Process Optimization of Tinospora cordifolia Extract-Loaded Water in Oil Nanoemulsion Developed by Ultrasound-Assisted Homogenization.

Nanoemulsions are gaining interest in a variety of products as a means of integrating easily degradable bioactive compounds, preserving them from oxidation, and increasing their bioavailability. However, preparing stable emulsion compositions with the desired characteristics is a difficult task. The aim of this study was to encapsulate the Tinospora cordifolia aqueous extract (TCAE) into a water in oil (W/O) nanoemulsion and identify its critical process and formulation variables, like oil (27-29.4 mL), the surfactant concentration (0.6-3 mL), and sonication amplitude (40% to 100%), using response surface methodology (RSM). The responses of this formulation were studied with an analysis of the particle size (PS), free fatty acids (FFAs), and encapsulation efficiency (EE). In between, we have studied a fishbone diagram that was used to measure risk and preliminary research. The optimized condition for the formation of a stable nanoemulsion using quality by design was surfactant (2.43 mL), oil concentration (27.61 mL), and sonication amplitude (88.6%), providing a PS of 171.62 nm, FFA content of 0.86 meq/kg oil and viscosity of 0.597 Pa.s for the blank sample compared to the enriched TCAE nanoemulsion with a PS of 243.60 nm, FFA content of 0.27 meq/kg oil and viscosity of 0.22 Pa.s. The EE increases with increasing concentrations of TCAE, from 56.88% to 85.45%. The RSM response demonstrated that both composition variables had a considerable impact on the properties of the W/O nanoemulsion. Furthermore, after the storage time, the enriched TCAE nanoemulsion showed better stability over the blank nanoemulsion, specially the FFAs, and the blank increased from 0.142 to 1.22 meq/kg oil, while TCAE showed 0.266 to 0.82 meq/kg.

Antimicrobial stewardship implementation before and during the COVID-19 pandemic in the acute care settings: a systematic review.

INTRODUCTION: Antibiotics are widely administered for various indications, leading to increased antimicrobial resistance (AMR) in acute care hospitals. Since the onset of the COVID-19 pandemic, Antimicrobial Stewardship (AMS) effective strategies should be used to maintain the rational use of antibiotics and decrease the threat of Antimicrobial Resistance (AMR). AIM: This systematic literature review aims to investigate the AMS intervention Before-the-pandemic (BP) and During-the-pandemic (DP) from the literature. DESIGN AND SETTING: Systematic literature review of primary studies on AMS implementation in acute care settings. METHODS: Relevant studies published between 2000 and March 2021 were obtained from Medline (via PubMed), OVID, CINAHL, International Pharmaceutical Abstracts, Psych Info, Scopus, Web of Science, Cochrane Library, OpenGrey, and Google Scholar, using a comprehensive list of search terms. Public Health England (PHE) toolkit was agreed upon as a gold standard for the AMS implementation. RESULTS: There were 8763 articles retrieved from the databases. Out of these, 13 full-text articles met the inclusion criteria for the review. The AMS implementation was identified in the included studies into AMS strategies (Core strategies & Supplemental strategies), and AMS measures BP and DP. CONCLUSION: This Systematic literature review summarises AMS implementation strategies and measures all over the previous 20 years of research. There are many lessons learnt from COVID-19 pandemic. The proper selection of the AMS implementation strategies and measures appeared to be effective in maintaining the appropriate use of antibiotics and decreasing the AMR threat, especially during the COVID-19 pandemic. Further studies are required to provide empirical data to evaluate the AMS implementation and identify which of these strategies and measures were effective BP and DP. In order to be prepared for any emergency/crisis or future pandemics.

Multi-stage structure-based virtual screening approach towards identification of potential SARS-CoV-2 NSP13 helicase inhibitors.

On account of its crucial role in the virus life cycle, SARS-COV-2 NSP13 helicase enzyme was exploited as a promising target to identify a novel potential inhibitor using multi-stage structure-based drug discovery approaches. Firstly, a 3D pharmacophore was generated based on the collected data from a protein-ligand interaction fingerprint (PLIF) study using key interactions between co-crystallised fragments and the NSP13 helicase active site. The ZINC database was screened through the generated 3D-pharmacophore retrieving 13 potential hits. All the retrieved hits exceeded the benchmark score of the co-crystallised fragments at the molecular docking step and the best five-hit compounds were selected for further analysis. Finally, a combination between molecular dynamics simulations and MM-PBSA based binding free energy calculations was conducted on the best hit (compound FWM-1) bound to NSP13 helicase enzyme, which identified FWM-1 as a potential potent NSP13 helicase inhibitor with binding free energy equals -328.6 ± 9.2 kcal/mol.

