Synthesis, Biological and In Silico Evaluation of Pure Nucleobase-Containing Spiro (Indane-Isoxazolidine) Derivatives as Potential Inhibitors of MDM2-p53 Interaction.

Nucleobase-containing isoxazolidines spiro-bonded to an indane core have been synthesized in very good yields by regio- and diastereoselective 1,3-dipolar cycloaddition starting from indanyl nitrones and N-vinylnucleobases by using environmentally benign microwave technology. The contemporary presence of various structural groups that are individually active scaffolds of different typology of drugs, has directed us to speculate that these compounds may act as inhibitors of MDM2-p53 interaction. Therefore, both computational calculations and antiproliferative screening against A549 human lung adenocarcinoma cells and human SH-SY5Y neuroblastoma cells were carried out to support this hypothesis.

Impact of an automated test results management system on patients' satisfaction about test result communication.

BACKGROUND: Few reliable and efficient systems support the communication of test results to outpatients, and this may lead to patient dissatisfaction with test result communication. The objective of this study was to assess the impact of physicians' use of a test results management tool embedded in an electronic health record on patient satisfaction with test result communication. METHODS: A prospective, cluster-randomized, controlled trial of 570 patient encounters in 26 outpatient primary care practices was performed from December 1, 2002, to April 31, 2005. Physicians in the intervention practices were trained and given access to a physician test results management tool with imbedded patient notification functions to evaluate whether patient satisfaction with communication of test results ordered by the primary care provider was improved. Patient satisfaction surveys were conducted by telephone after the patient underwent the test and were administered before and after the intervention in both arms. RESULTS: The survey response rate after successful patient contact was 74.2% (570/768). After adjusting for patient age, sex, race, socioeconomic status, and insurance type, the intervention significantly increased patient satisfaction with test results communication (odds ratio, 2.35; 95% confidence interval, 1.05-5.25; P = .03). In addition, patients in the postintervention group were more satisfied with information given them for medical treatments and conditions regarding their results (odds ratio, 3.45; 95% confidence interval, 1.30-9.17; P = .02). CONCLUSION: An automated test results management system can improve patient satisfaction with communication of test results ordered by their primary care provider and can improve patient satisfaction with the communication of information regarding their condition and treatment plans.

Patient, Provider, and System Factors Associated With Failure to Follow-Up Elevated Glucose Results in Patients Without Diagnosed Diabetes.

BACKGROUND: Although elevated glucose values are strongly associated with undiagnosed diabetes, they are frequently overlooked. Patient, provider, and system factors associated with failure to follow-up elevated glucose values in electronic medical records (EMRs) are not well described. METHODS: We conducted a chart review in a comprehensive EMR with a patient portal and results management features. Established primary care patients with no known diagnosis of diabetes and ≥ 1 glucose value >125 mg/dL were included. Follow-up failure was defined as (1) no documented comment on the glucose value or result communication to the patient within 30 days or (2) no hemoglobin A1c (HbA1c) ordered within 30 days or resulted within 12 months. Associations were examined using Wilcoxon and χ2 tests. RESULTS: Of 150 charts reviewed, 97 met inclusion criteria. The median glucose was 133 mg/dL, and 20% of patients had multiple values >125 mg/dL. Only 36% of elevated glucose values were followed up. No associations were observed between patient characteristics, diabetes risk factors, or provider characteristics and follow-up failures. Automated flagging of glucose values ≥140 mg/dL by highlighting them red in the EMR was not associated with improved follow-up (46% vs 32%; P = .19). Even when follow-up occurred (n = 35), only 31% completed gold standard diabetes testing (HbA1c) within 12 months. Of the resulted HbA1c tests (n = 11), 55% were in the prediabetes range (5.7%-6.4%). CONCLUSIONS: Two-thirds of elevated glucose values were not followed up, despite EMR features facilitating results management. Greater understanding of the results management process and improved EMR functionalities to support results management are needed.

Reasons for Lack of Diagnostic Colonoscopy After Positive Result on Fecal Immunochemical Test in a Safety-Net Health System.

