Statewide Antibiotic Stewardship: : An eBrightHealth Choosing Wisely Initiative.

OBJECTIVE: To implement a collaborative statewide antibiotic stewardship initiative in both the ambulatory and inpatient settings. METHODS: Five participating Delaware health systems each convened internal team(s) to translate the vision set forth by the eBrightHealth LLC Choosing Wisely Work Group into clinical action through process improvement efforts at their institutions. The teams focused on implementing antibiotic time-outs, and on improving antibiotic prescribing for upper respiratory infections in ambulatory settings. The learning network utilized an "all teach, all learn" methodology via monthly conference calls and quarterly face-to-face meetings. RESULTS: All inpatient teams implemented antibiotic time-outs for at least 1 unit. Other interventions included commitment posters; submitting antibiotic utilization data nationally; provider/patient surveys; local stewardship champions; and provider prescribing data feedback. Barriers to implementation included competing priorities, lack of reliable utilization data, and suboptimal provider engagement. Overall antibiotic utilization decreased by 9%, compared to the pre-intervention period. CONCLUSIONS: This initiative has demonstrated the value of multidisciplinary teams, from varying healthcare systems, coming together to work on a single project. While each team's interventions and specific goals differed slightly, all teams implemented new initiatives to promote appropriate use of antibiotics. POLICY IMPLICATIONS: Antibiotic stewardship is a national priority. Acute care hospitals are required to have antibiotic stewardship programs; similar programs are proposed for ambulatory settings.

Structural and functional cerebral bases of diminished inhibitory control during healthy aging.

Inhibitory control or the ability to refrain from incorrect responses is a critical executive function known to diminish during aging. Imaging studies have elucidated cerebral changes that may underlie the age-related deficits. However, it remains unclear whether the structural and functional changes occur in the same brain regions and whether reduced gray matter volumes (GMV) mediate decreased activation during inhibition. Here, in a sample of 149 participants, we addressed the issues using structural and functional magnetic resonance imaging. Individual's response inhibition was evaluated by the stop signal reaction time (SSRT) in a stop signal task. The results showed that age was associated with prolonged SSRT across participants. Many cortical and subcortical regions demonstrated age-related reduction in GMV and activation to response inhibition. Additionally, age-related diminution in inhibitory control, as indexed by the SSRT, was associated with both shared and distinct morphometric and functional changes. Voxel-based morphometry demonstrated age-related reduction in GMV in the right dorsolateral prefrontal cortex and caudate head as well as bilateral insula, in association with prolonged SSRT. In a contrast of stop success versus go success trials, age was associated with lower activation in the medial and inferior frontal cortex and inferior parietal cortex. Further, reduction in GMV mediated age-related differences in activations only of the medial prefrontal cortex, providing limited evidence for structure function association. Thus, the decline in inhibitory control, as evidenced in the stop signal task, manifest with both shared and distinct structural and functional processes during aging.

Resting state functional connectivity of the amygdala and problem drinking in non-dependent alcohol drinkers.

Alcohol misuse is associated with dysfunction of the amygdala-prefrontal cortical circuit. The amygdala and its cortical targets show decreased activity during a variety of task challenges in individuals engaged in problem drinking. On the other hand, it is less clear how amygdala resting state functional connectivity (rsFC) may be altered in association with alcohol misuse and whether such changes are restricted to prefrontal cortical structures. Further, the influences of comorbid substance use and depression and potential sex differences have not been assessed in earlier work. Here, with fMRI data from a Nathan Kline Institute/Rockland sample of 83 non-dependent alcohol drinkers (26 men), we addressed changes in whole brain rsFC of the amygdala in association with problem drinking as indexed by an alcohol involvement score. Imaging data were processed with Statistical Parametric Mapping following standard routines and all results were examined at voxel p < 0.001 uncorrected in combination with cluster p < 0.05 corrected for false discovery rate. Alcohol misuse was correlated with decreased amygdala connectivity with the dorsal anterior cingulate cortex (dACC) irrespective of depression and other substance use. Changes in amygdala-dACC connectivity manifested in the latero-basal subdivision of the amygdala. Further, men as compared to women showed a significantly stronger relationship in decreased amygdala-dACC connectivity and problem drinking, although it should be noted that men also showed a trend toward higher alcohol involvement score than women. The findings add to a growing literature documenting disrupted amygdala-prefrontal cortical functions in relation to alcohol misuse.

