Virginia Commonwealth University Medical Center

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis in the absence of a history of significant alcohol use or other known liver disease. Nonalcoholic steatohepatitis (NASH) is the progressive form of NAFLD. The Pathology Committee of the NASH Clinical Research Network designed and validated a histological feature scoring system that addresses the full spectrum of lesions of NAFLD and proposed a NAFLD activity score (NAS) for use in clinical trials. The scoring system comprised 14 histological features, 4 of which were evaluated semi-quantitatively: steatosis (0-3), lobular inflammation (0-2), hepatocellular ballooning (0-2), and fibrosis (0-4). Another nine features were recorded as present or absent. An anonymized study set of 50 cases (32 from adult hepatology services, 18 from pediatric hepatology services) was assembled, coded, and circulated. For the validation study, agreement on scoring and a diagnostic categorization ("NASH," "borderline," or "not NASH") were evaluated by using weighted kappa statistics. Inter-rater agreement on adult cases was: 0.84 for fibrosis, 0.79 for steatosis, 0.56 for injury, and 0.45 for lobular inflammation. Agreement on diagnostic category was 0.61. Using multiple logistic regression, five features were independently associated with the diagnosis of NASH in adult biopsies: steatosis (P = .009), hepatocellular ballooning (P = .0001), lobular inflammation (P = .0001), fibrosis (P = .0001), and the absence of lipogranulomas (P = .001). The proposed NAS is the unweighted sum of steatosis, lobular inflammation, and hepatocellular ballooning scores. In conclusion, we present a strong scoring system and NAS for NAFLD and NASH with reasonable inter-rater reproducibility that should be useful for studies of both adults and children with any degree of NAFLD. NAS of > or =5 correlated with a diagnosis of NASH, and biopsies with scores of less than 3 were diagnosed as "not NASH."

BACKGROUND\nTreatment with peginterferon alfa-2a alone produces significantly higher sustained virologic responses than treatment with interferon alfa-2a alone in patients with chronic hepatitis C virus (HCV) infection. We compared the efficacy and safety of peginterferon alfa-2a plus ribavirin, interferon alfa-2b plus ribavirin, and peginterferon alfa-2a alone in the initial treatment of chronic hepatitis C. METHODS\nA total of 1121 patients were randomly assigned to treatment and received at least one dose of study medication, consisting of 180 μg of peginterferon alfa-2a once weekly plus daily ribavirin (1000 or 1200 mg, depending on body weight), weekly peginterferon alfa-2a plus daily placebo, or 3 million units of interferon alfa-2b thrice weekly plus daily ribavirin for 48 weeks. RESULTS\nA significantly higher proportion of patients who received peginterferon alfa-2a plus ribavirin had a sustained virologic response (defined as the absence of detectable HCV RNA 24 weeks after cessation of therapy) than of patients who received interferon alfa-2b plus ribavirin (56 percent vs. 44 percent, P CONCLUSIONS\nIn patients with chronic hepatitis C, once-weekly peginterferon alfa-2a plus ribavirin was tolerated as well as interferon alfa-2b plus ribavirin and produced significant improvements in the rate of sustained virologic response, as compared with interferon alfa-2b plus ribavirin or peginterferon alfa-2a alone.

BACKGROUND: Nosocomial bloodstream infections (BSIs) are important causes of morbidity and mortality in the United States. METHODS: Data from a nationwide, concurrent surveillance study (Surveillance and Control of Pathogens of Epidemiological Importance [SCOPE]) were used to examine the secular trends in the epidemiology and microbiology of nosocomial BSIs. RESULTS: Our study detected 24,179 cases of nosocomial BSI in 49 US hospitals over a 7-year period from March 1995 through September 2002 (60 cases per 10,000 hospital admissions). Eighty-seven percent of BSIs were monomicrobial. Gram-positive organisms caused 65% of these BSIs, gram-negative organisms caused 25%, and fungi caused 9.5%. The crude mortality rate was 27%. The most-common organisms causing BSIs were coagulase-negative staphylococci (CoNS) (31% of isolates), Staphylococcus aureus (20%), enterococci (9%), and Candida species (9%). The mean interval between admission and infection was 13 days for infection with Escherichia coli, 16 days for S. aureus, 22 days for Candida species and Klebsiella species, 23 days for enterococci, and 26 days for Acinetobacter species. CoNS, Pseudomonas species, Enterobacter species, Serratia species, and Acinetobacter species were more likely to cause infections in patients in intensive care units (P<.001). In neutropenic patients, infections with Candida species, enterococci, and viridans group streptococci were significantly more common. The proportion of S. aureus isolates with methicillin resistance increased from 22% in 1995 to 57% in 2001 (P<.001, trend analysis). Vancomycin resistance was seen in 2% of Enterococcus faecalis isolates and in 60% of Enterococcus faecium isolates. CONCLUSION: In this study, one of the largest multicenter studies performed to date, we found that the proportion of nosocomial BSIs due to antibiotic-resistant organisms is increasing in US hospitals.

