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Saroglitazar is a novel peroxisome proliferator-activated receptor (PPAR) agonist with dual agonistic properties (α/γ). Due to a strong mechanistic rationale, we aimed to test the safety and efficacy of saroglitazar in patients with primary biliary cholangitis (PBC) who were either ursodeoxycholic acid (UDCA) resistant or intolerant.In this double-blind, phase II proof-of-concept trial, 37 patients with PBC were randomized to saroglitazar 4 mg (n = 13), saroglitazar 2 mg (n = 14), or placebo (n = 10) daily for 16 weeks. The primary efficacy endpoint was the reduction in alkaline phosphatase (ALP) level at Week 16.A significant reduction of mean ALP levels was observed at Week 16 relative to baseline in both the saroglitazar 4 mg (least-squares [LS] mean =-163.3 U/L, SE = 25.1, p0.001) and 2 mg (LS mean =-155.8 U/L, SE = 24.4, p0.001) groups, compared with placebo (LS mean =-21.1 U/L, SE = 28.9). Treatment with saroglitazar resulted in a rapid reduction of ALP concentration at Week 4 that was sustained through the study duration. At least 1 treatment-emergent adverse event occurred in 11 (84.6%) patients in the saroglitazar 4 mg group, in 12 (85.7%) patients in the 2 mg group and in 8 (80%) patients in the placebo group. Study drug was discontinued in 4 patients (3 patients in the 4 mg group and 1 patient in the 2 mg group) due to aminotransferase increases that promptly returned to baseline values after drug discontinuation.Saroglitazar at 2 mg and 4 mg daily was tolerated and resulted in rapid and sustained improvements in ALP. Further studies are underway at a daily dose of 2 mg and 1 mg due to the higher incidence of elevated liver enzymes observed with the 4 mg dose. CLINICALTRIALS.NCT03112681 LAY SUMMARY: Saroglitazar resulted in a rapid and sustained improvement in alkaline phosphatase levels in patients with primary biliary cholangitis. The mean percentage reductions in alkaline phosphatase levels were 49% and 51% in the saroglitazar 4 mg and 2 mg groups compared to 3% in the placebo group.

BACKGROUND Limited data exist on the burden and features of non-cirrhotic hepatocellular carcinoma (HCC) in the United States. AIM To evaluate characteristics, aetiologies, trends and outcomes of non-cirrhotic HCC from 2000 to 2014 at five large US centres METHODS: Patient, tumour and liver disease aetiology data were collected. The presence of underlying cirrhosis was assessed based on published criteria. RESULTS Of 5144 eligible patients with HCC, 11.7% had no underlying cirrhosis. Non-cirrhotic patients were older (64.1 vs 61.2 years), more frequently females (33.9% vs 20.8%) and less frequently black (8.3% vs 12.4%) (P

Introduction The impact of direct-acting antivirals (DAAs) for hepatitis C virus (HCV) on burden of cirrhotic and noncirrhotic hepatocellular carcinoma (HCC) has not been examined. We assessed recent trends in liver disease etiologies of HCC and proportion of noncirrhotic HCC since DAAs introduction. Methods Clinical characteristics including presence or absence of underlying cirrhosis were collected from 2,623 patients diagnosed with HCC between 2009 and 2019 at 2 large US centers. Logistic regression was performed to investigate the annual trends of HCC due to different liver diseases and proportions of noncirrhotic cases. Results In the DAA era (2014-2019), annual decline in HCV-HCC (odds ratio [OR] = 0.93, 95% confidence interval [CI] 0.88-0.99, P = 0.019), without change in trends of other liver diseases-related HCC, was observed. Annual increase in noncirrhotic HCC (OR 1.13, 95% CI 1.03-1.23, P = 0.009) and decline in cirrhotic HCC (OR 0.89, 95% CI 0.81-0.97, P = 0.009) along with similar trends for HCV-HCC-increase in noncirrhotic cases (OR 1.35, 95% CI 1.08-1.69, P = 0.009) and decrease in cirrhotic cases (OR 0.92, 95% CI 0.86-0.98, P = 0.012)-were observed during the DAA era. Compared with the pre-DAA era, HCC resection rate increased (10.7% vs 14.0%, P = 0.013) whereas liver transplantation rate decreased (15.1% vs 12.0%, P = 0.023) in the DAA era. Discussion Since introduction of DAAs, proportions of cirrhotic HCC have decreased, whereas proportions of noncirrhotic HCC have increased. These new trends were associated with change in utilization of liver resection and transplantation for HCC. The impact of changing patterns of DAA use on these trends will require further study.

© 2019 Elsevier Ltd. All rights reserved., Background: Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods: In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2-F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2-F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings: Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1-F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2-F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1-F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation: Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes.

INTRODUCTION Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide, affecting men to women at a ratio of about 4:1. Risk factors, characteristics, and outcomes for HCC in women in the United States remain poorly understood; therefore, we aim to explore gender differences further. METHODS Patients diagnosed with HCC between January 2000 and June 2014 at 5 large centers were identified. Clinical information, tumor characteristics, and survival data were extracted manually. The presence of underlying cirrhosis was assessed based on published criteria. RESULTS Of 5,327 patients with HCC in our cohort, 1,203 (22.6%) were women. There were important differences in the underlying etiology of liver disease between the 2 genders (P < 0.0001): women had a significantly higher frequency of nonalcoholic fatty liver disease (23% vs 12%) and lower frequency of alcoholic liver disease (5% vs 15%). The proportion of noncirrhotic HCC was significantly higher among women (17% vs 10%, P < 0.0001). Women had less-advanced HCC at presentation by tumor, node, metastasis staging (P < 0.0001) and a higher proportion within Milan criteria (39% vs 35%, P = 0.002). Women had a greater overall survival (2.5 ± 2.9 years vs 2.2 ± 2.7 years, P = 0.0031). DISCUSSION The frequency of underlying nonalcoholic fatty liver disease and noncirrhotic HCC were significantly higher in women than men in this large cohort. Women presented with less-advanced HCC and had a greater overall survival. Further investigation is warranted to explore potential mechanisms and implications for these gender differences, especially with noncirrhotic HCC (see Visual Abstract, Supplementary Digital Content 1, http://links.lww.com/AJG/B535).

Introduction: The burden of hepatocellular carcinoma (HCC) occurring in patients with alcoholic liver disease (ALD) is increasing at an alarming rate. The aims of this study were to compare the patient and tumor characteristics of HCC occurring in ALD-alone relative to and in addition to other chronic liver diseases. Methods: Patients diagnosed with HCC between 2000 and 2014 were identified at 5 US clinical centers. The patients were categorized as ALD-alone, ALD plus viral hepatitis, or a non-ALD etiology. Clinical and tumor characteristics among the 3 groups were compared, and survival probability was estimated by the Kaplan-Meier method. The frequency of noncirrhotic HCC was compared across the 3 groups. Results: A total of 5,327 patients with HCC were analyzed. Six hundred seventy (12.6%) developed HCC due to underlying ALD. Ninety-one percent of ALD-related HCC arose in men, in contrast to non-ALD etiologies where men accounted for 70% of HCCs cases (P < 0.001). Patients with ALD-alone-related HCC were older at diagnosis and had tumors less likely to be detected as part of routine surveillance. The ALD-alone cohort was least likely to be within the Milan criteria and to undergo liver transplantation. Overall survival in the ALD-alone HCC cohort was lower than the other 2 groups (1.07 vs 1.31 vs 1.41 years, P < 0.001). HCC in the noncirrhotic ALD cohorts occurred in only 3.5% of the patients compared with 15.7% in patients with non-ALD etiologies (P < 0.001). DISCUSSION: HCC occurring in patients with ALD occurred mostly in older men and almost exclusively in a cirrhotic background. They present with advanced tumors, and their survival is lower than HCCs occurring in non-ALD.

