The usage of the autoregressive integrated moving average model for forecasting milk production in Egypt (2022-2025).

Background: Milk is considered one of the most important capital goods and essential sources of animal protein in the diet of the Egyptian family, as well as an effective means to improve the economic condition of farmers, considering this important view, the policymakers need accurate and advance information regarding future supply for planning on the both short and long term. Aim: The study aims to forecast the production of milk in Egypt during the period from 2022 to 2025 using the Autoregressive Integrated Moving Average (ARIMA) model using time series data of milk production (MP) (1970-2021) obtained from the Central Agency for public mobilization and statistics (CAPMS). Methods: Augmented Dickey-Fullar Unit Root test, Partial autocorrelation function (PACF), and Autocorrelation function (ACF) of the time series sequence were used to judge the stationarity of the data. After confirming the stationarity of the data, the appropriate ARIMA model was selected based on certain statistical parameters like significant coefficients, values of adjusted R-squared, Akaike information criteria (AIC), Schwarz criterion (SC), and Standard Error of Regression. After the selection of the model based on the previous parameters, the verification of the model was employed by checking the residuals of the Correlogram-Q-Statistics test. Results: The most fitted model to predict the future levels of MP in Egypt was ARIMA (1, 1, and 3). Conclusion: Using the ARIMA (1, 1, 3) model, it could be forecasted that the production of milk in Egypt would show an increasing trend from 6,152.606 thousand tons in 2022 to 6,360.829 thousand tons in 2025.

Comparative effectiveness of cervical vs thoracic spinal-thrust manipulation for care of cervicogenic headache: A randomized controlled trial.

BACKGROUND: There is ample evidence supporting the use of different manipulative therapy techniques for Cervicogenic Headache (CgH). However, no technique can be singled as the best available treatment for patients with CgH. Therefore, the objective of the study is to find and compare the clinical effects of cervical spine over thoracic spine manipulation and conventional physiotherapy in patients with CgH. DESIGN, SETTING, AND PARTICIPANTS: It is a prospective, randomized controlled study conducted between July 2020 and January 2023 at the University hospital. N = 96 eligible patients with CgH were selected based on selection criteria and they were divided into cervical spine manipulation (CSM; n = 32), thoracic spine manipulation (TSM; n = 32) and conventional physiotherapy (CPT; n = 32) groups, and received the respective treatment for four weeks. Primary (CgH frequency) and secondary CgH pain intensity, CgH disability, neck pain frequency, neck pain intensity, neck pain threshold, cervical flexion rotation test (CFRT), neck disability index (NDI) and quality of life (QoL) scores were measured. The effects of treatment at various intervals were analyzed using a 3 × 4 linear mixed model analysis (LMM), with treatment group (cervical spine manipulation, thoracic spine manipulation, and conventional physiotherapy) and time intervals (baseline, 4 weeks, 8 weeks, and 6 months), and the statistical significance level was set at P < 0.05. RESULTS: The reports of the CSM, TSM and CPT groups were compared between the groups. Four weeks following treatment CSM group showed more significant changes in primary (CgH frequency) and secondary (CgH pain intensity, CgH disability, neck pain frequency, pain intensity, pain threshold, CFRT, NDI and QoL) than the TSM and CPT groups (p = 0.001). The same gradual improvement was seen in the CSM group when compared to TSM and CPT groups (p = 0.001) in the above variables at 8 weeks and 6 months follow-up. CONCLUSION: The reports of the current randomized clinical study found that CSM resulted in significantly better improvements in pain parameters (intensity, frequency and threshold) functional disability and quality of life in patients with CgH than thoracic spine manipulation and conventional physiotherapy. TRIAL REGISTRATION: Clinical trial registration: CTRI/2020/06/026092 trial was registered prospectively on 24/06/2020.

Anticoagulant Prescribing Patterns in New-Onset Atrial Fibrillation After Cardiac Surgery.