Components of heart rate variability have attracted considerable attention in psychology and medicine and have become important dependent measures in psychophysiology and behavioral medicine. Quantification and interpretation of heart rate variability, however, remain complex issues and are fraught with pitfalls. The present report (a) examines the physiological origins and mechanisms of heart rate variability, (b) considers quantitative approaches to measurement, and (c) highlights important caveats in the interpretation of heart rate variability. Summary guidelines for research in this area are outlined, and suggestions and prospects for future developments are considered.

BACKGROUND: Only 15 to 20 percent of patients with chronic hepatitis C have a sustained virologic response to interferon therapy. We compared the efficacy and safety of recombinant interferon alfa-2b alone with those of a combination of interferon alfa-2b and ribavirin for the initial treatment of patients with chronic hepatitis C. METHODS: We randomly assigned 912 patients with chronic hepatitis C to receive standard-dose interferon alfa-2b alone or in combination with ribavirin (1000 or 1200 mg orally per day, depending on body weight) for 24 or 48 weeks. Efficacy was assessed by measurements of serum hepatitis C virus (HCV) RNA and serum aminotransferases and by liver biopsy. RESULTS: The rate of sustained virologic response (defined as an undetectable serum HCV RNA level 24 weeks after treatment was completed) was higher among patients who received combination therapy for either 24 weeks (70 of 228 patients, 31 percent) or 48 weeks (87 of 228 patients, 38 percent) than among patients who received interferon alone for either 24 weeks (13 of 231 patients, 6 percent) or 48 weeks (29 of 225 patients, 13 percent) (P<0.001 for the comparison of interferon alone with both 24 weeks and 48 weeks of combination treatment). Among patients with HCV genotype 1 infection, the best response occurred in those who were treated for 48 weeks with interferon and ribavirin. Histologic improvement was more common in patients who were treated with combination therapy for either 24 weeks (57 percent) or 48 weeks (61 percent) than in those who were treated with interferon alone for either 24 weeks (44 percent) or 48 weeks (41 percent). The drug doses had to be reduced and treatment discontinued more often in patients who were treated with combination therapy. CONCLUSIONS: In patients with chronic hepatitis C, initial therapy with interferon and ribavirin was more effective than treatment with interferon alone.

Secondary bile acids, produced solely by intestinal bacteria, can accumulate to high levels in the enterohepatic circulation of some individuals and may contribute to the pathogenesis of colon cancer, gallstones, and other gastrointestinal (GI) diseases. Bile salt hydrolysis and hydroxy group dehydrogenation reactions are carried out by a broad spectrum of intestinal anaerobic bacteria, whereas bile acid 7-dehydroxylation appears restricted to a limited number of intestinal anaerobes representing a small fraction of the total colonic flora. Microbial enzymes modifying bile salts differ between species with respect to pH optima, enzyme kinetics, substrate specificity, cellular location, and possibly physiological function. Crystallization, site-directed mutagenesis, and comparisons of protein secondary structure have provided insight into the mechanisms of several bile acid-biotransforming enzymatic reactions. Molecular cloning of genes encoding bile salt-modifying enzymes has facilitated the understanding of the genetic organization of these pathways and is a means of developing probes for the detection of bile salt-modifying bacteria. The potential exists for altering the bile acid pool by targeting key enzymes in the 7alpha/beta-dehydroxylation pathway through the development of pharmaceuticals or sequestering bile acids biologically in probiotic bacteria, which may result in their effective removal from the host after excretion.

Recent evidence demonstrating multiple regions of human cerebral cortex activated by pain has prompted speculation about their individual contributions to this complex experience. To differentiate cortical areas involved in pain affect, hypnotic suggestions were used to alter selectively the unpleasantness of noxious stimuli, without changing the perceived intensity. Positron emission tomography revealed significant changes in pain-evoked activity within anterior cingulate cortex, consistent with the encoding of perceived unpleasantness, whereas primary somatosensory cortex activation was unaltered. These findings provide direct experimental evidence in humans linking frontal-lobe limbic activity with pain affect, as originally suggested by early clinical lesion studies.

autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

OBJECTIVE: Stressful life events are associated with the onset of episodes of major depression. However, exposure to stressful life events is influenced by genetic factors, and these factors are correlated with those that predispose to major depression. The aim of this study was to clarify the degree to which stressful life events cause major depression. METHOD: The authors assessed the occurrence of 15 classes of stressful life events and the onset of DSM-III-R major depression over a 1-year period in female twins ascertained from a population-based registry. The sample contained 24,648 person-months and 316 onsets of major depression. Stressful life events were individually rated on contextual threat and dependence (the degree to which the stressful life event could have resulted from the respondent's behavior). The nature of the relationship between stressful life events and major depression was tested by 1) discrete-time survival analysis examining the relationship between dependence and the depressogenic effect of stressful life events and 2) a co-twin control analysis. RESULTS: While independent stressful life events were significantly associated with onsets of depression, when level of threat was controlled, the association was significantly stronger for dependent events. The odds ratio for onset of major depression in the month of a stressful life event was 5.64 in all subjects, 4.52 within dizygotic pairs, and 3.58 within monozygotic pairs. CONCLUSIONS: Stressful life events have a substantial causal relationship with the onset of episodes of major depression. However, about one-third of the association between stressful life events and onsets of depression is noncausal, since individuals predisposed to major depression select themselves into high-risk environments.