Background & Aims Non-alcoholic steatohepatitis is a leading cause of end-stage liver disease. Hepatic steatosis and lipotoxicity cause chronic necroinflammation and direct hepatocellular injury resulting in cirrhosis, end-stage liver disease and hepatocellular carcinoma. Emricasan is a pan-caspase inhibitor that inhibits excessive apoptosis and inflammation; it has also been shown to decrease portal pressure and improve synthetic function in mice with carbon tetrachloride-induced cirrhosis. Methods This double-blind, placebo-controlled study randomized 217 individuals with decompensated NASH cirrhosis 1:1:1 to emricasan (5 mg or 25 mg) or placebo. Patients were stratified by decompensation status and baseline model for end-stage liver disease-sodium (MELD-Na) score. The primary endpoint comprised all-cause mortality, a new decompensation event (new or recurrent variceal hemorrhage, new ascites requiring diuretics, new unprecipitated hepatic encephalopathy ≥grade 2, hepatorenal syndrome, spontaneous bacterial peritonitis), or an increase in MELD-Na score ≥4 points. Results There was no difference in event rates between either of the emricasan treatment groups and placebo, with hazard ratios of 1.02 (95% CI 0.59–1.77; p = 0.94) and 1.28 (95% CI 0.75–2.21; p = 0.37) for 5 mg and 25 mg of emricasan, respectively. MELD-Na score progression was the most common outcome. There was no significant effect of emricasan treatment on MELD-Na score, international normalized ratio, total serum bilirubin, albumin level or Child-Pugh score. Emricasan was generally safe and well-tolerated. Conclusions Emricasan was safe but ineffective for the treatment of decompensated NASH cirrhosis. However, this study may guide the design and conduct of future clinical trials in decompensated NASH cirrhosis. Lay summary Patients with decompensated cirrhosis related to non-alcoholic steatohepatitis are at high risk of additional decompensation events and death. Post hoc analyses in previous pilot studies suggested that emricasan might improve portal hypertension and liver function. In this larger randomized study, emricasan did not decrease the number of decompensation events or improve liver function in patients with a history of decompensated cirrhosis related to non-alcoholic steatohepatitis. ClinicalTrials.gov Identifier NCT03205345 .

We evaluated the effects of therapeutic and supratherapeutic doses of tramadol hydrochloride on the corrected QT (QTc) interval in healthy adults (aged 18‐55 years) in a randomized, phase I, double‐blind, placebo‐ and positive‐controlled, multiple‐dose, 4‐way crossover study. Participants were randomized to receive 1 of 4 treatments (A‐D), 1 each in 4 treatment periods (1‐4), separated by a washout period (7‐15 days). Treatment A comprised tramadol 400 mg (therapeutic dose) on days 1 through 3, tramadol 100 mg and moxifloxacin‐matched placebo on day 4, and placebo on all 4 days. Treatment B comprised tramadol 600 mg (supratherapeutic dose) on days 1 through 3, and tramadol 150 mg and moxifloxacin‐matched placebo on day 4. Treatment C comprised placebo on days 1 through 4 and moxifloxacin‐matched placebo on day 4. Treatment D comprised placebo on days 1 through 4 and moxifloxacin 400 mg on day 4. Of 68 participants enrolled, 57 (83.8%) completed the study. Both therapeutic and supratherapeutic doses of tramadol were shown to be noninferior to placebo regarding their effect on QTc prolongation. Sixty‐one of 68 (89.7%) participants reported at least 1 treatment‐emergent adverse event (mild); nausea was the most frequently reported treatment‐emergent adverse event. Summarizing, tramadol at doses up to 600 mg/day did not cause clinically relevant QTc interval prolongation in healthy adults.

Background Limited data exists on the long-term effects of aneurysmal subarachnoid hemorrhage (SAH) on spatial memory. Herein, we used a computerized virtual water maze to evaluate the feasibility of spatial memory testing in pilot cohort of ten patients who survived previous SAH. Methods Ten SAH survivors (5.8 ± 5.1 years after initial hemorrhage) and 7 age-matched controls underwent testing in a virtual water maze computer program. Additional subgroup analyses were performed to evaluate spatial reference memory correlation for ventricular size on admission, placement of an external ventricular drain and placement of a shunt. Results With respect to the spatial memory acquisition phase, there was no significant difference of pathway length traveled to reach the platform between SAH survivors and control subjects. During the probe trial, control subjects spent significantly longer time in target quadrants compared to SAH survivors (F(3, 24) = 10.32, p = 0.0001; Target vs. Right: Mean percent difference 0.16 [0–0.32], p = 0.045; Target vs. Across: Mean percent difference 0.35 [0.19–0.51], p Conclusions Our data demonstrate that SAH survivors have persistent spatial reference memory deficits years after the hemorrhage. Hydrocephalus at presentation and external ventricular drainage were not found to be associated with poor spatial memory outcomes in this pilot cohort. Therefore, other causes such as global cerebral edema or magnitude of initial ICP spike, need to be considered to be examined as root cause as well in subsequent studies. The protocol described in this manuscript is able to demonstrate a spatial reference memory deficit and can be used to study risk factors for spatial memory impairment on a larger scale.

This randomized, double-blind, parallel-group multiple-ascending-dose study evaluated the safety, tolerability, and pharmacokinetics of tramadol hydrochloride in healthy adults to inform dosage and design for a subsequent QT/QTc study. Healthy men and women, 18 to 45 years old (inclusive), were sequentially assigned to the tramadol 200, 400, or 600 mg/day treatment cohort and within each cohort, randomized (4:1) to either tramadol or placebo every 6 hours for 9 oral doses. Of the 24 participants randomized to tramadol (n = 8/cohort), 22 (91.7%) completed the study. The AUCtau,ss of tramadol increased approximately 2.2- and 3.6-fold for the (+) enantiomer and 2.0- and 3.5-fold for the (-) enantiomer with increasing dose from 200 to 400 and 600 mg/day, whereas the Cmax,ss increased 2.1- and 3.3-fold for the (+) enantiomer and 2.0- and 3.2-fold for the (-) enantiomer. Overall, 21 participants (87.5%) participants reported ≥1 treatment-emergent adverse event; most frequent were nausea (17 of 24, 70.8%) and vomiting (7 of 24, 29.2%). Vomiting (affected participants and events) increased with increasing dose from 200 to 600 mg/day but was mild (5 of 24) or moderate (2 of 24) in severity. All tested dosage regimens of tramadol showed acceptable safety and tolerability profile for further investigation in a thorough QT/QTc study.

Cytomegalovirus (CMV) is a common opportunistic infection in solid organ transplant (SOT) recipients in the first 6 months after transplant. Late onset CMV infection or disease outside the classical risk period is uncommon and can present with atypical signs and symptoms. Here, we report a case of late onset CMV presenting as a colonic stricture more than 10 years after liver transplantation in the absence of traditional CMV risk factors. We also briefly review CMV colitis presenting as a mass or stricture in SOT recipients.

Health care has shifted to placing priority on quality and value instead of volume. Liver transplantation uses substantial resources and is associated with high readmission rates. Our goal was to determine if a protocol designed to reduce readmission after liver transplant was effective. We conducted a prospective study of a protocol designed to reduce readmission rates after liver transplantation by expanding outpatient services and alternatives to readmission. The 30-day readmission rate 1 year after implementing the protocol was compared to the 30-day rate for 2 years prior to implementation. Multivariate analysis was used to control for potential confounding factors. Over the study period, 167 adult primary liver transplants were performed with a mean biological Model for End-Stage Liver Disease score of 21 ± 8. Fifty-seven (34%) patients were readmitted. The most common reason for readmission was biliary complications (n = 13). The 30-day readmission rate decreased from 40% before implementing the protocol to 20% after implementation (P = 0.02). In multivariate analysis, the protocol remained associated with readmission (odds ratio, 0.39; 95% confidence interval, 0.16-0.92; P = 0.03). The mean length of stay after transplant was 13 ± 12 days preprotocol and 9 ± 5 days postprotocol (P = 0.09). Alternatives to readmission, including hospital lodging and observation status, were main factors in reducing readmission rates. If the most recent definitions of inpatient admission and observation status were applied over the entire study period, then the readmission rates preprotocol and postprotocol were 31% and 20% indicating that the revised definition of observation status accounted for 45% of the reduction in the readmission rate. Readmission after liver transplantation can be reduced without increasing length of stay by implementing a specifically designed protocol that expands outpatient services and alternatives to inpatient admission. Liver Transplantation 22 765-772 2016 AASLD.

Objectives We aimed to assess the feasibility of a text messaging intervention by determining the proportion of emergency department (ED) patients who responded to prompted home blood pressure (BP) self-monitoring and had persistent hypertension. We also explored the effect of the intervention on systolic blood pressure (sBP) over time. Methods We conducted a randomized, controlled trial of ED patients with expected discharge to home with elevated BP. Participants were identified by automated alerts from the electronic health record. Those who consented received a BP cuff to take home and enrolled in the 3-week screening phase. Text responders with persistent hypertension were randomized to control or weekly prompted BP self-monitoring and healthy behavior text messages. Results Among the 104 patients enrolled in the ED, 73 reported at least one home BP over the 3-week run-in (screening) period. A total of 55 of 73 reported a home BP of ≥140/90 and were randomized to SMS intervention (n = 28) or control (n = 27). The intervention group had significant sBP reduction over time with a mean drop of 9.1 mm Hg (95% confidence interval = 1.1 to 17.6). Conclusions The identification of ED patients with persistent hypertension using home BP self-monitoring and text messaging was feasible. The intervention was associated with a decrease in sBP likely to be clinically meaningful. Future studies are needed to further refine this approach and determine its efficacy.

