Antimicrobial stewardship programme implementation in the UAE: perspectives of key stakeholders using Consolidated Framework for Implementation Research.

BACKGROUND: Many studies report antimicrobial stewardship programme (ASP) implementation, but these are limited by a lack of theoretical underpinning. This may lead to missing key factors that are likely to influence the successful or unsuccessful implementation. AIM: To explore key stakeholders' perspectives of ASP implementation in UAE hospitals, with a focus on facilitators and barriers. METHODS: The study employed a qualitative approach using semi-structured interviews conducted with ASP stakeholders involved in clinical use of antimicrobials at the individual patient level and including ASP team members and non-members. An interview schedule based on published literature and grounded in the Consolidated Framework for Implementation Research (CFIR) was developed, reviewed, and piloted. Recruitment was via purposive and snowball sampling. Interviews were recorded, transcribed, and thematically analysed by two independent researchers using CFIR as a coding framework. FINDINGS: Data saturation was achieved at 31 interviews. Multiple CFIR constructs were identified as implementation facilitators or barriers. Facilitators included external policy requirements (both national and international), leadership support, stakeholders' engagement, collaborative culture, effective communication, and forward planning. Barriers included blame culture, complexity of ASP implementation, and a shortage of expert personnel. CONCLUSION: Numerous facilitators and barriers to ASP implementation from a stakeholders' perspective were identified in this research. The value of early leadership engagement to support provision of required resources, a need for effective planning and establishment of multiple engagement techniques, and valuable communication with healthcare providers are the main recommendations emerging to support improvement in clinical practice.

Experimental Demonstration of Compact Polymer Mass Transfer Device Manufactured by Additive Manufacturing with Hydrogel Integration to Bio-Mimic the Liver Functions.

In this paper, we designed and demonstrated a stimuli-responsive hydrogel that mimics the mass diffusion function of the liver. We have controlled the release mechanism using temperature and pH variations. Additive manufacturing technology was used to fabricate the device with nylon (PA-12), using selective laser sintering (SLS). The device has two compartment sections: the lower section handles the thermal management, and feeds temperature-regulated water into the mass transfer section of the upper compartment. The upper chamber has a two-layered serpentine concentric tube; the inner tube carries the temperature-regulated water to the hydrogel using the given pores. Here, the hydrogel is present in order to facilitate the release of the loaded methylene blue (MB) into the fluid. By adjusting the fluid's pH, flow rate, and temperature, the deswelling properties of the hydrogel were examined. The weight of the hydrogel was maximum at 10 mL/min and decreased by 25.29% to 10.12 g for the flow rate of 50 mL/min. The cumulative MB release at 30 °C increased to 47% for the lower flow rate of 10 mL/min, and the cumulative release at 40 °C climbed to 55%, which is 44.7% more than at 30 °C. The MB release rates considerably increased when the pH dropped from 12 to 8, showing that the lower pH had a major impact on the release of MB from the hydrogel. Only 19% of the MB was released at pH 12 after 50 min, and after that, the release rate remained nearly constant. At higher fluid temperatures, the hydrogels lost approximately 80% of their water in just 20 min, compared to a loss of 50% of their water at room temperature. The outcomes of this study may contribute to further developments in artificial organ design.

The impact of COVID-19 on antimicrobial stewardship programme implementation in hospitals - an exploration informed by the Consolidated Framework for Implementation Research.

