Systematic Down-Selection of Repurposed Drug Candidates for COVID-19.

SARS-CoV-2 is the cause of the COVID-19 pandemic which has claimed more than 6.5 million lives worldwide, devastating the economy and overwhelming healthcare systems globally. The development of new drug molecules and vaccines has played a critical role in managing the pandemic; however, new variants of concern still pose a significant threat as the current vaccines cannot prevent all infections. This situation calls for the collaboration of biomedical scientists and healthcare workers across the world. Repurposing approved drugs is an effective way of fast-tracking new treatments for recently emerged diseases. To this end, we have assembled and curated a database consisting of 7817 compounds from the Compounds Australia Open Drug collection. We developed a set of eight filters based on indicators of efficacy and safety that were applied sequentially to down-select drugs that showed promise for drug repurposing efforts against SARS-CoV-2. Considerable effort was made to evaluate approximately 14,000 assay data points for SARS-CoV-2 FDA/TGA-approved drugs and provide an average activity score for 3539 compounds. The filtering process identified 12 FDA-approved molecules with established safety profiles that have plausible mechanisms for treating COVID-19 disease. The methodology developed in our study provides a template for prioritising drug candidates that can be repurposed for the safe, efficacious, and cost-effective treatment of COVID-19, long COVID, or any other future disease. We present our database in an easy-to-use interactive interface (CoviRx that was also developed to enable the scientific community to access to the data of over 7000 potential drugs and to implement alternative prioritisation and down-selection strategies.

Correlation of aspergillus skin hypersensitivity with the duration and severity of asthma.

Asthma is a significant health problem worldwide and Allergic Bronchopulmonary aspergillosis (ABPA) complicates the course of 1-2% of patients of asthma. Aspergillus skin hypersensitivity (AH) is the first step for diagnosis of ABPA. This study was conducted to know the correlation of AH with severity and duration of asthma. Patients, age >15 years, of asthma attending this hospital from January 2015 to December 2015 were included. Asthma was diagnosed clinically and confirmed with spirometry. Of 282 patients 206 patients were AH positive. The AST-positivity in patients having severe asthma (96.8%) was higher than that in patients having mild (36.8%) and moderate asthma (80.4%). The median (IQR) duration of asthma of AH positive patients was 5.0 yrs. This study emphasized the need of ABPA screening by intradermal skin test especially in patients having severe asthma and/or those having asthma for longer duration in order for early diagnosis of ABPA.

Mucosa-Associated Lymphoid Tissue Surgeries as a Possible Risk for Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis.

Background: Inflammatory bowel disease (IBD) is a group of chronic inflammatory gastrointestinal disorders that are caused by genetic susceptibility and environmental factors and affects a significant portion of the global population. The gut-associated lymphoid tissue (GALT) is known to play a crucial role in immune modulation and maintaining gut microbiota balance. Dysbiosis in the latter has a known link to IBD. Therefore, the increasing prevalence of adenoidectomy in children should be explored for its potential association with IBD. The objective of this paper was to assess the association between adenoid tissue removal and the risk of developing Crohn's disease (CD) and ulcerative colitis (UC). Methods: We conducted a pooled meta-analysis to evaluate the extended clinical outcomes in patients who underwent appendicectomy and tonsillectomy compared to those who did not. Our approach involved systematically searching the PubMed database for relevant observational studies written in English. We followed the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines to collect data from various time periods, and to address the diversity in study results; we employed a random-effects analysis that considered heterogeneity. For outcomes, odds ratios (ORs) were pooled using a random-effects model. Results: Seven studies, out of a total of 114,537, met our inclusion criteria. Our meta-analysis revealed a significant association between appendicectomy and CD (OR: 1.57; 95% confidence interval (CI): 1.01 - 2.43; heterogeneity I2 = 93%). Similarly, we found a significant association between tonsillectomy and CD (OR: 1.93; 95% CI: 0.96 - 3.89; I2 = 62%). However, no significant association was observed between appendicectomy and UC (OR: 0.60; 95% CI: 0.24 - 1.47; I2 = 96%), while a modest association was found between tonsillectomy and UC (OR: 1.24; 95% CI: 1.18 - 1.30; I2 = 0%). Conclusions: In summary, we found that the trend of appendicectomy is linked to higher odds of CD, and tonsillectomy is more likely associated with increased odds for both CD and UC, with a risk of bias present.