Single implantation of microencapsulated islets into rats with streptozotocin-induced diabetes corrected the diabetic state for 2 to 3 weeks. The microencapsulated islets remained morphologically and functionally intact throughout long-term culture studies lasting over 15 weeks.

Originally published in Contemporary Psychology: APA Review of Books, 1996, Vol 41(6), 621. Insomnia affects from 20 to 40 percent of all adults, particularly women and the elderly, yet there is widespread belief that chronic insomnia is not really a medical problem and that it can be treated only w

As triage and resuscitation protocols evolve, it is critical to determine the major extracranial variables influencing outcome in the setting of severe head injury. We prospectively studied the outcome from severe head injury (GCS score < or = 8) in 717 cases in the Traumatic Coma Data Bank. We investigated the impact on outcome of hypotension (SBP < 90 mm Hg) and hypoxia (Pao2 < or = 60 mm Hg or apnea or cyanosis in the field) as secondary brain insults, occurring from injury through resuscitation. Hypoxia and hypotension were independently associated with significant increases in morbidity and mortality from severe head injury. Hypotension was profoundly detrimental, occurring in 34.6% of these patients and associated with a 150% increase in mortality. The increased morbidity and mortality related to severe trauma to an extracranial organ system appeared primarily attributable to associated hypotension. Improvements in trauma care delivery over the past decade have not markedly altered the adverse influence of hypotension. Hypoxia and hypotension are common and detrimental secondary brain insults. Hypotension, particularly, is a major determinant of outcome from severe head injury. Resuscitation protocols for brain injured patients should assiduously avoid hypovolemic shock on an absolute basis.

Acute wounds normally heal in a very orderly and efficient manner characterized by four distinct, but overlapping phases: hemostasis, inflammation, proliferation and remodeling. Specific biological markers characterize healing of acute wounds. Likewise, unique biologic markers also characterize pathologic responses resulting in fibrosis and chronic non-healing ulcers. This review describes the major biological processes associated with both normal and pathologic healing. The normal healing response begins the moment the tissue is injured. As the blood components spill into the site of injury, the platelets come into contact with exposed collagen and other elements of the extracellular matrix. This contact triggers the platelets to release clotting factors as well as essential growth factors and cytokines such as platelet-derived growth factor (PDGF) and transforming growth factor beta (TGF-beta). Following hemostasis, the neutrophils then enter the wound site and begin the critical task of phagocytosis to remove foreign materials, bacteria and damaged tissue. As part of this inflammatory phase, the macrophages appear and continue the process of phagocytosis as well as releasing more PDGF and TGF beta. Once the wound site is cleaned out, fibroblasts migrate in to begin the proliferative phase and deposit new extracellular matrix. The new collagen matrix then becomes cross-linked and organized during the final remodeling phase. In order for this efficient and highly controlled repair process to take place, there are numerous cell-signaling events that are required. In pathologic conditions such as non-healing pressure ulcers, this efficient and orderly process is lost and the ulcers are locked into a state of chronic inflammation characterized by abundant neutrophil infiltration with associated reactive oxygen species and destructive enzymes. Healing proceeds only after the inflammation is controlled. On the opposite end of the spectrum, fibrosis is characterized by excessive matrix deposition and reduced remodeling. Often fibrotic lesions are associated with increased densities of mast cells. By understanding the functional relationships of these biological processes of normal compared to abnormal wound healing, hopefully new strategies can be designed to treat the pathological conditions.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are increasingly a cause of cirrhosis and hepatocellular carcinoma globally. This burden is expected to increase as epidemics of obesity, diabetes and metabolic syndrome continue to grow. The goal of this analysis was to use a Markov model to forecast NAFLD disease burden using currently available data. METHODS: A model was used to estimate NAFLD and NASH disease progression in eight countries based on data for adult prevalence of obesity and type 2 diabetes mellitus (DM). Published estimates and expert consensus were used to build and validate the model projections. RESULTS: If obesity and DM level off in the future, we project a modest growth in total NAFLD cases (0-30%), between 2016-2030, with the highest growth in China as a result of urbanization and the lowest growth in Japan as a result of a shrinking population. However, at the same time, NASH prevalence will increase 15-56%, while liver mortality and advanced liver disease will more than double as a result of an aging/increasing population. CONCLUSIONS: NAFLD and NASH represent a large and growing public health problem and efforts to understand this epidemic and to mitigate the disease burden are needed. If obesity and DM continue to increase at current and historical rates, both NAFLD and NASH prevalence are expected to increase. Since both are reversible, public health campaigns to increase awareness and diagnosis, and to promote diet and exercise can help manage the growth in future disease burden. LAY SUMMARY: Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis can lead to advanced liver disease. Both conditions are becoming increasingly prevalent as the epidemics of obesity and diabetes continue to increase. A mathematical model was built to understand how the disease burden associated with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis will change over time. Results suggest increasing cases of advanced liver disease and liver-related mortality in the coming years.