Novel oxindole/benzofuran hybrids as potential dual CDK2/GSK-3ß inhibitors targeting breast cancer: design, synthesis, biological evaluation, and in silico studies.

The serine/threonine protein kinases CDK2 and GSK-3ß are key oncotargets in breast cancer cell lines, therefore, in the present study three series of oxindole-benzofuran hybrids were designed and synthesised as dual CDK2/GSK-3ß inhibitors targeting breast cancer (5a-g, 7a-h, and 13a-b). The N1 -unsubstituted oxindole derivatives, series 5, showed moderate to potent activity on both MCF-7 and T-47D breast cancer cell lines. Compounds 5d-f showed the most potent cytotoxic activity with IC50 of 3.41, 3.45 and 2.27 µM, respectively, on MCF-7 and of 3.82, 4.53 and 7.80 µM, respectively, on T-47D cell lines, in comparison to the used reference standard (staurosporine) IC50 of 4.81 and 4.34 µM, respectively. On the other hand, the N1 -substituted oxindole derivatives, series 7 and 13, showed moderate to weak cytotoxic activity on both breast cancer cell lines. CDK2 and GSK-3ß enzyme inhibition assay of series 5 revealed that compounds 5d and 5f are showing potent dual CDK2/GSK-3ß inhibitory activity with IC50 of 37.77 and 52.75 nM, respectively, on CDK2 and 32.09 and 40.13 nM, respectively, on GSK-3ß. The most potent compounds 5d-f caused cell cycle arrest in the G2/M phase in MCF-7 cells inducing cell apoptosis because of the CDK2/GSK-3ß inhibition. Molecular docking studies showed that the newly synthesised N1 -unsubstituted oxindole hybrids have comparable binding patterns in both CDK2 and GSK-3ß. The oxindole ring is accommodated in the hinge region interacting through hydrogen bonding with the backbone CO and NH of the key amino acids Glu81 and Leu83, respectively, in CDK2 and Asp133 and Val135, respectively, in GSK-3ß. Whereas, in series 7 and 13, the N1 -substitutions on the oxindole nucleus hinder the compounds from achieving these key interactions with hinge region amino acids what rationalises their moderate to low anti-proliferative activity.

In silico identification of novel SARS-COV-2 2'-O-methyltransferase (nsp16) inhibitors: structure-based virtual screening, molecular dynamics simulation and MM-PBSA approaches.

The novel coronavirus disease COVID-19, caused by the virus SARS CoV-2, has exerted a significant unprecedented economic and medical crisis, in addition to its impact on the daily life and health care systems all over the world. Regrettably, no vaccines or drugs are currently available for this new critical emerging human disease. Joining the global fight against COVID-19, in this study we aim at identifying a potential novel inhibitor for SARS COV-2 2'-O-methyltransferase (nsp16) which is one of the most attractive targets in the virus life cycle, responsible for the viral RNA protection via a cap formation process. Firstly, nsp16 enzyme bound to Sinefungin was retrieved from the protein data bank (PDB ID: 6WKQ), then, a 3D pharmacophore model was constructed to be applied to screen 48 Million drug-like compounds of the Zinc database. This resulted in only 24 compounds which were subsequently docked into the enzyme. The best four score-ordered hits from the docking outcome exhibited better scores compared to Sinefungin. Finally, three molecular dynamics (MD) simulation experiments for 150 ns were carried out as a refinement step for our proposed approach. The MD and MM-PBSA outputs revealed compound 11 as the best potential nsp16 inhibitor herein identified, as it displayed a better stability and average binding free energy for the ligand-enzyme complex compared to Sinefungin.

Development of 2-oindolin-3-ylidene-indole-3-carbohydrazide derivatives as novel apoptotic and anti-proliferative agents towards colorectal cancer cells.