BACKGROUND: Postoperative atrial fibrillation (POAF) is a common complication after cardiac surgery and is associated with an increased risk of thromboembolic stroke. Recommendations regarding the optimal anticoagulant, timing of initiation, and duration of therapy remain uncertain. METHODS: Administrative databases were used to include adult patients who presented with POAF after cardiac surgery between January 1, 2015, and December 31, 2020. Key exclusion criteria included preexisting atrial fibrillation, mechanical valve replacement, or anticoagulant prescription fill within 6 months before the index admission. RESULTS: A total of 3214 of patients were included, and 878 (27.3%) were prescribed an oral anticoagulant (OAC) on discharge, with 536 (61%) prescribed warfarin and 342 (39%) prescribed a direct OAC. More than half of the patients (56.1%) stopped their OAC by 6 months. There was no difference in stroke or systemic embolism at 30 days, 3 months, or 6 months between those with and without anticoagulation prescribed. However, those on any OAC had higher rates of any bleeding at all time points. CONCLUSIONS: A minority of patients who presented with POAF after cardiac surgery were prescribed OAC, with warfarin being the most common agent. OAC initiation was associated with increased bleeding risk, warranting special consideration when assessing a patient's risk of stroke with the increased risk of bleeding, particularly in the postoperative period.

Synthesis and molecular docking simulation of new benzimidazole-thiazole hybrids as cholinesterase inhibitors.

Dementia is a cognitive disturbance that is generally correlated with central nervous system diseases, especially Alzheimer's disease. The limited number of medications available is insufficient to improve the lifestyle of the patients suffering from this disease. Thus, new benzimidazole-thiazole hybrids (3-10) were designed and synthesized as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory agents. The in vitro evaluation displayed that the derivatives 4b, 4d, 5b, 6a, 7a, and 8b demonstrated dual inhibitory efficiency against both AChE with IC50 ranging from 4.55 to 8.62 µM and BChE with IC50 ranging from 3.50 to 8.32 µM. By analyzing the Lineweaver-Burk plot, an uncompetitive form of inhibition was determined for the highly active compound 4d, revealing its inhibition type. The human telomerase reverse transcriptase-immortalized retinal pigment epithelial cell line was used to ensure the safety of the most potent cholinesterase inhibitors. Furthermore, compounds 4b, 4d, 5b, 6a, 7a, and 8b were evaluated for their neuroprotective and antioxidant properties, as well as their ability to suppress COX-2. The results demonstrated that compounds 4d, 5b, and 8b presented significant neuroprotection efficiency against H2 O2 -induced damage in SH-SY5Y cells with % cell viability of 67.42 ± 7.90%, 62.51 ± 6.71%, and 72.61 ± 8.10%, respectively, while the tested candidates did not reveal significant antioxidant activity. Otherwise, compounds 4b, 6a, 7a, and 8b displayed outstanding COX-2 inhibition effects with IC50 ranging from 0.050 to 0.080 µM relative to celecoxib (IC50 = 0.050 µM). In addition, molecular docking was carried out for the potent benzimidazole-thiazole hybrids with the active sites of both AChE (PDB ID: 4EY7) and BChE (PDB code: 1P0P). The tested candidates fit well in the active sites of both portions, with docking scores ranging from -8.65 to -6.64 kcal/mol (for AChE) and -8.71 to -7.73 kcal/mol (for BChE). In silico results show that the synthesized benzimidazole-thiazole hybrids have good physicochemical and pharmacokinetic properties with no Lipinski rule violations. The preceding results exhibited that compound 4d could be used as a new template for developing more significant cholinesterase inhibitors in the future.

Hydrazone-sulfonate hybrids as potential cholinesterase inhibitors: design, synthesis and molecular modeling simulation.

Aim: Design and synthesis of a series of hydrazone-sulfonate hybrids, 5a-r. Methodology: The inhibitory properties of the synthesized compounds against acetylcholinesterase and butyrylcholinesterase were evaluated using donepezil as the reference standard. Results & conclusion: Compound 5e was identified as the most potent inhibitor of acetylcholinesterase (IC50 = 9.30 µM), and compound 5i was the most potent inhibitor of butyrylcholinesterase (IC50 = 11.82 µM). To confirm the safety of the most potent hits at the used doses, toxicological bioassays were conducted. Molecular docking was performed and the tested derivatives were found to fit well in the active sites of both enzymes. This study provides valuable insights into the potential of hydrazone-sulfonate hybrids as drug candidates.

In Vitro Evaluation and Bioinformatics Analysis of Schiff Bases Bearing Pyrazole Scaffold as Bioactive Agents: Antioxidant, Anti-Diabetic, Anti-Alzheimer, and Anti-Arthritic.