INTRODUCTION AND OBJECTIVES: The disruption of antimicrobial stewardship programmes (ASPs) caused by coronavirus disease 2019 (COVID-19) has been recognized but not explored in depth. This study used a theoretical, qualitative approach to understand the impact of COVID-19 on ASP implementation in hospitals. METHODS: Semi-structured online interviews, informed by the Consolidated Framework for Implementation Research (CFIR), were conducted with ASP team members and non-members in hospitals. Participants were recruited via purposeful and snowball sampling with interviews video recorded, transcribed and analysed independently by two researchers based on mapping against CFIR constructs. RESULTS: Thirty-one interviews were conducted across 11 hospitals. The following themes were identified: (i) increased complexity of ASP implementation and changes in prescribing behaviour influenced by COVID-19; (ii) adaptations, networking and cosmopolitanism to enhance integration of COVID-19 management into ASP services; and (iii) adaptations and networking to support continuity of the ASP implementation process. A disruption to pre-pandemic ASP activities was reported, with complexity of COVID-19 overwhelming the healthcare system. ASP team members and services showed an ability to adapt and repurpose roles to respond to the pandemic. Interventions included developing national guidelines for treatment of patients with COVID-19 and contributing to guideline management and monitoring. A gradual restoration of ASP activities was perceived. Technological adaptations and enhancements in networking were reported as positive impacts of the pandemic. CONCLUSION: Despite the initial disruption of ASP implementation caused by the pandemic, successful adaptation and evolution of ASP services reflects the high value and adaptability of ASP implementation in hospitals in the United Arab Emirates.

Comparison of risk assessment tools for cardiovascular diseases: results of an Iranian cohort study.

OBJECTIVES: Several popular cardiovascular risk assessment tools have been developed in Western countries; however, the predictive abilities of these tools have not been evaluated in Middle Eastern countries. The present study aimed to determine the abilities of cardiovascular risk assessment tools in a population-based study in Northern Iran. STUDY DESIGN: Population-based cohort study in Northern Iran. METHODS: In total, 2883 individuals (1629 men and 1254 women), aged 40-74 years, were included in the study. We determined the predictive abilities of the American College of Cardiology/American Heart Association (ACC/AHA) risk prediction tool, the Framingham general cardiovascular risk profile in primary care settings, and the Systematic Coronary Risk Evaluation (SCORE) equations for low- and high-risk European countries. Receiver operating characteristic (ROC) analysis was used to determine the predictive abilities of these four risk assessment tools. RESULTS: Based on areas under curve (AUC) values and related 95% confidence intervals (95% CIs), the discriminative abilities of the ACC/AHA tool, the Framingham approach, and the SCORE for low- and high-risk European countries to estimate non-fatal cardiovascular disease (CVD) events were 0.6625, 0.6517, 0.6476 and 0.6458, respectively, in men, and 0.7722, 0.7525, 0.7330 and 0.7331, respectively, in women. Moreover, the abilities of these four tools to estimate fatal CVD events were found to be 0.8614, 0.8329, 0.7996 and 0.7988 in men, and 0.8779, 0.8372, 0.8535 and 0.8518 in women, respectively. CONCLUSIONS: The cardiovascular risk assessment tools investigated in this study showed acceptable predictive abilities in women. The ACC/AHA approach showed slightly better performance compared with the SCORE tool; however, the SCORE tool benefited from the lowest cost compared with all the other tools.

Estimation of tumor parameters using neural networks for inverse bioheat problem.

BACKGROUND AND OBJECTIVE: Some types of cancer cause rapid cell growth, while others cause cells to grow and divide at a slower rate. Certain forms of cancer result in visible growths called tumors. This work proposes an inverse estimation of the size and location of the tumor using a feedforward Neural Network (FFNN) model. METHODS: The forward model is a 3D model of the breast induced with a tumor of various sizes at different locations within the breast, and it is solved using the Pennes equation. The data obtained from the simulation of the bioheat transfer is used for training the neural network. In order to optimize the neural network architecture, the work proposes varying the number of neurons in the hidden layer and thus finding the best fit to create a relationship between the temperature profile and tumor parameters which can be used to estimate the tumor parameters given the temperature profile. RESULTS: These simulations resulted in a temperature distribution profile that could thus be used to locate and determine the parameters of the cancerous tumor within the breast. The prediction accuracy showed the capacity of the trained Feed Forward Neural Network to estimate the unknown parameters within an acceptable range of error. The model validations use the Root Mean Square Error method to quantify and minimize the prediction error. CONCLUSIONS: In this work, a non-intrusive method for the diagnosis of breast cancer was modelled, which yields conclusive results for the estimation of the tumor parameters.

