Brooke Army Medical Center

BACKGROUND: Benign prostatic hyperplasia is commonly treated with alpha-adrenergic-receptor antagonists (alpha-blockers) or 5alpha-reductase inhibitors. The long-term effect of these drugs, singly or combined, on the risk of clinical progression is unknown. METHODS: We conducted a long-term, double-blind trial (mean follow-up, 4.5 years) involving 3047 men to compare the effects of placebo, doxazosin, finasteride, and combination therapy on measures of the clinical progression of benign prostatic hyperplasia. RESULTS: The risk of overall clinical progression--defined as an increase above base line of at least 4 points in the American Urological Association symptom score, acute urinary retention, urinary incontinence, renal insufficiency, or recurrent urinary tract infection--was significantly reduced by doxazosin (39 percent risk reduction, P<0.001) and finasteride (34 percent risk reduction, P=0.002), as compared with placebo. The reduction in risk associated with combination therapy (66 percent for the comparison with placebo, P<0.001) was significantly greater than that associated with doxazosin (P<0.001) or finasteride (P<0.001) alone. The risks of acute urinary retention and the need for invasive therapy were significantly reduced by combination therapy (P<0.001) and finasteride (P<0.001) but not by doxazosin. Doxazosin (P<0.001), finasteride (P=0.001), and combination therapy (P<0.001) each resulted in significant improvement in symptom scores, with combination therapy being superior to both doxazosin (P=0.006) and finasteride (P<0.001) alone. CONCLUSIONS: Long-term combination therapy with doxazosin and finasteride was safe and reduced the risk of overall clinical progression of benign prostatic hyperplasia significantly more than did treatment with either drug alone. Combination therapy and finasteride alone reduced the long-term risk of acute urinary retention and the need for invasive therapy.

BACKGROUND: No pharmacologic therapy has conclusively proved to be effective for the treatment of nonalcoholic steatohepatitis, which is characterized by insulin resistance, steatosis, and necroinflammation with or without centrilobular fibrosis. Pioglitazone is a thiazolidinedione that ameliorates insulin resistance and improves glucose and lipid metabolism in type 2 diabetes mellitus. METHODS: We randomly assigned 55 patients with impaired glucose tolerance or type 2 diabetes and liver biopsy-confirmed nonalcoholic steatohepatitis to 6 months of treatment with a hypocaloric diet (a reduction of 500 kcal per day in relation to the calculated daily intake required to maintain body weight) plus pioglitazone (45 mg daily) or a hypocaloric diet plus placebo. Before and after treatment, we assessed hepatic histologic features, hepatic fat content by means of magnetic resonance spectroscopy, and glucose turnover during an oral glucose tolerance test ([14C]glucose given with the oral glucose load and [3H]glucose given by intravenous infusion). RESULTS: Diet plus pioglitazone, as compared with diet plus placebo, improved glycemic control and glucose tolerance (P<0.001), normalized liver aminotransferase levels as it decreased plasma aspartate aminotransferase levels (by 40% vs. 21%, P=0.04), decreased alanine aminotransferase levels (by 58% vs. 34%, P<0.001), decreased hepatic fat content (by 54% vs. 0%, P<0.001), and increased hepatic insulin sensitivity (by 48% vs. 14%, P=0.008). Administration of pioglitazone, as compared with placebo, was associated with improvement in histologic findings with regard to steatosis (P=0.003), ballooning necrosis (P=0.02), and inflammation (P=0.008). Subjects in the pioglitazone group had a greater reduction in necroinflammation (85% vs. 38%, P=0.001), but the reduction in fibrosis did not differ significantly from that in the placebo group (P=0.08). Fatigue and mild lower-extremity edema developed in one subject who received pioglitazone; no other adverse events were observed. CONCLUSIONS: In this proof-of-concept study, the administration of pioglitazone led to metabolic and histologic improvement in subjects with nonalcoholic steatohepatitis. Larger controlled trials of longer duration are warranted to assess the long-term clinical benefit of pioglitazone. (ClinicalTrials.gov number, NCT00227110 [ClinicalTrials.gov] .).