Mitochondrial anti-apoptotic Bcl2 and BclxL proteins, are overexpressed in multiple tumour types, and has been involved in the progression and survival of malignant cells. Therefore, inhibition of such proteins has become a validated and attractive target for anticancer drug discovery. In this manner, the present studies developed a series of novel isatin-indole conjugates (7a-j and 9a-e) as potential anticancer Bcl2 and BclxL inhibitors. The progression of the two examined colorectal cancer cell lines was significantly inhibited by all of the prepared compounds with IC50 ranges132-611 nM compared to IC50 = 4.6 µM for 5FU, against HT-29 and IC50 ranges 37-468 nM compared to IC50 = 1.5 µM for 5FU, against SW-620. Thereafter, compounds 7c and 7g were selected for further investigations. Interestingly, both compounds exhibited selective cytotoxicity against both cell lines with high safety to normal fibroblast (HFF-1). In addition, both compounds 7c and 7g induced apoptosis and inhibited Bcl2 and BclxL expression in a dose-dependent manner. Collectively, the high potency and selective cytotoxicity suggested that conjugates 7c and 7g could be a starting point for further optimisation to develop novel pro-apoptotic and antitumor agents towards colon cancer.

GC/MS Analysis of Essential Oil and Enzyme Inhibitory Activities of Syzygium cumini (Pamposia) Grown in Egypt: Chemical Characterization and Molecular Docking Studies.

Syzygium cumini (Pomposia) is a well-known aromatic plant belonging to the family Myrtaceae, and has been reported for its various traditional and pharmacological potentials, such as its antioxidant, antimicrobial, anti-inflammatory, and antidiarrheal properties. The chemical composition of the leaf essential oil via gas chromatography-mass spectrometry (GC/MS) analysis revealed the identification of fifty-three compounds representing about 91.22% of the total oil. The identified oil was predominated by α-pinene (21.09%), followed by ß-(E)-ocimene (11.80%), D-limonene (8.08%), ß-pinene (7.33%), and α-terpineol (5.38%). The tested oil revealed a moderate cytotoxic effect against human liver cancer cells (HepG2) with an IC50 value of 38.15 ± 2.09 µg/mL. In addition, it effectively inhibited acetylcholinesterase with an IC50 value of 32.9 ± 2.1 µg/mL. Furthermore, it showed inhibitory properties against α-amylase and α-glucosidase with IC50 values of 57.80 ± 3.30 and 274.03 ± 12.37 µg/mL, respectively. The molecular docking studies revealed that (E)-ß-caryophyllene, one of the major compounds, achieved the best docking scores of -6.75, -5.61, and -7.75 for acetylcholinesterase, α-amylase, and α-glucosidase, respectively. Thus, it is concluded that S. cumini oil should be considered as a food supplement for the elderly to enhance memory performance and for diabetic patients to control blood glucose.

Antitumor activity, multitarget mechanisms, and molecular docking studies of quinazoline derivatives based on a benzenesulfonamide scaffold: Cell cycle analysis.

The in vitro cytotoxicity of some substituted quinazolinones, 1-15, was evaluated using NCI (10 µM) in a full NCI 59-cell line panel assay. Relative to the reference drug, imatinib (PCE = 20/59), compounds 3, 4, 7, 9, and 10 exhibited remarkable antitumor activity against the tested cell lines, with positive cytotoxic effects (PCE) of 29/59, 18/59, 17/59, 44/59, and 24/59 respectively. Enzymatic inhibitory assay conducted on 3, 4, 9, and 10 as the most potent antitumor agents against EGFR, HER2 and CDK9 kinases, and COX-2 enzyme. Compound 3 possessed good COX-2 inhibitory activity (IC50 = 0.775 µM) compared to the reference drug, celecoxib (IC50 = 0.153 µM). Compounds 4 and 9 were closely potent to the reference compounds against EGFR and (HER2) tyrosine kinases, with IC50 values of 90.17 (and 131.39 for HER2) for 4 and 145.35 (and 129.07 for HER2) nM for 9; the reference drugs in this case, namely, gefitinib and erlotinib, exhibited IC50 values of 55.58 (90) and 110 (79.28) nM against the EGFR and (HER2) tyrosine kinases, respectively. Compound 4 was approximately similar potent against CDK9 kinase (IC50 = 67.04 nM) like the reference compound, dinaciclib (IC50 = 53.12 nM). Compound 9 induced cytotoxicity in the MCF-7 cell line (GI % at 10.0 µM = 47%) through pre-G1 apoptosis, thereby inhibiting cell growth at the G2/M phase. Molecular docking models of 3 and 4 with COX-2, EGFR, and CDK9 were conducted to determine their binding mode within the putative binding pockets.

Antitumor properties of certain spirooxindoles towards hepatocellular carcinoma endowed with antioxidant activity.

