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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.

© 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.

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.

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.

Hepatocellular carcinoma (HCC) has a strong racial and ethnic association, with Hispanic patients having a higher incidence and mortality. However, there are limited data regarding clinical features and outcomes. This study includes Hispanic and non‐Hispanic White patients with HCC diagnosed between January 2000 and June 2014 from five United States academic medical centers. The chi‐square test for categorical variables and analysis of variance for continuous variables were used for statistical analysis, with two‐tailed P, Hispanic patients are more likely to have metabolic risk factors leading to their chronic liver disease risk for hepatocellular carcinoma in comparison to non‐Hispanic whites. Hispanic patients have similar overall survival despite being diagnosed with larger, more advanced HCC despite fewer curative interventions.

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 .

First-line therapy for autoimmune hepatitis (AIH) centers around initiation of predniso(lo)ne followed by the introduction of azathioprine to maintain a biochemical remission. Combination therapy during induction with subsequent tapering of steroids with the intent of maintaining remission with azathioprine monotherapy is the goal. A majority of patients with AIH are capable of attaining a remission with first-line therapy and can be cautiously considered for withdrawal of therapy following 3 years of therapy and after at least 2 years of normal transaminase and IgG levels. Relapse following tapering or after discontinuation of therapy is highly likely, and therefore requires close monitoring and timely resumption of therapy. Individualizing treatment to achieve a balance between maximizing the benefits of therapy while limiting toxicities is the foundation of first-line therapy for AIH.

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.

Chronic hepatitis B virus (HBV) and chronic hepatitis C virus (HCV) are associated with hepatic fibrosis and development of hepatocellular carcinoma (HCC). There are differences and variation with the incidence of HCC worldwide. Additionally, HCC develops via different pathways with these viral hepatitides. This review outlines the various mechanisms and pathophysiology that contributes to this process. There will also be a review on the recommended screening for HCC. Treatment considerations, which are different for these viruses, will be outlined in this review.

AIM To identify risk factors associated with hepatocellular carcinoma (HCC), describe tumor characteristics and treatments pursed for a cohort of individuals with nonalcoholic steatohepatitis (NASH) cirrhosis. METHODS We conducted a retrospective case-control study of a well-characterized cohort of patients among five liver transplant centers with NASH cirrhosis with (cases) and without HCC (controls). RESULTS Ninety-four cases and 150 controls were included. Cases were significantly more likely to be male than controls (67% vs 45%, P < 0.001) and of older age (61.9 years vs 58 years, P = 0.002). In addition, cases were more likely to have had complications of end stage liver disease (83% vs 71%, P = 0.032). On multivariate analysis, the strongest association with the presence of HCC were male gender (OR 4.3, 95%CI: 1.83-10.3, P = 0.001) and age (OR = 1.082, 95%CI: 1.03-1.13, P = 0.001). Hispanic ethnicity was associated with a decreased prevalence of HCC (OR = 0.3, 95%CI: 0.09-0.994, P = 0.048). HCC was predominantly in the form of a single lesion with regional lymph node(s) and distant metastasis in only 2.6% and 6.3%, respectively. Fifty-nine point three percent of individuals with HCC underwent locoregional therapy and 61.5% underwent liver transplantation for HCC. CONCLUSION Male gender, increased age and non-Hispanic ethnicity are associated with HCC in NASH cirrhosis. NASH cirrhosis associated HCC in this cohort was characterized by early stage disease at diagnosis and treatment with locoregional therapy and transplant.

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.