BACKGROUND: Patients with severe traumatic injuries often present with coagulopathy and require massive transfusion. The risk of death from hemorrhagic shock increases in this population. To treat the coagulopathy of trauma, some have suggested early, aggressive correction using a 1:1 ratio of plasma to red blood cell (RBC) units. METHODS: We performed a retrospective chart review of 246 patients at a US Army combat support hospital, each of who received a massive transfusion (>/=10 units of RBCs in 24 hours). Three groups of patients were constructed according to the plasma to RBC ratio transfused during massive transfusion. Mortality rates and the cause of death were compared among groups. RESULTS: For the low ratio group the plasma to RBC median ratio was 1:8 (interquartile range, 0:12-1:5), for the medium ratio group, 1:2.5 (interquartile range, 1:3.0-1:2.3), and for the high ratio group, 1:1.4 (interquartile range, 1:1.7-1:1.2) (p < 0.001). Median Injury Severity Score (ISS) was 18 for all groups (interquartile range, 14-25). For low, medium, and high plasma to RBC ratios, overall mortality rates were 65%, 34%, and 19%, (p < 0.001); and hemorrhage mortality rates were 92.5%, 78%, and 37%, respectively, (p < 0.001). Upon logistic regression, plasma to RBC ratio was independently associated with survival (odds ratio 8.6, 95% confidence interval 2.1-35.2). CONCLUSIONS: In patients with combat-related trauma requiring massive transfusion, a high 1:1.4 plasma to RBC ratio is independently associated with improved survival to hospital discharge, primarily by decreasing death from hemorrhage. For practical purposes, massive transfusion protocols should utilize a 1:1 ratio of plasma to RBCs for all patients who are hypocoagulable with traumatic injuries.

Hepatocellular carcinoma (HCC) is a common and deadly malignancy that is increasing in incidence in developed countries. The emergence of hepatitis C virus (HCV) accounts for about half of this increase in HCC, although the etiology of HCC in 15%-50% of new HCC cases remains unclear. The most common form of chronic liver disease in developed countries is nonalcoholic fatty liver disease (NAFLD), which encompasses a broad spectrum of histopathology. The prevalence of NAFLD, including the more aggressive nonalcoholic steatohepatitis (NASH), is increasing with the growing epidemics of diabetes and obesity. NASH can progress to cirrhosis and its related complications. Growing evidence suggests that NASH accounts for a large proportion of idiopathic or cryptogenic cirrhosis, which is associated with the typical risk factors for NASH. HCC is a rare, although important complication of NAFLD. Diabetes and obesity have been established as independent risk factors for the development of HCC. New evidence also suggests that hepatic iron deposition increases the risk of HCC in NASH-derived cirrhosis. Multiple case reports and case reviews of HCC in the setting of NASH support the associations of diabetes and obesity with the risk of HCC, as well as suggest age and advanced fibrosis as significant risks. Insulin resistance and its subsequent inflammatory cascade that is associated with the development of NASH appear to play a significant role in the carcinogenesis of HCC. The complications of NASH, including cirrhosis and HCC, are expected to increase with the growing epidemic of diabetes and obesity.

OBJECTIVE: To relate in-hospital mortality to early transfusion of plasma and/or platelets and to time-varying plasma:red blood cell (RBC) and platelet:RBC ratios. DESIGN: Prospective cohort study documenting the timing of transfusions during active resuscitation and patient outcomes. Data were analyzed using time-dependent proportional hazards models. SETTING: Ten US level I trauma centers. PATIENTS: Adult trauma patients surviving for 30 minutes after admission who received a transfusion of at least 1 unit of RBCs within 6 hours of admission (n = 1245, the original study group) and at least 3 total units (of RBCs, plasma, or platelets) within 24 hours (n = 905, the analysis group). MAIN OUTCOME MEASURE: In-hospital mortality. RESULTS: Plasma:RBC and platelet:RBC ratios were not constant during the first 24 hours (P < .001 for both). In a multivariable time-dependent Cox model, increased ratios of plasma:RBCs (adjusted hazard ratio = 0.31; 95% CI, 0.16-0.58) and platelets:RBCs (adjusted hazard ratio = 0.55; 95% CI, 0.31-0.98) were independently associated with decreased 6-hour mortality, when hemorrhagic death predominated. In the first 6 hours, patients with ratios less than 1:2 were 3 to 4 times more likely to die than patients with ratios of 1:1 or higher. After 24 hours, plasma and platelet ratios were unassociated with mortality, when competing risks from nonhemorrhagic causes prevailed. CONCLUSIONS: Higher plasma and platelet ratios early in resuscitation were associated with decreased mortality in patients who received transfusions of at least 3 units of blood products during the first 24 hours after admission. Among survivors at 24 hours, the subsequent risk of death by day 30 was not associated with plasma or platelet ratios.

