Explore the vast range of titles available.

A combination of pharmacological and genetic approaches was used to determine the role of type 4 cAMP-specific cyclic nucleotide phosphodiesterase 4 (PDE4) in reversing α2-adrenoceptor–mediated anesthesia, a behavioral correlate of emesis in non-vomiting species. Among the family-specific PDE inhibitors, PDE4 inhibitors reduced the duration of xylazine/ketamine–induced anesthesia in mice, with no effect on pentobarbital-induced anesthesia. The rank order of the PDE4 inhibitors tested was 6-(4-pyridylmethyl)-8-(3-nitrophenyl)quinoline (PMNPQ) > (R)-rolipram > (S)-rolipram >> (R)-N-4-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl]phenylN′-ethylurea (CT-2450). The specific roles of PDE4B and PDE4D in this model were studied using mice deficient in either subtype. PDE4D-deficient mice, but not PDE4B-deficient mice, had a shorter sleeping time than their wild-type littermates under xylazine/ketamine–induced anesthesia, but not under that induced with pentobarbital. Concomitantly, rolipram-sensitive PDE activity in the brain stem was decreased only in PDE4D-deficient mice compared with their wild-type littermates. While PMNPQ significantly reduced the xylazine/ketamine–induced anesthesia period in wild-type mice and in PDE4B-null mice, it had no effect in PDE4D-deficient mice. These findings strongly support the hypothesis that inhibition of PDE4D is pivotal to the anesthesia-reversing effect of PMNPQ and is likely responsible for emesis induced by PDE4 inhibitors.

A combination of pharmacological and genetic approaches was used to determine the role of type 4 cAMP-specific cyclic nucleotide phosphodiesterase 4 (PDE4) in reversing alpha(2)-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis in non-vomiting species. Among the family-specific PDE inhibitors, PDE4 inhibitors reduced the duration of xylazine/ketamine-induced anesthesia in mice, with no effect on pentobarbital-induced anesthesia. The rank order of the PDE4 inhibitors tested was 6-(4-pyridylmethyl)-8-(3-nitrophenyl)quinoline (PMNPQ) > (R)-rolipram > (S)-rolipram >> (R)-N-[4-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl]phenyl]N'-ethylurea (CT-2450). The specific roles of PDE4B and PDE4D in this model were studied using mice deficient in either subtype. PDE4D-deficient mice, but not PDE4B-deficient mice, had a shorter sleeping time than their wild-type littermates under xylazine/ketamine-induced anesthesia, but not under that induced with pentobarbital. Concomitantly, rolipram-sensitive PDE activity in the brain stem was decreased only in PDE4D-deficient mice compared with their wild-type littermates. While PMNPQ significantly reduced the xylazine/ketamine-induced anesthesia period in wild-type mice and in PDE4B-null mice, it had no effect in PDE4D-deficient mice. These findings strongly support the hypothesis that inhibition of PDE4D is pivotal to the anesthesia-reversing effect of PMNPQ and is likely responsible for emesis induced by PDE4 inhibitors.

A combination of pharmacological and genetic approaches was used to determine the role of type 4 cAMP-specific cyclic nucleotide phosphodiesterase 4 (PDE4) in reversing alpha(2)-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis in non-vomiting species. Among the family-specific PDE inhibitors, PDE4 inhibitors reduced the duration of xylazine/ketamine-induced anesthesia in mice, with no effect on pentobarbital-induced anesthesia. The rank order of the PDE4 inhibitors tested was 6-(4-pyridylmethyl)-8-(3-nitrophenyl)quinoline (PMNPQ) > (R)-rolipram > (S)-rolipram >> (R)-N-[4-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl]phenyl]N'-ethylurea (CT-2450). The specific roles of PDE4B and PDE4D in this model were studied using mice deficient in either subtype. PDE4D-deficient mice, but not PDE4B-deficient mice, had a shorter sleeping time than their wild-type littermates under xylazine/ketamine-induced anesthesia, but not under that induced with pentobarbital. Concomitantly, rolipram-sensitive PDE activity in the brain stem was decreased only in PDE4D-deficient mice compared with their wild-type littermates. While PMNPQ significantly reduced the xylazine/ketamine-induced anesthesia period in wild-type mice and in PDE4B-null mice, it had no effect in PDE4D-deficient mice. These findings strongly support the hypothesis that inhibition of PDE4D is pivotal to the anesthesia-reversing effect of PMNPQ and is likely responsible for emesis induced by PDE4 inhibitors.