Mapping hospital antimicrobial stewardship programmes in the Gulf Cooperation Council states against international standards: a systematic review.

BACKGROUND: While there is evidence of implementation of antimicrobial stewardship programmes (ASPs) in the Gulf Cooperation Council (GCC) states, there has been limited benchmarking and mapping to international standards and frameworks. AIM: To critically appraise and synthesize the evidence of ASP implementation in GCC hospitals with reference to the framework of the Centers for Disease Control and Prevention (CDC), identifying key facilitators and barriers. METHODS: A systematic review protocol was developed based on Preferred Reporting Items for Systematic Reviews and Meta-analyses for Protocols guidelines. Five electronic databases were searched for studies published in English from 2010 onwards. Study selection, quality assessment and data extraction were performed independently by two reviewers. A narrative synthesis was conducted with ASP interventions mapped to CDC core elements. FINDINGS: Seventeen studies were identified, most of which (N=11) were from Saudi Arabia. Mapping to the CDC framework identified key areas of strengths and weaknesses in reporting implementation. Studies more commonly reported core elements of pharmacy expertise, selected aspects of implementation actions, tracking, antibiotic use and resistance, and education. Little emphasis was placed on the reporting of leadership and accountability. Key implementation facilitators were physician and organization support, information systems and education, and barriers were dedicated staff, workload and funding. CONCLUSION: There is a need to enhance the reporting of ASP implementation in GCC hospitals. The CDC framework should be used as a guide during the development, implementation and reporting of ASP interventions. Action is required to identify facilitators and overcome barriers, where possible.

Integrative network analysis identifies novel drivers of pathogenesis and progression in newly diagnosed multiple myeloma.

Multiple myeloma (MM) is an incurable malignancy of bone marrow plasma cells characterized by wide clinical and molecular heterogeneity. In this study we applied an integrative network biology approach to molecular and clinical data measured from 450 patients with newly diagnosed MM from the MMRF (Multiple Myeloma Research Foundation) CoMMpass study. A novel network model of myeloma (MMNet) was constructed, revealing complex molecular disease patterns and novel associations between clinical traits and genomic markers. Genomic alterations and groups of coexpressed genes correlate with disease stage, tumor clonality and early progression. We validated CDC42BPA and CLEC11A as novel regulators and candidate therapeutic targets of MMSET-related myeloma. We then used MMNet to discover novel genes associated with high-risk myeloma and identified a novel four-gene prognostic signature. We identified new patient classes defined by network features and enriched for clinically relevant genetic events, pathways and deregulated genes. Finally, we demonstrated the ability of deep sequencing techniques to detect relevant structural rearrangements, providing evidence that encourages wider use of such technologies in clinical practice. An integrative network analysis of CoMMpass data identified new insights into multiple myeloma disease biology and provided improved molecular features for diagnosing and stratifying patients, as well as additional molecular targets for therapeutic alternatives.

Dual inhibition of CDK4/Rb and PI3K/AKT/mTOR pathways by ON123300 induces synthetic lethality in mantle cell lymphomas.

This study describes the characterization of a novel kinase inhibitor, ON123300, which inhibits CDK4/6 (cyclin-dependent kinases 4 and 6) and phosphatidylinositol 3 kinase-δ (PI3K-δ) and exhibits potent activity against mantle cell lymphomas (MCLs) both in vitro and in vivo. We examined the effects of PD0332991 and ON123300 on cell cycle progression, modulation of the retinoblastoma (Rb) and PI3K/AKT pathways, and the induction of apoptosis in MCL cell lines and patient-derived samples. When Granta 519 and Z138C cells were incubated with PD0332991 and ON123300, both compounds were equally efficient in their ability to inhibit the phosphorylation of Rb family proteins. However, only ON123300 inhibited the phosphorylation of proteins associated with the PI3K/AKT pathway. Cells treated with PD0332991 rapidly accumulated in the G0/G1 phase of cell cycle as a function of increasing concentration. Although ON123300-treated cells arrested similarly at lower concentrations, higher concentrations resulted in the induction of apoptosis, which was not observed in PD0332991-treated samples. Mouse xenograft assays also showed a strong inhibition of MCL tumor growth in ON123300-treated animals. Finally, treatment of ibrutinib-sensitive and -resistant patient-derived MCLs with ON123300 also triggered apoptosis and inhibition of the Rb and PI3K/AKT pathways, suggesting that this compound might be an effective agent in MCL, including ibrutinib-resistant forms of the disease.

