Mount Sinai Beth Israel

Risks of breast and ovarian cancer were determined for Ashkenazi Jewish women with inherited mutations in the tumor suppressor genes BRCA1 and BRCA2. We selected 1008 index cases, regardless of family history of cancer, and carried out molecular analysis across entire families. The lifetime risk of breast cancer among female mutation carriers was 82%, similar to risks in families with many cases. Risks appear to be increasing with time: Breast cancer risk by age 50 among mutation carriers born before 1940 was 24%, but among those born after 1940 it was 67%. Lifetime risks of ovarian cancer were 54% for BRCA1 and 23% for BRCA2 mutation carriers. Physical exercise and lack of obesity in adolescence were associated with significantly delayed breast cancer onset.

This report describes the consensus outcome of an international panel consisting of investigators with years of experience in this field that reviewed the definition and classification of dystonia. Agreement was obtained based on a consensus development methodology during 3 in-person meetings and manuscript review by mail. Dystonia is defined as a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Dystonic movements are typically patterned and twisting, and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation. Dystonia is classified along 2 axes: clinical characteristics, including age at onset, body distribution, temporal pattern and associated features (additional movement disorders or neurological features); and etiology, which includes nervous system pathology and inheritance. The clinical characteristics fall into several specific dystonia syndromes that help to guide diagnosis and treatment. We provide here a new general definition of dystonia and propose a new classification. We encourage clinicians and researchers to use these innovative definition and classification and test them in the clinical setting on a variety of patients with dystonia. © 2013 Movement Disorder Society.

Patients with neuropathic pain (NP) are challenging to manage and evidence-based clinical recommendations for pharmacologic management are needed. Systematic literature reviews, randomized clinical trials, and existing guidelines were evaluated at a consensus meeting. Medications were considered for recommendation if their efficacy was supported by at least one methodologically-sound, randomized clinical trial (RCT) demonstrating superiority to placebo or a relevant comparison treatment. Recommendations were based on the amount and consistency of evidence, degree of efficacy, safety, and clinical experience of the authors. Available RCTs typically evaluated chronic NP of moderate to severe intensity. Recommended first-line treatments include certain antidepressants (i.e., tricyclic antidepressants and dual reuptake inhibitors of both serotonin and norepinephrine), calcium channel alpha2-delta ligands (i.e., gabapentin and pregabalin), and topical lidocaine. Opioid analgesics and tramadol are recommended as generally second-line treatments that can be considered for first-line use in select clinical circumstances. Other medications that would generally be used as third-line treatments but that could also be used as second-line treatments in some circumstances include certain antiepileptic and antidepressant medications, mexiletine, N-methyl-D-aspartate receptor antagonists, and topical capsaicin. Medication selection should be individualized, considering side effects, potential beneficial or deleterious effects on comorbidities, and whether prompt onset of pain relief is necessary. To date, no medications have demonstrated efficacy in lumbosacral radiculopathy, which is probably the most common type of NP. Long-term studies, head-to-head comparisons between medications, studies involving combinations of medications, and RCTs examining treatment of central NP are lacking and should be a priority for future research.