Vitamin D Supplementation Reduces Induction of Epithelial-Mesenchymal Transition in Allergen Sensitized and Challenged Mice.

Asthma is a chronic disease of the lung associated with airway hyperresponsiveness (AHR), airway obstruction and airway remodeling. Airway remodeling involves differentiation of airway epithelial cells into myofibroblasts via epithelial-mesenchymal transition (EMT) to intensify the degree of subepithelial fibrosis. EMT involves loss in E-cadherin with an increase in mesenchymal markers, including vimentin and N-cadherin. There is growing evidence that vitamin D has immunomodulatory and anti-inflammatory properties. However, the underlying molecular mechanisms of these effects are still unclear. In this study, we examined the contribution of vitamin D on the AHR, airway inflammation and expression of EMT markers in the airways of mice sensitized and challenged with a combination of clinically relevant allergens, house dust mite, ragweed, and Alternaria (HRA). Female Balb/c mice were fed with vitamin D-sufficient (2000 IU/kg) or vitamin D-supplemented (10,000 IU/kg) diet followed by sensitization with HRA. The density of inflammatory cells in the bronchoalveolar lavage fluid (BALF), lung histology, and expression of EMT markers by immunofluorescence were examined. Vitamin D-supplementation decreased AHR, airway inflammation in the BALF and the features of airway remodeling compared to vitamin D-sufficiency in HRA-sensitized and -challenged mice. This was accompanied with increased expression of E-cadherin and decreased vimentin and N-cadherin expression in the airways. These results indicate that vitamin D may be a beneficial adjunct in the treatment regime in allergic asthma.

The impact of vitamin D on asthmatic human airway smooth muscle.

Asthma is a chronic heterogeneous disorder, which involves airway inflammation, airway hyperresponsiveness (AHR) and airway remodeling. The airway smooth muscle (ASM) bundle regulates the broncho-motor tone and plays a critical role in AHR as well as orchestrating inflammation. Vitamin D deficiency has been linked to increased severity and exacerbations of symptoms in asthmatic patients. It has been shown to modulate both immune and structural cells, including ASM cells, in inflammatory diseases. Given that current asthma therapies have not been successful in reversing airway remodeling, vitamin D supplementation as a potential therapeutic option has gained a great deal of attention. Here, we highlight the potential immunomodulatory properties of vitamin D in regulating ASM function and airway inflammation in bronchial asthma.

Robot-assisted retroperitoneal lymph node dissection in testicular cancer.

Robotic surgical techniques are now being applied in the setting of retroperitoneal lymphadenectomy (RPLND) for testicular cancer. While laparoscopic RPLND has not been widely accepted, reports of robot assisted RPLND (RARPLND) are emerging. This manuscript will review the application of RPLND for testicular cancer, evolution of minimally invasive techniques, the controversies, and current status of RARPLND.

Improving Clinic Productivity through a Shared Medical Appointment.

INTRODUCTION: Physicians are increasingly challenged to balance quality health care with fewer resources and limited time. To help achieve this balance, shared medical appointments have been described. We improved clinic-wide access to care by creating a shared medical appointment for minor penile complaints and anomalies. METHODS: We implemented a shared medical appointment in April 2013. We developed an intake form to efficiently gather patient history, and a standardized presentation to discuss diagnosis, treatment options, risks and benefits. Outcomes assessed included access to care time, the rate at which patients were seen within a target of 28 days, the number of appointments scheduled and patient complaints. To control for provider availability we evaluated the number of vacation days and operating room cases for the sole pediatric urologist. Data were analyzed using the Mann-Whitney U test. RESULTS: The periods of November 2012 to March 2013 and May 2013 to September 2013 were evaluated. There was a statistically significant improvement in median (IQR) access to care, with a decrease from 26.6 days (26.4, 29.4) before to 20 days (17.1, 24.3) after implementation of the shared medical appointment (p=0.0163). The goal access to care standard was met with a median (IQR) of 81.4% (56.7, 82.8) after the shared medical appointment compared to 44.3% (25.0, 46.9) before the shared appointment (p=0.0283). After implementation of the shared medical appointment, more appointments were scheduled per month at 161 (156, 165) vs 128 (120, 130; p=0.1172). CONCLUSIONS: We successfully implemented a shared medical appointment and significantly improved our clinic productivity. This program allowed us to improve access to care by almost 1 week and to increase the overall volume of patients seen monthly.

Etiology of azoospermia in a military population.