In the current medical era, spirooxindole motif stands out as a privileged heterospirocyclic scaffold that represents the core for a wide range of bioactive naturally isolated products (such as Strychnofoline and spirotryprostatins A and B) and synthetic compounds. Interestingly, no much attention has been paid to develop spirooxindole derivatives with dual antioxidant and anticancer activities. In this context, a series of spirooxindoles 6a-p was examined for their anticancer effect towards HepG2 hepatocellular carcinoma and PC-3 prostate cancer cell lines. Spirooxindole 6a was found to be an efficient anti-proliferative agent towards both HepG2 and PC-3 cells (IC50 = 6.9 and 11.8 µM, respectively). Afterwards, spirooxindole 6a was assessed for its apoptosis induction potential in HepG2 cells, where its pro-apoptotic impact was approved via the significant elevation in the Bax/Bcl-2 ratio and the expression levels of caspase-3.

The relationships between nurses' work environments and emotional exhaustion, job satisfaction, and intent to leave among nurses in Saudi Arabia.

AIMS: To examine relationships between components of nurses' work environments and emotional exhaustion, job satisfaction and intent to leave among nurses in Saudi Arabia. DESIGN: A descriptive correlational study with cross-sectional data. METHODS: Data were collected in 2017 from 497 Registered Nurses working in a large tertiary hospital in Riyadh, Saudi Arabia. Participants completed an online survey like that used in RN4Cast studies to measure nurses' perceptions of their work environments and nurse outcomes. Hierarchical linear regression and logistic regression were conducted to examine the relationships between components of nurses' work environments and nurse outcomes after controlling for nurse and patient characteristics. RESULTS: Nurse participation in hospital affairs was uniquely associated with all three nurse outcomes, whereas staffing and resource adequacy was associated with emotional exhaustion and job satisfaction, but not intent to leave. These two variables were also the components of the nursing practice environment that received the lowest ratings. Nurse manager ability, leadership and support of nurses, and nurse-physician relationships were associated with job satisfaction only. A nursing foundation for quality of care was not uniquely associated with any of the three outcomes. Finally, nurse emotional exhaustion and job satisfaction fully mediated the relationship between nurse participation in hospital affairs and intent to leave. CONCLUSION: Magnet-like work environments in Saudi Arabia are critical to recruiting and retaining nurses in a country with critical nursing shortages. IMPACT: This study addresses a gap in the literature regarding which components of the nurses' work environment are uniquely associated with emotional exhaustion, job satisfaction and intent to leave among nurses in Saudi Arabia. Study results will assist Saudi hospital administrators and nurse leaders to develop recruitment and retention strategies by focusing on those work environment components most associated with nurse outcomes: participation in hospital affairs and staffing and resource adequacy.

Synthesis, biological evaluation and in silico studies with 4-benzylidene-2-phenyl-5(4H)-imidazolone-based benzenesulfonamides as novel selective carbonic anhydrase IX inhibitors endowed with anticancer activity.

In the presented work, we report the synthesis of a series of 4-benzylidene-2-phenyl-5(4H)-imidazolone-based benzenesulfonamides 7a-fvia the Erlenmeyer-Plöchl reaction. All the prepared imidazolones 7a-f were evaluated as inhibitors of human (h) carbonic anhydrases (CA, EC 4.2.1.1) cytosolic isoforms hCA I and II, as well as transmembrane tumor-associated isoforms hCA IX and XII. All the tested hCA isoforms were inhibited by the prepared imidazolones 7a-f in variable degrees with the following KIs ranges: 673.2-8169 nM for hCA I, 61.2-592.1 nM for hCA II, 23-155.4 nM for hCA XI, and 21.8-179.6 nM for hCA XII. In particular, imidazolones 7a, 7e, and 7f exhibited good selectivity towards the tumor-associated isoforms (CAs IX and XII) over the off-target cytosolic (CAs I and II) with selectivity index (SI) in the range of 6.2-19.4 and 3.3-8, respectively. Moreover, imidazolones 7a-f were screened for their anticancer activity in one dose (10-5 M) assay against a panel of 60 cancer cell lines according to US-NCI protocol. Furthermore, 7a, 7e and 7f were evaluated for their anti-proliferative activity against colorectal cancer HCT-116 and breast cancer MCF-7 cell lines. Furthermore, 7e and 7f were screened for cell cycle disturbance and apoptosis induction in HCT-116 cells. Finally, a molecular docking study was carried out to rationalize the obtained results.

