 2) or allopurinol titrated in 100-mg increments from 200-400 mg or 300-600 mg (with dose determined according to kidney function). Changes from baseline in serum urate level, gout flares, and tophus resolution were key exploratory efficacy parameters in the overall population and in subgroups of patients who died and those who did not die from a CV-related cause. The latter subgroup included patients who died due to non-CV causes and those who did not die due to any cause., Results: Patients received treatment with febuxostat (n = 3,098) or allopurinol (n = 3,092) for a median follow-up period of 32 months (for a maximum of 85 months). In the overall population, mean serum urate levels were lower in those receiving febuxostat compared with those receiving allopurinol at most study visits. There were no associations between serum urate levels and death from CV causes with febuxostat. The number of gout flares requiring treatment was higher within 1 year of treatment with febuxostat compared with allopurinol (mean incidence of gout flares per patient-years of exposure 1.33 versus 1.20), but was comparable thereafter and decreased overall throughout the study period (mean incidence of gout flares per patient-years of exposure 0.35 versus 0.34 after 1 year of treatment; overall mean incidence 0.68 versus 0.63) irrespective of whether the patient died from a CV-related cause. Overall, 20.8% of patients had ≥1 tophus at baseline; tophus resolution rates were similar between treatment groups, with cumulative resolution rates of >50%., Conclusion: In the CARES trial, febuxostat and allopurinol (≤600 mg doses) had comparable efficacy in patients with gout and CV disease, and there was no evidence of a relationship between death from CV causes and serum urate levels, number of gout flares, or tophus resolution among the patients receiving febuxostat., (© 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: To assess the efficacy and safety of febuxostat extended release (XR) and immediate release (IR) in patients with gout and normal or impaired renal function., Methods: This was a 3-month, phase III, multicenter, double-blind, placebo-controlled study. Patients (n = 1,790) with a history of gout and normal or impaired (mild-to-severe) renal function were randomized to receive placebo, febuxostat IR 40 or 80 mg, or febuxostat XR 40 or 80 mg once daily (1:1:1:1:1 ratio). End points included proportions of patients with a serum urate (UA) level of <5.0 mg/dl at month 3 (primary end point), a serum UA level of <6.0 mg/dl at month 3, and ≥1 gout flare requiring treatment over 3 months (secondary end points)., Results: Both febuxostat formulations led to significantly greater proportions of patients achieving a serum UA level of <5.0 mg/dl or <6.0 mg/dl at month 3 (P < 0.001 for all comparisons versus placebo). Equivalent doses of febuxostat XR and IR had similar treatment effects on serum UA level end points; however, a significantly greater proportion of patients achieved a serum UA level of <5.0 mg/dl with XR 40 mg versus IR 40 mg. Similar proportions of patients experienced ≥1 gout flare across treatment groups. Rates of treatment-emergent adverse events were low and evenly distributed between treatment arms. A preplanned subgroup analysis demonstrated that febuxostat formulations were well tolerated and generally effective on serum UA level end points (versus placebo) across all renal function subgroups., Conclusion: Both formulations of febuxostat (XR and IR) were well tolerated and effective in patients with gout and normal or impaired renal function, including patients with severe renal impairment., (© 2018 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Background: Febuxostat immediate release (IR), a xanthine oxidase inhibitor, is indicated for the management of hyperuricemia in patients with gout by lowering urate levels. An extended release (XR) formulation of febuxostat was developed to provide equal or superior efficacy on urate lowering compared with the IR formulation and potentially lower the risk of treatment-initiated gout flares due to an altered pattern of drug exposure. The present study evaluated the efficacy and safety of febuxostat XR and IR formulations in patients with gout and moderate renal impairment (estimated glomerular filtrate rate ≥ 30 and < 60 ml/min)., Methods: This was an exploratory, 3-month, phase II, multicenter, placebo-controlled, double-blind proof-of-concept study. Patients (n = 189) were randomized 1:1:1:1:1 to receive placebo or febuxostat IR 40 mg, XR 40 mg, IR 80 mg, or XR 80 mg once daily. Endpoints included: proportion of patients with serum uric acid (sUA) < 5.0 mg/dl at month 3 (primary endpoint), proportion of patients with sUA < 6.0 mg/dl at month 3, and proportion of patients with ≥ 1 gout flare requiring treatment over 3 months., Results: At month 3, all febuxostat treatment groups were associated with greater proportions of patients achieving sUA < 5.0 mg/dl (p < 0.05 vs placebo). A greater proportion of patients receiving XR 40 mg achieved sUA < 5.0 mg/dl versus those receiving IR 40 mg (p = 0.034); proportions were similar in the IR 80 mg and XR 80 mg groups. Higher proportions of febuxostat-treated patients achieved sUA < 6.0 mg/dl at month 3 (p < 0.05 vs placebo) and experienced ≥ 1 gout flare (significant for all comparisons, except XR 40 mg). Incidences of treatment-related adverse events were low across all treatment groups; the majority were mild or moderate with no apparent trends correlating with IR or XR doses. The most common treatment-emergent adverse event was hypertension. One death (unrelated to the study drug) was reported., Conclusions: These exploratory data demonstrate that febuxostat (XR and IR) formulations were effective and well tolerated in patients with gout and moderate renal impairment., Trial Registration: ClinicalTrials.gov, NCT02128490 Registered on 29 April 2014.