BACKGROUND: The effects of the dose of dialysis and the level of flux of the dialyzer membrane on mortality and morbidity among patients undergoing maintenance hemodialysis are uncertain. METHODS: We undertook a randomized clinical trial in 1846 patients undergoing thrice-weekly dialysis, using a two-by-two factorial design to assign patients randomly to a standard or high dose of dialysis and to a low-flux or high-flux dialyzer. RESULTS: In the standard-dose group, the mean (+/-SD) urea-reduction ratio was 66.3+/-2.5 percent, the single-pool Kt/V was 1.32+/-0.09, and the equilibrated Kt/V was 1.16+/-0.08; in the high-dose group, the values were 75.2+/-2.5 percent, 1.71+/-0.11, and 1.53+/-0.09, respectively. Flux, estimated on the basis of beta2-microglobulin clearance, was 3+/-7 ml per minute in the low-flux group and 34+/-11 ml per minute in the high-flux group. The primary outcome, death from any cause, was not significantly influenced by the dose or flux assignment: the relative risk of death in the high-dose group as compared with the standard-dose group was 0.96 (95 percent confidence interval, 0.84 to 1.10; P=0.53), and the relative risk of death in the high-flux group as compared with the low-flux group was 0.92 (95 percent confidence interval, 0.81 to 1.05; P=0.23). The main secondary outcomes (first hospitalization for cardiac causes or death from any cause, first hospitalization for infection or death from any cause, first 15 percent decrease in the serum albumin level or death from any cause, and all hospitalizations not related to vascular access) also did not differ significantly between either the dose groups or the flux groups. Possible benefits of the dose or flux interventions were suggested in two of seven prespecified subgroups of patients. CONCLUSIONS: Patients undergoing hemodialysis thrice weekly appear to have no major benefit from a higher dialysis dose than that recommended by current U.S. guidelines or from the use of a high-flux membrane.

PURPOSE: This survey was designed to confirm the prevalence and duration of fatigue in the cancer population and to assess its physical, mental, social, and economic impacts on the lives of patients and caregivers. Patients and Methods. A 25-minute telephone interview was completed with 379 cancer patients having a prior history of chemotherapy. Patients were recruited from a sample of 6, 125 households in the United States identified as having a member with cancer. The median patient age was 62 years, and 79% of respondents were women. Patients reporting fatigue at least a few times a month were asked a series of questions to better describe their fatigue and its impact on quality of life. RESULTS: Seventy-six percent of patients experienced fatigue at least a few days each month during their most recent chemotherapy; 30% experienced fatigue on a daily basis. Ninety-one percent of those who experienced fatigue reported that it prevented a "normal" life, and 88% indicated that fatigue caused an alteration in their daily routine. Fatigue made it more difficult to participate in social activities and perform typical cognitive tasks. Of the 177 patients who were employed, 75% changed their employment status as a result of fatigue. Furthermore, 65% of patients indicated that their fatigue resulted in their caregivers taking at least one day (mean, 4.5 days) off work in a typical month. Physicians were the health care professionals most commonly consulted (79%) to discuss fatigue. Bed rest/ relaxation was the most common treatment recommendation (37%); 40% of patients were not offered any recommendations. CONCLUSIONS: Cancer-related fatigue is common among cancer patients who have received chemotherapy and results in substantial adverse physical, psychosocial, and economic consequences for both patients and caregivers. Given the impact of fatigue, treatment options should be routinely considered in the care of patients with cancer.

The purpose of this study was to determine the levels of change on standard pain scales that represent clinically important differences to patients. Data from analgesic studies are often difficult to interpret because the clinical importance of the results is not obvious. Differences between groups, as summarized by a change in mean values over time, can be difficult to apply to clinical care. Baseline scores vary widely and group mean differences could reflect large changes in a few patients, small changes in many patients, or any combination of these outcomes. Determination of the proportion of patients who have a clinically important improvement in their pain would provide a more interpretable result with direct clinical implications. However, determining a clinically important outcome requires information about the degree of change over time that is clinically important. Data from the titration phase of a multiple cross-over randomized clinical trial of oral transmucosal fentanyl citrate (OTFC) for the treatment of cancer-related breakthrough pain were re-analyzed to examine the differences in pain scores between treatment episodes that did and did not yield adequate pain relief. The scales evaluated were absolute pain intensity difference (PID, 0-10 scale), percentage pain intensity difference (PID%, 0-100% scale), pain relief (PR, 0 (none), 1 (slight), 2 (moderate), 3 (lots), 4 (complete)), sum of the pain intensity difference (SPID over 60 min), percentage of maximum total pain relief (% Max TOTPAR over 60 min), and global medication performance (0 (poor), 1 (fair), 2 (good), 3 (very good), 4 (excellent)). Adequate relief was defined by the patient's decision not to use another dose of opioid medication as a rescue, in addition to the study medication, to treat each painful episode. One hundred thirty OTFC naive patients contributed data on 1268 episodes of breakthrough pain. The scales that were converted to a percentage change yielded the best accuracy in predicting adequate relief, with balanced sensitivity and specificity. The best cut-off point for both the % Max TOTPAR and the PID% was 33%. The best cut-off points for the absolute scales were absolute pain intensity difference of 2, pain relief of 2 (moderate), and SPID of 2. The global medication performance of 2 (good) had excellent values as well. This study presents data-derived cut-off points for the changes in several pain scales, each reflecting the clinically important improvement for patients treating breakthrough cancer pain episodes with OTFC. Confirmation in other patient populations and different pain syndromes will be needed. The use of consistent clinically important cut-off points as the primary outcome in future pain therapy clinical trials will enhance their validity, comparability, and clinical applicability.