SLC-0111 enaminone analogs, 3/4-(3-aryl-3-oxopropenyl) aminobenzenesulfonamides, as novel selective subnanomolar inhibitors of the tumor-associated carbonic anhydrase isoform IX.

SLC-0111, an ureido substituted benzenesulfonamide, is a selective carbonic anhydrase (CA, EC 4.2.1.1) IX inhibitor that is currently in Phase I/II clinical trials for the treatment of advanced hypoxic tumors complicated with metastases. Herein we report the synthesis of two series of 3/4-(3-aryl-3-oxopropenyl) aminobenzenesulfonamides 5a-i and 6a-j as SLC-0111 enaminone congeners. The prepared enaminones were in vitro investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, II, IV and IX, using a stopped-flow CO2 hydrase assay. All these isoforms were inhibited by the enaminones reported here in variable degrees. The target tumor-associated isoform hCA IX was undeniably the most affected one (KIs: 0.21-7.1 nM), with 6- to 21-fold enhanced activity than SLC-0111 (KI = 45 nM). All the prepared enaminones displayed interesting selectivity towards hCA IX over hCA I (SI: 32 - >35714), hCA II (SI: 2 - 1689) and hCA IV (SI: 11 - >45454). Of particular interest, bioisosteric replacement of phenyl tail with the bulkier 2-naphthyl tail, sulfonamide 6h, achieved the higher II/IX selectivity herein reported with SI of 1689.

Novel Diamide-Based Benzenesulfonamides as Selective Carbonic Anhydrase IX Inhibitors Endowed with Antitumor Activity: Synthesis, Biological Evaluation and In Silico Insights.

In this work, we present the synthesis and biological evaluation of novel series of diamide-based benzenesulfonamides 5a-h as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, II, IX and XII. The target tumor-associated isoforms hCA IX and XII were undeniably the most affected ones (KIs: 8.3-123.3 and 9.8-134.5 nM, respectively). Notably, diamides 5a and 5h stood out as a single-digit nanomolar hCA IX inhibitors (KIs = 8.8 and 8.3 nM). The SAR outcomes highlighted that bioisosteric replacement of the benzylidene moiety, compounds 5a-g, with the hetero 2-furylidene moiety, compound 5h, achieved the best IX/I and IX/II selectivity herein reported with SIs of 985 and 13.8, respectively. Molecular docking simulations of the prepared diamides within CA IX active site revealed the ability of 5h to establish an additional H-bond between the heterocyclic oxygen and HE/Gln67. Moreover, benzenesulfonamides 5a, 5b and 5h were evaluated for their antitumor activity against renal cancer UO-31 cell line. Compound 5h was the most potent derivative with about 1.5-fold more enhanced activity (IC50 = 4.89 ± 0.22 µM) than the reference drug Staurosporine (IC50 = 7.25 ± 0.43 µM). Moreover, 5a and 5h were able to induce apoptosis in UO-31 cells as evidenced by the significant increase in the percent of annexinV-FITC positive apoptotic cells by 22.5- and 26.5-folds, respectively.

In-office bleaching efficacy on stain removal from CAD/CAM and direct resin composite materials.

OBJECTIVE: To evaluate the efficacy of in-office bleaching on stain removal from stained resin composite and ceramic computer-assisted design/computer-assisted manufacturing (CAD/CAM) blocks and direct resin composites. METHODS: Forty disk-shaped samples were fabricated from each of nine materials: six CAD/CAM (VITABLOCS Mark II, Paradigm MZ100, Exp Vita Hybrid Ceramic, VITA ENAMIC, Exp Kerr, and LAVA Ultimate) and three direct resin composites (Filtek Supreme, Venus Diamond, and Filtek Silorane). Samples were randomly divided into five groups (n = 8), each stained with a particular staining solution. Using a calibrated spectrophotometer and a black background, L*a*b* values were assessed before and after 120 days of staining. Samples were subjected to in-office bleaching using 40% hydrogen peroxide gel for one hour. At subsequent assessment, color change (ΔE) was calculated as the difference between L*a*b* values. Both ANOVA and the Duncan test were used to identify differences between groups (α = 0.05). RESULTS: Bleaching resulted in significant differences in ΔE values for all materials (P < .001). Bleaching efficacy was highly influenced by material composition and staining solution. Residual color values after bleaching for ceramic and hybrid ceramics ranged from -0.49 to 2.35, within the clinically acceptable maximum of 3.3. Values after bleaching for resin-based CAD/CAM ranged from -0.7 to 7.08 while direct resin composites values ranged from -1.47 to 25.13. Coffee left the greatest residual color on all materials. CONCLUSIONS: Based on material nature, 40% hydrogen peroxide bleaching can remove staining. The new resin-based CAD/CAM blocks showed promising results in terms of color stability. CLINICAL SIGNIFICANCE: Bleaching using 40% hydrogen peroxide can be an effective method to remove stains from dental restorations. In this way, restoration replacement as a result of discoloration may no longer be necessary.