Treatment of the tumor and dural margin with surgery and sometimes radiation are cornerstones of therapy for meningioma. Molecular classifications have provided insights into the biology of disease; however, response to treatment remains heterogeneous. In this study, we used retrospective data on 2,824 meningiomas, including molecular data on 1,686 tumors and 100 prospective meningiomas, from the RTOG-0539 phase 2 trial to define molecular biomarkers of treatment response. Using propensity score matching, we found that gross tumor resection was associated with longer progression-free survival (PFS) across all molecular groups and longer overall survival in proliferative meningiomas. Dural margin treatment (Simpson grade 1/2) prolonged PFS compared to no treatment (Simpson grade 3). Molecular group classification predicted response to radiotherapy, including in the RTOG-0539 cohort. We subsequently developed a molecular model to predict response to radiotherapy that discriminates outcome better than standard-of-care classification. This study highlights the potential for molecular profiling to refine surgical and radiotherapy decision-making. In a large, partially prospective cohort of patients with molecularly profiled and clinically annotated meningioma, the extent of surgical resection and radiotherapy (RT) response correlate with molecular classification, which can be used in a molecular model to predict clinical outcomes in response to RT.

Background Severe intracranial hypertension is strongly associated with mortality. Guidelines recommend medical management involving sedation, hyperosmotic agents, barbiturates, hypothermia, and surgical intervention. When these interventions are maximized or are contraindicated, refractory intracranial hypertension poses risk for herniation and death. We describe a novel intervention of verticalization for treating intracranial hypertension refractory to aggressive medical treatment. Methods This study was a single-center retrospective review of six cases of refractory intracranial hypertension in a tertiary care center. All patients were treated with a standard-of-care algorithm for lowering intracranial pressure (ICP) yet maintained an ICP greater than 20 mmHg. They were then treated with verticalization for at least 24 h. We compared the median ICP, the number of ICP spikes greater than 20 mmHg, and the percentage of ICP values greater than 20 mmHg in the 24 h before verticalization vs. after verticalization. We assessed the use of hyperosmotic therapies and any changes in the mean arterial pressure and cerebral perfusion pressure related with the intervention. Results Five patients were admitted with subarachnoid hemorrhage and one with intracerebral hemorrhage. All patients had ICP monitoring by external ventricular drain. The median opening pressure was 30 mmHg (25th–75th interquartile range 22.5–30 mmHg). All patients demonstrated a reduction in ICP after verticalization, with a significant decrease in the median ICP (12 vs. 8 mmHg; p  < 0.001), the number of ICP spikes (12 vs. 2; p  < 0.01), and the percentage of ICP values greater than 20 mmHg (50% vs. 8.3%; p  < 0.01). There was a decrease in total medical interventions after verticalization (79 vs. 41; p  = 0.05) and a lower total therapy intensity level score after verticalization. The most common adverse effects included asymptomatic bradycardia ( n  = 3) and pressure wounds ( n  = 4). Conclusions Verticalization is an effective noninvasive intervention for lowering ICP in intracranial hypertension that is refractory to aggressive standard management and warrants further study.

Objectives. We assessed changes in asthma-related health care use by low-income children in communities across the country where 6 Allies Against Asthma coalitions (Hampton Roads, VA; Washington, DC; Milwaukee, WI; King County/Seattle, WA; Long Beach, CA; and Philadelphia, PA) mobilized stakeholders to bring about policy changes conducive to asthma control. Methods. Allies intervention zip codes were matched with comparison communities by median household income, asthma prevalence, total population size, and race/ethnicity. Five years of data provided by the Center for Medicare and Medicaid Services on hospitalizations, emergency department (ED) use, and physician urgent care visits for children were analyzed. Intervention and comparison sites were compared with a stratified recurrent event analysis using a Cox proportional hazard model. Results. In most of the assessment years, children in Allies communities were significantly less likely (P < .04) to have an asthma-related hospitalization, ED visit, or urgent care visit than children in comparison communities. During the entire period, children in Allies communities were significantly less likely (P < .02) to have such health care use. Conclusions. Mobilizing a diverse group of stakeholders, and focusing on policy and system changes generated significant reductions in health care use for asthma in vulnerable communities.

