Novel 4-nitroimidazole analogues: synthesis, in vitro biological evaluation, in silico studies, and molecular dynamics simulation.

A new series of 4-nitroimidazole bearing aryl piperazines 7-16, tetrazole 17 and 1,3,4-thiadiazole 18 derivatives was synthesized. All derivatives were screened for their anticancer activity against eight diverse human cancer cell lines (Capan-1, HCT-116, LN229, NCI-H460, DND-41, HL-60, K562, and Z138). Compound 17 proved the most potent compound of the series inhibiting proliferation of most of the selected human cancer cell lines with IC50 values in the low micromolar range. In addition, compound 11 exhibited IC50 values ranging 8.60-64.0 µM against a selection of cancer cell lines. These findings suggest that derivative 17 can potentially be a new lead compound for further development of novel antiproliferative agents. Additionally, 17-18 were assessed for their antibacterial and antituberculosis activity. Derivatives 17 and 18 were the most potent compounds of this series against both Staphylococcus aureus strain Wichita and a methicillin resistant strain of S. aureus (MRSA), as well as against Mycobacterium tuberculosis strain mc26230. The antiviral activity of 7-18 was also evaluated against diverse viruses, but no activity was detected. The docking study of compound 17 with putative protein targets in acute myeloid leukemia had been studied. Furthermore, the molecular dynamics simulation of 17 and 18 had been investigated.

Phase 1 Trial of the Safety, Pharmacokinetics, and Antiviral Activity of EDP-514 in Untreated Viremic Chronic Hepatitis B Patients.

Background & Aims: Oral EDP-514 is a potent core protein inhibitor of hepatitis B virus (HBV) replication, which produced a >4-log viral load reduction in HBV-infected chimeric mice with human liver cells. This study evaluated the safety, pharmacokinetics (PK), and antiviral activity of three doses of EDP-514 in treatment naïve viremic patients with HBeAg-positive or -negative chronic HBV infection. Methods: Patients with HBsAg detectable at screening and at least 6 months previously were eligible. HBeAg-positive and -negative patients had a serum/plasma HBV DNA level ≥20,000 and ≥2,000 IU/mL, respectively. Twenty-five patients were randomized to EDP-514 200 (n=6), 400 (n=6) or 800 mg (n=7) or placebo (n=6) once daily for 28 days. Results: A dose-related increase in EDP-514 exposure (AUClast and Cmax) was observed across doses. At Day 28, mean reductions in HBV DNA were 2.9, 3.3, 3.5 and 0.2 log10 IU/mL with EDP-514 200 mg, 400 mg, 800 mg, and placebo groups, respectively. The corresponding mean change from baseline for HBV RNA levels was 2.9, 2.4, 2.0, and 0.02 log10 U/mL. No virologic failures were observed. No clinically meaningful changes from baseline were observed for HBsAg, HBeAg or HBcrAg. Nine patients reported treatment emergent adverse events (TEAEs) of mild or moderate severity with no discontinuations, serious AEs or deaths. Conclusions: In treatment-naïve viremic patients, oral EDP-514 was generally safe and well-tolerated, displayed PK profile supportive of once-daily dosing, and markedly reduced HBV DNA and HBV RNA.

Targeted demethylation and activation of NLRC5 augment cancer immunogenicity through MHC class I.

Impaired expression of MHC (major histocompatibility complex) class I in cancers constitutes a major mechanism of immune evasion. It has been well documented that the low level of MHC class I is associated with poor prognosis and resistance to checkpoint blockade therapies. However, there is lmited approaches to specifically induce MHC class I to date. Here, we show an approach for robust and specific induction of MHC class I by targeting an MHC class I transactivator (CITA)/NLRC5, using a CRISPR/Cas9-based gene-specific system, designated TRED-I (Targeted reactivation and demethylation for MHC-I). The TRED-I system specifically recruits a demethylating enzyme and transcriptional activators on the NLRC5 promoter, driving increased MHC class I antigen presentation and accelerated CD8+ T cell activation. Introduction of the TRED-I system in an animal cancer model exhibited tumor-suppressive effects accompanied with increased infiltration and activation of CD8+ T cells. Moreover, this approach boosted the efficacy of checkpoint blockade therapy using anti-PD1 (programmed cell death protein) antibody. Therefore, targeting NLRC5 by this strategy provides an attractive therapeutic approach for cancer.