In continuation of our research programs for the discovery, production, and development of the pharmacological activities of molecules for various disease treatments, Schiff bases and pyrazole scaffold have a broad spectrum of activities in biological applications. In this context, this manuscript aims to evaluate and study Schiff base-pyrazole molecules as a new class of antioxidant (total antioxidant capacity, iron-reducing power, scavenging activity against DPPH, and ABTS radicals), anti-diabetic (α-amylase% inhibition), anti-Alzheimer's (acetylcholinesterase% inhibition), and anti-arthritic (protein denaturation% and proteinase enzyme% inhibitions) therapeutics. Therefore, the Schiff bases bearing pyrazole scaffold (22a, b and 23a, b) were designed and synthesized for evaluation of their antioxidant, anti-diabetic, anti-Alzheimer's, and anti-arthritic properties. The results for compound 22b demonstrated significant antioxidant, anti-diabetic (α-amylase% inhibition), and anti-Alzheimer's (ACE%) activities, while compound 23a demonstrated significant anti-arthritic activity. Prediction of in silico bioinformatics analysis (physicochemical properties, bioavailability radar, drug-likeness, and medicinal chemistry) of the target derivatives (22a, b and 23a, b) was performed. The molecular lipophilicity potential (MLP) of the derivatives 22a, b and 23a, b was measured to determine which parts of the surface are hydrophobic and which are hydrophilic. In addition, the molecular polar surface area (PSA) was measured to determine the polar surface area and the non-polar surface area of the derivatives 22a, b and 23a, b. This study could be useful to help pharmaceutical researchers discover a new series of potent agents that may act as an antioxidant, anti-diabetic, anti-Alzheimer, and anti-arthritic.

Investigations of Electronic, Structural, and In Silico Anticancer Potential of Persuasive Phytoestrogenic Isoflavene-Based Mannich Bases.

Isoflavenes have received the greatest research attention among the many groups of phytoestrogens. In this study, various isoflavene-based Mannich bases were selected for their theoretical studies. The purpose of this research was to discover the binding potential of all the designated Mannich bases acting as inhibitors against cancerous proteins EGFR, cMet, hTrkA, and HER2 (PDB codes: 5GTY, 3RHK, 6PL2, and 7JXH, respectively). For their virtual screening, DFT calculations and molecular docking studies were undertaken using in silico software. Docking studies predicted that ligands 5 and 15 exhibited the highest docking score by forming hydrogen bonds within the active pocket of protein 6PL2, ligands 1 and 15 both with protein 3RHK, and 7JXH, 12, and 17 with protein 5GTY. Rendering to the trends in polarizability and dipole moment, the energy gap values (0.2175 eV, 0.2106 eV) for the firm conformers of Mannich bases (1 and 4) replicate the increase in bioactivity and chemical reactivity. The energy gap values (0.2214 eV and 0.2172 eV) of benzoxazine-substituted isoflavene-based Mannich bases (9 and 10) reflect the increase in chemical potential due to the most stable conformational arrangements. The energy gap values (0.2188 eV and 0.2181 eV) of isoflavenes with tertiary amine-based Mannich bases (14 and 17) reflect the increase in chemical reactivity and bioactivity due to the most stable conformational arrangements. ADME was also employed to explore the pharmacokinetic properties of targeted moieties. This study revealed that these ligands have a strong potential to be used as drugs for cancer treatment.

Tubercular meningitis and cortical venous thrombosis: A rare but potentially lethal combination-A case report and literature review.

Key Clinical Message: Cortical venous thrombosis is a rare but severe complication of TBM that requires a high index of suspicion for early diagnosis. The treatment of CVT in TBM is based on anticoagulant therapy, which is known to improve the outcomes of the patients. Abstract: The case report describes an 18-year-old male in India with symptoms of tubercular meningitis complicated by cortical venous thrombosis. Tubercular meningitis is a rare but severe form of meningitis caused by tuberculosis bacteria and is a significant public health concern in India. The patient presented to the emergency department with a history of fever, headache, and vomiting for the past month, with a positive Mycobacterium tuberculosis test. The patient was started on standard antitubercular therapy and was diagnosed with cortical venous thrombosis via an MRI scan. Treatment included antitubercular therapy, anticoagulation therapy, dexamethasone, and antiemetic drugs. The patient's symptoms improved over 2 weeks of therapy. The case highlights the importance of early detection, treatment, and prevention strategies, such as the National Tuberculosis elimination program, in controlling the spread of tuberculosis in India. It also emphasizes the importance of close monitoring for complications in patients with tubercular meningitis, such as cortical venous thrombosis, which can be life-threatening.