BACKGROUND: Acute changes in cerebral function after elective coronary bypass surgery is a difficult clinical problem. We carried out a multicenter study to determine the incidence and predictors of -- and the use of resources associated with -- perioperative adverse neurologic events, including cerebral injury. METHODS: In a prospective study, we evaluated 2108 patients from 24 U.S. institutions for two general categories of neurologic outcome: type I (focal injury, or stupor or coma at discharge) and type II (deterioration in intellectual function, memory deficit, or seizures). RESULTS: Adverse cerebral outcomes occurred in 129 patients (6.1 percent). A total of 3.1 percent had type I neurologic outcomes (8 died of cerebral injury, 55 had nonfatal strokes, 2 had transient ischemic attacks, and 1 had stupor), and 3.0 percent had type II outcomes (55 had deterioration of intellectual function and 8 had seizures). Patients with adverse cerebral outcomes had higher in-hospital mortality (21 percent of patients with type I outcomes died, vs. 10 percent of those with type II and 2 percent of those with no adverse cerebral outcome; P<0.001 for all comparisons), longer hospitalization (25 days with type I outcomes, 21 days with type II, and 10 days with no adverse outcome; P<0.001), and a higher rate of discharge to facilities for intermediate- or long-term care (69 percent, 39 percent, and 10 percent ; P<0.001). Predictors of type I outcomes were proximal aortic atherosclerosis, a history of neurologic disease, and older age; predictors of type II outcomes were older age, systolic hypertension on admission, pulmonary disease, and excessive consumption of alcohol. CONCLUSIONS: Adverse cerebral outcomes after coronary bypass surgery are relatively common and serious; they are associated with substantial increases in mortality, length of hospitalization, and use of intermediate- or long-term care facilities. New diagnostic and therapeutic strategies must be developed to lessen such injury.

BACKGROUND: Patterns of comorbidity suggest that the common psychiatric and substance use syndromes may be divisible into 2 broad groups of internalizing and externalizing disorders. We do not know how genetic and environmental risk factors contribute to this pattern of comorbidity or whether the etiologic structure of these groups differ in men and women. METHODS: Lifetime diagnoses for 10 psychiatric syndromes were obtained at a personal interview in more than 5600 members of male-male and female-female twin pairs ascertained from a population-based registry. Multivariate twin modeling was performed using the program Mx. RESULTS: We first fit models to the following 7 syndromes: major depression, generalized anxiety disorder, phobia, alcohol dependence, drug abuse/dependence, adult antisocial behavior, and conduct disorder. The full model, which could be constrained to equality in male and female subjects, identified 2 genetic factors. The first had strongest loadings on alcohol dependence, drug abuse/dependence, adult antisocial behavior, and conduct disorder; the second, on major depression, generalized anxiety disorder, and phobia. Alcohol dependence and drug abuse/dependence had substantial disorder-specific genetic risk factors. Shared environmental factors were most pronounced for conduct disorder and adult antisocial behavior. No clear internalizing/externalizing structure was seen for the unique environmental common factors. We then fit models to 5 internalizing syndromes. The full model, which could also be constrained to equality in men and women, revealed one genetic factor loading most heavily on major depression and generalized anxiety disorder and another loading most strongly on animal and situational phobia. CONCLUSIONS: The underlying structure of the genetic and environmental risk factors for the common psychiatric and drug abuse disorders in men and women is very similar. Genetic risk factors predispose to 2 broad groups of internalizing and externalizing disorders. Within the internalizing disorders, 2 genetic factors are seen that predispose to disorders dominated by anxious-misery and fear. Substance use disorders have disorder-specific genetic risks. The externalizing disorders of conduct disorder and adult antisocial behavior are significantly influenced by the shared environment. The pattern of lifetime comorbidity of common psychiatric and substance use disorders results largely from the effects of genetic risk factors.