Quality and safety issue: language barriers in healthcare, a qualitative study of non-Arab healthcare practitioners caring for Arabic patients in the UAE.

OBJECTIVES: To identify language-related communication barriers that expatriate (non-Arabic) healthcare practitioners in the UAE encounter in their daily practice. DESIGN: Qualitative study utilising semi-structured in-depth interviews. The interviews were conducted in English language. SETTING: Different healthcare facilities across the UAE. These facilities were accessed for data collection over a period of 3 months from January 2023 to March 2023. PARTICIPANTS: 14 purposively selected healthcare practitioners. INTERVENTION: No specific intervention was implemented; this study primarily aimed at gaining insights through interviews. PRIMARY AND SECONDARY OUTCOMES: To understand the implications of language barriers on service quality, patient safety, and healthcare providers' well-being. RESULTS: Three main themes emerged from our analysis of participants' narratives: Feeling left alone, Trying to come closer to their patients and Feeling guilty, scared and dissatisfied. CONCLUSIONS: Based on the perspectives and experiences of participating healthcare professionals, language barriers have notably influenced the delivery of healthcare services, patient safety and the well-being of both patients and practitioners in the UAE. There is a pressing need, as highlighted by these professionals, for the inclusion of professional interpreters and the provision of training to healthcare providers to enhance effective collaboration with these interpreters.

Hearing the voices of adolescents: Evaluating the quality of care for young adults with chronic illnesses in the UAE.

BACKGROUND: Quality care for adolescents and young adults with chronic illnesses has been under-explored in the United Arab Emirates (UAE) and internationally, especially from patients' perspectives. Most available international studies focused on quality of life and the transition to adulthood rather than service quality. AIM: This research assesses care quality for adolescents with chronic illnesses in the UAE, aiming to understand their perspectives, appraise current practices, and identify service gaps. METHODS: A cross-sectional survey employed a validated questionnaire examining 33 essential care components. Participants comprised 576 adolescents and young adults with chronic conditions from five UAE Emirates. RESULTS: Participant's reports indicated that none of the 33 care elements were received consistently. Most participants (80.6%) reported crucial care aspects were absent, and across most investigated items, 19.4%-46.5% of participants reported receiving the services they were supposed to receive only some or many of the times, indicating significant areas for improvement. CONCLUSIONS: Findings demonstrate significant care quality gaps for UAE's adolescents and young adults with chronic illnesses. These may critically affect their ability to manage their conditions and ensure holistic growth. These insights can guide healthcare enhancements tailored to this demographic. PRACTICE IMPLICATIONS: There is an urgency for enhanced patient-centered care in UAE healthcare, emphasizing clinicians' roles in supporting adolescents with chronic illnesses, especially during transitions. Healthcare managers should prioritize standardized care policies, improved communication, and training that emphasizes consistent patient feedback and transition readiness. Further research into care gaps and tailored interventions within the region's distinct sociocultural setting is essential.

EDP-297: A novel, farnesoid X receptor agonist-Results of a phase I study in healthy subjects.

EDP-297 is a farnesoid X receptor agonist under development for treating nonalcoholic steatohepatitis. The pharmacokinetic (PK), pharmacodynamic (PD), food effect, and safety were evaluated in a single ascending dose (SAD) and multiple ascending dose (MAD) phase I study. Healthy subjects received single EDP-297 doses of 20-600 µg or once daily doses of 5-90 µg for 14 days. Safety, PKs, and PDs were assessed, including fibroblast growth factor 19 (FGF-19) and 7-α-hydroxy-4-cholesten-3-one (C4). Among 82 subjects, EDP-297 was generally well-tolerated. Pruritus was observed in four subjects in the SAD phase and seven subjects in the MAD phase; four severe cases occurred at 90 µg in the MAD phase, including one that led to drug discontinuation. A grade 2 elevation in alanine aminotransferase occurred with 90 µg. Mean lipid values remained within normal range. Plasma exposures of EDP-297 increased with SADs and MADs, with mean half-life following multiple doses of 9-12.5 h. No food effect was observed. Mean FGF-19 increased and C4 decreased up to 95% and 92%, respectively. EDP-297 was generally well-tolerated up to 60 µg MAD, with linear PKs suitable for once daily oral dosing, target engagement, and no food effect.