Obesity is an independent risk factor for the development of liver fibrosis/cirrhosis and hepatocellular carcinoma (HCC). Tenascin-C (TnC), an extracellular matrix protein, is transiently expressed during tissue injury and plays a role in fibrogenesis and tumorigenesis. However, the mechanistic role of TnC signaling in the development of HCC remains unknown. We developed a diet-induced obesity HCC mouse model and examined TnC expression and liver injury. To determine the cellular mechanism of TnC signaling in promoting inflammation and hepatocyte epithelial-mesenchymal transition and migration, we used primary hepatocytes and hepatoma and macrophage cell lines. Further, to determine whether elevated TnC expression correlated with obesity-associated HCC, we measured plasma TnC in obese patients with various levels of liver injury. Increased tissue inflammation accompanied with elevated hepatic stellate cell-derived TnC and Toll-like receptor 4 expression was observed in the diet-induced obesity HCC animal model. In vitro studies found enhanced Toll-like receptor 4 signaling activated by TnC, promoting an increased inflammatory response, hepatocyte transformation, and migration. Further, obese patients with cirrhosis alone and in combination with HCC showed significant increases in plasma TnC compared with healthy volunteers and patients with less severe liver injury. Overall, these studies suggest TnC/Toll-like receptor 4 signaling as an important regulator in HCC; inhibiting this signaling axis may be a viable therapeutic target for impeding HCC.

Fibrotic liver injury is a significant healthcare burden in the United States. It represents a major cause of morbidity and mortality for which there are no effective Food and Drug Administration-approved treatment strategies. Fibrosis is considered a disruption of the normal wound healing responses mediated by fibroblastic cells, which are triggered and sustained by pro-fibrotic cytokines such as transforming growth factor beta 1 (TGF-β1). TGF-β1-mediated trans-differentiation of hepatic stellate cells (HSCs) from quiescent to activated myofibroblasts is a pivotal event in the development of fibrosis. Activation is accompanied by global changes in microRNA (miR) expression. It has been previously reported that miR19b is decreased in activated HSCs and contributes to increased expression of TGF-β receptor II and connective tissue growth factor, both confirmed targets of miR19b. An adeno-associated virus serotype 2 vector (AAV2) with a miR19b transgene downstream of enhanced green fluorescent protein under the murine collage alpha 1(I) promoter was developed specifically to target HSCs. Male Sprague Dawley rats (250 g) underwent sham or bile-duct ligation (BDL) surgery. Directly after BDL, rats received AAV2-miR19b, AAV2-control, or vehicle normal saline (NS) by portal-vein injection. After 2 weeks, the animals were euthanized, and blood was collected for alanine and aspartate aminotransferase, total and direct bilirubin, and alkaline phosphatase. Tissue was collected for RNA and protein extraction and histology. Fibrosis and measures of hepatic injury were significantly reduced in AAV2-miR19b-treated rats in combination with significant improvements in total and direct bilirubin. Histological analysis of collagen by PicroSirius Red staining revealed a ∼50% reduction compared to AAV2-control or NS-injected animals. Pro-fibrotic markers, smooth-muscle alpha-actin, TGF-β receptor II, and collagen alpha 2(I) mRNA and protein were significantly decreased compared to AAV2-control and NS groups. AAV2-mediated reintroduction of miR-19b, specifically expressed in HSCs, improved liver function, inhibited fibrosis, and improved measures of hepatic injury in a BDL model.

Hepatitis C virus (HCV)-related cirrhosis, one of the most common etiologies of liver cirrhosis in the Western world, is a risk factor for hepatocellular carcinoma. To confirm and improve current effectiveness of screening and prognosis of patients with established cirrhosis, a credible, simple plasma biomarker is needed. Hepatic stellate cell activation, a pivotal event in cirrhosis development, results in increased secretion of extracellular matrix proteins, including tenascin-C (TnC). Herein, we tested TnC as a simple biomarker to identify cirrhotic patients with active HCV infection from those with HCV eradication. A prospective study of subjects with HCV-related cirrhosis, stratified into two groups, HCV or virologic cure, was conducted. Plasma TnC expression was measured by ELISA and Western blots. TnC values were correlated with markers of liver injury and ROC analyses performed between groups. The HCV cirrhotic cohort, consisting mostly of men (56%), Caucasians (76%), and genotype 1a or 1b (84%), was compared to healthy controls (HCs). Plasma TnC was significantly higher in HCV cirrhotic patients with active infection compared to HCs (P

Drug-induced liver injury (DILI) with features of autoimmunity (AI) represents an important category of hepatotoxicity due to medication exposure. Drugs repeatedly associated with AI-DILI include diclofenac, α-methyl DOPA, hydralazine, nitrofurantoin, minocycline, and more recently statins and anti-TNF-α agents. Usually, symptoms of acute liver injury occur within a few months after initiation of a culprit medication, but a longer latency period is possible. Like idiopathic autoimmune hepatitis, circulating autoantibodies and a hypergammaglobulinemia are frequently present in sera from patients with AI-DILI. If performed, a liver biopsy should demonstrate interface hepatitis with a prominent plasma cell infiltrate. The severity of AI-DILI is variable, but a complete resolution after withdrawal of the offending medication is the expectation. A response to corticosteroid therapy supports the diagnosis, whereas a lack of recurrence of symptoms or signs following corticosteroid cessation distinguishes AI-DILI from idiopathic autoimmune hepatitis.

Purpose At our level 1 pediatric trauma center, 9-54 intermediate-level ("level 2") trauma activations are received per month. Previously, the surgery team was required to respond to and assume responsibility for all patients who had "level 2" trauma activations. In 8/2011, we implemented a protocol where the emergency room (ER) physician primarily manages these patients with trauma consultation for surgical evaluation or admission. The purpose of this study was to prospectively evaluate the effects of the new protocol to ensure that patient safety and quality of care were maintained. Methods We compared outcomes of patients treated PRE-implementation (10/2010-7/2011) and POST-implementation (9/2011-5/2012), including surgeon consultation rate, utilization of imaging and laboratory testing, ER length of stay, admission rate, and missed injuries or readmissions. Statistical analysis included chi-square and Student's t-test. Results We identified 472 patients: 179 in the PRE and 293 in the POST period. The populations had similar baseline clinical characteristics. The surgical consultation rate in the POST period was only 42%, with no missed injuries or readmissions. The ER length of stay did not change. However, in the POST period there were significant decreases in the admission rate (73% to 44%) and the mean number of CT scans (1.4 to 1), radiographs (2.4 to 1.7), and laboratory tests (5.1 to 3.3) ordered in the emergency room (all p Conclusion Intermediate-level pediatric trauma patients can be efficiently and safely managed by pediatric emergency room physicians, with surgical consultation only as needed. The protocol change improved resource utilization by decreasing testing and admissions and streamlining resident utilization in an era of reduced duty hours.

Background An outbreak of serogroup C meningococcal disease (MD) that involved employees from an oil refinery occurred in Paulinia, from March to June 2010, and spread to the community of Cosmopolis, both situated in Sao Paulo State, Brazil. The aim of this study was to describe the epidemiological and laboratory aspects, and the control measures that were implemented. Methods Descriptive and molecular epidemiological analysis was used to define the extent of the outbreak and the common risk factors among outbreak related cases. Vaccination initiative targeted the employees from the oil refinery and the community-based individuals. Results A total of six outbreak-related cases of MD in the oil refinery and 12 cases in the city of Cosmopolis, Sao Paulo State occurred in a three-month period. All 18 MD cases were confirmed as serogroup C either by culture, real time polymerase chain reaction (RT-PCR), or counterimmunoelectrophoresis (CIE). The meningococcal isolates (n = 15) had the phenotype C:23:P1.14-6 and showed close genetic relationship by pulsed field gel electrophoresis (PFGE). Multilocus sequence typing (MLST) characterization showed that the clones were ST 3780, ST-103 complex. The isolates were susceptible to the antibiotics tested. Vaccination was administered to 15,848 persons at the oil refinery and 18,571 persons of the community. Conclusions The molecular characterization of the Neisseria meningitidis (N. meningitidis) strains, and the efficient investigation and the prompt measures implemented were essential for controlling the disease in the region.

Background Exposure to alcohol and its metabolites can initiate hepatic injury and fibrogenesis. Fibrosis is mediated through hepatic stellate cell (HSC) activation, leading to global changes in mRNA and microRNA (miR) expression. miRs are expressed in cells or shuttled to exosomes which can be detected in tissue culture media (TCM) and biological fluids. The mechanisms and function underlying the differential expression and processing of miRs and their downstream effects during hepatic injury remain poorly understood. Methods Expression of primary (pri)-miR17-92. and individual members of this cluster, miR17a, 18a, 19a, 20a, 19b, and 92, were examined in primary HSCs and human LX2 cells exposed to alcohol-conditioned media (CM), liver tissue from a rodent model of alcoholic injury, and in exosomes from TCM and plasma of rodent models and patients with alcoholic liver disease (ALD). miR expression was examined in HSCs transduced with an AAV2 vector carrying GFP-miR19b or GFP-control transgene under the collagen promoter. Results Profibrotic markers were enhanced in primary HSCs and LX2 cells exposed to alcohol-CM, concomitant with decreased miR19b expression and a significant increase in pri-miR17-92. Increased pri-miR17-92 was confirmed in a rodent model of alcohol-induced liver injury. Individual members of the cluster were inversely proportionate in cells and exosomes. AAV2-mediated miR19b overexpression inhibited miR17-92 and altered expression of individual cluster members in cells and exosomes. Expression of individual miR17-92 cluster members in plasma exosomes isolated from patients with ALD was similar to that seen in a rodent model of alcoholic injury and in vitro. Conclusions Reintroduction of miR19b inhibits HSC activation and modulates expression of pri-miR17-92 and the inverse expression of individual cluster members in cells and exosomes. Better understanding of miR17-92 processing may provide mechanistic insights into the role of individual miRs and exosomes during hepatic injury, revealing new therapeutic targets.

