The efficacy of Zafirlukast as a SARS-CoV-2 helicase inhibitor in adult patients with moderate COVID-19 Pneumonia (pilot randomized clinical trial).

OBJECTIVE: To assess the efficacy of Zafirlukast as a SARS-CoV-2 Helicase Inhibitor in adult patients with moderate COVID-19 symptoms (hospitalized patients with COVID-19 pneumonia who were not admitted to an intensive care unit). METHODS: We conducted a randomized, double blind, placebo-controlled, pilot trial with adult patients with moderate COVID-19 pneumonia. The sample was randomized to Zafirlukast 10 mg BD for 10 days plus standard care vs placebo plus standard care. The primary outcome was the complete resolution of all symptoms. The secondary outcomes were the duration of oxygen therapy, and length of hospital stay (LOS). RESULTS: In total, 40 patients were randomized (20 to Zafirlukast and 20 to the control). The time to the resolution of clinical symptoms in both groups was not significantly different. Regarding the fever, 0.3 days [95 % CI, - 1.19, 0.69], p = 0.76, for shortness of breath, the difference was 0.4 days [95 % CI, - 2.67, 3.46], p = 0.68, for cough the difference was 0.2 days [95 % CI, - 1.45, 1.95], p = 0.98, for sputum the difference was 0.5 days [95 % CI, - 0.75, 1.85], p = 0.09, for vomiting the difference was 0.1 days [95 % CI, - 0.50, 0.30], p = 0.93, for fatigue the difference was 0.3 days [95 % CI, - 4.32, 3.62], p = 0.64. The LOS per day for the two groups was not significantly different, 1.1 days [95 % CI,- 2.03, 4.28], p = 0.94, nor was the duration of oxygen therapy per days, 1.3 days [95 % CI, - 1.79, 4.49], p = 0.49. Regarding the 7 category ordinary scale, there was no significant difference between the two groups at day 7 (p-value = 0.62), day 14 (p-value = 0.60) and day 28 (p-value = 0.48). CONCLUSION: Among adult patients hospitalized with COVID-19 pneumonia, the treatment with Zafirlukast, compared to placebo, did not significantly improve symptoms resolution.

The Prevalence and Risk Factors of Plantar Fasciitis Amongst the Population of Jazan.

Background Plantar fasciitis develops as a consequence of irritation of the plantar fascia, which is responsible for supporting the arches and absorbing shock. Multiple factors can contribute to plantar fasciitis, but the most common factor is overuse stress. The classical presentation is a sharp pain that is felt at the plantar aponeurosis (near the area of its insertion on the medial process of the calcaneal tuberosity), and it is possible to find a heel spur (osteophyte) in some cases. Most treatments for plantar fasciitis are ineffective and unsatisfactory for patients. Objective To estimate the prevalence and assess risk factors for plantar fasciitis among the population of the Jazan region. Methods A cross-sectional online survey was conducted on the population of the Jazan region. An online Google form questionnaire was prepared and distributed to the study population. Data was then entered and analyzed using IBM SPSS (Statistical Package for the Social Sciences) Statistics, version 21.0. Results A total of 695 participants were enrolled in the study. Out of that, 350 (50.4%) of the participants were males, while 345 (49.6%) were females. About the age of the participants, 507 (72.9%) were younger than 40 years of age. Participants with hypertension were 43 (6.2%), and 37 (5.3%) participants had diabetes. In terms of occupation, 120 (17.3%) worked in healthcare, 187 (26.9%) taught, and 43 (6.2%) served in the military. A great quantity of standing or walking was necessary for the jobs for 127 people (18.3%), while moderate amounts were recorded for 273 people (39.3%). The most commonly reported lower limb conditions were: pes planus (low arches) in 26 (3.7%) participants; and weakness of the gastrocnemius, soleus, and intrinsic foot muscles. The most commonly reported exercises were walking for 499 (71.8%) participants and jogging for 97 (14%) participants. The prevalence of plantar fasciitis was found to be 37% of the participants. Regarding the Foot and Ankle Outcome Score (FAOS) survey, the mean symptoms subscale score was 57.81 + 11.28, the mean pain subscale score was 72.87±20.84, the mean daily living subscale score was 72.73 ± 22.25, the mean sports and recreation subscale score was 76.83 ± 23.06, and the mean quality of life subscale score was 70.23 ± 25.17. Multivariate logistic regression was done and the following factors predicted a higher rate of plantar fasciitis: being 40 to 55 years old (p < 0.001, odds ratio = 2.15), being 56 to 65 years old (p = 0.037, odds ratio = 3.58), being obese (p = 0.031, odds ratio = 2.16), having weakness of the gastrocnemius, soleus, and the intrinsic foot muscles (p = 0.003, odds ratio = 7.39), jobs requiring a great amount of time standing or walking (p < 0.001, odds ratio = 3.17), and jobs requiring a moderate amount of time standing or walking (p = 0.012, odds ratio = 1.83). Being male predicted a lower rate of plantar fasciitis (p < 0.001, odds ratio = 0.52). Conclusion Plantar fasciitis is a prevalent and disabling condition with considerable effects on quality of life. Jobs that require long hours of walking or standing were associated with an increased risk of developing plantar fasciitis. Middle age, prolonged exercise, and gastrocnemius muscle tightness were also associated with plantar fasciitis. Efforts should be directed towards health education of the population regarding the risk factors and management of plantar fasciitis.