Spatial atmospheric pressure molecular layer deposition of alucone films using dimethylaluminum isopropoxide as the precursor.

Trimethylaluminum is the most used aluminum precursor in atomic and molecular layer deposition (ALD/MLD). It provides high growth-per-cycle (GPC), is highly reactive and is relatively low cost. However, in the deposition of hybrid alucone films, TMA tends to infiltrate into the films requiring very long purge steps and thereby limiting the deposition rate (nm s-1) of the process. From our previous studies, we know that dimethylaluminum isopropoxide (DMAI) could be a potential candidate to substitute TMA in alucone depositions as it does not seem to infiltrate into the films. In this study, we perform a more detailed investigation of MLD of alucone on an atmospheric pressure spatial MLD system using DMAI as the aluminum precursor. The effect of deposition temperature and reactant purge times on the overall GPC has been investigated and a decreasing GPC with increasing deposition temperature and increasing EG purge time has been observed. Furthermore, the DMAI alucone films have been compared for their chemical environment and degradation with the films prepared using TMA and EG, showing striking similarities between the two. The results demonstrate that DMAI can be used as an alternative precursor to TMA for MLD of alucone films and this work can be used as a guide for designing efficient MLD processes in the future.

Arrhythmogenic Right Ventricular Cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC), formerly called arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/ARVC), is a myocardial structural abnormality disease with clinical presentation of cardiac arrhythmia. It is characterized by the replacement of the myocardium with fibrofatty tissue. We present a case of a young male who met two major criteria for definite diagnosis of ARVC: early transition inverted t waves in lead V1-V4 and MRI showed right ventricle (RV) dyskinesia with RV ejection fraction (EF) < 40%, both satisfying the two major criteria of EKG and MRI required for definitive diagnosis.

About the importance of purge time in molecular layer deposition of alucone films.

The deposition rate and properties of MLD films are for a large part determined by what happens during the reactant exposure step. In some cases, however, the purge step is of equal importance, for example in MLD of alucone using trimethylaluminum (TMA) and ethylene glycol (EG). We show that infiltration of TMA into the alucone film followed by its continuous outgassing during the subsequent EG exposure step can lead to undesired CVD effects. To avoid the CVD effects, very long TMA purge times are required which in turn significantly impact the obtainable deposition rates. We also developed a kinetic model that correlates process parameters like reactant partial pressures, exposure times, purge time and deposition temperature to the CVD component in the film growth. We observed that the overall GPC decreases exponentially with TMA purge time attributed to the decreasing CVD component and after a long enough purge time reaches a steady-state value of growth only due to the MLD component. It was also observed that the CVD contributions reduced with decreasing partial pressure of TMA and increasing deposition temperature. With an intention to improve the outgassing efficiency of TMA, the influence of purge gas flow on the CVD growth component is also briefly discussed. Moreover, to mitigate the problem of infiltration, we show that a bulkier substitute of TMA like dimethylaluminum isopropoxide (DMAI) shows no infiltration and can improve the alucone deposition rate by at least an order of magnitude.

A durability study of a compression ignition engine operating with Thumba (Citrullus colocyntis) vegetable oil.

Vegetable oils are found suitable alternate of diesel fuel as per the results of short-run studies. Long-run studies with vegetable oil as a fuel pointed out the problems related to wear and maintenance of the engine. A single cylinder, variable compression ratio diesel engine was tested for 512 h (32 cycles of 16 h per day) to investigate longevity implications of fueling Thumba vegetable oil. Results of the study revealed that a very little damage was observed over the running surface of the cylinder liner, piston rings, valves, and valve seats. Wear in the piston outer diameter was observed to be 13 to 30 microns. Cylinder wear was about 80 microns. The closed gap in the oil piston ring increased up to 200 microns. Heavy carbon deposition was found on different internal parts of the engine, which indicates poor combustion of fuel. Amount of copper (66 mg/kg) and silicon (112 mg/kg) dissolved in the lubricating oil was found more than permissible limits (Cu 50 mg/kg, Si 25 mg/kg), after 450-h engine test run. But all the dissolve materials remain in allowable limits when the durability test conducted with diesel. Smoke, CO, HC, and NOX emissions were found to increase initially then decrease in the further engine running hours. But these emissions were found inferior to the engine emissions fueled with diesel in all the running hours. CO2 emissions were found superior throughout the test with the preheated T20 Thumba oil blend than diesel. The maximum reduction in the viscosity of the lubricating oil, during endurance testing, was found 60 centipoises but it was found 25 centipoises when the test conducted with diesel.