BACKGROUND: Effective colorectal cancer screening depends on timely diagnostic evaluation in patients with abnormal results on fecal immunochemical tests (FITs). Although prior studies suggest low rates of follow-up colonoscopy, there is little information among patients in safety-net health systems and few data characterizing reasons for low follow-up rates. This study aimed to characterize factors contributing to lack of follow-up colonoscopy in a racially diverse and socioeconomically disadvantaged cohort of patients with abnormal results on FIT ("abnormal FIT" for brevity) receiving care in an integrated safety-net health system. METHODS: We performed a retrospective electronic medical record review of patients aged 50-64 years with abnormal FIT at a population-based safety-net health system between January 2010 and July 2013. Review of electronic medical records focused on patients without follow-up colonoscopy to characterize patient-, provider-, and system-level reasons for lack of diagnostic evaluation. We used logistic regression analysis to identify predictors of follow-up colonoscopy within 12 months of abnormal FIT. RESULTS: Of 1267 patients with abnormal FIT, 536 (42.3%) failed to undergo follow-up colonoscopy within 1 year. Failure was attributable to patient-level factors in 307 (57%) cases, provider factors in 97 (18%) cases, and system factors in 118 (22%) cases. In multivariate analysis, follow-up colonoscopy was less likely among those aged 61-64 years (odds ratio 0.63, 95% confidence interval 0.46-0.87) compared with 50-55 year olds. CONCLUSIONS: Nearly half (42%) of patients with abnormal FIT failed to undergo follow-up colonoscopy within 1 year. Lack of diagnostic evaluation is related to a combination of patient-, provider-, and system-level factors, highlighting the need for multilevel interventions to improve follow-up colonoscopy completion rates.

Study on the Pulmonary Delivery System of Apigenin-Loaded Albumin Nanocarriers with Antioxidant Activity.

BACKGROUND: Respiratory diseases are mainly derived from acute and chronic inflammation of the alveoli and bronchi. The pathophysiological mechanisms of pulmonary inflammation mainly arise from oxidative damage that could ultimately lead to acute lung injury. Apigenin (Api) is a natural polyphenol with prominent antioxidant and anti-inflammatory properties in the lung. Inhalable formulations that consist of nanoparticles (NPs) have several advantages over other administration routes, and therefore, this study investigated the application of apigenin-loaded bovine serum albumin nanoparticles (BSA-Api-NPs) for pulmonary delivery. METHODS: Dry powder formulations of BSA-Api-NPs were prepared by spray drying and characterized by laser diffraction particle sizing, scanning electron microscopy, differential scanning calorimetry, and powder X-ray diffraction. The influence of dispersibility enhancers (lactose monohydrate and l-leucine) on the in vitro aerosol deposition using a next-generation impactor was investigated in comparison to excipient-free formulation. The dissolution of Api was determined in simulated lung fluid by using the Franz cell apparatus. The antioxidant activity was determined by 2,2-diphenyl-1-picrylhydrazyl (DPPH⋅) free radical scavenging assay. RESULTS: The encapsulation efficiency and the drug loading were measured to be 82.61% ± 4.56% and 7.51% ± 0.415%. The optimized spray drying conditions were suitable to produce particles with low residual moisture content. The spray-dried BSA-Api-NPs possessed good aerodynamic properties due to small and wrinkled particles with low mass median aerodynamic diameter, high emitted dose, and fine particle fraction. The aerodynamic properties were enhanced by leucine and decreased by lactose, however, the dissolution was reversely affected. The DPPH⋅ assay confirmed that the antioxidant activity of encapsulated Api was preserved. CONCLUSION: This study provides evidence to support that albumin nanoparticles are suitable carriers of Api and the use of traditional or novel excipients should be taken into consideration. The developed BSA-Api-NPs are a novel delivery system against lung injury with potential antioxidant activity.

Patient safety concerns arising from test results that return after hospital discharge.