EDP-514 in healthy subjects and nucleos(t)ide reverse transcriptase inhibitor-suppressed patients with chronic hepatitis B.

BACKGROUND: Chronic hepatitis B (CHB) remains a major cause of morbidity and mortality. EDP-514 is a potent core inhibitor of hepatitis B virus (HBV) that reduces viral load reduction in HBV-infected chimeric mice. This first-in-human study evaluated the safety, tolerability, and pharmacokinetics (PK) of EDP-514 in healthy subjects and antiviral activity in patients with CHB. METHODS: In Part 1, 82 subjects received placebo or EDP-514 in fed or fasted state as single ascending doses of 50-800 mg and multiple ascending doses of 200-800 mg for 14 days. In Part 2, 24 HBV DNA-suppressed, nucleos(t)ide (NUC)-treated (i.e., NUC-suppressed) CHB patients received EDP-514 200-800 mg or placebo for 28 days. RESULTS: EDP-514 was well tolerated in healthy subjects and CHB patients with most adverse events of mild intensity. In Part 1, EDP-514 exposure increased in an approximately dose proportional manner up to 600 mg after single doses and up to 400 mg after 14-day dosing. In Part 2, EDP-514 exposure increased linearly with dose on Day 1 and Day 28, with some accumulation for Day 28 and median trough concentrations (Ctrough) approximately 20-fold above the protein-adjusted 50% effective concentration (EC50) for the dose range. Mean change in HBV RNA from baseline to Day 28 was -2.03, -1.67, -1.87, and -0.58 log U/mL in the 200 mg, 400 mg, 800 mg, and placebo CHB groups, respectively. CONCLUSIONS: EDP-514 was well tolerated, had a PK profile supporting once daily dosing, and reduced HBV RNA levels in NUC-suppressed CHB patients.

SPINE20 recommendations 2022: spine care-working together to recover stronger.

PURPOSE: Globally, spine disorders are the leading cause of disability, affecting more than half a billion individuals. However, less than 50% of G20 countries specifically identify spine health within their public policy priorities. Therefore, it is crucial to raise awareness among policy makers of the disabling effect of spine disorders and their impact on the economic welfare of G20 nations. In 2019, SPINE20 was established as the leading advocacy group to bring global attention to spine disorders. METHODS: Recommendations were developed through two Delphi methods with international and multi-professional panels. RESULTS: In 2022, seven recommendations were delivered to the leaders of G20 countries, urging them to: Develop action plans to provide universal access to evidence-based spine care that incorporates the needs of minorities and vulnerable populations. Invest in the development of sustainable human resource capacity, through multisectoral and inter-professional competency-based education and training to promote evidence-based approaches to spine care, and to build an appropriate healthcare working environment that optimizes the delivery of safe health services. Develop policies using the best available evidence to properly manage spine disorders and to prolong functional healthy life expectancy in the era of an aging population. Create a competent workforce and improve the healthcare infrastructure/facilities including equipment to provide evidence-based inter-professional rehabilitation services to patients with spinal cord injury throughout their continuum of care. Build collaborative and innovative translational research capacity within national, regional, and global healthcare systems for state-of-the-art and cost-effective spine care across the healthcare continuum ensuring equality, diversity, and inclusion of all stakeholders. Develop international consensus statements on patient outcomes and how they can be used to define and develop pathways for value-based care. Recognize that intervening on determinants of health including physical activity, nutrition, physical and psychosocial workplace environment, and smoking-free lifestyle can reduce the burden of spine disabilities and improve the health status and wellness of the population. At the third SPINE20 summit 2022 which took place in Bali, Indonesia, in August 2022, 17 associations endorsed its recommendations. CONCLUSION: SPINE20 advocacy efforts focus on developing public policy recommendations to improve the health, welfare, and wellness of all who suffer from spinal pain and disability. We propose that focusing on facilitating access to systems that prioritize value-based care delivered by a competent healthcare workforce will reduce disability and improve the productivity of the G20 nations.

Assessment of drug-drug interaction potential with EDP-305, a farnesoid X receptor agonist, in healthy subjects.