Alleviative effects of pinostrobin against cadmium-induced renal toxicity in rats by reducing oxidative stress, apoptosis, inflammation, and mitochondrial dysfunction.

Introduction: Cadmium (Cd) is a highly toxic heavy metal that can be found everywhere in the environment and can have harmful effects on both human and animal health. Pinostrobin (PSB) is a bioactive natural flavonoid isolated from Boesenbergia rotunda with several pharmacological properties, such as antiinflammatory, anticancer, antioxidant, and antiviral. This investigation was intended to assess the therapeutic potential of PSB against Cd-induced kidney damage in rats. Methods: In total, 48 Sprague Dawley rats were divided into four groups: a control, a Cd (5 mg/kg), a Cd + PSB group (5 mg/kg Cd and 10 mg/kg PSB), and a PSB group (10 mg/kg) that received supplementation for 30 days. Results: Exposure to Cd led to a decrease in the activities of catalase (CAT), glutathione reductase (GSR), superoxide dismutase (SOD), and glutathione peroxidase (GSH-PX), whereas levels of reactive oxygen species (ROS) and malondialdehyde (MDA) increased. Cd exposure also caused a substantial increase in urea, kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and creatinine levels. Moreover, a noticeable decline was noticed in creatinine clearance. Moreover, Cd exposure considerably increased the levels of inflammatory indices, including interleukin-1b (IL-1b), tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), nuclear factor kappa-B (NF-kB), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) activity. Cd treatment decreased the expression of the antiapoptotic markers (Bcl-2) while increasing the expression of apoptotic markers (Bax and Caspase-3). Furthermore, Cd treatment substantially reduced the TCA cycle enzyme activity, such as alpha-ketoglutarate dehydrogenase, succinate dehydrogenase, malate dehydrogenase, and isocitrate dehydrogenase. Moreover, mitochondrial electron transport chain enzymes, succinatedehydrogenase, NADH dehydrogenase, cytochrome c-oxidase, and coenzyme Q-cytochrome reductase activities were also decreased following Cd exposure. PSB administration substantially reduced the mitochondrial membrane potential while inducing significant histological damage. However, PSB treatment significantly reduced Cd-mediated renal damage in rats. Conclusion: Thus, the present investigation discovered that PSB has ameliorative potential against Cd-induced renal dysfunction in rats.

Anti-inflammatory activity of novel derivatives of pyrazolo [3,4d] pyridazine against digestive system inflammation.

The digestive system is exposed to severe inflammation as a result of taking some medications that have gastrointestinal side effects. Sixty Swiss-albino male mice were randomly distributed into six groups to treat inflammations of the colon, stomach, and small intestine caused by taking high doses of diclofenac (D), with two novel synthesized compounds, pyrazolo [3,4 d] pyridazine derivatives (Co1 and Co2). Myeloperoxidase enzyme activity was determined in the colon and small intestinal tissues. Serum contents of TNF-α, IL-22, IgG, and IgM were determined by ELISA. Histopathological examinations of the colon, small intestinal, and stomach tissues were microscopically analyzed. TNF-α, IL-22, and TNFSF11 gene expression were measured in the colon, intestinal, and spleen using qRT-PCR. Diclofenac caused surface columnar epithelial cell loss, focal necrosis of the gastric mucosa, inflammatory cell infiltration, and congested blood vessels in the stomach, colon, and small intestinal tissues. Co1 component was found to be better than Co2 component in reducing the focal necrosis of gastric mucosa and improving the histological structures of the stomach, colon, and small intestinal tissues. After 14 days, the activity of the myeloperoxidase enzyme was increased in group D and decreased in groups DCo1, DCo2, Co1, and Co2. Serum concentrations of TNF-α and IgG were increased, while IL-22 and IGM were reduced in the D, DCo1, and DCo2 groups compared with the Co1 and control groups. TNF-α gene was upregulated in the D group and downregulated in the Co1 group, while the IL-22 gene was downregulated in the D group and upregulated in the Co1 group compared with the control group. The CO1 component may be useful in reducing digestive system inflammation.

Exploring Antimicrobial Features for New Imidazo[4,5-b]pyridine Derivatives Based on Experimental and Theoretical Study.