BACKGROUND: Failure to relay information about test results pending when patients are discharged from the hospital may pose an important patient-safety problem. Few data are available on the epidemiology of test results pending at discharge or on physician awareness of these results. OBJECTIVE: To determine the prevalence, characteristics, and physician awareness of potentially actionable laboratory and radiologic test results returning after hospital discharge. DESIGN: Cross-sectional study. SETTING: Two tertiary care academic hospitals. PATIENTS: 2644 consecutive patients discharged from hospitalist services from February to June 2004. MEASUREMENTS: The main outcomes were the prevalence and characteristics of potentially actionable test results returning after hospital discharge, awareness of these results by inpatient and primary care physicians, and satisfaction of inpatient physicians with current systems for follow-up on test results. The authors prospectively collected data on test results pending at the time of discharge and, as results returned after discharge, surveyed hospitalists, junior residents, and primary care physicians about those results that were potentially actionable according to a physician-reviewer. RESULTS: A total of 1095 patients (41%) had 2033 test results return after discharge. Of these results, 191 (9.4% [95% CI, 8.0% to 11.0%]) were potentially actionable. Surveys were sent regarding 155 results, and 105 responses were returned. Of the 105 results in the surveys with responses, physicians had been unaware of 65 (61.6% [CI, 51.3% to 70.9%]); of these 65, they agreed with physician-reviewers that 24 (37.1% [CI, 25.7% to 50.2%]) were actionable and 8 (12.6% [CI, 6.4% to 23.3%]) required urgent action. Inpatient physicians were dissatisfied with their systems for following up on test results returning after discharge. LIMITATIONS: The authors were unable to determine whether physicians' lack of awareness of test results returning after discharge was associated with adverse outcomes. CONCLUSIONS: Many patients are discharged from hospitals with test results still pending, and physicians are often unaware of potentially actionable test results returning after discharge. Further work is needed to design better follow-up systems for test results returning after hospital discharge.

Primary-Care Weight-Management Strategies: Parental Priorities and Preferences.

OBJECTIVE: To examine parental perspectives/rankings of the most important weight-management clinical practices and to determine whether preferences/rankings differ when parents disagree that their child is overweight. METHODS: We performed mixed-methods analysis of a 32-question survey of parents of 2- to 18-year-old overweight children assessing parental agreement that their child is overweight, the single most important thing providers can do to improve weight status, ranking American Academy of Pediatrics-recommended clinical practices, and preferred follow-up interval. Four independent reviewers analyzed open-response data to identify qualitative themes/subthemes. Multivariable analyses examined parental rankings, preferred follow-up interval, and differences by agreement with their child's overweight assessment. RESULTS: Thirty-six percent of 219 children were overweight, 42% obese, and 22% severely obese; 16% of parents disagreed with their child's overweight assessment. Qualitative analysis of the most important practice to help overweight children yielded 10 themes; unique to parents disagreeing with their children's overweight assessments was "change weight-status assessments." After adjustment, the 3 highest-ranked clinical practices included, "check for weight-related problems," "review growth chart," and "recommend general dietary changes" (all P < .01); parents disagreeing with their children's overweight assessments ranked "review growth chart" as less important and ranked "reducing screen time" and "general activity changes" as more important. The mean preferred weight-management follow-up interval (10-12 weeks) did not differ by agreement with children's overweight assessments. CONCLUSIONS: Parents prefer weight-management strategies that prioritize evaluating weight-related problems, growth-chart review, and regular follow-up. Parents who disagree that their child is overweight want changes in how overweight is assessed. Using parent-preferred weight-management strategies may prove useful in improving child weight status.

A New Era of Pulmonary Delivery of Nano-antimicrobial Therapeutics to Treat Chronic Pulmonary Infections.