EDP-305 is a farnesoid X receptor (FXR) agonist that selectively activates FXR and is a potential treatment for patients with nonalcoholic steatohepatitis (NASH) with liver fibrosis. Results from preclinical studies indicate that CYP3A4 is the primary enzyme involved in EDP-305 metabolism and that EDP-305 has low potential to inhibit or induce cytochrome (CYP) isoenzymes and drug transporters. Four studies were conducted in healthy volunteers to evaluate the drug-drug interaction (DDI) potential of EDP-305 co-administered with drugs known to be substrates for drug metabolizing enzymes or transporters, and to assess the effect of inhibitors and inducers of CYP3A4 on EDP-305. Results suggest caution when substrates of CYP3A4 are administered concomitantly with EDP-305. A potential for increased exposure is apparent when CYP1A2 substrates with a narrow therapeutic index are administered with EDP-305. In contrast, substrates of drug transporters can be administered concomitantly with EDP-305 with a low potential for interactions. Coadministration of EDP-305 and a combined OC had no relevant effects on plasma concentrations of the combined OC. Co-administration of EDP-305 with strong or moderate inhibitors and inducers of CYP3A4 is not recommended. These results indicate low overall likelihood of interaction of EDP-305 and other substrates through CYP mediated interactions. The interaction potential of EDP-305 with drug transporters was low and of unlikely clinical significance. The EDP-305 DDI profile allows for convenient administration in patients with NASH and other patient populations with comorbidities, with minimal dose modification of concomitant medications.

EDP-938, a Respiratory Syncytial Virus Inhibitor, in a Human Virus Challenge.

BACKGROUND: Respiratory syncytial virus (RSV) infection causes substantial morbidity and mortality among infants, older adults, and immunocompromised adults. EDP-938, a nonfusion replication inhibitor of RSV, acts by modulating the viral nucleoprotein. METHODS: In a two-part, phase 2a, randomized, double-blind, placebo-controlled challenge trial, we assigned participants who had been inoculated with RSV-A Memphis 37b to receive EDP-938 or placebo. Different doses of EDP-938 were assessed. Nasal-wash samples were obtained from day 2 until day 12 for assessments. Clinical symptoms were assessed by the participants, and pharmacokinetic profiles were obtained. The primary end point was the area under the curve (AUC) for the RSV viral load, as measured by reverse-transcriptase-quantitative polymerase-chain-reaction assay. The key secondary end point was the AUC for the total symptom score. RESULTS: In part 1 of the trial, 115 participants were assigned to receive EDP-938 (600 mg once daily [600-mg once-daily group] or 300 mg twice daily after a 500-mg loading dose [300-mg twice-daily group]) or placebo. In part 2, a total of 63 participants were assigned to receive EDP-938 (300 mg once daily after a 600-mg loading dose [300-mg once-daily group] or 200 mg twice daily after a 400-mg loading dose [200-mg twice-daily group]) or placebo. In part 1, the AUC for the mean viral load (hours × log10 copies per milliliter) was 204.0 in the 600-mg once-daily group, 217.7 in the 300-mg twice-daily group, and 790.2 in the placebo group. The AUC for the mean total symptom score (hours × score, with higher values indicating greater severity) was 124.5 in the 600-mg once-daily group, 181.8 in the 300-mg twice-daily group, and 478.8 in the placebo group. The results in part 2 followed a pattern similar to that in part 1: the AUC for the mean viral load was 173.9 in the 300-mg once-daily group, 196.2 in the 200-mg twice-daily group, and 879.0 in the placebo group, and the AUC for the mean total symptom score was 99.3, 89.6, and 432.2, respectively. In both parts, mucus production was more than 70% lower in each EDP-938 group than in the placebo group. The four EDP-938 regimens had a safety profile similar to that of placebo. Across all dosing regimens, the EDP-938 median time to maximum concentration ranged from 4 to 5 hours, and the geometric mean half-life ranged from 13.7 to 14.5 hours. CONCLUSIONS: All EDP-938 regimens were superior to placebo with regard to lowering of the viral load, total symptom scores, and mucus weight without apparent safety concerns. (ClinicalTrials.gov number, NCT03691623.).

EDP-305 in patients with NASH: A phase II double-blind placebo-controlled dose-ranging study.