Background & AimsElafibranor is an agonist of the peroxisome proliferator−activated receptor-α and peroxisome proliferator−activated receptor-δ. Elafibranor improves insulin sensitivity, glucose homeostasis, and lipid metabolism and reduces inflammation. We assessed the safety and efficacy of elafibranor in an international, randomized, double-blind placebo-controlled trial of patients with nonalcoholic steatohepatitis (NASH).MethodsPatients with NASH without cirrhosis were randomly assigned to groups given elafibranor 80 mg (n = 93), elafibranor 120 mg (n = 91), or placebo (n = 92) each day for 52 weeks at sites in Europe and the United States. Clinical and laboratory evaluations were performed every 2 months during this 1-year period. Liver biopsies were then collected and patients were assessed 3 months later. The primary outcome was resolution of NASH without fibrosis worsening, using protocol-defined and modified definitions. Data from the groups given the different doses of elafibranor were compared with those from the placebo group using step-down logistic regression, adjusting for baseline nonalcoholic fatty liver disease activity score.ResultsIn intention-to-treat analysis, there was no significant difference between the elafibranor and placebo groups in the protocol-defined primary outcome. However, NASH resolved without fibrosis worsening in a higher proportion of patients in the 120-mg elafibranor group vs the placebo group (19% vs 12%; odds ratio = 2.31; 95% confidence interval: 1.02−5.24; P = .045), based on a post-hoc analysis for the modified definition. In post-hoc analyses of patients with nonalcoholic fatty liver disease activity score ≥4 (n = 234), elafibranor 120 mg resolved NASH in larger proportions of patients than placebo based on the protocol definition (20% vs 11%; odds ratio = 3.16; 95% confidence interval: 1.22−8.13; P = .018) and the modified definitions (19% vs 9%; odds ratio = 3.52; 95% confidence interval: 1.32–9.40; P = .013). Patients with NASH resolution after receiving elafibranor 120 mg had reduced liver fibrosis stages compared with those without NASH resolution (mean reduction of 0.65 ± 0.61 in responders for the primary outcome vs an increase of 0.10 ± 0.98 in nonresponders; P < .001). Liver enzymes, lipids, glucose profiles, and markers of systemic inflammation were significantly reduced in the elafibranor 120-mg group vs the placebo group. Elafibranor was well tolerated and did not cause weight gain or cardiac events, but did produce a mild, reversible increase in serum creatinine (effect size vs placebo: increase of 4.31 ± 1.19 μmol/L; P < .001).ConclusionsA post-hoc analysis of data from trial of patients with NASH showed that elafibranor (120 mg/d for 1 year) resolved NASH without fibrosis worsening, based on a modified definition, in the intention-to-treat analysis and in patients with moderate or severe NASH. However, the predefined end point was not met in the intention to treat population. Elafibranor was well tolerated and improved patients’ cardiometabolic risk profile. ClinicalTrials.gov number: NCT01694849. Elafibranor is an agonist of the peroxisome proliferator−activated receptor-α and peroxisome proliferator−activated receptor-δ. Elafibranor improves insulin sensitivity, glucose homeostasis, and lipid metabolism and reduces inflammation. We assessed the safety and efficacy of elafibranor in an international, randomized, double-blind placebo-controlled trial of patients with nonalcoholic steatohepatitis (NASH). Patients with NASH without cirrhosis were randomly assigned to groups given elafibranor 80 mg (n = 93), elafibranor 120 mg (n = 91), or placebo (n = 92) each day for 52 weeks at sites in Europe and the United States. Clinical and laboratory evaluations were performed every 2 months during this 1-year period. Liver biopsies were then collected and patients were assessed 3 months later. The primary outcome was resolution of NASH without fibrosis worsening, using protocol-defined and modified definitions. Data from the groups given the different doses of elafibranor were compared with those from the placebo group using step-down logistic regression, adjusting for baseline nonalcoholic fatty liver disease activity score. In intention-to-treat analysis, there was no significant difference between the elafibranor and placebo groups in the protocol-defined primary outcome. However, NASH resolved without fibrosis worsening in a higher proportion of patients in the 120-mg elafibranor group vs the placebo group (19% vs 12%; odds ratio = 2.31; 95% confidence interval: 1.02−5.24; P = .045), based on a post-hoc analysis for the modified definition. In post-hoc analyses of patients with nonalcoholic fatty liver disease activity score ≥4 (n = 234), elafibranor 120 mg resolved NASH in larger proportions of patients than placebo based on the protocol definition (20% vs 11%; odds ratio = 3.16; 95% confidence interval: 1.22−8.13; P = .018) and the modified definitions (19% vs 9%; odds ratio = 3.52; 95% confidence interval: 1.32–9.40; P = .013). Patients with NASH resolution after receiving elafibranor 120 mg had reduced liver fibrosis stages compared with those without NASH resolution (mean reduction of 0.65 ± 0.61 in responders for the primary outcome vs an increase of 0.10 ± 0.98 in nonresponders; P < .001). Liver enzymes, lipids, glucose profiles, and markers of systemic inflammation were significantly reduced in the elafibranor 120-mg group vs the placebo group. Elafibranor was well tolerated and did not cause weight gain or cardiac events, but did produce a mild, reversible increase in serum creatinine (effect size vs placebo: increase of 4.31 ± 1.19 μmol/L; P < .001). A post-hoc analysis of data from trial of patients with NASH showed that elafibranor (120 mg/d for 1 year) resolved NASH without fibrosis worsening, based on a modified definition, in the intention-to-treat analysis and in patients with moderate or severe NASH. However, the predefined end point was not met in the intention to treat population. Elafibranor was well tolerated and improved patients’ cardiometabolic risk profile. ClinicalTrials.gov number: NCT01694849.