Pulmonary infections may be fatal especially in immunocompromised patients and patients with underlying pulmonary dysfunction, such as those with cystic fibrosis, chronic obstructive pulmonary disorder, etc. According to the WHO, lower respiratory tract infections ranked first amongst the leading causes of death in 2012, and tuberculosis was included in the top 10 causes of death in low income countries, placing a considerable strain on their economies and healthcare systems. Eradication of lower respiratory infections is arduous, leading to high healthcare costs and requiring higher doses of antibiotics to reach optimal concentrations at the site of pulmonary infection for protracted periods. Hence direct inhalation to the respiratory epithelium has been investigated extensively in the past decade, and seems to be an attractive approach to eradicate and hence overcome this widespread problem. Moreover, engineering inhalation formulations wherein the antibiotics are encapsulated within nanoscale carriers could serve to overcome many of the limitations faced by conventional antibiotics, like difficulty in treating intracellular pathogens such as mycobacteria spp. and salmonella spp., biofilmassociated pathogens like Pseudomonas aeruginosa and Staphylococcus aureus, passage through the sputum associated with disorders like cystic fibrosis and chronic obstructive pulmonary disorder, systemic side effects following oral/parenteral delivery and inadequate concentrations of antibiotic at the site of infection leading to resistance. Encapsulation of antibiotics in nanocarriers may help in providing a protective environment to combat antibiotic degradation, confer controlled-release properties, hence reducing dosing frequency, and may increase uptake via specific and non-specific targeting modalities. Hence nanotechnology combined with direct administration to the airways using commercially available delivery devices, is a highly attractive formulation strategy to eradicate microorganisms from the lower respiratory tract, which might otherwise present opportunities for multi-drug resistance.

Dry powder pulmonary delivery of cationic PGA-co-PDL nanoparticles with surface adsorbed model protein.

Pulmonary delivery of macromolecules has been the focus of attention as an alternate route of delivery with benefits such as; large surface area, thin alveolar epithelium, rapid absorption and extensive vasculature. In this study, a model protein, bovine serum albumin (BSA) was adsorbed onto cationic PGA-co-PDL polymeric nanoparticles (NPs) prepared by a single emulsion solvent evaporation method using a cationic surfactant didodecyldimethylammonium bromide (DMAB) at 2% w/w (particle size: 128.64±06.01 nm and zeta-potential: +42.32±02.70 mV). The optimum cationic NPs were then surface adsorbed with BSA, NP:BSA (100:4) ratio yielded 10.01±1.19 µg of BSA per mg of NPs. The BSA adsorbed NPs (5 mg/ml) were then spray-dried in an aqueous suspension of L-leucine (7.5 mg/ml, corresponding to a ratio of 1:1.5/NP:L-leu) using a Büchi-290 mini-spray dryer to produce nanocomposite microparticles (NCMPs) containing cationic NPs. The aerosol properties showed a fine particle fraction (FPF, dae<4.46 µm) of 70.67±4.07% and mass median aerodynamic diameter (MMAD) of 2.80±0.21 µm suggesting a deposition in the respiratory bronchiolar region of the lungs.The cell viability was 75.76±03.55% (A549 cell line) at 156.25 µg/ml concentration after 24 h exposure. SDS-PAGE and circular dichroism (CD) confirmed that the primary and secondary structure of the released BSA was maintained. Moreover, the released BSA showed 78.76±1.54% relative esterolytic activity compared to standard BSA.

Ascorbyl palmitate/DSPE-PEG nanocarriers for oral iron delivery: preparation, characterisation and in vitro evaluation.

The objective of this study was to encapsulate iron in nanocarriers formulated with ascorbyl palmitate and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine polyethylene glycol (DSPE-PEG) for oral delivery. Blank and iron (Fe) loaded nanocarriers were prepared by a modified thin film method using ascorbyl palmitate and DSPE-PEG. Surface charge of the nanocarriers was modified by the inclusion of chitosan (CHI) during the formulation process. Blank and iron loaded ascorbyl palmitate/DSPE nanocarriers were visualised by transmission electron microscopy (TEM) and physiochemical characterisations of the nanocarriers carried out to determine the mean particle size and zeta potential. Inclusion of chitosan imparted a net positive charge on the nanocarrier surface and also led to an increase in mean particle size. Iron entrapment in ascorbyl palmitate-Fe and ascorbyl palmitate-CHI-Fe nanocarriers was 67% and 76% respectively, suggesting a beneficial effect of chitosan on nanocarrier Fe entrapment. Iron absorption was estimated by measuring Caco-2 cell ferritin formation using ferrous sulphate as a reference standard. Iron absorption from ascorbyl palmitate-Fe (592.17±21.12 ng/mg cell protein) and ascorbyl palmitate-CHI-Fe (800.12±47.6 ng/mg, cell protein) nanocarriers was 1.35-fold and 1.5-fold higher than that from free ferrous sulphate, respectively (505.74±23.73 ng/mg cell protein) (n=6, p<0.05). This study demonstrates for the first time preparation and characterisation of iron loaded ascorbyl palmitate/DSPE PEG nanocarriers, and that engineering of the nanocarriers with chitosan leads to a significant augmentation of iron absorption.