BACKGROUND & AIMS: EDP-305 is an oral farnesoid X receptor (FXR) agonist under development for the treatment of non-alcoholic steatohepatitis (NASH). Herein, we aimed to assess the efficacy, safety and tolerability of EDP-305 in patients with fibrotic NASH. METHODS: In this double-blind phase II study, patients with fibrotic NASH (without cirrhosis), diagnosed by historical biopsy or phenotypically, were randomized to EDP-305 1 mg, EDP-305 2.5 mg, or placebo, for 12 weeks. The primary endpoint was mean change in alanine aminotransferase (ALT) from baseline to Week 12, and the key secondary endpoint was mean change in liver fat content from baseline to Week 12. RESULTS: Between January 2018 and July 2019, 134 patients were randomized and 132 were evaluated. At Week 12, the least squares mean reductions from baseline in ALT for patients receiving 2.5 mg EDP-305 and 1 mg EDP-305 were -27.9 U/L (95% CI 0.03 to 24.9; p = 0.049) and -21.7 U/L (-5.8 to 18.3: p = 0.304), respectively, compared to -15.4 U/L for those receiving placebo. Absolute liver fat reduction was -7.1% (2.0-7.5; p = 0.0009) with 2.5 mg EDP-305, -3.3% with EDP-305 1 mg, and -2.4% with placebo. The most common (≥5%) adverse events were pruritus, nausea, vomiting, diarrhea, headache, and dizziness. Pruritus occurred in 50.9%, 9.1%, and 4.2% of patients in the 2.5 mg, 1 mg, and placebo groups, respectively, and led to study drug discontinuation in 20.8% of patients in the 2.5 mg group and 1.8% in the 1 mg group. CONCLUSIONS: EDP-305 reduced ALT levels and liver fat content, providing support for a longer-term trial assessing histological endpoints in patients with NASH. CLINICALTRIALS. GOV NUMBER: NCT03421431 LAY SUMMARY: Non-alcoholic fatty liver disease is a chronic hepatic disease that can progress to non-alcoholic steatohepatitis (NASH), which is associated with an increased risk of cirrhosis and liver cancer. Results from this phase II study support continued development of EDP-305, an oral farnesoid X receptor agonist, for the treatment of patients with NASH.

Missing the point: Quality-driven healthcare institutions may mistakenly disregard their role in nursing and medical education.

Aligned with international standards, the UAE Government and many other developing countries in the region (GCC and MENA) have started to implement strict quality improvement initiatives to develop their healthcare systems. Most of these initiatives are geared toward meeting patient satisfaction and avoiding circumstances or events that would dissatisfy patients. It is also used to measure healthcare institution performance, assess efficiency and determine their funding and reimbursement. With this emphasis on quality, it is also important for healthcare organizations to fulfill their other functions. Among the most important is performing their teaching role to prepare future healthcare professionals, and attracting and retaining healthcare professionals. These roles are also a paramount for a quality, sustained healthcare system. However, clinical educators and managers reflect on how these roles seem to be frequently missed or at least compromised while applying the quality assurance measures in the region developing countries. This reflective paper discusses this concern and suggests possible strategies that may help overcome this challenge and thus contributing to the achievement of the quality goal of the service in a more comprehensive and sustainable manner. The similarities between the UAE healthcare system and neighboring Gulf Cooperation Council and the Middle East/North African countries mean these challenges and solutions may resonate with these countries and support the implementation of effective health services in these countries as well.

Clinical effectiveness of a topical subgingival application of injectable platelet-rich fibrin as adjunctive therapy to scaling and root planing: a double-blind, split-mouth, randomized, prospective, comparative controlled trial.

