Background & Aims Enteric neurons have been reported to be increased in inflamed regions of the bowel in patients with inflammatory bowel disease (IBD) or intestinal neurogangliomatosis. It is impossible to determine whether this hyperinnervation predates intestinal inflammation, results from it, or contributes to its severity in humans, so we studied this process in mice. Methods To determine whether the density of enteric neurons determines the severity of inflammation, we studied transgenic mice that have greater-than-normal (Hand2+/− mice) or fewer-than-normal (NSE-noggin mice, which overexpress noggin under the control of the neuron-specific enolase promoter) numbers of neurons in the enteric nervous system (ENS). Colitis was induced with trinitrobenzene sulfonic acid or dextran sulfate sodium and the intensity of the resulting inflammation in Hand2+/− and NSE-noggin mice was compared with that of wild-type littermates. Results Severity of each form of colitis (based on survival, symptom, and histologic scores; intestinal expression of genes that encode proinflammatory molecules; and levels of neutrophil elastase and p50 NF- Hand2+/− mice and significantly increased in NSE-noggin animals. Neither mouse differed from wild-type in the severity of delayed-type hypersensitivity (edema, T-cell and neutrophil infiltration, or expression of interleukin- - - -dinitro-1-fluorobenzene. Transgene effects on inflammation were therefore restricted to the gastrointestinal tract. Conclusion The severity of intestinal inflammation is associated with the density of the enteric innervation in mice. Abnormalities in ENS development might therefore contribute to the pathogenesis of IBD.

Background & Aims Hand2 is a basic helix-loop-helix transcription factor required for terminal differentiation of enteric neurons. We studied Hand2 haploinsufficient mice, to determine whether reduced expression of Hand2 allows sufficient enteric neurogenesis for survival but not for development of a normal enteric nervous system (ENS). Methods Enteric transcripts that encode Hand2 and the neuron-specific embryonic lethal abnormal vision proteins HuB, HuC, and HuD were quantified. Immunocytochemistry was used to identify and quantify neurons. Apoptosis was analyzed with the TUNEL procedure. Intracellular microelectrodes were used to record inhibitory junction potentials. Gastrointestinal transit and colonic motility were measured in vivo. Results Levels of of enteric Hand2 transcripts were associated with genotypes of mice, in the following order: Hand2+/+ > Hand2LoxP/+ > Hand2+/− > Hand2LoxP/−. Parallel reductions were found in expression of HuD and, in regional and phenotypic manners, numbers of neurons; numbers of nNOS+ and calretinin+, but not substance P+ or vasoactive intestinal peptide+ neurons, decreased. No effects were observed in stomach or cecum. Apoptosis was not detected, consistent with the concept that Hand2 inhibits neuronal differentiation, rather than regulates survival. The amplitude of inhibitory junction potentials in colonic circular muscle was similar in Hand2 wild-type and haploinsufficient mice, although in haploinsufficient mice, the purinergic component was reduced and a nitrergic component appeared. The abnormal ENS of haploinsufficient mice slowed gastrointestinal motility but protected mice against colitis. Conclusion Reduced expression of factors required for development of the ENS can cause defects in the ENS that are subtle enough to escape detection yet cause significant abnormalities in bowel function.

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The use of the EC agent Definity is safe in hospitalized patients with PHT.

Purpose: Appropriate use criteria (AUC) defines the appropriateness of imaging procedures for specific clinical scenarios to promote evidence-based utilization and improve cost-effective care. The goal of this study was to assess the diagnostic yield and downstream health care resource utilization according to the AUC categorization for coronary computed tomography angiography (CCTA) in emergency department (ED) patients presenting with chest pain. Materials and Methods: A total of 789 consecutive patients in the ED with chest pain and no known coronary artery disease (CAD) who underwent CCTA were classified as appropriate, uncertain, or inappropriate use according to the 2010 AUC. We abstracted index and 30-day data from the electronic medical record to determine diagnostic yield (rate of obstructive CAD and revascularization) and health care resource utilization (downstream stress test and 30-d hospital return rate). Results: Rates of appropriate, uncertain, and inappropriate utilization were 48.4%, 48.8%, and 2.8%. Among appropriate, uncertain, and inappropriate classifications, rates of obstructive CAD were 9%, 8%, and 32% (P=0.002); rates of revascularization were 3%, 1%, and 36% (P<0.001); downstream stress test utilization rates were 5% versus 5% versus 14% (P=0.17), and 30-day hospital return rates were 6% versus 6% versus 5% (P>0.99), respectively. Conclusions: Appropriate and uncertain uses were associated with low diagnostic yield compared with inappropriate use; however, our findings do not demonstrate differences between appropriate use categories with respect to downstream health care resource utilization. Further studies are needed to define the role of AUC for CCTA in the ED setting.

were excluded. Follow-up began after index date and continued until end of first drug exposure, end of continuous enrollment, all-cause death, or end of data, whichever was first. Multivariable Cox proportional hazard and Poisson regression was used to compare the effects of oral treprostinil to selexipag on PH-related hospitalization risk and rates, respectively. RESULTS: The study population included 99 patients treated with oral treprostinil and 123 patients treated with selexipag. The study population, on average, was 61 years old and predominately female (71%). After adjusting for confounders, selexipag reduced the risk for first PH-related hospitalization by 47% compared to oral treprostinil (hazard ratio: 0.53; 95% CI (confidence interval): 0.31, 0.93; p-value: 0.03). Compared to oral treprostinil, PH-related hospitalization rate with selexipag was reduced by 46% after adjusting for confounders (rate ratio: 0.54; 95% CI: 0.35, 0.82; p-value: 0.004). CONCLUSIONS: Selexipag is associated with lower PHrelated hospitalization risk and rates compared to oral treprostinil. OBJECTIVES:A popular approach to estimate treatment effects is the meta-analysis of individual participant data (IPD). This study aimed to assess through IPD the impact of exercise-based cardiac rehabilitation (ExCR) on exercise capacity and health-related quality of life (HRQoL) and identify subgroups of patients with heart failure (HF) that may respond differently to ExCR. METHODS: The Exercise Training Meta-Analysis of Trials for Chronic Heart Failure (ExTraMATCH II) collected IPD from RCTs that compared exercise rehabilitation with a non-exercise control and a minimum follow-up of 6 months. Outcomes of interest were the 6 Minutes Walk Test (6MWT), peak volume of oxygen consumption (pVO2), the Minnesota Living with Heart Failure (MLHF) or other HRQoL questionnaires. The primary analyses included one-stage and two-stage IPD meta-analyses carried out at 6 and 12 months. All primary analyses used IPD hierarchical random effects regression models, adjusted for the baseline value of the outcome measure. RESULTS: Thirteen studies provided anonymised IPD for 3,000 patients (1,496 ExCR, 1,504 control) with a median followup of 33 weeks. Compared to control, average treatment effects from the one-stage meta-analysis over 12 months showed a significant improvement in MLHF: 5.94 (95% CI 1.0 to 10.9), standardised HRQoL score: 0.20 (95% CI 0.03 to 0.37), 6MWT: 21.0 (95% CI 1.57 to 40.4) and standardised exercise capacity score: 0.27 (95% CI 0.11 to 0.43) for patients assigned to ExCR. No significant difference in peak VO2 was observed: 1.01 (95% CI -0.42 to 2.44). Interaction analyses revealed no consistent interaction between the effect of ExCR and the predefined subgroups. CONCLUSIONS: Access to individual data from several RCTs allows to address important questions on the benefits of ExCR in HF failure. Results from this IPD must be discussed in light of findings from previous aggregate data meta-analyses on the same topic.

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