Background: Although peak creatine kinase-myocardial band (CK-MB) and troponin levels have been correlated with mortality among patients with acute myocardial infarction (AMI), the independent prognostic implications of these markers have not been compared. Hypothesis: We hypothesized that in patients with AMI, peak troponin levels (as compared to peak CK-MB levels) would have greater prognostic value. Methods: We examined AMI patients in the National Cardiovascular Data Registry ACTION Registry–GWTG (Acute Coronary Treatment and Intervention Outcomes Network Registry–Get With The Guidelines) with CK-MB and troponin I levels recorded, excluding patients who were transferred in or out. Peak marker levels, standardized by the local laboratory upper limit of normal and assay standard deviation, were fitted into the previously validated ACTION Registry–GWTG mortality model to compare prognostic value. Results: Between January 2007 and March 2009, 16 009 ST-segment elevation myocardial infarction (STEMI) and 26854 non–ST-segment elevation myocardial infarction (NSTEMI) patients were identified. Peak marker ratios were directly associated with in-hospital mortality in both STEMI and NSTEMI patients. Peak CK-MB had slightly greater discrimination compared with peak troponin I in predicting mortality in both STEMI (model C-statistic 0.881 vs 0.877, P = 0.011) and NSTEMI (C-statistic 0.831 vs 0.824, P = 0.001) patients. Conclusions: Both peak CK-MB and peak troponin I levels are independently associated with in-hospital mortality in this large contemporary database of AMI patients treated in routine practice. Peak marker values slightly improved model performance in prognosticating in-hospital mortality; the incremental value was higher with CK-MB than with troponin I. These findings may help to guide future risk stratification algorithms and contribute to more efficient use of serial cardiac marker measurements in clinical practice. Clin. Cardiol. 2011 DOI: 10.1002/clc.21980 This project was supported by grant number U18HS016964 from the Agency for Healthcare Research and Quality (AHRQ). The content is solely the responsibility of the authors and does not necessarily represent the official views of the AHRQ. The funding source had no role in the design or implementation of the study, or in the decision to seek publication. The authors have no other funding, financial relationships, or conflicts of interest to disclose.

Increased BMI is associated with a higher risk of gastroesophageal reflux disease.To investigate whether overweight/obesity (BMI≥25 kg/m(2)) affects rabeprazole clinical efficacy versus omeprazole in patients with erosive esophagitis (EE).Post-hoc analysis of EE healing rate and symptom response stratified by patient BMI was performed on data from a multicenter, double-blind, randomized, 4-to-8-week trial comparing EE healing with rabeprazole (20 mg daily) and omeprazole (20 mg daily). Analysis of variance, two-sample t-test, Blackwelder's test for equivalence, log-rank, and Cochran-Mantel-Haenszel tests were used to analyze comparisons.In the two BMI groups (25 kg/m(2) and ≥25 kg/m(2) respectively), rabeprazole and omeprazole were equally effective for mucosal healing regardless of patient's BMI (N=542, P0.05). However, in overweight/obese patients, rabeprazole was significantly faster than omeprazole in inducing heartburn relief during the first treatment week (P0.0001).Results of this study show that the clinical efficacy of rabeprazole is maintained in overweight/obese patients with gastroesophageal reflux disease and suggest that this subgroup of patients may derive, from rabeprazole, even greater benefit than lean patients.

Background: Several studies have shown that the modulation of fibrotic scar in cardiac diseases has beneficial effects on cardiac arrhythmias. In addition, recent reports suggest a potential role of mineralocorticoid receptor upregulation in atrial fibrillation (AF). The role of spironolactone, a mineralocorticoid receptor blocker and a potent antifibrotic agent, in AF is as yet unexplored. The aim of this study was to determine if spironolactone, a mineralocorticoid receptor blocker with potent antifibrotic properties, has beneficial effects on AF. Hypothesis: Spironolactone therapy in patients with atrial fibrillation provides additional clinical benefits in addition to the current conventional pharmacological agents. Methods: A comprehensive retrospective analysis was performed on 83 patients with AF, including 23 who were treated with spironolactone for ≥3 months. The combined primary outcome of hospitalization for AF or direct current cardioversion (DCCV) was compared between patients treated with spironolactone in addition to the usual care for AF and those receiving conventional medical therapy alone. Results: Patients receiving spironolactone had significantly fewer primary outcome events (AF-related hospitalizations or DCCV) (22% vs 53%, P = 0.027). Conclusions: Spironolactone therapy is associated with a reduction in the burden of AF, as reflected by a combination of hospitalizations for AF and DCCV. Larger randomized controlled studies should be performed to evaluate the efficacy and safety of spironolactone as an adjunctive therapy for patients with AF. © 2011 Wiley Periodicals, Inc. This work was supported by American Heart Association grants 0705170Y, 0830313N (RHN), and 0640084N (JAH), and National Institutes of Health grants HL-075173, HL-090842, and HL-080144 (JAH). The authors have no other funding, financial relationships, or conflicts of interest to disclose.

This 12-week, multicenter, randomized, double-blind, placebo-controlled, dose-ranging trial evaluated tramadol ER (extended-release tramadol) in the management of osteoarthritis pain. Adults with knee and/or hip osteoarthritis and baseline pain intensity of ≥40 on a 100-mm visual analog scale (0 = no pain, 100 = extreme pain) received once-daily tramadol ER 100 mg (n = 201), 200 mg (n = 199), or 300 mg (n = 199), celecoxib 200 mg (n = 202; to test model sensitivity), or placebo (n = 200). Coprimary efficacy variables were Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale, WOMAC physical function subscale, and patient global assessment of disease activity. Tramadol ER 300 mg significantly improved patient global assessment scores compared with placebo (P ≤ 0.05), but not the other 2 coprimary efficacy variables. Tramadol ER 200 and 100 mg were not significantly different from placebo for the coprimary efficacy variables. Daily diary arthritis pain intensity scores improved significantly for tramadol ER 300 and 200 mg compared with placebo. WOMAC joint stiffness subscale, physician's global assessment, arthritis pain intensity in index and nonindex joints, and overall sleep quality scores improved significantly for tramadol ER 300 mg compared with placebo. Significant differences in efficacy between celecoxib and placebo validated the model sensitivity. Adverse events occurred more frequently with tramadol ER than placebo in the gastrointestinal (nausea, constipation, diarrhea) and central nervous (dizziness, headache) systems. In this study, tramadol ER 300 mg was effective in the management of moderate to severe painful osteoarthritis of the hip or knee. A large, increasing placebo response during the study may have contributed to the lack of statistical separation between tramadol ER 200 or 100 mg and placebo.

To provide additional efficacy data in patients treated with rabeprazole through week 4, and to validate sustained relief of gastroesophageal reflux disease symptoms through week 8 as well as to further analyze rabeprazole safety in patients with wide-ranging demographic and clinical characteristics. Patients in this study (N = 2,449) demonstrated significant overall improvement versus baseline (P

Amoxicillin-clavulanate (AC) is the most frequent cause of idiosyncratic drug-induced injury (DILI) in the US DILI Network (DILIN) registry. Here, we examined a large cohort of AC-DILI cases and compared features of AC-DILI to those of other drugs.Subjects with suspected DILI were enrolled prospectively, and cases were adjudicated as previously described. Clinical variables and outcomes of patients with AC-DILI were compared to the overall DILIN cohort and to DILI caused by other antimicrobials.One hundred and seventeen subjects with AC-DILI were identified from the cohort (n = 1038) representing 11 % of all cases and 24 % of those due to antimicrobial agents (n = 479). Those with AC-DILI were older (60 vs. 48 years, P 0.001). AC-DILI was more frequent in men than women (62 vs. 39 %) compared to the overall cohort (40 vs. 60 %, P 0.001). The mean time to symptom onset was 31 days. The Tb, ALT, and ALP were 7 mg/dL, 478, and 325 U/L at onset. Nearly all liver biopsies showed prominent cholestatic features. Resolution of AC-DILI, defined by return of Tb to2.5 mg/dL, occurred on average 55 days after the peak value. Three female subjects required liver transplantation, and none died due to DILI.AC-DILI causes a moderately severe, mixed hepatocellular-cholestatic injury, particularly in older men, unlike DILI in general, which predominates in women. Although often protracted, eventual apparent recovery is typical, particularly for men and usually in women, but three women required liver transplantation.