Objective: To assess the effect of treatment with febuxostat versus placebo on joint damage in hyperuricemic subjects with early gout (1 or 2 gout flares)., Methods: In this double-blind, placebo-controlled study, 314 subjects with hyperuricemia (serum uric acid [UA] level of ≥7.0 mg/dl) and early gout were randomized 1:1 to receive once-daily febuxostat 40 mg (increased to 80 mg if the serum UA level was ≥6.0 mg/dl on day 14) or placebo. The primary efficacy end point was the mean change from baseline to month 24 in the modified Sharp/van der Heijde erosion score for the single affected joint. Additional efficacy end points included change from baseline to month 24 in the Rheumatoid Arthritis Magnetic Resonance Imaging Scoring (RAMRIS) scores for synovitis, erosion, and edema in the single affected joint, the incidence of gout flares, and serum UA levels. Safety was assessed throughout the study., Results: Treatment with febuxostat did not lead to any notable changes in joint erosion over 2 years. In both treatment groups, the mean change from baseline to month 24 in the modified Sharp/van der Heijde erosion score for the single affected joint was minimal, with no between-group differences. However, treatment with febuxostat significantly improved the RAMRIS synovitis score at month 24 compared with placebo treatment (change from baseline -0.43 versus -0.07; P <0.001), decreased the overall incidence of gout flares (29.3% versus 41.4%; P < 0.05), and improved serum UA control (62.8% versus 5.7%; P < 0.001). No major safety concerns were reported., Conclusion: Urate-lowering therapy with febuxostat improved magnetic resonance imaging-determined synovitis and reduced the incidence of gout flares in subjects with early gout., (© 2017 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Background: Hyperuricemia is associated with hypertension, with elevated serum uric acid levels postulated to have a causal role in the development of hypertension. Consequently, serum uric acid reduction may help lower blood pressure (BP). A Phase 2, double-blind, placebo-controlled trial was conducted to assess the potential BP-lowering effects of the xanthine oxidase inhibitor febuxostat in subjects with hypertension and hyperuricemia (serum uric acid ≥0.42 mmol/L [≥7.0 mg/dL])., Methods and Results: Subjects (n=121) were randomized 1:1 to febuxostat 80 mg once daily or to placebo. The primary end point was change from baseline to Week 6 in 24-hour mean ambulatory systolic BP (SBP). Additional end points included the following: change from baseline to Week 3 in 24-hour mean SBP and changes from baseline to Weeks 3 and 6 in 24-hour mean ambulatory diastolic BP, serum uric acid, mean daytime and nighttime ambulatory SBP/diastolic BP, and clinic SBP/diastolic BP. For the overall study population, there were no significant differences between febuxostat and placebo for changes from baseline to Weeks 3 or 6 in ambulatory, daytime or nighttime, or clinic SBP or diastolic BP. However, in a preplanned subgroup analysis, there was a significant decrease in SBP from baseline to Week 6 in subjects with normal renal function (estimated glomerular filtration rate ≥90 mL/min) treated with febuxostat versus placebo; least squares mean difference, -6.7; 95% confidence interval -13.3 to -0.0; P =0.049., Conclusions: This study suggests that febuxostat may lower BP in hyperuricemic patients with hypertension and normal renal function; further studies should be conducted to confirm this finding., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01496469., (© 2017 The Authors and Takeda Pharmaceuticals. Published on behalf of the American Heart Association, Inc., by Wiley.)