OBJECTIVE: The purpose of this randomized, controlled, split-mouth clinical trial was to clarify the clinical efficacy of using injectable platelet-rich fibrin (i-PRF) as an adjunctive subgingival irrigation to scaling and root planing (SRP) in the treatment of periodontitis. METHOD AND MATERIALS: The study was conducted in 15 patients suffering from stage II to III with grade B to C periodontitis with bilateral periodontal pockets (≥ 5 mm) on a minimum of two teeth without degree II or III of furcation involvement or tooth mobility. The evaluated clinical parameters were: Plaque Index (PI), bleeding on probing (BOP), probing pocket depth (PPD), clinical attachment level (CAL), and gingival recession at baseline and after 3 months. After full-mouth supra- and subgingival SRP, the sites were randomly divided into test sites receiving the subgingival application of i-PRF and controls treated with saline. The Wilcoxon test and Mann-Whitney U test were used for intra- and inter-group comparisons, respectively. RESULTS: In total, 726 sites were treated (388 test group and 338 control group) with no uneventful healing effects. Statistically significant decreases in PI (P = .001), BOP (P = .001 for both groups), PPD (P = .001 and P = .000 for test and control groups, respectively), CAL (P = .015 and P = .001 for test and control groups, respectively) between pretreatment and 3 months posttreatment were noted in both test and control groups. For inter-group comparisons, there was no statistically significant difference in all clinical indices (P > .05). CONCLUSION: In this study, both groups were clinically effective as nonsurgical periodontal treatments, without any clinical benefits of using i-PRF.

Synthesizing core nursing skills to support behavioural-based interviews for nurses in the UAE: A nominal group study.

AIM: To develop a bank of core clinical and performance skills to inform the future development of structured interview questions to aid the recruitment of nurses in the United Arab Emirates (UAE). BACKGROUND: The UAE depends on expatriate nurses with variable clinical and educational backgrounds. Given the global shortage of nurses, the UAE requires innovative recruitment methods to attract and retain quality nurses and ensure high-quality health care services. METHOD: Three cycles of a virtual nominal group technique (NGT) were used to elicit consensus from thirty (n = 30) frontline nurses on the core clinical and performance skills needed to work in three specialty areas (paediatric, outpatient and telemetry/transitional care). RESULTS: Ten performance skills and ten clinical skills were identified for each specialty area. Performance skills included communication and critical thinking with key clinical skills being medication administration/use, cardiac monitoring troubleshooting and recognizing arrhythmias. CONCLUSION: The identified core performance and clinical nursing skills provide the basis for the future development of specialty-specific questions or scenarios to aid interviewers in achieving an informed selection process. IMPLICATIONS FOR NURSING MANAGEMENT: The identified core performance and clinical skills provide the foundations for an appropriate interviewing/selection process, staff orientation, staff appraisal and continuous professional development.

Anti-MAdCAM-1 antibody (PF-00547659) for active refractory Crohn's disease in Japanese and Korean patients: the OPERA study.

BACKGROUND/AIMS: PF-00547659 is a monoclonal antibody against human mucosal addressin cell adhesion molecule-1 (MAdCAM-1) that prevents the binding of α4ß7+ lymphocytes to MAdCAM-expressing sites in the gastrointestinal tract with high affinity and selectivity, and is being developed for the treatment of Crohn's disease (CD). METHODS: OPERA is a randomized, multicenter, double-blind, placebo-controlled study to investigate the efficacy, safety, and pharmacokinetics of PF-00547659 following subcutaneous administration in subjects with active CD, a history of failure or intolerance to anti-tumor necrosis factor and/or immunosuppressants, high-sensitivity C-reactive protein > 3.0 mg/L, and ulcers on colonoscopy. The primary endpoint was Crohn's Disease Activity Index-70 response at week 8 or 12. Subpopulation analyses for Asian subjects were performed as some differences are observed in genetics and clinical phenotypes in Asian CD patients compared with Western patients. RESULTS: In this study, 265 CD subjects were randomized, with a subpopulation of 21 subjects (8 Japanese and 13 Korean) defined as the Asian population. In the overall and Asian populations; PF-00547659 was pharmacologically active as evidenced by soluble MAdCAM and circulating ß7+ central memory CD4+ T-lymphocytes, although no clear evidence of efficacy was observed in any clinical endpoints; pharmacokinetics of PF-00547659 in the Asian subpopulation was generally comparable to the overall population; and the safety profile of PF-00547659 appeared acceptable up to 12 weeks of treatment. CONCLUSIONS: In the overall and Asian populations, efficacy of PF-00547659 could not be demonstrated using any clinical endpoints compared with placebo. Pharmacokinetics and safety of PF-00547659 were generally comparable. Further studies with larger numbers of patients are required to confirm our results. (Trial Registration Number: NCT01276509).