To update the long-term outcomes after subclavian artery (SA) resection and reconstruction during surgery for thoracic inlet (TI) cancer through the anterior transclavicular approach.Between 1985 and 2014, 85 patients (60 men and 25 women; mean age, 52 years) underwent en bloc resection of thoracic-inlet non-small cell lung cancer (NSCLC) (n=69), sarcoma (n=11), breast carcinoma (n=3) or thyroid carcinoma (n=2) involving the SA. L-shaped transclavicular cervicothoracotomy was performed, with posterolateral thoracotomy in 18 patients or a posterior midline approach in 15 patients. Resection extended to the chest wall (2 ribs, n=60), lung (n=76), and spine (n=15). Revascularization was by end-to-end anastomosis (n=48), polytetrafluoroethylene (PTFE) graft interposition (n=28), subclavian-to-common carotid artery transposition (n=8), or grafting of the autologous superficial femoral artery in an anterolateral thigh free flap (n=1). Complete R0 resection was achieved in 75 patients and microscopic R1 resection in 10 patients. Postoperative radiation therapy was given to 51 patients.There were no cases of postoperative death, neurological sequelae, graft infection or occlusion, or limb ischemia. Postoperative morbidity consisted of pneumonia (n=16), phrenic nerve palsy (n=2), recurrent nerve palsy (n=4), bleeding (n=4), acute pulmonary embolism (n=1), cerebrospinal fluid leakage (n=1), chylothorax (n=1), and wound infection (n=2). Five-year survival and disease-free survival rates were 32% and 22%, respectively. Long-term survival was not observed after R1 resection.Subclavian arteries invaded by TI malignancies can be safely resected and reconstructed through the anterior transclavicular approach, with good long-term survival provided complete R0 resection is achieved.

Cholesteryl ester transfer protein (CETP) mediates the exchange of cholesteryl ester for triglyceride between high density lipoprotein (HDL) and very low density lipoprotein. The B2 allele of the TaqIB polymorphism located in the first intron of the CETP gene occurs with an allele frequency of about 0.40 in Caucasians and is associated with decreased CETP levels and activity and with higher HDL-cholesterol (HDL-C) levels in this racial group. We hypothesized that the higher levels of HDL-C seen in African Americans compared with Caucasians could be in part explained by a higher frequency of the TaqI B2 allele. We determined the distribution of this polymorphism in a total of 395 African Americans and 362 Caucasian ascertained as two independent cohorts: one of healthy volunteers (NORM) and the other of patients undergoing cardiac catheterization (CATH). Of the 244 NORM-African Americans studied, 56% were B1B1, 37% B1B2 and 7% B2B2, compared with the 224 NORM-Caucasians of which 33% were B1B1, 45% B1B2 and 22% B2B2. In the CATH-African American group (n=151) 51% were B1B1, 41% B1B2 and 8% B2B2 compared with 35% CATH-Caucasians B1B1, 54% B1B2 and 11% B2B2. The frequency of the B2 allele in the Caucasian subjects in both cohorts was similar to that reported in the literature. The frequency of the B2 allele was significantly lower in African Americans than in Caucasians in the NORM group (0.26 vs 0.44; chi(2)=36.5, P0.001) and in the CATH group (0.28 vs 0.38, chi(2)=4.7, P=0.01). Carriers of the B2 allele had higher HDL-C levels compared with B1B1 subjects in Caucasians (NORM: 57 vs 53 mg/dl, P=0.035; CATH: 47 vs 42 mg/dl, P=0.049) and in CATH-African Americans (48 vs 43 mg/dl, P=0.028), but not in NORM-African Americans (55 vs 54 mg/dl, P=0.494). There were no other significant associations between this polymorphism and other lipids and lipoproteins in the subjects studied. These results suggest that, in contrast to our hypothesis, the B2 allele of the TaqIB polymorphism is less frequent in African Americans compared with Caucasians and that this polymorphism is unlikely to contribute to the higher levels of HDL-C reported in the African American population.

Background P2Y12 antagonist therapy improves outcomes in acute myocardial infarction ( MI ) patients. Novel agents in this class are now available in the US . We studied the introduction of prasugrel into contemporary MI practice to understand the appropriateness of its use and assess for changes in antiplatelet management practices. Methods and Results Using ACTION Registry‐ GWTG (Get‐with‐the‐Guidelines), we evaluated patterns of P2Y12 antagonist use within 24 hours of admission in 100 228 ST elevation myocardial infarction (STEMI) and 158 492 Non‐ST elevation myocardial infarction (NSTEMI) patients at 548 hospitals between October 2009 and September 2012. Rates of early P2Y12 antagonist use were approximately 90% among STEMI and 57% among NSTEMI patients. From 2009 to 2012, prasugrel use increased significantly from 3% to 18% (5% to 30% in STEMI ; 2% to 10% in NSTEMI ; P for trend NSTEMI patients. Although contraindicated, 3.0% of patients with prior stroke received prasugrel. Prasugrel was used in 1.9% of patients ≥75 years and 4.5% of patients with weight STEMI and NSTEMI , prasugrel was most frequently used in patients at the lowest predicted risk for bleeding and mortality. Despite lack of supporting evidence, prasugrel was initiated before cardiac catheterization in 18% of NSTEMI patients. Conclusions With prasugrel as an antiplatelet treatment option, contemporary practice shows low uptake of prasugrel and delays in P2Y12 antagonist initiation among NSTEMI patients. We also note concerning evidence of inappropriate use of prasugrel, and inadequate targeting of this more potent therapy to maximize the benefit/risk ratio.

Objective: To review the clinical outcomes of stroke patients treated with IV tissue plasminogen activator (tPA; alteplase) in a community setting and to compare outcomes when treatment was initiated by a neurologist or an emergency department (ED) physician in telephone consultation with a neurologist and radiologist. Methods: Clinical information was prospectively collected for 43 stroke patients treated with IV tPA (alteplase) within a five-hospital network of affiliated community hospitals. Blinded 3-month outcomes were obtained with telephone interview or patient visit. Results: Excellent functional recovery measured by a Modified Rankin score of 0 to 1 (42%), symptomatic intracerebral hemorrhages (7%), and mortality (16.3%) were similar to those reported by National Institute of Neurological Disorders and Stroke (39%, 7.7%, 17.3%). After initial screening by an ED physician, 20 patients were directly examined by a stroke neurologist who then prescribed tPA. Twenty-three patients received tPA prescribed by an ED physician after telephone consultation with a neurologist and review of the head CT by a radiologist. Functional outcome, symptomatic intracerebral bleeding rate, and mortality rate were similar between these groups. Door-to-needle time was similar. Protocol deviations were much higher when ED physicians prescribed the tPA compared to when neurologists did (30% versus 5%). These protocol deviations were reduced with staff education. Conclusions: The clinical results of the National Institute of Neurological Disorders and Stroke tPA Stroke Trial were replicated in this small series of patients treated in a community setting. Outcomes were similar whether the prescribing physician was a neurologist or an ED physician.

Tommerdahl, M., K. A. Delemos, O. V. Favorov, C. B. Metz, C. J. Viereck, Jr., and B. L. Whitsel. Response of anterior parietal cortex to different modes of same-site skin stimulation. J. Neurophysiol. 80: 3272–3283, 1998. Intrinsic optical signal (IOS) imaging was used to study responses of the anterior parietal cortical hindlimb region (1 subject) and forelimb region (3 subjects) to repetitive skin stimulation. Subjects were four squirrel monkeys anesthetized with a halothane/nitrous oxide/oxygen gas mixtures. Cutaneous flutter of 25 Hz evoked a reflectance decrease in the sectors of cytoarchitectonic areas 3b and/or 1 that receive input from the stimulated skin site. The intrinsic signal evoked by 25-Hz flutter attained maximal intensity ≤2.5–3.5 s after stimulus onset, remained well maintained as long as stimulation was continued, and disappeared rapidly (usually ≤2–5 s) after stimulus termination. Repetitive skin heating stimuli were delivered via a probe/thermode in stationary contact with the skin (6 temperature ramps/trial; within-trial ramp frequency 0.42 Hz; intertrial interval 180 s; initial temperature 32–36°C; maximal temperature 48–52°C; rate of temperature change 19°C/s). Skin heating led to a large-amplitude reflectance decrease within a zone of area 3a, which neighbored the region in areas 3b/1 that emitted an intrinsic signal in response to same-site 25-Hz flutter in the same subject. In three of four subjects a lower-amplitude decrease in reflectance also occurred in a region of area 4 continuous with the area 3a region that responded maximally to same-site skin heating. The reflectance decrease evoked in areas 3a/4 by skin heating consistently exceeded in both intensity and spatial extent the decrease in reflectance evoked in areas 3b/1 by same-site 25-Hz cutaneous flutter. These findings are viewed as consistent with the proposal that area 3a plays a leading role in the anterior parietal cortical processing of the afferent drive evoked by skin-heating stimuli perceived as painful. In all four subjects the reflectance decrease evoked in areas 3a/4 by skin heating was accompanied by a simultaneous but opposite change in reflectance (a reflectance increase) within a large territory located immediately posterior to the regions that responded with a decrease in reflectance—an observation that raised the possibility that skin heating evoked opposing influences on the activity of area 3a and 3b/1 regions that receive input from the stimulated skin site. This was evaluated with the method of correlation mapping. The observations obtained with correlation mapping appear consistent with demonstrations by others that skin-heating stimuli perceived as painful by conscious subjects suppress/inhibit the anterior parietal response to innocuous mechanical skin stimulation. The opposing (relative to the response of area 3a) optical response of area 1 and/or area 3b during skin heating stimulation is attributed to suppression/inhibition of area 1 and/or area 3b neuron activity.