Influence of Friction Stir Process on the Physical, Microstructural, Corrosive, and Electrical Properties of an Al-Mg Alloy Modified with Ti-B Additives.

In this study, two successive methods were used to improve the grain structure and the mechanical and physical properties of Al 5052 aluminum alloy. The modifying elements, 0.99 wt.% of titanium (Ti) and 0.2 wt.% of boron (B), were added during the casting process. After solidification, single- and double-pass friction stir processing (FSP) were performed to achieve additional grain refinement and disperse the newly formed phases well. The addition of Ti-B modifiers significantly improved the mechanical and physical properties of the Al 5052 aluminum alloy. Nevertheless, only a 3% improvement in microhardness was achieved. The ultimate strength (US), yield strength (YS), and elastic modulus were investigated. In addition, the electrical conductivity was reduced by 56% compared to the base alloys. The effects of grain refinement on thermal expansion and corrosion rate were studied; the modified alloy with Ti-B in the as-cast state showed lower dimension stability than the samples treated with the FSP method. The grain refinement significantly affected the corrosion resistance; for example, single and double FSP passes reduced the corrosion rate by 11.4 times and 19.2 times, respectively. The successive FSP passes, resulting in a non-porous structure, increased the bulk density and formed precipitates with high bulk density.

Discovery of Zafirlukast as a novel SARS-CoV-2 helicase inhibitor using in silico modelling and a FRET-based assay.

The coronavirus helicase is an essential enzyme required for viral replication/transcription pathways. Structural studies revealed a sulphate moiety that interacts with key residues within the nucleotide-binding site of the helicase. Compounds with a sulphoxide or a sulphone moiety could interfere with these interactions and consequently inhibit the enzyme. The molecular operating environment (MOE) was used to dock 189 sulphoxide and sulphone-containing FDA-approved compounds to the nucleotide-binding site. Zafirlukast, a leukotriene receptor antagonist used to treat chronic asthma, achieved the lowest docking score at -8.75 kcals/mol. The inhibitory effect of the compounds on the SARS-CoV-2 helicase dsDNA unwinding activity was tested by a FRET-based assay. Zafirlukast was the only compound to inhibit the enzyme (IC50 = 16.3 µM). The treatment of Vero E6 cells with 25 µM zafirlukast prior to SARS-CoV-2 infection decreased the cytopathic effects of SARS-CoV-2 significantly. These results suggest that zafirlukast alleviates SARS-CoV-2 pathogenicity by inhibiting the viral helicase and impairing the viral replication/transcription pathway. Zafirlukast could be clinically developed as a new antiviral treatment for SARS-CoV-2 and other coronavirus diseases. This discovery is based on molecular modelling, in vitro inhibition of the SARS-CoV helicase activity and cell-based SARS-CoV-2 viral replication.