5-bromopyridine-2,3-diamine reacted with benzaldehyde to afford the corresponding 6-Bromo-2-phenyl-3H-imidazo[4,5-b]pyridine (1). The reaction of the latter compound (1) with a series of halogenated derivatives under conditions of phase transfer catalysis solid-liquid (CTP) allows the isolation of the expected regioisomers compounds (2-8). The alkylation reaction of (1) gives, each time, two regioisomers, N3 and N4; in the case of ethyl bromoactate, the reaction gives, at the same time, the three N1, N3 and N4 regioisomers. The structures of synthesized compounds were elucidated on the basis of different spectral data (1H NMR, 13C NMR), X-Ray diffraction and theoretical study using the DFT method, and confirmed for each compound. Hirshfeld surface analysis was used to determine the intermolecular interactions responsible for the stabilization of the molecule. Density functional theory was used to optimize the compounds, and the HOMO-LUMO energy gap was calculated, which was used to examine the inter/intra molecular charge transfer. The molecular electrostatic potential map was calculated to investigate the reactive sites that were present in the molecule. In order to determine the potential mode of interactions with DHFR active sites, the three N1, N3 and N4 regioisomers were further subjected to molecular docking study. The results confirmed that these analogs adopted numerous important interactions, with the amino acid of the enzyme being targeted. Thus, the most docking efficient molecules, 2 and 4, were tested in vitro for their antibacterial activity against Gram-positive bacteria (Bacillus cereus) and Gram-negative bacteria (Escherichia coli). Gram-positive bacteria were more sensitive to the action of these compounds compared to the Gram-negative, which were much more resistant.

Direct oral anticoagulants for atrial fibrillation in early postoperative valve repair or bioprosthetic replacement.

OBJECTIVE: Despite increased use of direct oral anticoagulants (DOACs), limited evidence guides their use in the early postoperative period after bioprosthetic valve implantation in patients with atrial fibrillation. Our objective was to describe the efficacy and safety of DOACs and warfarin in the first 3 months after surgical bioprosthetic valve replacement or repair in patients with atrial fibrillation. METHODS: This was a retrospective, registry-informed cohort study of surgical patients who underwent bioprosthetic valve replacement or repair, had concomitant atrial fibrillation and received oral anticoagulation at discharge. The primary efficacy outcome was a composite of death, ischemic stroke, transient ischemic attack, and systemic embolism; the primary safety outcome was a composite of major bleeding. Key secondary outcomes were comparative analyses of primary outcomes, temporal anticoagulation prescribing patterns, and 30-day readmission rates. RESULTS: A total of 1743 patients were included. Of the 570 patients in the DOAC group, 17 (2%) met the composite efficacy outcome and 55 (10%) met the composite safety outcome. Of the 1173 patients receiving warfarin, 41 (3%) and 114 (10%) met the composite efficacy and safety outcomes, respectively. Comparative secondary analysis was not statistically significant for either the efficacy (adjusted odds ratio, 0.85; 95% confidence interval, 0.46-1.55, P = .59) or safety (adjusted odds ratio, 0.94; 95% confidence interval, 0.66-1.34, P = .76) outcomes. The 30-day readmission rates were similar between both groups. CONCLUSIONS: Our results suggest DOACs may be safe and effective alternatives to warfarin in the early postoperative period after valve repair or surgical bioprosthetic replacement. Confirmation awaits adequately powered prospective studies.

Effects of a Computerized Prescriber Order Entry System on Pharmacist Prescribing.

Background: In Alberta, pharmacists are eligible to obtain additional prescribing authority (APA). At the University of Alberta Hospital, a transition was made from a paper-based prescriber order entry system to a computerized prescriber order entry (CPOE) system. Objectives: The primary objective was to quantify any change in pharmacist prescribing after CPOE implementation. The secondary objective was to compare the paper-based and CPOE systems in terms of drug schedule, order type, medication class, and the pharmacist's area of clinical practice. Methods: A retrospective comparative review of pharmacist orders was completed using 2-week periods of data from each of the paper-based order entry system and the CPOE system, spaced 1 year apart (in January 2019 and January 2020). Results: Pharmacists prescribed a mean of 3.76 (95% confidence interval 1.97-5.96) more orders per day within the CPOE system than in the paper-based system (p < 0.001). Schedule I medications accounted for a higher proportion of pharmacists' prescriptions in the CPOE system than in the paper-based system (77.7% versus 70.5%, p < 0.001). In terms of order type, discontinuation orders accounted for a much higher proportion of pharmacists' orders in the CPOE system than in the paper-based order entry system (58.0% versus 19.8%, p < 0.001). Conclusions: This study showed that a CPOE system resulted in more use of APA by pharmacists, with schedule I medications accounting for a higher proportion of pharmacists' prescriptions. With the CPOE system, pharmacists used their prescribing privileges to discontinue a higher proportion of orders than was the case with the paper-based system. Therefore, the CPOE system is a potential facilitator of pharmacist prescribing.