Although inhaled nitric oxide (iNO) causes selective pulmonary vasodilation and improves oxygenation in newborn infants with persistent pulmonary hypertension, its effects are variable. We hypothesized (1) that the response to iNO therapy is dependent on the primary disease associated with persistent pulmonary hypertension of the newborn (PPHN) and (2) that the combination of high-frequency oscillatory ventilation (HFOV) with iNO would be efficacious in patients for whom either therapy alone had failed.To determine the relative roles of iNO and HFOV in the treatment of severe PPHN, we enrolled 205 neonates in a randomized, multicenter clinical trial. Patients were stratified by predominant disease category: respiratory distress syndrome (n = 70), meconium aspiration syndrome (n = 58), idiopathic PPHN or pulmonary hypoplasia (excluding congenital diaphragmatic hernia) ("other": n = 43), and congenital diaphragmatic hernia (n = 34); they were then randomly assigned to treatment with iNO and conventional ventilation or to HFOV without iNO. Treatment failure (partial pressure of arterial oxygen [PaO2]60 mm Hg) resulted in crossover to the alternative treatment; treatment failure after crossover led to combination treatment with HFOV plus iNO. Treatment response with the assigned therapy was defined as sustained PaO2 of 60 mm Hg or greater.Baseline oxygenation index and PaO2 were 48 +/- 2 and 41 +/- 1 mm Hg, respectively, during treatment with conventional ventilation. Ninety-eight patients were randomly assigned to initial treatment with HFOV, and 107 patients to iNO. Fifty-three patients (26%) recovered with the initially assigned therapy without crossover (30 with iNO [28%] and 23 with HFOV [23%]; p = 0.33). Within this group, survival was 100% and there were no differences in days of mechanical ventilation, air leak, or supplemental oxygen requirement at 28 days. Of patients whose initial treatment failed, crossover treatment with the alternate therapy was successful in 21% and 14% for iNO and HFOV, respectively (p = not significant). Of 125 patients in whom both treatment strategies failed, 32% responded to combination treatment with HFOV plus iNO. Overall, 123 patients (60%) responded to either treatment alone or combination therapy. By disease category, response rates for HFOV plus iNO in the group with respiratory syndrome and the group with meconium aspiration syndrome were better than for HFOV alone or iNO with conventional ventilation (p0.05). Marked differences in outcomes were noted among centers (percent death or treatment with extracorporeal membrane oxygenation = 29% to 75%).We conclude that treatment with HFOV plus iNO is often more successful than treatment with HFOV or iNO alone in severe PPHN. Differences in responses are partly related to the specific disease associated with PPHN.

1. The response of anterior parietal cortex to skin stimuli was evaluated with optical intrinsic signal imaging and extracellular microelectrode recording methods in anesthetized squirrel monkeys. 2. Nonnoxious mechanical stimulation (vibrotactile or skin tapping) of the contralateral radial interdigital pad was accompanied by a decrease in reflectance (at 833 nm) in sectors of cytoarchitectonic areas 3b and 1. This intrinsic signal was in register with regions shown by previous receptive field mapping studies to receive low-threshold mechanoreceptor input from the radial interdigital pad. 3. A skin-heating stimulus applied to the contralateral radial interdigital pad with a stationary probe/thermode evoked no discernable intrinsic signal in areas 3b and 1, but evoked a signal within a circumscribed part of area 3a. The region of area 3a responsive to skin heating with the stationary probe/thermode was adjacent to the areas 3b and 1 regions that developed an intrinsic signal in response to vibrotactile stimulation of the same skin site. Skin heating with a stationary probe/thermode also evoked intrinsic signal in regions of areas 4 and 2 neighboring the area 3b/1 regions activated by vibrotactile stimulation of the contralateral radial interdigital pad. 4. The intrinsic signal evoked in area 3a by a series of heating stimuli to the contralateral radial interdigital pad (applied with a stationary probe/thermode) increased progressively in magnitude with repeated stimulation (exhibited slow temporal summation) and remained above prestimulus levels for a prolonged period after termination of repetitive stimulation. 5. Brief mechanical stimuli (,taps”) applied to the contralateral radial interdigital pad with a probe/thermode maintained either at 37 degrees C or at 52 degrees C were accompanied by the development of an intrinsic signal in both area 3a and areas 3b/1. For the 52 degrees C stimulus, the area 3a intrinsic signal was larger and the intrinsic signal in areas 3b/1 smaller than the corresponding signals evoked by the 37 degrees C stimulus. 6. Spike discharge activity was recorded from area 3a neurons during a repetitive heating stimulus applied with a stationary probe/ thermode to the contralateral radial interdigital pad. Like the area 3a intrinsic signal elicited by repetitive heating of the same skin site, the area 3a neuron spike discharge activity also exhibited slow temporal summation and poststimulus response persistence. 7. The experimental findings suggest 1) a leading role for area 3a in the anterior parietal cortical processing of skin-heating stimuli, and 2) the presence of inhibitory interactions between the anterior parietal responses to painful and vibrotactile stimuli consistent with those demonstrated in recent cortical imaging and psychophysical studies of human subjects.

Background: Increased body mass index (BMI) is associated with a higher risk of gastroesophageal reflux disease (GORD). Aim: To investigate whether overweight/obesity affects proton pump inhibitor pharmacodynamics when used in a single dose in patients with GORD. Methods: Post hoc analyses by patient BMI were performed on data from two single-center, double-blind, single-dose, crossover studies comparing the pharmacodynamics of rabeprazole 20 mg and pantoprazole 40 mg in GORD patients with a history of nocturnal heartburn. The primary endpoint was the mean percentage of time with intragastric pH >4 between lean and overweight/obese patients (BMI Results: 24 h baseline intragastric pH values were not different between BMI groups. The pharmacodynamic effects of both proton pump inhibitors were not significantly different between BMI groups, and no evidence was found for an interaction between BMI and treatment. As compared with pantoprazole, rabeprazole showed a significantly greater effect on the antisecretory response for both BMI groups. Conclusions: Overweight/obesity in GORD patients does not appear to affect the antisecretory efficacy of a single dose of rabeprazole and pantoprazole. These data do not support adapting the dosage of rabeprazole and pantoprazole according to BMI in GORD patients when administered as an on-demand therapy schedule.

BackgroundPatients in neurological critical care units often have lengthy stays that require extended vascular access and invasive hemodynamic monitoring. The traditional approach for these patients has relied heavily on central venous and pulmonary artery catheters. The aim of this study was to evaluate peripherally inserted central catheters as an alternative to central venous catheters in neurocritical care settings.MethodsData on 35 patients who had peripherally inserted central catheters rather than central venous or pulmonary artery catheters for intravascular access and monitoring were collected from a prospective registry of neurological critical care admissions. These data were cross-referenced with information from hospital-based data registries for peripherally inserted central catheters and subarachnoid hemorrhage.ResultsComplete data were available on 33 patients with Hunt-Hess grade IV–V aneurysmal subarachnoid hemorrhage. Catheters remained in place a total of 649 days (mean, 19 days; range, 4–64 days). One patient (3%) had deep vein thrombosis in an upper extremity. In 2 patients, central venous pressure measured with a peripherally inserted catheter was higher than pressure measured concurrently with a central venous catheter. None of the 33 patients had a central catheter bloodstream infection or persistent insertion-related complications.ConclusionsUse of peripherally inserted central catheters rather than central venous catheters or pulmonary artery catheters in the neurocritical care unit reduced procedural and infection risk without compromising patient management.