Contributing Authors Isam Alobid, MD, PhD 1 , Nithin D. Adappa, MD 2 , Henry P. Barham, MD 3 , Thiago Bezerra, MD 4 , Nadieska Caballero, MD 5 , Eugene G. Chang, MD 6 , Gaurav Chawdhary, MD 7 , Philip Chen, MD 8 , John P. Dahl, MD, PhD 9 , Anthony Del Signore, MD 10 , Carrie Flanagan, MD 11 , Daniel N. Frank, PhD 12 , Kai Fruth, MD, PhD 13 , Anne Getz, MD 14 , Samuel Greig, MD 15 , Elisa A. Illing, MD 16 , David W. Jang, MD 17 , Yong Gi Jung, MD 18 , Sammy Khalili, MD, MSc 19 , Cristobal Langdon, MD 20 , Kent Lam, MD 21 , Stella Lee, MD 22 , Seth Lieberman, MD 23 , Patricia Loftus, MD 24 , Luis Macias‐Valle, MD 25 , R. Peter Manes, MD 26 , Jill Mazza, MD 27 , Leandra Mfuna, MD 28 , David Morrissey, MD 29 , Sue Jean Mun, MD 30 , Jonathan B. Overdevest, MD, PhD 31 , Jayant M. Pinto, MD 32 , Jain Ravi, MD 33 , Douglas Reh, MD 34 , Peta L. Sacks, MD 35 , Michael H. Saste, MD 36 , John Schneider, MD, MA 37 , Ahmad R. Sedaghat, MD, PhD 38 , Zachary M. Soler, MD 39 , Neville Teo, MD 40 , Kota Wada, MD 41 , Kevin Welch, MD 42 , Troy D. Woodard, MD 43 , Alan Workman 44 , Yi Chen Zhao, MD 45 , David Zopf, MD 46 Contributing Author Affiliations 1 Universidad de Barcelona; 2 University of Pennsylvania; 3 Louisiana State University Health Sciences Center; 4 Universidade de São Paulo; 5 ENT Specialists of Illinois; 6 University of Arizona; 7 University of Oxford; 8 University of Texas; 9 University of Indiana; 10 Mount Sinai Beth Israel; 11 Emory University; 12 University of Colorado; 13 Wiesbaden, Germany; 14 University of Colorado; 15 University of Alberta; 16 University of Alabama at Birmingham; 17 Duke University; 18 Sungkyunkwan University; 19 University of Pennsylvania; 20 Universidad de Barcelona; 21 Northwestern University; 22 University of Pittsburgh; 23 New York University; 24 Emory University; 25 University of British Columbia; 26 Yale University School of Medicine; 27 Private Practice; 28 Department of Otolaryngology, Hôtel‐Dieu Hospital, Centre de Recherche du Centre Hospitalier de l'Université de Montréal; 29 University of Adelaide; 30 Pusan National University; 31 University of California, San Francisco; 32 University of Chicago; 33 University of Auckland; 34 Johns Hopkins University; 35 University of New South Wales, Australia; 36 Stanford University; 37 Washington University; 38 Harvard Medical School; 39 Medical University of South Carolina; 40 Singapore General Hospital; 41 Taho University; 42 Northwestern University; 43 Cleveland Clinic Foundation; 44 University of Pennsylvania; 45 University of Adelaide; 46 University of Michigan