PURPOSE: Male infertility is commonly seen at urology clinics and 10% to 20% of infertile males are found to be azoospermic. Azoospermia is classically categorized as nonobstructive or obstructive. This classification tailors the evaluation, diagnosis and proper treatment. We performed a retrospective study to provide an updated etiology of azoospermia in patients in the United States in a universal health care model. MATERIALS AND METHODS: We retrospectively reviewed the records of men with azoospermia who presented to our institution between 2004 and 2012. Laboratory data were analyzed, included semen analysis, follicle-stimulating hormone, luteinizing hormone, testosterone, semen fructose and genetic studies. Patients underwent scrotal exploration as indicated for testis biopsy and sperm extraction. RESULTS: We reviewed 139 outpatient records. Nonobstructive azoospermia was diagnosed in 99 men (71%), including 33 (34%) identified with Sertoli-cell only syndrome. Other etiologies included an idiopathic cause in 25 cases (26%), Klinefelter syndrome in 9 (9%), maturation arrest in 9 (9%), Y chromosome microdeletion in 5 (5%), cryptorchidism in 4 (4%), trauma in 4 (4%), exogenous testosterone supplementation in 4 (4%) and other genetic disorders in 6 (6%). Obstructive azoospermia was identified in 40 men (29%), of whom 16 (40%) had congenital bilateral absence of the vas deferens. Other etiologies included an idiopathic cause in 11 cases (28%), an iatrogenic condition due to a surgical cause in 5 (13%), ejaculatory duct obstruction in 3 (8%), trauma in 1 (3%), retrograde ejaculation in 1 (3%), vas deferens occlusion in 2 (5%) and unilateral absence of the vas deferens in 1 (3%). CONCLUSIONS: This study delineates the etiology of azoospermia in men with universal access to care.

Vitamin D regulating TGF-ß induced epithelial-mesenchymal transition.

BACKGROUND: Subepithelial fibrosis is a characteristic hallmark of airway remodeling in asthma. A critical regulator of fibrosis, transforming growth factor ß (TGF-ß), can induce airway remodeling in epithelial cells through induction of epithelial-mesenchymal transition (EMT). Vitamin D has immunomodulatory functions, however, its effect on controlling subepithelial fibrosis is not known. METHODS: Human bronchial epithelial cells (BEAS-2B) were exposed to calcitriol followed by stimulation with TGF-ß1 or TGF-ß2. The protein expression and mRNA transcripts for E-cadherin, Snail, vimentin, and N-cadherin were analyzed by Western blot and qPCR. An invasion assay and scratch wound assay were performed to identify the migratory properties of the cells following treatments. RESULTS: TGF-ß1 decreased E-cadherin expression and increased protein expression and mRNA transcripts of Snail, vimentin, and N-cadherin together with increased cell invasion and migration. TGF-ß2 elicited migratory response similar to TGF-ß1 but induced the expression of EMT markers differently from that by TGF-ß1. Calcitriol attenuated TGF-ß1- and TGF-ß2-induced cell motility. Also, calcitriol inhibited the expression of EMT markers in TGF-ß1-treated epithelial cells with less effect on TGF-ß2. CONCLUSIONS: These data suggest that calcitriol inhibits both migration and invasion induced by TGF-ß1 and TGF-ß2 in human airway epithelial cells. However, the regulatory effect of vitamin D in epithelial-mesenchymal transition was more effective to TGF-ß1-induced changes. Thus, calcitriol could be a potential therapeutic agent in the prevention and management of subepithelial fibrosis and airway remodeling.

Hematopoietic stem and progenitor cells in inflammation and allergy.

Hematopoietic stem and progenitor cells contribute to allergic inflammation. Pro-inflammatory cytokines that are generated following allergen challenge can impact the differentiation of hematopoietic progenitor cells leading to increased production of effector cells such as eosinophils and basophils, which are key cells involved in the pathogenesis of allergic airway inflammation. Homing of stem cells to the lungs is associated with inflammatory and remodeling changes in asthmatics. Factors that modulate the differentiation and increased migration of stem cells to the site of inflammation in asthma remain to be defined. Stem cells can mature at the site of inflammation in response to inflammatory mediators and other components in the milieu. While the available data suggest that hematopoietic cells traffic to target tissues, the molecular factors underlying in situ differentiation have yet to be specified. Here, we critically evaluate the potential role of hematopoietic progenitors in contributing to the increased immune cell infiltrate in allergic asthma and the factors that drive their differentiation.

Both texting and eating are associated with impaired simulated driving performance.