Objective: Renal impairment is a risk factor for gout and a barrier to optimal gout management. We undertook this exploratory study to obtain data that have been heretofore limited regarding the safety and efficacy of febuxostat in patients with moderate-to-severe renal impairment (estimated glomerular filtration rate [GFR] 15-50 ml/minute/1.73 m(2) )., Methods: Ninety-six gout patients with moderate-to-severe renal impairment were enrolled in a 12-month multicenter, randomized, double-blind, placebo-controlled study. Patients were randomly assigned at a 1:1:1 ratio to receive 30 mg febuxostat twice daily, 40/80 mg febuxostat once daily, or placebo. The primary efficacy end point was the change in serum creatinine (Cr) level from baseline to month 12. Secondary end points included the change in estimated GFR from baseline to month 12 and the proportion of patients with a serum uric acid (UA) level of <6.0 mg/dl at month 12., Results: At month 12, there were no significant differences in the change in serum Cr level from baseline, or in the change in estimated GFR from baseline, in either febuxostat group compared to the placebo group. The proportion of patients with a serum UA level of <6.0 mg/dl at month 12 was significantly greater in both febuxostat groups compared to the placebo group (both P < 0.001). At least 1 treatment-emergent adverse event (TEAE) occurred in 78.1% of patients receiving 30 mg febuxostat twice daily, 87.5% of patients receiving 40/80 mg febuxostat once daily, and 78.1% of patients receiving placebo. TEAEs most frequently involved the categories of renal failure and impairment and renal function analyses., Conclusion: Febuxostat proved to be efficacious in serum UA reduction and was well tolerated in gout patients with moderate-to-severe renal impairment. Patients randomly assigned to receive febuxostat demonstrated significantly lower serum UA levels and no significant deterioration in renal function., (© 2016, American College of Rheumatology.)

Asthma is a heterogeneous inflammatory airways disorder where interleukin (IL)-1β is thought to be a key mediator, especially in the neutrophilic subtype of asthma. The generation of active IL-1β requires proteolytic cleavage typically mediated through the formation of a caspase-1-containing inflammasome. This study hypothesised that an IL-1β endotype associated with the nucleotide-binding domain, leucine-rich repeat-containing family protein (NLRP)3/apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC)/caspase-1 inflammasome is characteristic of patients with the neutrophilic subtype of asthma. Participants with asthma (n=85) and healthy controls (n=27) underwent clinical assessment, spirometry and sputum induction. Sputum was processed for differential cell count, gene expression and protein mediators. NLRP3 and caspase-1 expression was also determined by immunocytochemistry. Sputum macrophages were isolated (n=8) and gene expression of NLRP3 and IL-1β determined. There was significantly elevated gene expression of NLRP3, caspase-1, caspase-4, caspase-5 and IL-1β in participants with neutrophilic asthma. Protein levels of IL-1β were significantly higher in those with neutrophilic asthma and correlated with sputum IL-8 levels. Sputum macrophages, as well as sputum neutrophils in neutrophilic asthma, expressed NLRP3 and caspase-1 protein. NLRP3 inflammasome is upregulated in neutrophilic asthma and may regulate the inflammation process observed in this asthma phenotype through production of IL-1β.

Background and Objectives: Higher urinary uric acid excretion is a suspected risk factor for calcium oxalate stone formation. Febuxostat, a xanthine oxidoreductase inhibitor, is effective in lowering serum urate concentration and urinary uric acid excretion in healthy volunteers and people with gout. This work studied whether febuxostat, compared with allopurinol and placebo, would reduce 24-hour urinary uric acid excretion and prevent stone growth or new stone formation., Design, Setting, Participants, & Measurements: In this 6-month, double-blind, multicenter, randomized controlled trial, hyperuricosuric participants with a recent history of calcium stones and one or more radio-opaque calcium stone ≥ 3 mm (as seen by multidetector computed tomography) received daily febuxostat at 80 mg, allopurinol at 300 mg, or placebo. The primary end point was percent change from baseline to month 6 in 24-hour urinary uric acid. Secondary end points included percent change from baseline to month 6 in size of index stone and change from baseline in the mean number of stones and 24-hour creatinine clearance., Results: Of 99 enrolled participants, 86 participants completed the study. Febuxostat led to significantly greater reduction in 24-hour urinary uric acid (-58.6%) than either allopurinol (-36.4%; P=0.003) or placebo (-12.7%; P<0.001). Percent change from baseline in the size of the largest calcium stone was not different with febuxostat compared with allopurinol or placebo. There was no change in stone size, stone number, or renal function. No new safety concerns were noted for either drug., Conclusions: Febuxostat (80 mg) lowered 24-hour urinary uric acid significantly more than allopurinol (300 mg) in stone formers with higher urinary uric acid excretion after 6 months of treatment. There was no change in stone size or number over the 6-month period.