BACKGROUND: Clinical predictors of advanced non-alcoholic liver disease (NAFLD) are needed to guide diagnostic evaluation and treatment. METHODS: To better understand the demographics of NAFLD and risk factors for advanced disease, this study analysed 827 patients with NAFLD at two geographically separate tertiary medical centres. RESULTS: The cohort was 51% female and had a median body mass index (BMI) of 33 kg/m(2); 3% had a normal BMI. Common co-morbidities included hypertension (60%) and diabetes (35%); insulin resistance was present in 91% and advanced fibrosis in 24% of patients. When comparing patients with no fibrosis or mild fibrosis to those with advanced fibrosis, BMI > or = 28 kg/m(2), age > 50 years, and aspartate transaminase/alanine aminotransferase (AST/ALT) ratio > or = 0.8, a quantitative assessment check index (QUICKI) score < 0.294 (equivalent to homeostasis model assessment (HOMA) > 6.2) and the presence of diabetes mellitus (DM) were individually associated by univariate analysis with odds ratios (ORs) of > or = 2.4 for advanced fibrosis. Based on the results of forced entry logistic regression analysis, three variables were combined in a weighted sum (BMI > or = 28 = 1 point, AAR of > or = 0.8 = 2 points, DM = 1 point) to form an easily calculated composite score for predicting advanced fibrosis called the BARD score. A score of 2-4 was associated with an OR for advanced fibrosis of 17 (confidence interval 9.2 to 31.9) and a negative predictive value of 96%. CONCLUSIONS: Insulin resistance and its co-morbidities are often present in patients with NAFLD. An easily calculated score based on readily available clinical data can reliably exclude the presence of advanced fibrosis in these patients, particularly among non-diabetics.

Thyroid cancer incidence has been rising in the United States, and this trend has often been attributed to heightened medical surveillance and the use of improved diagnostics. Thyroid cancer incidence varies by sex and race/ethnicity, and these factors also influence access to and utilization of healthcare. We therefore examined thyroid cancer incidence rates by demographic and tumor characteristics based on 48,403 thyroid cancer patients diagnosed during 1980-2005 from the Surveillance, Epidemiology and End Results program of the National Cancer Institute. The rates varied by histologic type, sex, and race/ethnicity. Papillary carcinoma was the only histologic type for which incidence rates increased consistently among all racial/ethnic groups. Subsequent analyses focused on the 39,706 papillary thyroid cancers diagnosed during this period. Papillary carcinoma rates increased most rapidly among females. Between 1992-1995 and 2003-2005, they increased nearly 100% among White non-Hispanics and Black females but only 20% to 50% among White Hispanics, Asian/Pacific Islanders, and Black males. The increases were most rapid for localized stage and small tumors; however, rates also increased for large tumors and tumors of regional and distant stage. Since 1992-1995, half the overall increase in papillary carcinoma rates was due to increasing rates of very small (<or=1.0 cm) cancers, 30% to cancers 1.1 to 2 cm, and 20% to cancers>2 cm. Among White females, the rate of increase for cancers>5 cm almost equaled that for the smallest cancers. Medical surveillance and more sensitive diagnostic procedures cannot completely explain the observed increases in papillary thyroid cancer rates. Thus, other possible explanations should be explored.

BACKGROUND: The burden of non-alcoholic fatty liver disease (NAFLD) is increasing globally, and a major priority is to identify patients with non-alcoholic steatohepatitis (NASH) who are at greater risk of progression to cirrhosis, and who will be candidates for clinical trials and emerging new pharmacotherapies. We aimed to develop a score to identify patients with NASH, elevated NAFLD activity score (NAS≥4), and advanced fibrosis (stage 2 or higher [F≥2]). METHODS: This prospective study included a derivation cohort before validation in multiple international cohorts. The derivation cohort was a cross-sectional, multicentre study of patients aged 18 years or older, scheduled to have a liver biopsy for suspicion of NAFLD at seven tertiary care liver centres in England. This was a prespecified secondary outcome of a study for which the primary endpoints have already been reported. Liver stiffness measurement (LSM) by vibration-controlled transient elastography and controlled attenuation parameter (CAP) measured by FibroScan device were combined with aspartate aminotransferase (AST), alanine aminotransferase (ALT), or AST:ALT ratio. To identify those patients with NASH, an elevated NAS, and significant fibrosis, the best fitting multivariable logistic regression model was identified and internally validated using boot-strapping. Score calibration and discrimination performance were determined in both the derivation dataset in England, and seven independent international (France, USA, China, Malaysia, Turkey) histologically confirmed cohorts of patients with NAFLD (external validation cohorts). This study is registered with ClinicalTrials.gov, number NCT01985009. FINDINGS: Between March 20, 2014, and Jan 17, 2017, 350 patients with suspected NAFLD attending liver clinics in England were prospectively enrolled in the derivation cohort. The most predictive model combined LSM, CAP, and AST, and was designated FAST (FibroScan-AST). Performance was satisfactory in the derivation dataset (C-statistic 0·80, 95% CI 0·76-0·85) and was well calibrated. In external validation cohorts, calibration of the score was satisfactory and discrimination was good across the full range of validation cohorts (C-statistic range 0·74-0·95, 0·85; 95% CI 0·83-0·87 in the pooled external validation patients' cohort; n=1026). Cutoff was 0·35 for sensitivity of 0·90 or greater and 0·67 for specificity of 0·90 or greater in the derivation cohort, leading to a positive predictive value (PPV) of 0·83 (84/101) and a negative predictive value (NPV) of 0·85 (93/110). In the external validation cohorts, PPV ranged from 0·33 to 0·81 and NPV from 0·73 to 1·0. INTERPRETATION: The FAST score provides an efficient way to non-invasively identify patients at risk of progressive NASH for clinical trials or treatments when they become available, and thereby reduce unnecessary liver biopsy in patients unlikely to have significant disease. FUNDING: Echosens and UK National Institute for Health Research.