Contexte: En Alberta, les pharmaciens peuvent obtenir des pouvoirs de prescription supplémentaires (PPS). À l'hôpital de l'Université de l'Alberta, le système de saisie des ordonnances est passé d'un système sur papier à un système de saisie électronique des ordonnances (SSEO) par les prescripteurs. Objectifs: L'objectif principal consistait à quantifier tout changement dans la prescription des pharmaciens après la mise en place du SSEO. L'objectif secondaire visait à comparer le système sur papier et le SSEO en matière d'annexe des médicaments, de type d'ordonnance, de catégorie de médicament et de domaine de pratique clinique du pharmacien. Méthodes: Un examen comparatif rétrospectif des ordonnances des pharmaciens a été réalisé à l'aide de périodes de données de 2 semaines provenant de chacun des systèmes (papier et électronique), avec un intervalle d'un an (janvier 2019 et janvier 2020). Résultats: Les pharmaciens prescrivaient en moyenne 3,76 (intervalle de confiance à 95 % 1,97­5,96) ordonnances de plus par jour avec le SSEO qu'avec le système sur papier (p < 0,001). La part des ordonnances de médicaments de l'annexe I était plus importante avec le SSEO qu'avec le système sur papier (77,7 % contre 70,5 %, p < 0,001). En ce qui concerne le type d'ordonnance, la part des ordonnances de cessation était beaucoup plus élevée avec le SSEO qu'avec le système de saisie sur papier (58,0 % contre 19,8 %, p < 0,001). Conclusions: Cette étude a démontré un plus grand recours au PPS lorsque les pharmaciens utilisaient un SSEO et les médicaments de l'annexe I représentant une proportion plus élevée des ordonnances. Avec le SSEO, les pharmaciens ont utilisé leur pouvoir de prescription pour interrompre une part plus élevée d'ordonnances que ce n'était le cas avec le système sur papier. Le SSEO est donc un facilitateur potentiel de la prescription par les pharmaciens.

Clinical and radiological effects of Corticosteroid injection combined with deep transverse friction massage and Mill's manipulation in lateral epicondylalgia-A prospective, randomized, single-blinded, sham controlled trial.

BACKGROUND: The knowledge about the effective implementation of corticosteroid injection (CS) with deep transverse friction massage (DTFM) and Mill's manipulation (MM) on clinical and radiological changes (Magnetic resonance imaging-MRI and Ultra sound) in lateral epicondylalgia (LE) is lacking. Therefore, the objective of this study is proposed to find and compare the effects of corticosteroid injection (CS) DTFM and Mill's manipulation on clinical and radiological changes in lateral epicondylalgia. DESIGN, SETTING, PARTICIPANTS: Randomized, single-blinded, controlled study was conducted on 60 LE participants at university hospital. The active MM group (n = 30) received corticosteroid injection with DTFM and active Mill's manipulation (MM) three sessions a week for 4 weeks and the sham MM group received corticosteroid injection with sham manipulation. The primary outcome was pain intensity, measured with the visual analog scale. The other outcome measures were percentage of injury measured by MRI and ultrasound, functional disability, handgrip strength, patient perception, kinesiophobia, depression status and quality of life which were measured at 4 weeks, 8weeks and at 6 months follow up. RESULTS: The between-group difference in pain intensity at 4 weeks was 1.6 (CI 95% 0.97 to 2.22), which shows improvement in the active group than sham group. The similar effects have been noted after 8 weeks and at 6 months 2.0 (CI 95% 1.66 to 2.33) follow up in pain intensity. Similar improvements were also found on percentage of injury, functional disability, handgrip strength, patient perception, kinesiophobia, depression status and quality of life (p = 0.001). CONCLUSION: Corticosteroid injection with DTFM and Mill's manipulation was superior to sham group for improving pain, percentage of injury, functional disability, handgrip strength, patient perception, kinesiophobia, depression status and quality of life in people with lateral epicondylalgia. TRIAL REGISTRATION: Clinical trial registration: CTRI/2020/05/025135 trial registered prospectively on 12/05/2020. https://trialsearch.who.int/Trial2.aspx?TrialID=CTRI/2020/05/025135.