Role of Stabilizing Surfactants on Capacitance, Charge, and Ion Transport in Organic Nanoparticle-Based Electronic Devices.

Deposition of functionalized nanoparticles onto solid surfaces has created a new revolution in electronic devices. Surface adsorbates such as ionic surfactants or additives are often used to stabilize such nanoparticle suspensions; however, little is presently known about the influence of such surfactants and additives on specific electronic and chemical functionality of nanoparticulate electronic devices. This work combines experimental measurements and theoretical models to probe the role of an ionic surfactant in the fundamental physical chemistry and electronic charge carrier behavior of photodiode devices prepared using multicomponent organic electronic nanoparticles. A large capacitance was detected, which could be subsequently manipulated using the external stimuli of light, temperature, and electric fields. It was demonstrated that analyzing this capacitance through the framework of classical semiconductor analysis produced substantially misleading information on the electronic trap density of the nanoparticles. Electrochemical impedance measurements demonstrated that it is actually the stabilizing surfactant that creates capacitance through two distinct mechanisms, each of which influenced charge carrier behavior differently. The first mechanism involved a dipole layer created at the contact interfaces by mobile ions, a mechanism that could be replicated by addition of ions to solution-cast devices and was shown to be the major origin of restricted electronic performance. The second mechanism consisted of immobile ionic shells around individual nanoparticles and was shown to have a minor impact on device performance as it could be removed upon addition of electronic charge in the photodiodes through either illumination or external bias. The results confirmed that the surfactant ions do not create a significantly increased level of charge carrier traps as has been previously suspected, but rather, preventing the diffusion of mobile ions through the nanoparticulate film and their accumulation at contacts is critical to optimize the performance.

Nurse-identified patient care and health services research priorities in the United Arab Emirates: a Delphi study.

BACKGROUND: The need for improved research on ill health has been recognized internationally and locally in the United Arab Emirates (UAE). The UAE Nursing and Midwifery Council recently committed to enhancing the status and contributions of nursing in healthcare research across the UAE by establishing a National Committee for Research Development. This study using a Delphi method to identify research priorities from the perspective of nurses delivering frontline healthcare. METHODS: A two-phase Delphi design was implemented with 1032 nurses participating in phase one of the study and 1339 in phase two. RESULTS: The most important priority was patient safety and healthcare professionals' awareness of international patient safety goals (including staffing levels and shift length) and potential effects on patient safety. Other important priorities were infection control practices and management of communicable diseases. CONCLUSIONS: These priorities may inform nursing research programs to improve patient care and health outcomes in the UAE and similar contexts worldwide.

Phase II evaluation of anti-MAdCAM antibody PF-00547659 in the treatment of Crohn's disease: report of the OPERA study.

OBJECTIVE: This phase II, randomised, double-blind, placebo-controlled clinical trial was designed to evaluate the efficacy and safety of PF-00547659, a fully human monoclonal antibody that binds to human mucosal addressin cell adhesion molecule (MAdCAM) to selectively reduce lymphocyte homing to the intestinal tract, in patients with moderate-to-severe Crohn's disease (CD). DESIGN: Eligible adults were aged 18-75 years, with active moderate-to-severe CD (Crohn's Disease Activity Index (CDAI) 220-450), a history of failure or intolerance to antitumour necrosis factor and/or immunosuppressive agents, high-sensitivity C reactive protein >3.0 mg/L and ulcers on colonoscopy. Patients were randomised to PF-00547659 22.5 mg, 75 mg or 225 mg or placebo. The primary endpoint was CDAI 70-point decrease from baseline (CDAI-70) at week 8 or 12. RESULTS: In all, 265 patients were eligible for study entry. Although CDAI-70 response was not significantly different with placebo versus PF-00547659 treatment at weeks 8 or 12, remission rate was greater in patients with higher baseline C reactive protein (>5 mg/L vs >18.8 mg/L, respectively). Soluble MAdCAM decreased significantly from baseline to week 2 in a dose-related manner and remained low during the study in PF-00547659-treated patients. Circulating ß7+ CD4+ central memory T-lymphocytes increased at weeks 8 and 12 with PF-00547659 treatment. No safety signal was seen. CONCLUSIONS: Clinical endpoint differences between PF-00547659 and placebo did not reach statistical significance in patients with moderate-to-severe CD. PF-00547659 was pharmacologically active, as shown by a sustained dose-related decrease in soluble MAdCAM and a dose-related increase in circulating ß7+ central memory T cells. TRIAL REGISTRATION NUMBER: NCT01276509; Results.