Hypermetabolism characterizes the metabolic response to thermal injury and the extent of energy production is positively related to the rate of urinary catecholamine excretion. Alpha and beta adrenergic blockade decreased metabolism from 69.6 +/- 5.3 Kcal/m(2)/hr to 57.4 +/- 5.2 (p < 0.01), and infusion of 6 microgm epinephrine/minute in normal man significantly increased metabolic rate. Twenty noninfected burned adults with a mean burn size of 45% total body surface (range 7-84%) and four normal controls were studied in an environmental chamber at two or more temperatures between 19 and 33 C with vapor pressure constant at 11.88 mm Hg. All burn patients were hypermetabolic at all temperatures studied and their core and mean skin temperatures were significantly elevated above control values. Between 25 and 33 C ambient, metabolism was unchanged in controls and burns of less than 40% total body surface (48.9 +/- 4.6 Kcal/m(2)/hr vs. 48.9 +/- 4.5), but metabolic rate decreased in larger burns in the warmer environment (72.0 +/- 1.9 vs. 65.8 +/- 1.7, p < 0.001). At 21 C, metabolism and catecholamines increased, except in four nonsurvivors who became hypothermic with decreased catechol elaboration. Metabolic rate in ten patients with bacteremia was below predicted levels while catecholamines were markedly elevated suggesting interference with tissue uptake of the neurohormonal transmitters. Feeding burn patients or administering glucose and insulin improved nitrogen retention and altered substrate flow but did not significantly reduce urinary catecholamines or metabolic rate. Burned patients are internally warm, not externally cold, and catecholamines appear to mediate their increased heat production. Hypermetabolism may be modified by ambient temperature, infection, and pharmacologic means. Alterations in hypothalamic function due to injury, resulting in increased catecholamine elaboration, would explain the metabolic response to thermal injury.

BACKGROUND: Asymptomatic colonization with methicillin-resistant Staphylococcus aureus (MRSA) has been described as a risk factor for subsequent MRSA infection. MRSA is an important nosocomial pathogen but has currently been reported in patients without typical risk factors for nosocomial acquisition. This study was designed to evaluate the impact of asymptomatic nares MRSA colonization on the development of subsequent MRSA infection. The incidence of MRSA infection was examined in patients with and patients without MRSA or methicillin-susceptible S. aureus (MSSA) colonization at admission to the hospital and in those who developed colonization during hospitalization. METHODS: Patients admitted to 5 representative hospital units were prospectively evaluated. Nares samples were obtained for culture at admission and during hospitalization. Laboratory culture results were monitored to identify all MRSA infections that occurred during the study period and 1 year thereafter. RESULTS: Of the 758 patients who had cultures of nares samples performed at admission, 3.4% were colonized with MRSA, and 21% were colonized with MSSA. A total of 19% of patients with MRSA colonization at admission and 25% who acquired MRSA colonization during hospitalization developed infection with MRSA, compared with 1.5% and 2.0% of patients colonized with MSSA (P<.01) and uncolonized (P<.01), respectively, at admission. MRSA colonization at admission increased the risk of subsequent MRSA infection, compared with MSSA colonization (relative risk [RR], 13; 95% confidence interval [CI], 2.7-64) or no staphylococcal colonization (RR, 9.5; 95% CI, 3.6-25) at admission. Acquisition of MRSA colonization also increased the risk for subsequent MRSA infection, compared with no acquisition (RR, 12; 95% CI, 4.0-38). CONCLUSION: MRSA colonization of nares, either present at admission to the hospital or acquired during hospitalization, increases the risk for MRSA infection. Identifying MRSA colonization at admission could target a high-risk population that may benefit from interventions to decrease the risk for subsequent MRSA infection.