Laparoscopic-assisted ureteroureterostomy for duplication anomalies in children.

PURPOSE: To describe a novel laparoscopic-assisted technique for ureteroureterostomy for the surgical management of a completely duplicated collecting system with an obstructed and/or ectopic ureter. PATIENTS AND METHODS: A camera is placed through a 5-mm infraumbilical port and the duplicated ureters identified and delivered through a small inguinal incision with a laparoscopic Babcock clamp. The ureteroureterostomy is performed in an open fashion. The mean operative time, length of stay, success, and complications of nine patients who underwent this technique were reviewed and compared with a cohort of patients who underwent open ureteroureterostomy at a single institution. In addition, the existing literature on laparoscopic and robot-assisted ureteroureterostomy is reviewed. RESULTS: There were no statistically significant differences in operative time (134 vs 133 min, P=0.950), length of stay (0.32 vs 0.33 days, P=0.929), complications (2 and 2, P=0.574), or rates of success (95% vs 100%, P=1.00) between the open and laparoscopic-assisted ureteroureterostomy groups. In addition, the operative times and length of stay in our laparoscopic cohort were shorter than a majority of the laparoscopic and robotic cases reported in the literature. CONCLUSIONS: Laparoscopic-assisted ureteroureterostomy is a successful technique for the management of an ectopic and/or obstructed ureter in a completely duplicated collecting system. This technique combines the speed and ease of the open technique with the improved cosmesis and visualization of a laparoscopic approach and is thus a useful approach for the pediatric urologist.

Engineering hydrophobically modified chitosan for enhancing the dispersion of respirable microparticles of levofloxacin.

The potential of amphiphilic chitosan formed by grafting octanoyl chains on the chitosan backbone for pulmonary delivery of levofloxacin has been studied. The success of polymer synthesis was confirmed using FT-IR and NMR, whilst antimicrobial activity was assessed against Pseudomonas aeruginosa. Highly dispersible dry powders for delivery as aerosols were prepared with different amounts of chitosan and octanoyl chitosan to study the effect of hydrophobic modification and varying concentration of polymer on aerosolization of drug. Powders were prepared by spray-drying from an aqueous solution containing levofloxacin and chitosan/amphiphilic octanoyl chitosan. l-leucine was also used to assess its effect on aerosolization. Following spray-drying, the resultant powders were characterized using scanning electron microscopy, laser diffraction, dynamic light scattering, HPLC, differential scanning calorimetry, thermogravimetric analysis and X-ray powder diffraction. The in vitro aerosolization profile was determined using a Next Generation Impactor, whilst in vitro antimicrobial assessment was performed using MIC assay. Microparticles of chitosan have the property of mucoadhesion leading to potential increased residence time in the pulmonary mucus, making it important to test the toxicity of these formulations. In-vitro cytotoxicity evaluation using MTT assay was performed on A549 cell line to determine the toxicity of formulations and hence feasibility of use. The MTT assay confirmed that the polymers and the formulations were non-cytotoxic. Hydrophobically modifying chitosan showed significantly lower MIC (4-fold) than the commercial chitosan against P. aeruginosa. The powders generated were of suitable aerodynamic size for inhalation having a mass median aerodynamic diameter less than 4.5µm for formulations containing octanoyl chitosan. These highly dispersible powders have minimal moisture adsorption and hence an emitted dose of more than 90% and a fine particle fraction (FPF) of 52%. Powders with non-modified chitosan showed lower dispersibility, with an emitted dose of 72% and FPF of 20%, as a result of high moisture adsorption onto the chitosan matrix leading to cohesiveness and subsequently decreased dispersibility.