Short- and Long-Term Effects of Vitamin D Treatment on Bacillus Calmette-Guerin-Induced Depressive-Like Behavior in Mice.

PURPOSE: Depression is one of the most common psychological disorders. The nutritional etiology of the depression proposes that vitamin D may play a significant role in the pathogenesis of depression. Further, vitamin D deficiency has been found to aggravate depression in animals. Therefore, vitamin D treatment might be a potential therapeutic aid in depression management. This study aimed to explore the antidepressant effects of vitamin D in a Bacillus Calmette-Guerin (BCG)-induced depression model. METHODS: Thirty-six mice were randomly assigned to short-term and long-term experimental groups. In each group, mice were randomly subcategorized into three subgroups: 1. control (received vehicle), 2. BCG (received BCG [107 CFU/mouse]), and 3. BCG + vitamin D (received vitamin D [60.000 IU/kg] before BCG [107 CFU/mouse] inoculation). After completion of the two experimental periods (3 days for the short-term group and 2 weeks for the long-term group), the mice underwent three behavioral tests: locomotor activity, the forced swimming test (FST), and the tail suspension test (TST). RESULTS: Locomotor activity did not significantly differ among the subgroups in either the long-term or short-term groups. In the short-term group, the total immobility time on the FST was decreased in the vitamin D-treated group compared to the BCG group. However, in the TST, no significant difference was found between the vitamin D-treated group and the BCG group. In the long-term group, the immobility time on the FST was decreased in the vitamin D-treated group compared to the BCG group. Similarly, the total immobility time on the TST was also significantly lower in the vitamin D-treated mice than in the BCG-treated mice. CONCLUSION: Vitamin D is useful in the management of depressive behavior. The potential role of vitamin D in the etiology of depression should be investigated in future work.

Using in silico modelling and FRET-based assays in the discovery of novel FDA-approved drugs as inhibitors of MERS-CoV helicase.

A Förster resonance energy transfer (FRET)-based assay was used to screen the FDA-approved compound library against the MERS-CoV helicase, an essential enzyme for virus replication within the host cell. Five compounds inhibited the helicase activity with submicromolar potencies (IC50, 0.73-1.65 µM) and ten compounds inhibited the enzyme with micromolar potencies (IC50, 19.6-502 µM). The molecular operating environment (MOE) was used to dock the identified inhibitors on the MERS-CoV helicase nucleotide binding. Strong inhibitors docked well in the nucleotide-binding site and established interactions with some of the essential residues. There was a reasonable correlation between the observed IC50 values and the MOE docking scores of the strong inhibitors (r 2 = 0.74), indicating the ability of the in silico docking model to predict the binding of strong inhibitors. In silico docking could be a useful complementary tool used with the FRET-based assay to predict new MERS-CoV helicase inhibitors. The identified inhibitors could potentially be used in the clinical development of new antiviral treatment for MERS-CoV and other coronavirus related diseases, including coronavirus disease 2019 (COVID-19).

Patient-Ventilator Asynchrony in Critical Care Settings: National Outcomes of Ventilator Waveform Analysis.

BACKGROUND: Patient-ventilator asynchrony (PVA) is a prevalent and often underrecognized problem in mechanically ventilated patients. Ventilator waveform analysis is a noninvasive and reliable means of detecting PVAs, but the use of this tool has not been broadly studied. METHODS: Our observational analysis leveraged a validated evaluation tool to assess the ability of critical care practitioners (CCPs) to detect different PVA types as presented in three videos. This tool consisted of three videos of common PVAs (i.e., double-triggering, auto-triggering, and ineffective triggering). Data were collected via an evaluation sheet distributed to 39 hospitals among the various CCPs, including respiratory therapists (RTs), nurses, and physicians. RESULTS: A total of 411 CCPs were assessed; of these, only 41 (10.2%) correctly identified the three PVA types, while 92 (22.4%) correctly detected two types and 174 (42.3%) correctly detected one; 25.3% did not recognize any PVA. There were statistically significant differences between trained and untrained CCPs in terms of recognition (three PVAs, p < 0.001; two PVAs, p = 0.001). The majority of CCPs who identified one or zero PVAs were untrained, and such differences among groups were statistically significant (one PVA, p = 0.001; zero PVAs, p = 0.004). Female gender and prior training on ventilator waveforms were found to increase the odds of identifying more than two PVAs correctly, with odds ratios (ORs) (95% confidence intervals [CIs]) of 1.93 (1.07-3.49) and 5.41 (3.26-8.98), respectively. Profession, experience, and hospital characteristics were not found to correlate with increased odds of detecting PVAs; this association generally held after applying a regression model on the RT profession, with the ORs (95% CIs) of prior training (2.89 [1.28-6.51]) and female gender (2.49 [1.15-5.39]) showing the increased odds of detecting two or more PVAs. CONCLUSION: Common PVAs detection were found low in critical care settings, with about 25% of PVA going undetected by CCPs. Female gender and prior training on ventilator graphics were the only significant predictive factors among CCPs and RTs in correctly identifying PVAs. There is an urgent need to establish teaching and training programs, policies, and guidelines vis-à-vis the early detection and management of PVAs in mechanically ventilated patients, so as to improve their outcomes.