Introduction Although cardiovascular diseases (CVD) are the leading cause of death among Americans, significant disparities persist in CVD prevalence, morbidity, and mortality based on race and ethnicity. However, few studies have examined risk factor reduction among the poor and ethnic minorities. Methods Community-based participatory research (CBPR) study using a cluster randomized design — African-American church congregations are the units of randomization and individuals within the congregations are the units of analysis. Outcome variables include dietary change (Diet History Questionnaire), level of physical activity (7-Day Physical Activity Recall), lipoprotein levels, blood pressure, fasting glucose, and hemoglobin A1c. Results Eighteen (18) church congregations were randomized to either a health maintenance intervention or a control condition. Complete data were obtained on 392 African-American individuals, 18 to 70 years of age, predominantly employed women with more than a high school diploma. Treatment and intervention groups were similar at baseline on saturated fat intake, metabolic equivalent of tasks (METS) per day, and other risk factors for CVD. Conclusions The GoodNEWS trial successfully recruited and evaluated CVD-related risk among African-American participants using a CBPR approach. Several logistical challenges resulted in extending the recruitment, preliminary training, and measurement periods. The challenges were overcome with the assistance of a local community consultant and a professional event planner. Our experience supports the need for incorporating non-traditional community-based staff into the design and operational plan of CBPR trials.

Aliment Pharmacol Ther 31, 950–960 Summary Background Optimal long-term management of symptomatic gastro-oesophageal reflux disease (sGERD) patients has not been established. Aim To determine the clinical value of maintenance intermittent treatment with rabeprazole 20 mg vs. placebo in patients with sGERD. Methods This multicentre, US study enrolled patients with sGERD (≥3-month history of GERD symptoms and ≥4 days/week of heartburn during a 2-week placebo run-in) without oesophageal erosions. Patients with complete heartburn control after 4 weeks of open-label rabeprazole 20 mg daily treatment were randomized to 6-month, double-blind, maintenance intermittent treatment (7- to 14-day courses when heartburn recurred) with rabeprazole 20 mg or placebo. Results The primary efficacy end point, mean percentage of heartburn-free days, was significantly greater with rabeprazole vs. placebo: 82.58% and 62.17% (ITT; P

Aliment Pharmacol Ther 31, 991–1000 Summary Background Nocturnal heartburn is common in patients with gastro-oesophageal reflux disease (GERD). Aim To compare the effects of single doses of rabeprazole 20 mg and pantoprazole 40 mg on 24-h intragastric acidity and oesophageal acid exposure (OAE). Methods A total of 52 subjects with GERD and a ≥6-month history of heartburn were randomized into a blinded, 2 × 2 crossover trial. Subjects’ intragastric pH was monitored in two 48-h study periods with 6- to 13-day washout between periods. Patients received placebo on day 1, a single dose of rabeprazole 20 mg or pantoprazole 40 mg on day 2, and standardized meals throughout. Results The mean percentage time with intragastric pH >4 was significantly greater with rabeprazole vs. pantoprazole for the 24-h postdose interval (44.0% vs. 32.8%; P 4 during the nighttime, daytime, and 24-h periods. Differences between treatments in OAE were not demonstrated. This trial is registered with http://clinicaltrials.gov, number NCT00237367.

The emergence of methicillin-resistant Staphylococcus aureus (MRSA) has posed a challenge in the treatment of neurosurgical patients. The authors investigated the impact of MRSA colonization and infection in the neurosurgical population at a community-based, tertiary care referral center.Hospitalized patients under the care of the Kaiser Permanente inpatient neurosurgery service were prospectively entered into a database. In Phase I of the study, 492 consecutive patients were followed. Per hospital policy, the 260 patients from this group who were admitted to the intensive care unit (ICU) underwent screening for MRSA based on nasal swab cultures and a review of their medical history for prior MRSA infections. These patients were designated as either MRSA positive (17 patients, 6.5% of screened patients) or MRSA negative (243 patients). The 232 patients admitted to non-ICU nursing units did not undergo MRSA screening and were designated as unscreened. In Phase II of the study, the authors reviewed 1005 neurosurgical admissions and completed a detailed chart review in 62 MRSA-positive patients (6.2%). Eleven patients received nonoperative treatment. Five patients presented with community-acquired neurosurgical infections, and the causative organism was MRSA in 3 cases. Forty-six patients underwent 55 procedures, and the authors reviewed their perioperative management.In Phase I of the study, the authors found that for the MRSA-positive, MRSA-negative, and unscreened groups, the rates of postoperative neurosurgical wound infections caused by all pathogens were 23.5, 4.1, and 1.3%, respectively. For MRSA wound infections, the rates were 23.5, 0.8, and 0%, respectively. In Phase II, patients with MRSA were noted to have the following clinical features: male sex in 63%, a malignancy in 39.1%, diabetes in 34.8%, prior MRSA infection in 21.7%, immunosuppressed state in 17.4%, and a traumatic injury in 15.2%. The rate of postoperative neurosurgical wound infection in patients who received MRSA-specific prophylactic antibiotic therapy (usually vancomycin) was 7.4% (27 procedures) compared with 32.1% (28 procedures) in patients who received the standard treatment (usually cefazolin) (p = 0.04). Wound care for ICU patients was standardized for postoperative Days 0-7 with chlorhexidine cleaning at bandage changes at 3-day intervals. Wound cultures from neurosurgical site infections in patients with prior MRSA colonization or infection grew MRSA in 7 of 11 patients.Neurosurgical patients identified with MRSA colonization or a prior history of MRSA infections benefit from specific perioperative care, including prophylactic antibiotics active against MRSA (such as vancomycin) and postoperative wound care with coverings and chlorhexidine antisepsis to reduce MRSA wound colonization.

To assess whether or not liver transplantation and subsequent immunosuppression with cyclosporine and prednisone affect ulcerative colitis symptomatology, we surveyed by questionnaire all 23 surviving patients with pretransplant colonoscopy-documented ulcerative colitis who were transplanted for primary sclerosing cholangitis between June 1982 and September 1985. At follow-up [89.8 +/- 7.6 weeks (mean +/- SEM], all six patients who had had asymptomatic colonoscopy-documented ulcerative colitis reported continued ulcerative colitis quiescence. Among the 17 patients who had had symptomatic colonoscopy-documented ulcerative colitis at time of liver transplantation, 88.2% reported improvement in overall ulcerative colitis severity (P less than 0.001), with significant improvement in the frequency of bowel movements reported by 100%, in crampy abdominal pain by 87.5%, in bowel urgency by 75%, in the occurrence of pus or mucus in stool by 87.5%, in the incidence of ulcerative colitis flares by 81.8%, and in the number of days unable to function normally due to ulcerative colitis symptoms by 78.6% (all at least P less than 0.01). These data demonstrate that ulcerative colitis symptom severity significantly improves following liver transplantation with immunosuppression with cyclosporine and prednisone.

Threshold amplitude for vibration is elevated if testing is preceded by extended exposure to a vibratory adapting stimulus of appropriate amplitude and frequency. This phenomenon, previously studied almost exclusively on the hand, is here shown for the first time to occur on the face as well. Adaptation is then used analytically to determine that the two-branched threshold. versus-frequency function obtained on the face by Verrillo and Ecker (1977) represents the activity of two distinct mechanisms. Action spectra of vibrotactile adaptation reveal the presence of both mechanisms even in subjects whose unadapted threshold function (like that reported by Barlow, 1987) shows no sign of duplexity. Finally, the data suggest that on the face (unlike the hand), cross-channel adaptation may occur at high adapting amplitudes.

Short-term exposure to 0.5 parts per million (ppm) ozone has been shown to cause an increase in respiratory resistance in primates that can be diminished by 50% with pretreatment with cromolyn sodium. Because of the known membrane-stabilizing effects of cromolyn and the resultant inhibition of mediator production, we hypothesized a role for the products of arachidonic acid (AA) metabolism in these events. We exposed five adult male baboons to 0.5 ppm ozone on two occasions, once with cromolyn pretreatment and once without. Pulmonary resistance (RL) was monitored and bronchoalveolar lavage (BAL) was performed before and after each exposure. The BAL was analyzed for a stable hydrolysis product of prostacyclin, 6-keto-prostaglandin (PG) F1 alpha, PGE2, a stable hydrolysis product of thromboxane (Tx) A2, TxB2, and PGF2 alpha. RL increased after ozone exposure (1.62 +/- 0.23 to 3.77 +/- 0.51 cmH2O.l-1.s, difference 2.15; P less than 0.02), and this effect was partially blocked by cromolyn (1.93 +/- 0.09 to 3.18 +/- 0.40 cmH2O.l-1.s, difference 1.25; P less than 0.02). The base-line levels of the metabolites of AA in the BAL were as follows (in pg/ml): 6-keto-PGF1 alpha 72.78 +/- 12.6, PGE2 145.92 +/- 30.52, TxB2 52.52 +/- 9.56, and PGF2 alpha 22.28 +/- 5.42. Ozone exposure had no effect on the level of any of these prostanoids (P = NS). These studies quantify the magnitude of cyclooxygenase products of AA metabolism in BAL from baboon lungs and demonstrate that changes in the levels of these mediators in BAL are not prerequisites for ozone-induced increases in respiratory resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Ablation of mouse olfactory bulbs lengthened the circadian period of wheel-running activity by 43 min and delayed the onset of entrained activity by 108 min. A transient increase in activity during the light phase of the 12:12 h light-dark photoperiod also occurred following surgery. These disruptions suggest that olfactory systems can modulate mammalian circadian rhythms.