Stain susceptibility of composite and ceramic CAD/CAM blocks versus direct resin composites with different resinous matrices.

To evaluate the stain susceptibility of CAD/CAM blocks and direct composite after long term exposure to various staining agents. 40 disk-shaped samples were fabricated from each of nine materials; six CAD/CAM (Vitablocs Mark II, Paradigm MZ100, Experimental Vita Hybrid Ceramic, Vita Enamic, Experimental Kerr and Lava Ultimate) and three direct composites (Filtek Supreme, Venus Diamond and Filtek Silorane). Samples were randomly divided into five groups (n = 8) according to different staining solutions (distilled water, tea, red wine, coffee and artificial saliva). Initial L*a*b* values were assessed using a calibrated digital spectrophotometer. Specimens were immersed in staining solutions and stored in an incubator at 37 °C for 120 days. L*a*b* values were assessed again and color change (∆E) was calculated as difference between recorded L*a*b* values. ANOVA, and Duncan test were used to identify differences between groups (α = 0.05). Significant differences in ∆E values were detected between materials (p = 0.000). Among all staining solutions, the highest ∆E value was observed with red wine. The new CAD/CAM blocks (Vita Enamic, Vita Hybrid Ceramic and Lava Ultimate) showed the highest resistance to staining compared to the MZ100 composite resin blocks. Filtek Silorane, a direct composite, showed high stain resistance values compared to CAD/CAM materials and other direct composites. Ceramic and composite CAD/CAM blocks had lower staining susceptibility than methacrylate based direct composite. Staining susceptibility of the new resin based CAD/CAM materials Vita Enamic and Lava Ultimate was comparable to feldspathic ceramic blocks (Vitablocs Mark II). Filtek Silorane showed promising results that were comparable to some CAD/CAM blocks.

Semidirect composite onlay with cavity sealing: a review of clinical procedures.

UNLABELLED: The evolution in adhesive dentistry has broadened the indication of esthetic restorative procedures especially with the use of resin composite material. Depending on the clinical situation, some restorative techniques are best indicated. As an example, indirect adhesive restorations offer many advantages over direct techniques in extended cavities. In general, the indirect technique requires two appointments and a laboratory involvement, or it can be prepared chairside in a single visit either conventionally or by the use of computer-aided design/computer-aided manufacturing systems. In both cases, there will be an extra cost as well as the need of specific materials. This paper describes the clinical procedures for the chairside semidirect technique for composite onlay fabrication without the use of special equipments. The use of this technique combines the advantages of the direct and the indirect restoration. CLINICAL SIGNIFICANCE: The semidirect technique for composite onlays offers the advantages of an indirect restoration and low cost, and can be the ideal treatment option for extended cavities in case of financial limitations.

Understanding factors influencing the implementation of medicine risk communications by healthcare professionals in clinical practice: a systematic review using the Theoretical Domains Framework.