High-resolution chromatin immunoprecipitation (ChIP) sequencing reveals novel binding targets and prognostic role for SOX11 in mantle cell lymphoma.

Sex determining region Y-box 11 (SOX11) expression is specific for mantle cell lymphoma (MCL) as compared with other non-Hodgkin's lymphomas. However, the function and direct-binding targets of SOX11 in MCL are largely unknown. We used high-resolution chromatin immunoprecipitation sequencing to identify the direct target genes of SOX11 in a genome-wide, unbiased manner and elucidate its functional significance. Pathway analysis identified WNT, PKA and TGF-beta signaling pathways as significantly enriched by SOX11-target genes. Quantitative chromatin immunoprecipitation sequencing and promoter reporter assays confirmed that SOX11 directly binds to individual genes and modulates their transcription activities in these pathways in MCL. Functional studies using RNA interference demonstrate that SOX11 directly regulates WNT in MCL. We analyzed SOX11 expression in three independent well-annotated tissue microarrays from the University of Wisconsin (UW), Karolinska Institute and British Columbia Cancer Agency. Our findings suggest that high SOX11 expression is associated with improved survival in a subset of MCL patients, particularly those treated with intensive chemotherapy. Transcriptional regulation of WNT and other biological pathways affected by SOX11-target genes may help explain the impact of SOX11 expression on patient outcomes.

Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor.

Heterosexual transmission of human immunodeficiency virus (HIV) remains the major route of infection worldwide; thus, there is an urgent need for additional prevention strategies, particularly strategies that could be controlled by women, such as topical microbicides. Potential microbicide candidates must be both safe and effective. Using cellular and tissue explant models, we have evaluated the activity of the nonnucleoside reverse transcriptase inhibitor (NNRTI) dapivirine as a vaginal microbicide. In tissue compatibility studies, dapivirine was well tolerated by epithelial cells, T cells, macrophages, and cervical tissue explants. Dapivirine demonstrated potent dose-dependent inhibitory effects against a broad panel of HIV type 1 isolates from different clades. Furthermore, dapivirine demonstrated potent activity against a wide range of NNRTI-resistant isolates. In human cervical explant cultures, dapivirine was able not only to inhibit direct infection of mucosal tissue but also to prevent the dissemination of the virus by migratory cells. Activity was retained in the presence of semen or a cervical mucus simulant. Furthermore, dapivirine demonstrated prolonged inhibitory effects: it was able to prevent both localized and disseminated infection for as long as 6 days posttreatment. The prolonged protection observed following pretreatment of genital tissue and the lack of observable toxicity suggest that dapivirine has considerable promise as a potential microbicide candidate.

Age-related differences in the normal human cornea: a laser scanning in vivo confocal microscopy study.

AIMS: To quantify and establish baseline normative data for age-related differences in cellular and innervation density in the normal, healthy, human cornea using laser scanning in vivo confocal microscopy. METHODS: Cross-sectional study of 85 normal subjects assessed via corneal topography and laser scanning in vivo confocal microscopy. RESULTS: Mean age was 38+/-16 years (range 18-87 years) and 60% of subjects were female. Anterior keratocyte density declined by 0.9% per year (r = -0.423, p<0.001), posterior keratocyte density declined by 0.3% per year (r = -0.250, p = 0.021) and endothelial cell density declined by 0.5% per year (r = -0.615, p<0.001). Sub-basal nerve fibre density declined by 0.9% per year (r = -0.423, p<0.001). No association was observed between age and basal epithelial cell density, or between age and central corneal thickness, corneal astigmatism or horizontal corneal diameter (p>0.05). No association was observed between subject gender and corneal cell or innervation density. CONCLUSIONS: Using laser scanning in vivo confocal microscopy this study highlights a significant, and relatively linear, reduction in keratocyte and endothelial cell density with increasing subject age. Interestingly, corneal sub-basal nerve fibre density also significantly decreases with increasing age. In vivo laser scanning confocal microscopy provides a safe, non-invasive method for the establishment of normative data and assessment of alterations in human corneal microstructure following surgery or disease processes.