Traumatic brain injury (TBI), according to the World Health Organization, will surpass many diseases as the major cause of death and disability by the year 2020. With an estimated 10 million people affected annually by TBI, the burden of mortality and morbidity that this condition imposes on society, makes TBI a pressing public health and medical problem. The burden of TBI is manifest throughout the world, and is especially prominent in Low and Middle Income Countries which face a higher preponderance of risk factors for causes of TBI and have inadequately prepared health systems to address the associated health outcomes. Latin America and Sub Saharan Africa demonstrate a higher TBI-related incidence rate varying from 150-170 per 100,000 respectively due to RTIs compared to a global rate of 106 per 100,000. As highlighted in this global review of TBI, there is a large gap in data on incidence, risk factors, sequelae, financial costs, and social impact of TBI. This should be addressed through planning of comprehensive TBI prevention programs in LMICs through well-established surveillance systems. Greater resources for research and prioritized interventions are critical to promote evidence-based policy for TBI.

Background— Dual-chamber (DDDR) pacing preserves AV synchrony and may reduce heart failure (HF) and atrial fibrillation (AF) compared with ventricular (VVIR) pacing in sinus node dysfunction (SND). However, DDDR pacing often results in prolonged QRS durations (QRSd) as the result of right ventricular stimulation, and ventricular desynchronization may result. The effect of pacing-induced ventricular desynchronization in patients with normal baseline QRSd is unknown. Methods and Results— Baseline QRSd was obtained from 12-lead ECGs before pacemaker implantation in MOST, a 2010-patient, 6-year, randomized trial of DDDR versus VVIR pacing in SND. Cumulative percent ventricular paced (Cum%VP) was determined from stored pacemaker data. Baseline QRSd &lt;120 ms was observed in 1339 patients (707 DDDR, 632 VVIR). Cum%VP was greater in DDDR versus VVIR (90% versus 58%, P =0.001). Cox models demonstrated that the time-dependent covariate Cum%VP was a strong predictor of HF hospitalization in DDDR (hazard ratio [HR], 2.99 [95% CI, 1.15 to 7.75] for Cum%VP &gt;40%) and VVIR (HR 2.56 [95% CI, 1.48 to 4.43] for Cum%VP &gt;80%). The risk of AF increased linearly with Cum%VP from 0% to 85% in both groups (DDDR, HR 1.36 [95% CI, 1.09, 1.69]; VVIR, HR 1.21 [95% CI 1.02, 1.43], for each 25% increase in Cum%VP). Model results were unaffected by adjustment for known baseline predictors of HF hospitalization and AF. Conclusions— Ventricular desynchronization imposed by ventricular pacing even when AV synchrony is preserved increases the risk of HF hospitalization and AF in SND with normal baseline QRSd.