Discovery of novel thioquinazoline-N-aryl-acetamide/N-arylacetohydrazide hybrids as anti-SARS-CoV-2 agents: Synthesis, in vitro biological evaluation, and molecular docking studies.

In the current investigation, two novel series of (tetrahydro)thioquinazoline-N-arylacetamides and (tetrahydro)thioquinazoline-N-arylacetohydrazides were designed, synthesized and investigated for their antiviral activity against SARS-CoV-2. The thioquinazoline-N-arylacetamide 17g as well as the tetrahydrothioquinazoline-N-arylacetohydrazides 18c and 18f showed potent antiviral activity with IC50 of 21.4, 38.45 and 26.4 µM, respectively. In addition, 18c and 18f demonstrated potential selectivity toward the SARS-CoV-2 over the host cells with SI of 10.67 and 16.04, respectively. Further evaluation of the mechanism of action of the three derivatives 17g, 18c, and 18f displayed that they can inhibit the virus at the adsorption as well as at the replication stages, in addition to their virucidal properties. In addition, 17g, 18c, and 18f demonstrated satisfactory physicochemical properties as well as drug-likeness properties to be further optimized for the discovery of novel antiviral agents. The docking simulation on Mpro binding site predicted the binding pattern of the target compounds rationalizing their differential activity based on their hydrophobic interaction and fitting in the hydrophobic S2 subsite of the binding site.

Fatty acyl-CoA reductase influences wax biosynthesis in the cotton mealybug, Phenacoccus solenopsis Tinsley.

Mealybugs are highly aggressive to a diversity of plants. The waxy layer covering the outermost part of the integument is an important protective defense of these pests. However, the molecular mechanisms underlying wax biosynthesis in mealybugs remain largely unknown. Here, we analyzed multi-omics data on wax biosynthesis by the cotton mealybug, Phenacoccus solenopsis Tinsley, and found that a fatty acyl-CoA reductase (PsFAR) gene, which was highly expressed in the fat bodies of female mealybugs, contributed to wax biosynthesis by regulating the production of the dominant chemical components of wax, cuticular hydrocarbons (CHCs). RNA interference (RNAi) against PsFAR by dsRNA microinjection and allowing mealybugs to feed on transgenic tobacco expressing target dsRNA resulted in a reduction of CHC contents in the waxy layer, and an increase in mealybug mortality under desiccation and deltamethrin treatments. In conclusion, PsFAR plays crucial roles in the wax biosynthesis of mealybugs, thereby contributing to their adaptation to water loss and insecticide stress.

Novel 2-substituted thioquinazoline-benzenesulfonamide derivatives as carbonic anhydrase inhibitors with potential anticancer activity.

A novel series of 2-thioquinazoline-benzenesulfonamide hybrids were designed as carbonic anhydrase (CA) inhibitors. The design approach relies on molecular hybridization between the benzenesulfonamide scaffold as a Zn2+ binding group and 2-substituted thioquinazolines as a tail. Assaying the thioquinazoline-benzenesulfonamide conjugates against four different CA isoforms revealed that compounds 12f and 12p are the most potent derivatives. They exhibit Ki = 0.09 and 0.05 µM on CA II, 0.32 and 0.47 µM on CA IX, and 0.58 and 0.46 µM on CA XII, respectively. In addition, 12p demonstrated high selectivity for CA II over CA I with selectivity index (SI) = 92, and slightly higher specificity for CA II over CA IX and CA XII with SI = 9.40 and 9.20, respectively. The synthesized compounds were screened for their cytotoxic activity at 10 µM concentration and derivatives 12o, 12n, and 12f turned out to be the most potent ones from the synthesized series; they exhibit mean growth inhibition % values of 89.38%, 58.75%, and 54.71%, respectively, while 12p demonstrated moderate activity against the NCI cancer cell lines, with mean growth inhibition % = 29.62%. The analysis of the MCF-7 cell cycle after treatment with 5.0 µM of 12f displayed that it arrests the cell cycle at the G2/M phase. Molecular docking simulation of the thioquinazoline-benzenesulfonamide hybrids in the CA II active site rationalized the potent activity to the settlement of the sulfonamide moiety at the depth of the CA II active site and its stabilization by performing the important interactions with the Zn2+ ion as well as with the key amino acids Thr199 and/or Thr200, while the thioquinazoline moiety with different (un)substituted phenyl tails is stabilized by the formation of various hydrogen bonding and hydrophobic interactions with the surrounding amino acids in the binding site.