Taeniectomy pouch as neorectum after low rectal resection.

Background and purpose The functional outcomes of incontinence and high stool frequency resulting from restorative surgery are often criticised. The aim of this study was to assess the taeniectomy pouch in comparison with other pouches described in the literature. Material and methods This was a prospective cohort study. All patients who were candidate for low rectal resection presenting to the colorectal unit at Cairo University hospitals during the period February 2013 to February 2015 were included in the study (90 patients). Safety and feasibility of the new technique were assessed, including operative time, leakage, postoperative urgency, incontinence, number of daily motions and difficulty in evacuation. These parameters were assessed clinically, by means of defecography and anorectal manometry. Results The mean age of patients was 49.6 years. Percentages of postoperative mortality and leakage were 2.2% and 3.4%, respectively. Mean operative time was 117 minutes. Mean numbers of daily motions were 3.04 and 1.52 at 3 and 12 months, respectively. Mean Wexner score for continence at 3 and 12 months were 3.21 and 1.32, respectively. Mean resting pressure was 51.63 mmHg, squeeze pressure was 130.42 mmHg and mean threshold volume was 118.68 ml. Conclusions Taeniectomy is a novel technique for pouch formation after low rectal resection, which can be used as an alternative to other pouches, especially the widely used transverse coloplasty.

Carcinogen DNA adducts and the risk of colon cancer: case-control study.

Colorectal cancer represents 8.5% of all tumours at the King Faisal Specialist Hospital & Research Centre. Environmental and dietary carcinogens such as polycyclic aromatic hydrocarbons (PAHs) and heterocyclic amines (HCAs) have long been suspected to play a prominent role in colon cancer aetiology. We designed a case-control study to test the hypothesis of whether or not the presence of DNA adducts can play a role in the aetiology of colon cancer. DNA adducts were measured in 24 cancerous and 20 non-cancerous tissue samples of newly diagnosed colon cancer patients by (32)P-post-labelling technique. Normal tissue from 19 hospital patients served as controls. The mean levels of adducts per 10(10) nucleotides in cancerous and non-cancerous tissue were 151.75+/-217.27 and 114.81+/-186.10, respectively; however, only adducts in cancerous tissue were significantly higher than controls (32.78+/-57.51 per 10(10) nucleotides) with p-values of 0.017. No BPDE-DNA adducts were found. No relationship was found between urinary cotinine as a marker of tobacco smoke and 1-hydroxypyrene as an indicator of an individual's internal dose of PAHs and DNA adducts. In a logistic regression model, only adducts in cancerous tissue were associated with the subsequent risk of colon cancer, with an odds ratio of 3.587 (95% confidence interval 0.833-15.448) after adjustment for age and the duration of living in the current region, but of a borderline significance (p=0.086). Although it is difficult to arrive at a definite conclusion from a small dataset, our preliminary results suggest the potential role of DNA adducts in the colon carcinogenesis process. Additional studies with larger sample sizes are needed to confirm our preliminary finding. It is also important to identify the structural characterization of these unknown DNA adducts in order to have a better understanding of whether or not environmental carcinogens play a role in the aetiology of colon cancer.