BACKGROUND A novel protocol to standardize the emergency center (EC) management of abdominal trauma in children was developed and implemented at our trauma center. The purpose of this study was to evaluate whether this protocol improved patient safety by decreasing unnecessary computed tomography (CT) radiation and improved quality of care by decreasing EC length of stay (LOS) and laboratory costs. METHODS We performed a prospective, longitudinal study of children who presented to the EC with a mechanism for abdominal trauma and received an abdominal CT scan from January 2011 to September 2014. Patients were divided into protocol periods: preimplementation (January 2011 to December 2011), Postimplementation 1 (January 2012 to August 2013), and Postimplementation 2 (September 2013 to September 2014). Outcome measures included protocol adherence, rates of clinically positive CT results, the EC LOS, and the cost of laboratory studies. χ and analysis of variance were used for statistical analysis. RESULTS During the study period, 117 patients in the preimplementation, 148 patients in the Postimplementation 1, and 56 patients in the Postimplementation 2 periods were identified. Protocol adherence improved from 70% to 82% (p = 0.11) from the Postimplementation 1 to Postimplementation 2 periods. The rate of positive CT scan results increased from 23% to 31% to 46% (p = 0.003) from preimplementation to Postimplementation 1 and Postimplementation 2, respectively. When the protocol was followed, the proportion of clinically significant scans was higher than when it was not followed (31% vs. 8%, p = 0.001). The EC LOS was unchanged (median [range], 271 minutes [16-1,039 minutes] vs. 233 minutes [40-1,396 minutes], p = 0.34). The median cost of laboratory studies remained the same from preimplementation to Postimplementation 1 ($166 [$0-$454] vs. $352 [$0-$448], p = 0.29) and decreased after the second protocol revision included an emphasis on laboratory work in Postimplementation 2 ($139 [$33-$426], p = 0.005). CONCLUSION The use of an institutional abdominal trauma management algorithm is an effective method of improving resource use by decreasing unnecessary CT scan use and laboratory costs. LEVEL OF EVIDENCE Economic analysis, level IV; therapeutic/care management study, level IV.

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.

In a patient with liver disease, the degree of liver impairment should be evaluated carefully before surgery. The Model for End-stage Liver Disease (MELD) score, used to prioritize candidates awaiting liver transplantation, can also be used to help predict the risk of postoperative mortality in patients with cirrhosis. Strategies to mitigate the risk of liver-related morbidity in patients with cirrhosis undergoing surgery include avoiding hypotension, minimizing the duration of anesthesia, and limiting exposure to narcotics and sedatives to avoid precipitating hepatic encephalopathy. For treatment of hepatocellular carcinoma, minimally invasive surgery with radiofrequency or microwave ablation is increasingly used in patients with cirrhosis, with excellent outcomes. Postoperative patients with ascites who require volume expansion, should receive 25% albumin or blood products rather than crystalloid. In addition, it is crucial to avoid nephrotoxic agents such as nonsteroidal antiinflammatory drugs to prevent the development of hepatorenal syndrome. Postoperative jaundice can occur in patients with or without liver disease due to an increase in serum bilirubin levels from blood transfusions or resorption of hematomas or from intrahepatic cholestasis resulting from drug-induced liver injury, sepsis, ischemia, or total parenteral nutrition.

IntroductionCombined modality treatment regimens have provided modest gains in locoregional control rates of cancers of the head and neck (HNC), and intensity-modulated radiation therapy (IMRT) has gained widespread use. The methodology for determining contours of the gross tumour volume (GTV) in the radiation treatment plan is often based on combined anatomic and metabolic data from positron emission tomography–computed tomography (PET-CT). This study aimed to retrospectively evaluate the overall survival and disease-free survival outcomes of patients with HNC who received definitive IMRT with or without chemotherapy, planned with PET-CT.Materials and MethodsA total of 1,200 patients underwent treatment for HNC during the study period, from 1 January 2002 to 31 December 2010. Of those, 261 cases had evaluable data that met the inclusion criteria for the study. The incidence and timing of locoregional recurrence, distant metastatic disease, new primary malignancies and death were evaluated retrospectively. Overall and disease-free survival (survival to time of first recurrence) were determined by the life table method. Incidence of distance metastatic disease and additional cancers were also studied.ResultsMedian follow-up from treatment initiation was 26·4 months (range 1·2–84·7 months). Overall survival and disease-free survival rates were 0·883 and 0·791, respectively, at 1 year; 0·793 and 0·688, respectively, at 2 years; and 0·732 and 0·619, respectively, at 3 years. The cumulative risk of recurrence was 22·6% at 3 years following definitive IMRT and the median time to recurrence was 345 days. There was an overall low incidence of distant metastatic disease (3·07%) and additional cancers (8·05%).ConclusionOverall and disease-free survival outcomes of a large cohort of HNC patients treated with definitive IMRT radiotherapy following treatment planning with PET-CT shows a similar high level of disease control and mortality rate as previously published outcome studies of shorter terms and/or smaller numbers of patients.