Long-term visual outcome and its predictors in macular oedema secondary to retinal vein occlusion treated with dexamethasone implant.

BACKGROUND: To evaluate the functional long-term outcome in patients with macular oedema (MO) secondary to central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO) treated with dexamethasone implant (DEX implant) and to identify its clinical predictors. METHODS: A 24-month, retrospective, multinational, real-world study. Chart review of patients with either naïve or recurrent MO secondary to CRVO/BRVO treated with DEX implant, including best-corrected visual acuity (BCVA), central subfield thickness (CST), demographic baseline characteristics and details of any additional treatment during follow-up. RESULTS: A total of 155 eyes (65 CRVO, 90 BRVO) from 155 patients were included. At 24 months, mean BCVA did not change significantly in CRVO (-2.1±24.5 letters, p=0.96) and BRVO patients (1.3±27.0 letters, p=0.07). A worse baseline BCVA (p<0.001), visual acuity (VA) gain ≥5 letters at 2 months (p=0.006) and no need for adjunctive intravitreal therapy after first DEX implant (p=0.001) were associated with a better final BCVA gain. Treatment-naïve patients (p=0.006, OR: 0.25, 95% CI 0.11 to 0.57) and those with a baseline CST≤400 µm (p=0.02, OR: 0.25, 95% CI 0.10 to 0.63) were identified as being less likely to need additional intravitreal therapy. CONCLUSION: Clinical baseline characteristics and the early treatment response were identified as possible predictors for long-term outcome and the need of adjunctive intravitreal therapy in MO secondary to BRVO/CRVO treated by DEX implant.

Dexamethasone implant (0.7 mg) in Indian patients with macular edema: Real-life scenario.

CONTEXT: Role of Ozurdex in macular edema due to various posterior segment pathologies. AIM: The aim of this study is to report outcome of Ozurdex implant in macular edema (ME) secondary to various posterior segment pathologies. SETTINGS AND DESIGN: This was a single-center, retrospective, interventional study. SUBJECTS AND METHODS: Patients of ME were treated with one or more Ozurdex implants (0.7 mg). Data collection included demographic details, best-corrected visual acuity (BCVA), central foveal thickness (CFT), duration of efficacy, and record of adverse events (if any) within 24 weeks. STATISTICAL ANALYSIS USED: Paired sample t-test, Stata data analysis, and statistical software, version 12.1, StataCorp, College Station, TX, USA, were used in the study. RESULTS: One hundred and sixteen eyes of 104 patients were studied which had a diagnosis of diabetic ME (n = 46), retinal vein occlusion (n = 40), and uveitis (n = 30). The average age of patients (mean ± standard deviation) was 50.2 ± 21.9 years. Baseline mean ± SD (standard deviation) logMAR BCVA, CFT, and intraocular pressure (IOP) were 0.636 ± 0.4, 527.8 ± 210.1 µm, and 15.3 ± 3.8 mmHg, respectively. The reinjection interval was around 12-18 weeks. Ozurdex proved its efficacy in improving mean logMAR visual acuity and reduction of CFT from baseline till 12 weeks' follow-up period (0.414 ± 0.5 and 301.5 ± 278.5, respectively; P < 0.05), and after 12 weeks' follow-up, it started worsening (0.530 ± 0.9 and 444.8 ± 375.2, respectively; P > 0.05). The most common reported adverse event was significant rise of IOP (>5 mmHg), with a total of 12 cases followed by cataract 9 cases. CONCLUSION: Ozurdex implant leads to a significant improvement in BCVA and CFT values till 12 weeks, followed by a gradual decline for all the pathologies studied together. No new safety concerns were observed with the Ozurdex implant. The duration of efficacy was found to be <24 weeks.