Effects of Virtual Reality Exercises versus Isokinetic Exercises in comparison with Conventional Exercises on the Imaging Findings and Inflammatory Biomarker Changes in Soccer Players with Non-Specific Low Back Pain: A Randomized Controlled Trial.

Chronic non-specific low back pain (CNLBP) is the most common musculoskeletal problem. The purpose of this study was to investigate the effects of advanced physiotherapeutic exercise programs on imaging findings and inflammatory biomarkers in soccer players with CNLBP. In total, 60 CNLBP participants were divided into virtual reality exercise (VRE; n = 20), isokinetic exercise (IKE; n = 20), and conventional exercise (n = 20) groups. Pain intensity, imaging findings (muscle cross-sectional area (CSA) and muscle thickness), and changes in inflammatory biomarkers (CRP, TNF-α, IL-2, IL-4, and IL-6) were measured at baseline and after four weeks. After four weeks of intervention, there was a significant improvement (p = 0.001) in pain intensity for the VRE vs. IKE (0.7; CI 95% 0.38 to 1.07) and VRE vs. conventional (3.0 CI 95% 2.68 to 3.31) groups. The IKE group showed a greater number of significant changes in muscle CSA and muscle thickness than the other two groups (p < 0.001). Moreover, the VRE group showed significant improvement in inflammatory biomarker measures compared with the other two groups (p < 0.001). In CNLBP, virtual and isokinetic exercises had equal effects on reducing pain intensity. Isokinetic exercise is beneficial in increasing the muscle CSA and thickness, and virtual exercises are helpful for attenuating the inflammation process in soccer players with CNLBP.

Application of the dual-tail approach for the design and synthesis of novel Thiopyrimidine-Benzenesulfonamide hybrids as selective carbonic anhydrase inhibitors.

A dual-tail approach was applied to the design of a novel series of 2-thiopyrimidine-benzenesulfonamides as carbonic anhydrase (CA) inhibitors. The design strategy is based on the hybridization between a benzenesulfonamide moiety as Zn2+ binding group and 2,4-disubstituted thiopyridimidine as a tail. Among the synthesized compounds, 14h displayed the highest potency (Ki = 1.72 nM) and selectivity for CA II over the isoforms CA IX and CA XII with selectivity indexes of 50 and 5.26, respectively. Meanwhile, compounds 14a and 14l displayed a potent inhibitory activity against CA IX (Ki = 7.4 and 7.0 nM, respectively) compared with the reference drug acetazolamide (AAZ) (Ki = 25 nM), and compound 14l showed higher potency (Ki = 4.67 nM) than AAZ (Ki = 5.7 nM) against the tumor-associated isoform CA XII. Evaluation of the antiproliferative activity in NCI single-dose testing of selected hybrids revealed a pronounced potency of the selective CA II inhibitor 14h against most of the tested NCI cancer cell lines. Moreover, compound 14h demonstrated an IC50 values ranging from 2.40 to 4.50 µM against MCF-7, T-47D, MDA-MB-231, HCT-116, HT29 and SW-620. These results demonstrate that CA II inhibition can be an alternative therapeutic target for cancer treatment. A cell cycle analysis of MCF-7 and MDA-MB-231 showed that treatment with 14h arrested both cell lines at the G2/M phase with significant accumulation of cells in the pre-G1 phase. Moreover, compound 14h showed a noticeable induction of late apoptosis and necrotic cell death of both cell lines compared with untreated cells as a control. A molecular docking study suggested that the sulfonamide moiety accommodates deeply in the CA active site and interacts with the Zn2+ ion while the dual-tail extension interacts with the surrounding amino acids via several hydrophilic and hydrophobic interactions, which affects the potency and selectivity of the hybrids.