The study investigated the utility and timing of 18F-FDG PET-CT to evaluate for residual/recurrent or metastatic HNC in patients treated with definitive intensity modulated radiation therapy (IMRT) with or without chemotherapy, planned with 18F-FDG PET-CT. The incidence and timing of locoregional recurrence, distant metastatic disease, new primary malignancies, and death were evaluated in 261 patients retrospectively. Findings were classified based on pathology or clinical follow-up and the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of FDG PET-CT were determined overall as well as at the time of each 18F-FDG PET-CT. The overall accuracy for 18F-FDG PET in the detection of residual/recurrent malignancy or metastatic disease was 96.4%. Of those in whom cancer recurred locally, 57% were identified based on physical examination and other imaging findings and 43% were identified initially on 18F-FDG PET-CT surveillance imaging when no disease was evident clinically. 18F-FDG PET-CT has a high diagnostic capability of detecting residual/recurrent malignancy or malignant metastatic disease in patients with HNC following IMRT ± concurrent chemotherapy, supporting 18F- FDG PET-CT’s use to evaluate patients for recurrent malignancy in the post-IMRT period, even without clinical evidence of disease.

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

An exciting paradigm shift is occurring in the treatment of hepatitis C virus (HCV). We now have the capacity to specifically target therapy to HCV proteins, and thereby directly interrupt the viral life cycle. The first direct-acting antivirals (DAAs), the NS3-4A serine protease inhibitors boceprevir and telaprevir, improved the rate of sustained virologic response (SVR), but their toxicities combined with PEG-IFN and RBV limited their overall efficacy. Sofosbuvir, a nucleotide HCV polymerase inhibitor, is now available and offers better tolerability and efficacy across all HCV genotypes. The next phase of therapy will be combining several classes of DAAs without IFN in order to make sustained clearance of hepatitis C deliverable to a much larger number of infected individuals.

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 and Aims Hospital admissions in cirrhotic patients are a source of significant health care expenditure. Most studies to date have focused on readmissions in patients with decompensated cirrhosis. We sought to describe predictors of hospital admissions in an ambulatory cirrhosis cohort consisting of both compensated and decompensated patients to identify patients who could benefit from intensified outpatient chronic disease management.

Systemic causes of cholestasis constitute a diverse group of diseases across organ systems. The pathophysiology of cholestasis in systemic disease can be a consequence of direct involvement of a disease process within the liver or extrahepatic biliary system or secondary to immune-mediated changes in bile flow. Evaluating a patient with cholestasis for a systemic cause requires an understanding of the patient's risk factors, clinical setting (eg, hospitalized or immunosuppressed patient), clinical features, and pattern of laboratory abnormalities.

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

Summary Background 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. Aim To compare antisecretory effects of single doses of rabeprazole and pantoprazole in patients with GERD and a history of nocturnal heartburn. Methods 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. Results 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 pH > 3 and >4 was significantly greater after rabeprazole than pantoprazole in all time intervals (P ≤ 0.004). Conclusion 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.

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.

Objectives 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. Background 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. Methods 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. Results 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 (p Conclusions 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.