Effect of PF-00547659 on Central Nervous System Immune Surveillance and Circulating ß7+ T Cells in Crohn's Disease: Report of the TOSCA Study.

BACKGROUND AND AIMS: Progressive multifocal leukoencephalopathy [PML], a brain infection associated with anti-integrin drugs that inhibit lymphocyte translocation from bloodstream to tissue, can be fatal. Decreased central nervous system [CNS] immune surveillance leading to this infection has been reported in patients with multiple sclerosis or Crohn's disease treated with anti-integrin antibody natalizumab. PF-00547659 is an investigational human monoclonal antibody for inflammatory bowel disease, targeted against α4ß7-mucosal addressin cell-adhesion molecule-1 [the integrin ligand selectively expressed in the gut]. We hypothesised that this selective agent would not affect central nervous system immune surveillance. METHODS: Cerebrospinal fluid from five healthy volunteers, and from 10 patients with Crohn's disease previously treated with immunosuppressants, was evaluated to assess the feasibility of the study. Subsequently, 39 patients with active Crohn's disease and previous immunosuppression were evaluated over 12 weeks of PF-00547659-induction therapy. We measured total lymphocytes, T cell subsets in cerebrospinal fluid, and circulating ß7+ memory cells. Disease activity was assessed using the Harvey-Bradshaw Index. RESULTS: Patients treated with PF-00547659 had no reduction of cerebrospinal fluid lymphocytes, T-lymphocyte subsets, or CD4:CD8 ratio, whereas circulating ß7+ memory cells increased significantly. A total of 28/35 [80%] patients had a clinical response and 27/34 [79%] had disease remission. Treatment-related adverse events, none serious, were reported in 23/49 [47%] patients. CONCLUSIONS: In patients with active Crohn's disease, natalizumab therapy increases the risk for PML, and the increased risk is thought to be associated with iatrogenic leukopenia within the CNS. PML under PF-00547659 may be a lesser concern, as this agent did not reduce lymphocytes or T cell subsets in the cerebrospinal fluid.

Anti-MAdCAM Antibody Increases ß7+ T Cells and CCR9 Gene Expression in the Peripheral Blood of Patients With Crohn's Disease.

OBJECTIVE: To define pharmacodynamic biomarkers in the peripheral blood of patients with Crohn's disease [CD] after treatment with PF-00547659, an anti-human mucosal addressin cell adhesion molecule-1 [MAdCAM-1] monoclonal antibody. METHODS: In this Phase 2, randomised, double-blind, controlled study [OPERA], blood samples were analysed from patients with moderate to severe active CD who received placebo or 22.5 mg, 75 mg, or 225 mg of PF-00547659 subcutaneously at baseline and at Weeks 4 and 8, with follow-up at Week 12. Soluble MAdCAM [sMAdCAM] was measured by mass spectrometry, ß7-expressing T cells by flow cytometry, and gene transcriptome by RNA sequencing. RESULTS: A slight increase in sMAdCAM was measured in the placebo group from baseline to Week 12 [6%], compared with significant decreases in all PF-00547659 groups [-87% to -98%]. A slight increase from baseline to Week 12 was observed in frequency and molecules of equivalent soluble fluorochrome for ß7+ central memory T cells in the placebo group [4%], versus statistically significant increases in the active treatment groups [48% to 81%]. Similar trends were seen for ß7+ effector memory T cells [placebo, 8%; PF-00547659, 84-138%] and ß7+ naïve T cells [8%; 13-50%]. CCR9 gene expression had statistically significant up-regulation [p = 1.09e-06; false discovery rate < 0.1] with PF-00547659 treatment, and was associated with an increase in ß7+ T cells. CONCLUSIONS: Results of the OPERA study demonstrate positive pharmacology and dose-dependent changes in pharmacodynamic biomarker measurements in blood, including changes in cellular composition of lymphocytes and corresponding CCR9 gene expression changes.