Splanchnic artery aneurysms were encountered in 45 patients. This experience and a comprehensive review of the literature since 1960 resulted in revision of many preexisting concepts concerning the pathogenesis and prognostic implications of these lesions. Most significant is that multiparity may result in medial degeneration with subsequent development of splenic artery aneurysms. A previously unrecognized association of renal artery fibromuscular disease and splenic artery aneurysms was documented. The established morbidity and mortality attributed to all aneurysms of the splanchnic arteries justifies prompt surgical treatment once their presence is known.

von Hippel-Lindau disease (VHL) is an inherited neoplastic disease characterized by a predisposition to develop retinal angiomas, central nervous system hemangioblastomas, renal cell carcinomas, pancreatic cysts, and pheochromocytomas. The VHL gene was recently isolated by positional cloning. The cDNA encodes 852 nucleotides in 3 exons. The VHL gene is unrelated to any known gene families. We identified germline mutations in 85/114 (75%) of VHL families. Clinical heterogeneity is a well-known feature of VHL. VHL families were classified into 2 types based on the presence or absence of pheochromocytoma. The types of mutations responsible for VHL without pheochromocytoma (VHL type 1) differed from those responsible for VHL with pheochromocytoma (VHL type 2). Fifty-six % of the mutations responsible for VHL type 1 were microdeletions/insertions, nonsense mutations, or deletions; 96% of the mutations responsible for VHL type 2 were missense mutations. Specific mutations in codon 238 accounted for 43% of the mutations responsible for VHL type 2. The mutations identified in these families will be useful in presymptomatic diagnosis. The identification of mutations associated with phenotypes contributes to the understanding of fundamental genetic mechanisms of VHL disease.

BACKGROUND: Critical examination of the quality and validity of available allergic rhinitis (AR) literature is necessary to improve understanding and to appropriately translate this knowledge to clinical care of the AR patient. To evaluate the existing AR literature, international multidisciplinary experts with an interest in AR have produced the International Consensus statement on Allergy and Rhinology: Allergic Rhinitis (ICAR:AR). METHODS: Using previously described methodology, specific topics were developed relating to AR. Each topic was assigned a literature review, evidence-based review (EBR), or evidence-based review with recommendations (EBRR) format as dictated by available evidence and purpose within the ICAR:AR document. Following iterative reviews of each topic, the ICAR:AR document was synthesized and reviewed by all authors for consensus. RESULTS: The ICAR:AR document addresses over 100 individual topics related to AR, including diagnosis, pathophysiology, epidemiology, disease burden, risk factors for the development of AR, allergy testing modalities, treatment, and other conditions/comorbidities associated with AR. CONCLUSION: This critical review of the AR literature has identified several strengths; providers can be confident that treatment decisions are supported by rigorous studies. However, there are also substantial gaps in the AR literature. These knowledge gaps should be viewed as opportunities for improvement, as often the things that we teach and the medicine that we practice are not based on the best quality evidence. This document aims to highlight the strengths and weaknesses of the AR literature to identify areas for future AR research and improved understanding.

The Journal of Trauma: Injury, Infection, and Critical Care: November 1968 - Volume 8 - Issue 6 - p 1049-1051

To help mitigate the expanding global impact of malaria, with its associated increasing drug resistance, implementation of prompt and accurate diagnosis is needed. Malaria is diagnosed predominantly by using clinical criteria, with microscopy as the current gold standard for detecting parasitemia, even though it is clearly inadequate in many health care settings. Rapid diagnostic tests (RDTs) have been recognized as an ideal method for diagnosing infectious diseases, including malaria, in recent years. There have been a number of RDTs developed and evaluated widely for malaria diagnosis, but a number of issues related to these products have arisen. This review highlights RDTs, including challenges in assessing their performance, internationally available RDTs, their effectiveness in various health care settings, and the selection of RDTs for different health care systems.

OBJECTIVES: We aimed to define nonalcoholic steatohepatitis (NASH) histopathological change over time and to correlate changes with clinical characteristics. METHODS: We retrieved nonalcoholic fatty liver cases from our histopathology database covering 1985 to 2001. We also identified patients in clinic with NASH on biopsy >1 yr prior. All patients were evaluated and clinical data obtained in clinic. Those patients qualifying for NASH therapeutic trials underwent liver biopsy pretreatment. One pathologist (S.T.) read all slides using a NASH grading and staging system. RESULTS: A total of 22 patients had repeat biopsies a mean of 5.7 yr (range 1.4-15.7 yr) after the first biopsy. Nine were women, nine had diabetes, 11 had hypertension, and 14 had hyperlipidemia. Mean body mass index was 33.8 kg/m(2) (range 26.5-48.6 yr). Mean age was 50.6 yr (range 33-64 yr). Ten patients (45%) had fibrosis stage 1 or 2, and two patients (9%) had bridging fibrosis or cirrhosis (stage 3 or 4) on first biopsy. Seven (32%) had increases in fibrosis score. Four patients (18%) had decreases in fibrosis score. The percentage of patients with stage 3 or 4 increased from 9% to 18%. In two patients the disease progressed rapidly (fibrosis scores from 1 to 3 in 1.4 yr and from 2 to 4 in 2.6 yr). Only serum AST at last biopsy correlated with histological change, being higher in those with disease progression. Three patients progressed from steatosis to steatohepatitis with fibrosis. CONCLUSIONS: NASH has a variable histological course. However, one third of patients have fibrosis progression, and one third of these have rapid progression to advanced fibrosis. Histological progression correlated with higher serum AST but no other clinical factors. Steatosis alone may progress to NASH with fibrosis.