End stage liver disease from hepatitis C is the most common indication for liver transplantation in many parts of the world accounting for up to 40% of liver transplants. Antiviral therapy either before or after liver transplantation is challenging due to side effects and lower efficacy in patients with cirrhosis and liver transplant recipients, as well as from drug interactions with immunosuppressants. Factors that may affect recurrent hepatitis C include donor age, immunosuppression, IL28B genotype, cytomegalovirus infection, and metabolic syndrome. Older donor age has persistently been shown to have the greatest impact on recurrent hepatitis C. After liver transplantation, distinguishing recurrent hepatitis C from acute cellular rejection may be difficult, although the development of molecular markers may help in making the correct diagnosis. The advent of interferon free regimens with direct acting antiviral agents that include NS3/4A protease inhibitors, NS5B polymerase inhibitors and NS5A inhibitors holds great promise in improving outcomes for liver transplant candidates and recipients.

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.

The use of thrombolytic therapy represents one of many recent developments in the management of acute ischemic stroke. The development of stroke teams and protocols has been driven by these new demands for an urgent response to ischemic stroke. The short time window of 3 hours for therapy with intravenous recombinant tissue plasminogen activator requires efficient evaluation and treatment of stroke patients and also necessitates a rigorous approach to blood pressure management, electrolytes, fluids, and temperature. Anticoagulation has not been proven to safely prevent progression or early recurrence of stroke, but antiplatelet therapy is worthwhile.

OBJECTIVES: The aim of this study is to measure baseline serum cortisol levels and clinical response to glucocorticoid therapy in a group of term infants with refractory hypotension. STUDY DESIGN: Seven term newborns with refractory hypotension were included. Serum cortisol levels were drawn before initiation of glucocorticoid therapy and measured by either fluorescence polarization immunoassay or radioimmunoassay. Baseline blood pressures, heart rate, and inotropes doses were recorded at baseline, then 4, 8, 12, 24, 48, 72, and 96 hours after glucocorticoid therapy. Urine output and volume expanders the infants received were recorded 24 hours before and after glucocorticoid therapy. Dexamethasone was used at a starting dose of 0.2 mg/kg per day divided every 12 hours. The statistical analysis was done using analysis of variance with repeated measures and paired t-test. RESULTS: Serum cortisol levels of the infants ranged from 2.0 to 15.4 μg/dl. After initiation of glucocorticoid therapy, there was significant improvement of blood pressure. Vasopressors were rapidly weaned and discontinued within 72 hours. In three of seven infants, no volume expanders were required after initiation of steroids, and none needed volume expanders after 2 days. Urine output increased significantly within 24 hours. All infants survived. CONCLUSIONS: Glucocorticoids improved pressure and stabilized clinical conditions of a group of term newborns with refractory hypotension. Serum cortisol levels of these infants were relatively low. We speculate that a subset of critically ill term infants has relative adrenal insufficiency and glucocorticoid therapy may be essential.

An infant with congenital diaphragmatic hernia was delivered by vacuum extraction, with a resultant subgaleal hemorrhage that excluded him from ECMO. The literature regarding vacuum-assisted delivery and birth trauma is reviewed in the context of congenital anomalies that may require ECMO support, and recommendations for perinatal management are suggested.

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.

Background The intratracheal administration of a perfluorocarbon liquid during continuous positive-pressure ventilation (partial liquid ventilation) improves lung function in animals with surfactant deficiency. Whether partial liquid ventilation is effective in the treatment of infants with severe respiratory distress syndrome is not known. Methods We studied the efficacy of partial liquid ventilation with perflubron in 13 premature infants with severe respiratory distress syndrome in whom conventional treatment, including surfactant therapy, had failed. Partial liquid ventilation was initiated by instilling perflubron during conventional mechanical ventilation to a volume approximating the functional residual capacity. Infants were considered to have completed the study if they received partial liquid ventilation for at least 24 hours. Results Ten infants received partial liquid ventilation for 24 to 76 hours. In the other three infants, partial liquid ventilation was discontinued within four hours in fa...