BACKGROUND: Adverse drug reactions (ADRs) are known to cause hospitalisation, longer hospital stays, as well as higher healthcare costs and mortality. Unrecognised ADRs are anticipated throughout the medicine lifecycle as, before the medicine reaches the market, clinical trials are conducted for a short period on a limited number of people, who might underrepresent the actual population. After the medicine reaches the market, emergent information that could affect its benefit-to-risk balance is usually shared by regulatory agencies and pharmaceutical companies through medicine risk communications. Medicines risk communications aim to prevent harm to patients by targeting their behaviour, knowledge, and attitudes, as well as those of health care professionals (HCPs). Despite their important role in translating these communications into their clinical practice, HCPs do not always adhere to the recommendations provided in risk communications. Measurement of medicine risk communications' effectiveness does not necessarily guarantee their implementation, cost-effectiveness, or transferability in real-world situations. To enhance the impact of drug regulatory interventions, implementation science has been encouraged. However, implementation science was not previously used to identify factors affecting HCPs' implementation of medicines risk communications. A recently widely used framework is the Theoretical Domain Framework (TDF). In this systematic review, the TDF was employed to categorise a range of different factors that could affect HCPs' implementation of medicine risk communications within their clinical contexts. METHODS: The search strategy involved a set of predefined search terms and fifteen databases, such as EMBASE, PubMed, Web of Science and CINAHL PLUS. Searches were conducted from April to May 2018 and updated in June 2021 using PubMed, Scopus, and CINAHL PLUS. A second reviewer independently conducted the screening process of the initial search. The total number of records screened was 10,475. A study was included if it reported any factors influencing HCPs' uptake of medicine risk communications. Only studies with English or Arabic abstracts were included. Those studies that did not include pharmacovigilance-related medicine risk communications were excluded. Additionally, studies only assessing HCPs' practice or evaluating the effectiveness of risk minimisation measures were excluded. Likewise, studies related to occupational hazards, case reports, interventional studies, and studies not involving HCPs were excluded. In case the published information was insufficient to decide whether to include or exclude a study, the authors were contacted. Furthermore, the authors of seven eligible abstracts were contacted for full-text articles. The mixed method appraisal tool (MMAT) was used to evaluate the quality of the included studies. All included studies were assessed by one reviewer, and a total of 16 studies were assessed by two reviewers independently. Disagreements were resolved through discussion. Using thematic analysis and concept mapping, a narrative synthesis was performed, followed by a critical reflection on the synthesis process. This review presents the results of the concept mapping, which involved matching the identified factors to the TDF. RESULTS: A total of 28 studies were included. Eleven domains influenced HCPs' implementation of medicine risk communications. A large number of studies included factors related to the "Knowledge" domain (n = 23), followed by "Beliefs about Consequences" (n = 13), "Memory, Attention and Decision Processes" (n = 12) and "Environmental Context and Resources" domains (n = 12). Seven studies reported "social influences" and six studies included factors relating to "Goals", followed by four studies involving factors related to "Social/Professional Role and Identity". Underrepresented domains included "Emotion" (n = 2), "Beliefs about Capabilities" (n = 2), "Behavioural Regulation" (n = 1), and "Reinforcement" (n = 1). On the other hand, none of the identified factors were related to the "Skills", "Optimism", or "Intentions" domains. Except for "Beliefs about Consequences", most studies contributing to the other three most commonly reported domains ("Knowledge"; "Environmental Context and Resources"; and "Memory, Attention and Decision Processes") scored low (1 or 2 out of 5) on the MMAT quality assessment. Moreover, the same number of studies (n = 5) contributing to the "Beliefs about Consequences" domain had low (1 or 2 out of 5), and intermediate (3 out of 5) scores on the MMAT. CONCLUSION: Medicines risk communications are important tools for disseminating information that may influence the benefit-to-risk balance of medicines. Even though HCPs are required to implement the recommendations of these communications, they do not always adhere to them. Using the TDF enabled the categorization of the range of factors that affect whether or not HCPs implement the recommendations provided in a medicine risk communication. However, most of these factors relate to four domains only ("Knowledge"; "Beliefs about Consequences"; "Memory, Attention and Decision Processes"; and "Environmental Context and Resources"). Additionally, most of the studies contributing to three of these four domains were of low quality. Future research should focus on using implementation science to identify target behaviours for actionable medicine risk communications. Regulators should use such science to develop cost-effective strategies for improving the implementation of medicines risk communication by HCPs.

A Systematic Evaluation of the Quality of Health Information on Cleft Lip and Palate in the Arabic Language.

Background: The internet serves as a vital health information resource, yet the quality of data on specific health conditions, especially in Arabic, is often overlooked. This research assesses the quality of Arabic online information about cleft lip and palate (CLP) and proposes avenues for enhancement. Methods: From July to August 2022, a systematic evaluation of Arabic articles on CLP was performed using the DISCERN tool for quality assessment. Searches on Google and Bing resulted in 119 articles that met the study's criteria. Results: The quality of available Arabic information on CLP displayed substantial gaps. Commercial sources dominated (49.6%), followed by private (32.8%) and nonprofit entities (17.6%). The average DISCERN score was 2.26 of 5 (SD = 1.06), indicating the need for enhanced content, particularly concerning treatment risks. Conclusions: The study underscores the subpar quality of Arabic CLP information online, which might mislead patients and impede access to accurate advice. Nonprofit organizations should bolster their online footprint, offering refined health content. A deep dive into DISCERN scores reveals pinpointed improvement areas. Clinicians should direct patients and their families to reliable information sources. Addressing these gaps promises improved CLP knowledge in Arabic, fostering superior patient education and outcomes for those with this condition.