The Three Mile Island nuclear release exemplifies why there is public and policy interest in the high-technology, highly visible end of the nuclear cycle. The environmental and health consequences of the early steps in the cycle—mining, milling, and processing of uranium ore—may be less appreciated. We examined 2 large unintended acute releases of uranium—at Kerr McGee’s Sequoyah Fuels Corporation in Oklahoma and United Nuclear Corporation’s Church Rock uranium mill in New Mexico, which were incidents with comparable magnitude to the Three Mile Island release. We urge exploration of whether there is limited national interest and concern for the primarily rural, low-income, and American Indian communities affected by these releases. More attention should be given to the early stages of the nuclear cycle and their impacts on health and the environment.

Previous studies have shown that compared with white patients, non-white patients with ST elevation myocardial infarction (STEMI) have worse clinical outcomes. Differences in co-morbidities, extent and severity of coronary artery disease, health insurance, and socioeconomic status have been identified as possible reasons for this disparity. However, an alternative explanation for such observed disparities in outcomes could be differences in process of care. For example, in most of these studies, non-white patients were less likely to receive reperfusion therapy, and if treated, were more likely to receive thrombolysis than to undergo primary percutaneous coronary intervention (PCI). We hypothesized that if all patients were treated similarly with primary PCI, there would be no difference in clinical outcomes. We analyzed the demographic, angiographic, in-hospital clinical outcomes, and long-term mortality rates of a racially diverse group of patients presenting to the same hospital with STEMI, all of whom were treated with primary PCI. Our data demonstrate that compared with white patients, non-white patients with STEMI who undergo primary PCI have similar in-hospital clinical outcomes and one-year mortality. This suggests that the previously observed differences in mortality rates may be, at least in part, attributable to differences in the process of care, and not solely to differences in patient factors or differential therapeutic effects.

Background Most hospitals that perform primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) in the United States exceed the recommended door-to-balloon time. There is heightened interest in identifying and eliminating factors that introduce delay. Methods We performed a key process analysis of our primary PCI program, assessed the relative contribution of individual time intervals on total ischemic time, and identified predictors of delay. Results Median times and predictors of delay within each time interval were determined for the entire STEMI cohort (“real world”) and after exclusion of patients with atypical symptoms and/or presentations of STEMI that resulted in inherent delay in diagnosis and treatment (“ideal world”). Delays in therapy were symptom onset to presentation (120 minutes [interquartile range, IQR, 60-310 minutes, ideal world] and 150 minutes [IQR 60-360 minutes, real world]; predictors of delay were peripheral vascular disease, self-transportation, daytime and weekend presentation); door-to-balloon time (118.5 minutes [IQR 96-141 minutes, ideal world] and 125 minutes [IQR 100-170 minutes, real world]; predictors of delay were female sex, previous stroke, nighttime and weekend presentation, and cardiogenic shock); and symptom onset to first balloon inflation (272 minutes [IQR 187-465 minutes, ideal world] and 297 minutes [IQR 198-560 minutes, real world]; predictors of delay were peripheral vascular disease, weekend presentation, and self-transportation). Conclusions Key process analysis of a primary PCI program identifies treatment delays unique to the hospital and the patient population it serves.

Rabeprazole and pantoprazole are both used for symptomatic treatment of gastro-oesophageal reflux disease (GERD). Speed and duration of acid suppression and intensity of effect after a single dose may be important pharmacodynamic properties in clinical use.To compare antisecretory effects of single doses of rabeprazole and pantoprazole in patients with GERD and a history of nocturnal heartburn.An open-label, randomized, two-way crossover, clinical pharmacology study was conducted. Twenty-nine Helicobacter pylori-negative GERD patients (17 men, mean age 44 years), with a history of nocturnal heartburn (mean frequency 4.7 episodes/week), received a single dose of rabeprazole 20 mg or pantoprazole 40 mg, with a 14-day 'washout'. Intragastric pH was recorded continuously from 24 h before to 24 h after dosing.Mean area under the intragastric pH-time curve (AUC) was significantly higher after dosing with rabeprazole 20 mg than with pantoprazole 40 mg in all time intervals analysed, including night (P/= 0.02). Mean percentage time with pH3 and4 was significantly greater after rabeprazole than pantoprazole in all time intervals (P/= 0.004).In GERD patients with nocturnal heartburn, a single oral dose of rabeprazole 20 mg increased intragastric pH more than pantoprazole 40 mg did throughout the 24 h after dosing.

Background— Elevated high-density lipoprotein cholesterol (HDL-C) is associated with reduced risk of cardiovascular disease, and variation in HDL-C levels has been shown to be ≈50% heritable. Overexpression of endothelial lipase (EL), a member of the lipoprotein lipase gene family, markedly reduces HDL-C levels in mouse models. We hypothesized that genetic variation in EL might be associated with elevated HDL-C. Methods and Results— All exons and 1.2 kilobase of promoter of the EL gene were sequenced in 20 unrelated human subjects with high HDL-C levels. A total of 17 variants were identified. Six of these were potentially functional and were confirmed by restriction enzyme analysis. Four variants result in amino acid changes (Gly26Ser, Thr111Ile, Thr298Ser, and Asn396Ser,) and 2 variants were in the promoter (−303A/C and −410C/G). The genotype frequencies of each variant were determined in 176 black controls, 165 white controls, and 123 whites with high HDL-C. The Thr111Ile variant was the most common, with an allele frequency of 10.3% in blacks, 31.2% in white controls, and 32.6% in the high HDL-C group. The remaining variants all had allele frequencies Conclusions— Six new potentially functional variants in EL were discovered through sequencing of the EL gene in subjects with high HDL-C levels. Differences in allele frequencies exist between blacks and whites and between control subjects and those with high HDL-C levels.

The Early Retavase-Thrombolysis In Myocardial Infarction (ER-TIMI) 19 trial tested the feasibility of prehospital initiation of the bolus fibrinolytic reteplase (rPA) and determined the time saved by prehospital rPA in the setting of contemporary emergency cardiac care.Newer bolus fibrinolytics have undergone only limited evaluation for prehospital administration. In addition, as door-to-drug times have decreased, the relevance of findings from prior trials of prehospital fibrinolysis has become less certain.Patients (n = 315) with ST-elevation myocardial infarction (STEMI) were enrolled in 20 emergency medical systems in North America. The time from emergency medical service (EMS) arrival to administration of a fibrinolytic was compared between study patients receiving prehospital rPA and sequential control patients from 6 to 12 months before the study who received a fibrinolytic in the hospital.Acute myocardial infarction was confirmed in 98%. The median time from EMS arrival to initiation of rPA was 31 min (25th to 75th percentile, 24 min to 37 min). The time from EMS arrival to in-hospital fibrinolytic for 630 control patients was 63 min (25th to 75th percentile, 48 min to 89 min), resulting in a time saved of 32 min (p0.0001). By 30 min after first medical contact, 49% of study patients had received the first bolus of fibrinolytic compared with only 5% of controls (p0.0001). In-hospital mortality was 4.7%. Intracranial hemorrhage occurred in 1.0%.Prehospital administration of rPA is a feasible approach to accelerating reperfusion in patients with STEMI. Valuable time savings can be achieved in the setting of contemporary transport and door-to-drug times and may translate into an improvement in clinical outcomes.

Calcific aortic stenosis is common in the elderly; indeed, 30-60% of patients with mild 'senile' aortic stenosis will progress to severe obstruction. Nonetheless, predictors of progression are incompletely defined, and non-invasive technologies capable of quantifying aortic valve calcium are needed. The reliability of electron beam computed tomography (EBCT) was evaluated for quantification of aortic valve calcium content.Nineteen patients with and without restrictive valve calcification underwent EBCT scanning. Separate calcium scores, 30 s apart, were obtained in all patients, and the Spearman correlation coefficient was calculated between measurements. The relationship between dichotomized mean calcium score and aortic valve area was also investigated.There was excellent correlation between calcium scores (R = 0.99, p = 0.0001), as well as a significant inverse relationship between calcium scores in the upper and lower ranges and aortic valve area (p = 0.002).EBCT can be used for reproducible quantitation of aortic valve calcification. While at their extremes, calcium scores are inversely related to aortic valve area, further evaluation is needed to define the precise nature of this relationship throughout the spectrum of stenosis severity. EBCT holds promise in the longitudinal assessment of valvular calcification progression and its response to potential medical therapies.