This guideline has been approved by the American Association for the Study of Liver Diseases and the American College of Gastroenterology and represents the position of both associations. These recommendations provide a data-supported approach to the management of patients with varices and variceal hemorrhage. They are based on the following: (1) formal review and analysis of the recently published world literature on the topic (Medline search); (2) several consensus conferences among experts; (3) the American College of Physicians' Manual for Assessing Health Practices and Designing Practice Guidelines1; (4) guideline policies, including the American Association for the Study of Liver Diseases' Policy Statement on Development and Use of Practice Guidelines and the American Gastroenterological Association's Policy Statement on the Use of Medical Practice Guidelines2; and (5) the authors' years of experience caring for patients with cirrhosis and varices. Intended for use by healthcare providers, these recommendations suggest preferred approaches to the diagnostic, therapeutic, and preventive aspects of care. As with other practice guidelines, this guideline is not intended to replace clinical judgment but rather to provide general guidelines applicable to the majority of patients. They are intended to be flexible, in contrast to standards of care, which are inflexible policies designed to be followed in every case. Specific recommendations are based on relevant published information. To more fully characterize the quality of evidence supporting recommendations, the Practice Guidelines Committee of the AASLD requires a class (reflecting benefit versus risk) and level (assessing strength or certainty) of evidence to be assigned and reported with each recommendation (Table 1, adapted from the American College of Cardiology and the American Heart Association Practice Guidelines3, 4). When little or no data exist from well-designed prospective trials, emphasis is given to results from large series and reports from recognized experts. Further controlled clinical studies are needed to clarify aspects of this statement, and revision may be necessary as new data appear. Clinical considerations may justify a course of action that differs from these recommendations. These recommendations are fully endorsed by the American Association for the Study of Liver Diseases and the American College of Gastroenterology. Portal hypertension is a progressive complication of cirrhosis. Therefore, the management of the patient with cirrhosis and portal hypertensive gastrointestinal bleeding depends on the phase of portal hypertension at which the patient is situated, from the patient with cirrhosis and portal hypertension who has not yet developed varices to the patient with acute variceal hemorrhage for whom the objective is to control the active episode and prevent rebleeding. Practice guidelines for the diagnosis and treatment of gastroesophageal variceal hemorrhage, endorsed by the American Association for the Study of Liver Diseases (AASLD), American College of Gastroenterology (ACG), American Gastroenterological Association (AGA), and American Society of Gastrointestinal Endoscopy (ASGE), were published in 1997.5 Since then, a number of randomized controlled trials have advanced our approach to managing variceal hemorrhage. Three international consensus conferences have been held (Baveno III in 2000, Baveno IV in 2005, and an AASLD/EASL single topic conference in 2007) in which experts in the field have evaluated the changes that have occurred in our understanding of the pathophysiology and management of gastroesophageal hemorrhage.6, 7 In this updated practice guideline we have reviewed the randomized controlled trials and meta-analyses published in the last decade and have incorporated recommendations made by consensus. Cirrhosis, the end stage of any chronic liver disease, can lead to portal hypertension. Portal pressure increases initially as a consequence of an increased resistance to flow mostly due to an architectural distortion of the liver secondary to fibrous tissue and regenerative nodules. In addition to this structural resistance to blood flow, there is an active intrahepatic vasoconstriction that accounts for 20%-30% of the increased intrahepatic resistance,8 and that is mostly due to a decrease in the endogenous production of nitric oxide.9, 10 Portal hypertension leads to the formation of porto-systemic collaterals. However, portal hypertension persists despite the development of these collaterals for 2 reasons: (1) an increase in portal venous inflow that results from splanchnic arteriolar vasodilatation occurring concomitant with the formation of collaterals11; and (2) insufficient portal decompression through collaterals as these have a higher resistance than that of the normal liver.12 Therefore, an increased portal pressure gradient results from both an increase in resistance to portal flow (intrahepatic and collateral) and an increase in portal blood inflow. The preferred, albeit indirect, method for assessing portal pressure is the wedged hepatic venous pressure (WHVP) measurement, which is obtained by placing a catheter in the hepatic vein and wedging it into a small branch or, better still, by inflating a balloon and occluding a larger branch of the hepatic vein. The WHVP has been shown to correlate very closely with portal pressure both in alcoholic and non-alcoholic cirrhosis.13 The WHVP is always corrected for increases in intraabdominal pressure (e.g., ascites) by subtracting the free hepatic vein pressure (FHVP) or the intraabdominal inferior vena cava which as The pressure is the hepatic venous pressure gradient which is with the use of a balloon with a is very and Since it is a of the be in intrahepatic of portal as but be normal in of portal as portal vein The normal is The and changes in that have for the development of the of variceal the development of of portal and are in the of both and are to to and of liver to the use of are the of and to guidelines that and as as varices are the relevant porto-systemic collaterals results in variceal hemorrhage, the complication of cirrhosis. and variceal hemorrhage are the of cirrhosis that from portal hypertension. with cirrhosis and gastroesophageal varices have an of at varices are in of patients with cirrhosis. with the of liver (Table of patients have are in of with cirrhosis may varices and variceal hemorrhage in the course of the in the of has been shown that of patients with and have varices at a of and the for development of varices in with cirrhosis who have no varices at the of is an with small varices large varices at a of cirrhosis alcoholic and of as on the variceal at the of are the with the from small to large hemorrhage at a of and the of hemorrhage is the of with the of hemorrhage occurring in patients with large of hemorrhage are cirrhosis and the of bleeding from varices in to of and despite in the last it is with a of at at with an of variceal have been as at a higher for bleeding the of or to control bleeding and a higher to with in of mostly years of the is the that variceal is of the of variceal an a large a small not of the of variceal is the pressure the which is to the Therefore, a in lead to a decrease in variceal the of variceal hemorrhage not the is to has been shown that the of with in than from to or at from not have a of variceal but have a of and varices are than varices and are in of patients with portal hypertension with a reported of bleeding of in 2 with a higher bleeding for for variceal hemorrhage the of varices as and class and of variceal as or on the of a varices are based on with varices as as in the varices are an of varices and are into 2 The are which the They are of varices and be 2 varices the and to be and more varices in the of varices and are into 2 are in the and to be and and 2 are in the or the The of varices requires the of vein The in the diagnosis of varices is In a consensus it that the be as as in 2 and by or by with a of with large varices than When varices are in or in by a small varices as the varices as than of the and large varices as more than of the recommendations for varices are the as for large this is were in As shown prevent bleeding in more than of patients with or large varices. 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In the majority of the published the of to decrease the from However, is not and a in not correlate with in the of is to is at a of a is is at a of a a randomized that the of bleeding treatment with is be of patients from trials have to the use of as of and The to in cirrhosis are and of of these with or treatment in of patients. in which have reported of than have not been variceal has been to in several randomized trials in patients with varices varices with or meta-analyses of these trials have been the trials and with with and the studies with with that is with a small but of variceal hemorrhage in The results are the fully published trials or trials are the has a of the are more and bleeding from in 10 patients 2 and in This last complication is to given the use of that the use of for In the of of the 10 patients on of 2 of the more studies in these meta-analyses to be the number of patients and a of analysis a higher number of treatment or a in the to the The of this is in that that bleeding were not and that in the have the In the 2 randomized and a more not in the have shown that is to or to in the variceal hemorrhage. review of the a consensus of experts that both and are in variceal hemorrhage and the be based on patient and and not for The of a and has a portal and be more than in variceal In a with a of hemorrhage in the with These results were of in However, 2 more larger trials were to these and a number of were in the Therefore, the use of a of a and be for there is of The of a and has been shown to portal pressure by and splanchnic blood has been recently in a The results suggest that the addition of not increase the of in the of variceal hemorrhage. 