OBJECTIVE: Distracted driving is a known contributor to traffic accidents, and many states have banned texting while driving. However, little is known about the potential accident risk of other common activities while driving, such as eating. The objective of the current study was to examine the adverse impact of eating/drinking behavior relative to texting and nondistracted behaviors on a simulated driving task. METHODS: A total of 186 participants were recruited from undergraduate psychology courses over 2 semesters at Kent State University. We utilized the Kent Multidimensional Assessment Driving Simulation (K-MADS) to compare simulated driving performance among participants randomly assigned to texting (N = 45), eating (N = 45), and control (N = 96) conditions. Multivariate analyses of variance (MANOVA) were conducted to examine between-group differences on simulated driving indices. RESULTS: MANOVA analyses indicated that groups differed in simulated driving performance, F(14, 366) = 7.70, P < .001. Both texting and eating produced impaired driving performance relative to controls, though these behaviors had approximately equal effect. Specifically, both texting and eating groups had more collisions, pedestrian strikes, and center line crossings than controls. In addition, the texting group had more road edge excursions than either eating or control participants and the eating group missed more stop signs than controls. CONCLUSIONS: These findings suggest that both texting and eating are associated with poorer simulated driving performance. Future work is needed to determine whether these findings generalize to real-world driving and the development of strategies to reduce distracted driving.

Structure-activity relationship studies of fostriecin, cytostatin, and key analogs, with PP1, PP2A, PP5, and( beta12-beta13)-chimeras (PP1/PP2A and PP5/PP2A), provide further insight into the inhibitory actions of fostriecin family inhibitors.

Fostriecin and cytostatin are structurally related natural inhibitors of serine/threonine phosphatases, with promising antitumor activity. The total synthesis of these antitumor agents has enabled the production of structural analogs, which are useful to explore the biological significance of features contained in the parent compounds. Here, the inhibitory activity of fostriecin, cytostatin, and 10 key structural analogs were tested in side-by-side phosphatase assays to further characterize their inhibitory activity against PP1c (Ser/Thr protein phosphatase 1 catalytic subunit), PP2Ac (Ser/Thr protein phosphatase 2A catalytic subunit), PP5c (Ser/Thr protein phosphatase 5 catalytic subunit), and chimeras of PP1 (Ser/Thr protein phosphatase 1) and PP5 (Ser/Thr protein phosphatase 5), in which key residues predicted for inhibitor contact with PP2A (Ser/Thr protein phosphatase 2A) were introduced into PP1 and PP5 using site-directed mutagenesis. The data confirm the importance of the C9-phosphate and C11-alcohol for general inhibition and further demonstrate the importance of a predicted C3 interaction with a unique cysteine (Cys(269)) in the beta12-beta13 loop of PP2A. The data also indicate that additional features beyond the unsaturated lactone contribute to inhibitory potency and selectivity. Notably, a derivative of fostriecin lacking the entire lactone subunit demonstrated marked potency and selectivity for PP2A, while having substantially reduced and similar activity against PP1 and PP1/PP2A- PP5/PP2A-chimeras that have greatly increased sensitivity to both fostriecin and cytostatin. This suggests that other features [e.g., the (Z,Z,E)-triene] also contribute to inhibitory selectivity. When considered together with previous data, these studies suggest that, despite the high structural conservation of the catalytic site in PP1, PP2A and PP5, the development of highly selective catalytic inhibitors should be feasible.

Cerebral malaria is associated with low levels of circulating endothelial progenitor cells in African children.

Damage to the cerebral microvasculature is a feature of cerebral malaria. Circulating endothelial progenitor cells are needed for microvascular repair. Based on this knowledge, we hypothesized that the failure to mobilize sufficient circulating endothelial progenitor cells to the cerebral microvasculature is a pathophysiologic feature of cerebral malaria. To test this hypothesis, we compared peripheral blood levels of CD34 (+)/VEGFR2(+) and CD34 (+)/CD133(+) cells and plasma levels of the chemokine stromal cell-derived growth factor 1 (SDF-1) in 214 children in Accra, Ghana. Children with cerebral malaria had lower levels of CD34 (+)/VEGFR2(+) and CD34 (+)/CD133(+) cells compared with those with uncomplicated malaria, asymptomatic parasitemia, or healthy controls. SDF-1 levels were higher in children with acute malaria compared with healthy controls. Together, these results uncover a potentially novel role for endothelial progenitor cell mobilization in the pathophysiology of cerebral malaria.