The aim of this study was to determine if orlistat, an inhibitor of fat absorption, combined with caloric restriction in overweight subjects with nonalcoholic steatohepatitis results in weight loss and improved liver histology. Fifty overweight subjects (body mass index = >or=27) with biopsy proven nonalcoholic steatohepatitis were randomized to receive a 1,400 Kcal/day diet plus vitamin E (800 IU) daily with or without orlistat (120 mg three times a day) for 36 weeks. Liver biopsies were repeated at week 36. Twenty-three subjects in the orlistat/diet/vitamin E group and 18 in the diet/vitamin E group completed the study. The mean age was 47 +/- 9.0 (standard deviation) years and mean body mass index was 36.4 +/- 6.3 kg/m(2). Four subjects were diabetic. The orlistat group lost a mean of 8.3% body weight compared to 6.0% in the diet plus vitamin E group (not significant). Both groups also had similarly improved serum aminotransferases, hepatic steatosis, necroinflammation, ballooning, and nonalcoholic fatty liver disease activity scores. Stratified according to weight loss instead of treatment group, a loss of >or=5% body weight (n = 24) compared to <5% body weight (n = 17) correlated with improvement in insulin sensitivity (P = 0.001) and steatosis (P = 0.015). Comparing subjects who lost >or=9% of body weight (n = 16), to those that did not (n = 25), improved insulin sensitivity (P < 0.001), adiponectin (P = 0.03), steatosis (P = 0.005), ballooning (P = 0.04), inflammation (P = 0.045), and nonalcoholic fatty liver disease activity score (P = 0.009) were seen. Increases in adiponectin strongly correlated with improved ballooning and nonalcoholic fatty liver disease activity score (P = 0.03). Orlistat did not enhance weight loss or improve liver enzymes, measures of insulin resistance, and histopathology. However, subjects who lost >or=5% of body weight over 9 months improved insulin resistance and steatosis, and those subjects who lost >or=9% also achieved improved hepatic histologic changes.

UNLABELLED: The role of adipose tissue insulin resistance in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) remains unclear. To evaluate this, we measured in 207 patients with NAFLD (age = 51 ± 1, body mass index = 34.1 ± 0.3 kg/m(2) ) and 22 controls without NAFLD (no NAFLD) adipose tissue insulin resistance by means of a validated index (Adipo-IR(i) = plasma free fatty acids [FFA] x insulin [FPI] concentration) and as the suppression of plasma FFA during an oral glucose tolerance test and by a low-dose insulin infusion. We also explored the relationship between adipose tissue insulin resistance with metabolic and histological parameters by dividing them based on quartiles of adipose tissue insulin resistance (Adipo-IR(i) quartiles: Q1 = more sensitive; Q4 = more insulin resistant). Hepatic insulin resistance, measured as an index derived from endogenous glucose production x FPI (HIRi), and muscle insulin sensitivity, were assessed during a euglycemic insulin clamp with 3-[(3) H] glucose. Liver fat was measured by magnetic resonance imaging and spectroscopy, and a liver biopsy was performed to assess liver histology. Compared to patients without steatosis, patients with NAFLD were insulin resistant at the level of adipose tissue, liver, and skeletal muscle and had higher plasma aspartate aminotransferase and alanine aminotransferase, triglycerides, and lower high-density lipoprotein cholesterol and adiponectin levels (all P < 0.01). Metabolic parameters, hepatic insulin resistance, and liver fibrosis (but not necroinflammation) deteriorated as quartiles of adipose tissue insulin resistance worsened (all P < 0.01). CONCLUSION: Adipose tissue insulin resistance plays a key role in the development of metabolic and histological abnormalities of obese patients with NAFLD. Treatment strategies targeting adipose tissue insulin resistance (e.g., weight loss and thiazolidinediones) may be of value in this population.