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In patients with varices that have not but have a of hemorrhage or variceal on or may be for the of variceal hemorrhage In patients with varices that have not and are not at the of hemorrhage patients and no are preferred and be in patients with or or to a patient is on a it be to the is a patient is with it be every with the and every to for variceal or in with or not be in the of variceal hemorrhage is evidence that treatment for acute variceal hemorrhage, including general and have in an both in the and with acute variceal hemorrhage be to an for and including assessing the and venous be but with with the of and a of This recommendation is based on studies that that of blood leads to increases in portal pressure to higher than and to more and with be in addition to variceal hemorrhage, this can or the of or at other that of blood can or more may be for to in patients with concomitant hepatic The of and can be in patients with of in patients with gastrointestinal hemorrhage to a of analysis of a of and patients that of the of patients with to control variceal studies are needed this can be in patients with and variceal patients with bleeding have a of and other that are with of variceal hemorrhage and a patients with liver are at an increased of this is in with more liver and The use of in patients with cirrhosis and hemorrhage with or has been shown not to decrease the of but to increase This is to a decrease in the of in patients with variceal hemorrhage who Therefore, be practice in patients with cirrhosis and acute variceal The is at a of for 7 The the of a is the at of in the the of However, with of as be When is not can be In a in patients with advanced cirrhosis and hemorrhage, IV more than in mostly due to The of in the not and this have to the has the of applicable and of as as a diagnosis of variceal hemorrhage is to of trials and treatment or a with with that be treatment of variceal not be in the acute as decrease blood pressure and a increase in with is the splanchnic blood flow to splanchnic to a decrease in portal venous inflow and to a decrease in portal The clinical of is by which are to including and and and are by the addition of of are higher than with or it can be at the for a of to the development of is at a IV of that can be increased to a of always be by IV at a of which can be increased to a of to a blood pressure a of that has a and is in acute variceal hemorrhage and has been with a but is not yet in the is at an of 2 IV every and can be to IV every hemorrhage is and as and splanchnic vasoconstriction at it has been that this is due to an of the of studies suggest that has a The of and as and is that are and can be for or is in the and it has been mostly as an IV of followed by a of Use of of a IV followed by of is given as a IV followed by of However, results of meta-analyses of trials of are and a more of trials of in general a The may not be is has been with and a more to However, as shown to be as an to be the diagnosis of variceal hemorrhage is be as as (e.g., and be the variceal of hemorrhage is the a of 10 randomized controlled trials including patients an benefit of in the control of bleeding to of with a of In of the studies in the that increased both and it for the of the in the to by Therefore, by is the preferred of for acute variceal is in patients in whom is not of and is the approach in the treatment of acute variceal hemorrhage. The use of with to the which the of is the of trials to or the control of bleeding and in or variceal bleeding be controlled or in of patients. of has been shown to be of treatment or has clinical as for patients who to to or has reported control of bleeding and a with the of of of bleeding in patients a This approach has not been by other and is not a small has that of is with a in in patients as with an with acute variceal These results in a larger number of patients followed for a can be The of both and are on is very in bleeding with control of hemorrhage in of However, use is with as and of the with as as Therefore, it be to patients with bleeding for whom a more (e.g., is of is balloon is hemorrhage in a patient with cirrhosis is an that requires with and blood to a of 7 be in any patient with cirrhosis and hemorrhage or patients in whom is not is the In patients with advanced cirrhosis may be in with a of or and be as as variceal hemorrhage is and for diagnosis is be to the diagnosis and to variceal hemorrhage, with or is in patients in whom hemorrhage from varices be controlled or in whom bleeding despite and be as a in patients with bleeding for whom a more (e.g., or is The literature on the management of variceal hemorrhage is not as as that for variceal hemorrhage. there are controlled clinical trials, can be on guidelines for the management of varices. varices an of varices the of the Therefore, the approach to management be the as for varices the other there are very data the management of bleeding from are secondary to vein in which of to or variceal with tissue as or is more for acute variceal with better control of hemorrhage as as of large randomized variceal with versus in patients with acute variceal hemorrhage that control of active bleeding in both but that a of years occurred in the with an of In an an approved for in the has been as for and from Therefore, the use of these is preferred in the of varices. However, in the of these or the is with this of be studies the of for bleeding from varices with bleeding control of it been that bleeding from varices more to control with than bleeding from a prospective in patients with versus variceal bleeding and with control of hemorrhage in but patient in each The to for variceal hemorrhage is than for variceal hemorrhage and can be is not or a single of In patients who from variceal tissue as is preferred, is an be in patients in whom hemorrhage from varices be controlled or in whom bleeding despite and who an episode of acute variceal hemorrhage have a very of and The in is years of the hemorrhage, with a of is that patients who have from an episode of variceal hemorrhage and have no evidence of hemorrhage for at be on to prevent to from the who to control the acute episode not preventive these patients be to a are a or a or of variceal to patients with have a higher of However, there are better and the of a and has a portal and be more than has a the of and in patients with variceal This a benefit of but it not from randomized clinical trials that the in patients with is than that obtained with Therefore, the of in the of variceal is the of a and a However, this has to and is in clinical practice that patients end is the method of for variceal it has been shown to be to from randomized clinical trials a in patients with of are at to variceal which requires 2 to is every to to for variceal and for of in of but are The complication is and at the of each are the and may In a small randomized of IV followed by every for the number of at 10 the in both were in the not bleeding occurred in the These results the use of in patients with versus has been in randomized studies a benefit of a benefit of and a no treatment despite a in of These the of patient to be at in the of variceal with of is the approach to variceal and prevent variceal randomized trials the of versus in these 2 trials were and for to and for These results the use of to prevent a consensus conference or as in The a is in patients who variceal hemorrhage or on or a The of variceal is obtained in patients who are that patients in whom or leads to a in to or a from In patients who are it not be to use As the be to the to prevent variceal in the of this of the including the to the studies have the a of the and there is evidence that the of the in is with is very in rebleeding. However, it increases the of hepatic and has no on meta-analyses of trials that to as is with more and there is no in a than in it with and more in class with than Therefore, not be as a but as a for patients who have large of versus of and in patients with or cirrhosis who with a higher of in the both have the is on and to the and the trials have been The of that have been shown to have a and of may increase the for However, given results with it is that a not for secondary no be in the secondary of variceal hemorrhage. of trials which patients versus in the of variceal that the of variceal is by there were no in are and with and the number of needed to is than with suggest that is followed by a higher of variceal in with the no in variceal the of with in variceal has been 7 and a more no in or number of to variceal and a higher of in the Therefore, not be with with cirrhosis who an episode of active variceal hemorrhage to prevent of variceal hemorrhage of is the for secondary of variceal hemorrhage The be to the be every with the and every to for variceal be in patients who are or who experience variceal hemorrhage despite and In the is can be in patients who are be to a for that of varices of in the diagnosis of varices and variceal hemorrhage of in to with a on for varices and variceal hemorrhage In the decade the practice guidelines were a number of have our management of variceal hemorrhage. have been as a and have no in the of the development of varices but are the in the of variceal hemorrhage in patients with varices. variceal has been as an to for the of variceal hemorrhage. The of and variceal is the preferred approach to the management of acute variceal hemorrhage. is of as treatment of the acute bleeding and have been for the of variceal hemorrhage. of or are the the management of patients with varices may with the of that the intrahepatic more for and of liver This guideline in with the Practice Guidelines Committee of the American Association for the Study of Liver Diseases and the Practice Committee of the American College of Gastroenterology. These review of the of the AASLD Practice Guidelines Committee and of the Practice Committee and