This document presents the official position of the American Association for the Study of Liver Diseases (AASLD) on the application of serum alanine aminotransferase (ALT) activity, based upon an analysis of the currently available scientific data. Its authorship was selected by the Public Policy Committee. The document is fully endorsed by the AASLD Governing Board. Physicians caring for patients with liver disease, predominantly hepatologists and gastroenterologists, have long been aware that measurements of liver enzyme activities (serum aminotransferases, including ALT [alanine aminotransferase] and AST [asparate amniotransferase]) are critical in the diagnosis and assessment of liver disease. These enzymes were formerly referred to as SGPT and SGOT, respectively. The serum ALT activity (hereafter termed ALT) has been regarded as a reliable and sensitive marker of liver disease. ALT may also be a good indicator of overall health, particularly in the context of obesity, the metabolic syndrome, and presence of cardiovascular disease, as many patients affected by these conditions also are at risk of having non-alcoholic fatty liver disease. Despite all these considerations, abnormal ALT activity is often ignored or minimized by practitioners as most patients are asymptomatic. Minor elevations are often construed to be clinically insignificant, in part because of lack of a longitudinal perspective about the impact of abnormal ALT on long-term outcome such as end-stage liver disease or premature mortality. This document summarizes the position of the American Association for the Study of Liver Disease regarding ALT and includes review of its physiology, its distribution in health and disease, and its role as a screening and diagnostic test and clinical tool. Specifically, the significance of ALT measurements for determining general health, liver health and liver disease is addressed. The purpose of this document is to reinforce that the significance and etiology of a persistently elevated ALT must be evaluated regardless of the degree of elevation and to examine ALT as a population screening tool for early detection of liver disease. Alanine aminotransferase (ALT) is an enzyme that catalyzes the transfer of amino groups to form the hepatic metabolite oxaloacetate.1 It is composed of 496 amino acids, which are encoded by a gene located in the long arm of chromosome 8.2, 3 ALT is found abundantly in the cytosol of the hepatocyte. ALT activity in the liver is about 3000 times that of serum activity. Thus, in the case of hepatocellular injury or death, release of ALT from damaged liver cells increases measured ALT activity in the serum. Although it is generally thought to be specific to the liver, it is also found in the kidney, and, in much smaller quantities, in heart and skeletal muscle cells. ALT released in the blood is catabolized in the liver with a resulting plasma half life of 47 ± 10 hours, which is considerably longer than that of AST (17 ± 5 hours).1 ALT activity varies day to day, by 10% to 30%. Within a given day, there is a significant diurnal variation, with ALT activities being up to 45% higher in the afternoon than in the early morning.4, 5 In acute hepatocellular injury, serum AST levels usually rise immediately, reaching a higher level than ALT initially, due to the higher activity of AST in hepatocytes and its release with liver injury. Within 24 to 48 hours, particularly if ongoing damage occurs, ALT will become higher than AST, because of its longer plasma half-life. In chronic hepatocellular injury, ALT is more commonly elevated than AST; however, as fibrosis progresses, ALT activities typically decline, and the ratio of AST to ALT gradually increases, so that by the time cirrhosis is present, AST is often higher than ALT.6, 7 One notable exception to the predominance of serum ALT activity in chronic liver disease is alcoholic liver disease where AST activity is generally higher than ALT levels. AIH, autoimmune hepatitis; ALD, alcoholic liver disease; ALT, alanine aminotransferase; ANA, antinuclear antibofy; AST, aspartate aminotransferase; BMI, body mass index; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; HDL, high-density