The Effect of Lower Limb Combined Neuromuscular Electrical Stimulation on Skeletal Muscle Signaling for Glucose Utilization, Myofiber Distribution, and Metabolic Function after Spinal Cord Injury.

Maintaining healthy myofiber type and metabolic function early after spinal cord injury (SCI) may prevent chronic metabolic disorders. This study compares the effects of a 2-5 week combined (aerobic + resistance) neuromuscular electrical stimulation (Comb-NMES) regimen versus a sham control treatment on muscle protein signaling for glucose uptake, myofiber type distribution, and metabolic function. Twenty participants (31 ± 9 years of age) with an SCI (C4-L1, AIS level A-C) within 14 days of the SCI were randomly assigned to control (N = 8) or Comb-NMES (N = 12). Sessions were given three times per week. Fasting blood samples and vastus lateralis muscle biopsies were collected 24-48 h before or after the last session. Western blots were performed to quantify proteins, immunohistochemical analyses determined muscle myofiber distribution, and enzymatic assays were performed to measure serum glucose, insulin, and lipids. Our main findings include a decrease in fasting glucose (p < 0.05) and LDL-C (p < 0.05) levels, an upregulation of CamKII and Hexokinase (p < 0.05), and an increase in type I (+9%) and a decrease in type IIx (-36%) myofiber distribution in response to Comb-NMES. Our findings suggest that maintaining healthy myofiber type and metabolic function may be achieved via early utilization of Comb-NMES.

Factors influencing the implementation of medicine risk communications by healthcare professionals in clinical practice: A systematic review.

BACKGROUND: Regulatory medicines risk communications aim to prevent patient harm through the dissemination of safety information to healthcare professionals (HCPs), patients, and the public. Evidence suggests that in addition to implementing the required changes, HCPs also respond to these communications through unintended and unwarranted actions and behaviours such as stopping medicine courses unnecessarily, and blanket actions spilling over to unintended patients' populations. Misunderstanding and mis-implementation of medicines risk communications could jeopardise patients' safety and clinical outcomes. Therefore, it is important to understand the determinants that affect HCPs responses to medicines risk communications. This systematic review aims to identify the factors that affect the implementation of risk communications by healthcare professionals. METHODS: Fifteen databases, including EMBASE, PubMed, Scopus, Web of science, CINAHL PLUS were searched in April-May 2018, and the search was updated again in June 2021 to identify studies reporting on factors influencing HCPs' uptake of medicine risk alerts. We used keywords such as risk communication, safety update, and safety regulation. Studies were excluded if they did not involve pharmacovigilance or patient safety alerts; or if they only focused on measuring HCPs' practice after alerts; or evaluating the effectiveness of risk minimisation measures without reporting on factors affecting HCPs' actions. Studies relating to occupational hazards, case reports, interventional studies, and studies not involving HCPs were also excluded. The Mixed Method Appraisal Tool (MMAT) was used to assess the quality of the included studies. A Narrative synthesis approach was undertaken using thematic analysis and concept mapping, followed by a critical reflection of the synthesis. RESULTS: Twenty-eight studies met our criteria and were included in the synthesis. We identified four themes summarising the factors influencing HCPs' implementation of risk communications. These include HCPs: knowledge of medicine alerts; perceptions of alerts; attitudes, and concerns regarding medicine alerts; and the self-reported impact of these alerts. Our concept mapping exercise identified key interactions between different stakeholders, and these interactions determine HCPs' implementation of medicine risk communications. These stakeholders comprise of alert developers, including the sources and senders of safety information, and the receivers of safety information including health care institutions, HCPs, patients and their carers. CONCLUSIONS: Healthcare professionals are crucial to translating risk communication messages into clinical practice. However, if they have inadequate information about the content of the alert, and have inaccurate perceptions about the alert, they may not implement the required clinical changes as intended. Communication of medicine risk alerts does not always translate into improved patient care, due to a complex interaction between stakeholders involved in the creation and implementation of these alerts. These complex interactions should be the subject of future research efforts to understand the alert-implementation trajectory and identify the mediators for change and interventions to improve implementation.