Background: Descriptive epidemiology of total joint replacement procedures is limited to annual procedure volumes (incidence). The prevalence of the growing number of individuals living with a total hip or total knee replacement is currently unknown. Our objective was to estimate the prevalence of total hip and total knee replacement in the United States. Methods: Prevalence was estimated using the counting method by combining historical incidence data from the National Hospital Discharge Survey and the Healthcare Cost and Utilization Project (HCUP) State Inpatient Databases from 1969 to 2010 with general population census and mortality counts. We accounted for relative differences in mortality rates between those who have had total hip or knee replacement and the general population. Results: The 2010 prevalence of total hip and total knee replacement in the total U.S. population was 0.83% and 1.52%, respectively. Prevalence was higher among women than among men and increased with age, reaching 5.26% for total hip replacement and 10.38% for total knee replacement at eighty years. These estimates corresponded to 2.5 million individuals (1.4 million women and 1.1 million men) with total hip replacement and 4.7 million individuals (3.0 million women and 1.7 million men) with total knee replacement in 2010. Secular trends indicated a substantial rise in prevalence over time and a shift to younger ages. Conclusions: Around 7 million Americans are living with a hip or knee replacement, and consequently, in most cases, are mobile, despite advanced arthritis. These numbers underscore the substantial public health impact of total hip and knee arthroplasties.