Formulation of rate-modulating pellets for the release of ibuprofen: an extrusion-spheronization process.

PURPOSE: To develop a stable and reproducible modified release pellet formulation containing ibuprofen. METHODS: Using extrusion-spheronization technology to produce pellets. RESULTS: The percentage yield, size distribution and overall pellet shape within the desired size range of 1000-1400 microm was found to be dependent on various process variables. These include extrusion and spheronization speed, spheronization time and composition of the granulation fluid. Formulation factors such as viscosity grade of hydroxypropylmethylcellulose and concentration of microcrystalline cellulose were shown to influence the drug release rate of the pellets. In vitro dissolution studies revealed that the pellets behaved in a pH-dependent manner. Pellets exposed to different drying techniques exhibited an increase in drug release rate in the order corresponding to oven-dried, vacuum-dried, fluid bed-dried and freeze-dried pellets. In conjunction with scanning electron microscopy, kinetic modelling and statistical treatment of dissolution data, it was confirmed that the predominant release rate-controlling mechanism was diffusion, as evidenced from the power law expressions incorporating Fickian and relaxational parameters (M(t) /M(infinity) = K(1)t(n); M(t) /M(infinity) = K(1)t(2n)). Matrix swelling and erosion were not significant factors in modulating the drug release rate. CONCLUSIONS: The pH-dependent property of the pellets may be strategically employed towards development of a site-specific drug delivery system for non-steroidal anti-inflammatory agents. In general, targeting the delivery of an agent with potential for gastric irritation to the proximal intestine/colon may effectively reduce its ulcerogenic effect and ultimately contribute towards improved patient compliance.

Microencapsulation of ibuprofen and Eudragit RS 100 by the emulsion solvent diffusion technique.

The emulsion solvent diffusion was employed to prepare modified release microspheres of ibuprofen. The technique was optimised for the following processing variables: the absence/presence of baffles in the reaction vessel, agitation rate and drying time. Thereafter, the influence of various formulation factors on the microencapsulation efficiency, in vitro drug release and micromeritic properties was examined. The variables included the methacrylic polymer, Eudragit(R) RS 100, ibuprofen content and the volume of ethanol used during microencapsulation. The results obtained were then interpreted on a triangular phase diagram to map the region of microencapsulation, as well as those formulations that yielded suitable modified release ibuprofen microspheres.

Effect of formulation variables on in vitro drug release and micromeritic properties of modified release ibuprofen microspheres.

Modified release microspheres of the non-steroidal anti-inflammatory drug, ibuprofen, were formulated and prepared using the emulsion solvent diffusion technique. The contribution of various dispersed phase and continuous phase formulation factors on in vitro drug release and micromeritic characteristics of microspheres was examined. The results demonstrated that the use of Eudragit RS 100 and Eudragit RL 100 as embedding polymers modified the drug release properties as a function of polymer type and concentration. Eudragit RS 100 retarded ibuprofen release from the microspheres to a greater extent than Eudragit RL 100. The drug/polymer concentration of the dispersed phase influenced the particle size and drug release properties of the formed microspheres. It was found that the presence of emulsifier was essential for microsphere formation. Increasing the concentration of emulsifier, sucrose fatty acid ester F-70, decreased the particle size which contributed to increased drug release properties. Scanning electron microscopy revealed profound distortion in both the shape and surface morphology of the microspheres with the use of magnesium stearate as added emulsifier. The application of an additional Eudragit RS 100 coat onto formed microspheres using fluid bed technology was successful and modulated the drug release properties of the coated microspheres.