Objectives. We assessed policy and system changes and health outcomes produced by the Allies Against Asthma program, a 5-year collaborative effort by 7 community coalitions to address childhood asthma. We also explored associations between community engagement and outcomes. Methods. We interviewed a sample of 1477 parents of children with asthma in coalition target areas and comparison areas at baseline and 1 year to assess quality-of-life and symptom changes. An extensive tracking and documentation procedure and a survey of 284 participating individuals and organizations were used to ascertain policy and system changes and community engagement levels. Results. A total of 89 policy and system changes were achieved, ranging from changes in interinstitutional and intrainstitutional practices to statewide legislation. Allies children experienced fewer daytime (P = .008) and nighttime (P = .004) asthma symptoms than comparison children. In addition, Allies parents felt less helpless, frightened, and angry (P = .01) about their child's asthma. Type of community engagement was associated with number of policy and system changes. Conclusions. Community coalitions can successfully achieve asthma policy and system changes and improve health outcomes. Increased core and ongoing community stakeholder participation rather than a higher overall number of participants was associated with more change.

IntroductionAcute kidney injury (AKI) is a common complication in hospitalised patients. It imposes significant risk for major morbidity and mortality. Moreover, patients suffering an episode of AKI consume considerable health resources. Recently, a number of studies have evaluated the implementation of automated electronic alerts (e-alerts) configured from electronic medical records (EMR) and clinical information systems (CIS) to warn healthcare providers of early or impending AKI in hospitalised patients. The impact of e-alerts on care processes, patient outcomes and health resource use, however, remains uncertain.Methods and analysisWe will perform a systematic review to describe and appraise e-alerts for AKI, and evaluate their impact on processes of care, clinical outcomes and health services use. In consultation with a research librarian, a search strategy will be developed and electronic databases (ie, MEDLINE, EMBASE, CINAHL, Cochrane Library and Inspec via Engineering Village) searched. Selected grey literature sources will also be searched. Search themes will focus on e-alerts and AKI. Citation screening, selection, quality assessment and data abstraction will be performed in duplicate. The primary analysis will be narrative; however, where feasible, pooled analysis will be performed. Each e-alert will be described according to trigger, type of alert, target recipient and degree of intrusiveness. Pooled effect estimates will be described, where applicable.Ethics and disseminationOur systematic review will synthesise the literature on the value of e-alerts to detect AKI, and their impact on processes, patient-centred outcomes and resource use, and also identify key knowledge gaps and barriers to implementation. This is a fundamental step in a broader research programme aimed to understand the ideal structure of e-alerts, target population and methods for implementation, to derive benefit. Research ethics approval is not required for this review.Systematic review registration numberCRD42016033033.

Catalytic leadership is a type of multidimensional leadership that facilitates cross-sector collaboration to enact systems and policy changes within communities. Catalytic leaders provide opportunities for stakeholders to partner and merge their efforts to create new opportunities for their work. Catalytic leaders are individuals, organizations, and collaborative partnerships that stimulate partnership alliances. Additionally, catalytic partnerships facilitate the process of collaboration through encouraging and supporting stakeholders to work together effectively and successfully. This article provides examples of catalytic leadership roles that emerged from the Food & Fitness community partnerships. These partnerships were funded by the W.K. Kellogg Foundation to increase access to locally grown food and safe places to play for children and families through systems and policy changes in communities throughout the United States. Key strategies and types of support (i.e., informational and instrumental support) provided through Food & Fitness catalytic leadership that sustained the work of these partnerships was discussed. Based on catalytic leadership strategies identified and types of support provided, outcomes that emerged from this work were also described. We conclude with key recommendations for community partnerships interested in serving as catalytic leaders for large-scale initiatives in their communities.