lipoprotein; MAST, Michigan alcoholism screening test; NAFLD, non-alcoholic fatty liver disease; SMA, smooth muscle actin; SMR, standardized mortality ratio; ULN, upper limit of normal. ALT measurement affords a readily available, low-cost blood test that is utilized throughout the United States as a tool for detection of liver disease. ALT is a valuable screening test to detect otherwise inapparent liver disease, such as asymptomatic viral hepatitis and non-alcoholic fatty liver disease, both of which represent an epidemic that remains largely undiagnosed in the United States. Apart from liver disease, however, serum ALT activity may be affected by a number of factors not associated with hepatic necrosis. ALT levels differ with gender, with higher values in men than in women.8 Additional factors that affect serum ALT levels include body mass index (BMI) and triglyceride levels, regardless of gender.9-11 Total cholesterol levels and alcohol consumption among men have a positive correlation, whereas smoking, physical activity and age have a negative correlation with ALT levels.11-13 Glucose levels, in women, have a positive correlation with ALT activities, whereas use of oral contraceptives tends to lower ALT values. Some of these correlations (such as BMI) may be explained by ALT being higher in people with fatty liver disease. Similarly, patients with hyperlipidemia or hyperglycemia may also have fatty liver disease, as a part of the metabolic syndrome. In light of the increasing prevalence of obesity in Americans, the distribution of ALT in the apparently healthy population has changed such that some patients with non-alcoholic fatty liver disease may have ALTs in the normal range as determined by the mean ± 2 standard deviations.9 In response, some physicians have advocated lowering the normal range.8 To the extent that there is a rough correlation between ALT and degree of hepatic inflammation in general, patients with high ALT levels tend to have more severe inflammation in the liver than those with normal ALT values. In contrast, the correlation between ALT and degree of hepatic fibrosis, the parameter that is most relevant to the prognosis of the patient, is not very strong, as exemplified by the common observation that a cirrhotic patient may have normal or only mildly elevated ALT. Since serum ALT levels rise in disease states that cause hepatocellular injury, serum ALT levels can effectively identify an ongoing liver disease process. The probability of clinically significant liver disease increases, particularly if the elevated ALT is associated with symptoms such as fatigue, anorexia or pruritus. The utility of additional evaluation of a patient with asymptomatic elevation of ALT depends upon the findings of history and physical examination, the length of time that ALT has been elevated and the level of ALT elevation. Whereas one study suggested that the majority of asymptomatic people with elevated ALT do not have significant liver disease, a Scandinavian study of 151 consecutive patients with mild to moderate elevations of serum aminotransferase levels for at least 6 months revealed that liver disease was common.14, 15 Diagnoses included non-alcoholic steatohepatitis and hepatic steatosis (noted in 42%), chronic HCV (15%), alcoholic liver disease (8%) and autoimmune hepatitis, primary biliary cirrhosis and alpha1 antitrypsin deficiency in smaller numbers. The level of ALT also guides the urgency and extent of further investigation. A serum ALT level less than 5 times the upper limit of the normal range should be rechecked before an extensive work-up is undertaken. If elevated ALT levels are confirmed and if they remain persistently elevated, additional work-up is indicated. ALT levels greater than 5 times the upper limit of the normal range suggest a potentially serious, active liver disease process and work-up should be initiated without waiting to confirm the persistence of abnormal ALT. ALT levels greater than 15 times the normal range indicate severe acute liver cell injury and evaluation should be initiated immediately. The differential diagnosis for patients with severe acute liver injury (ALT levels >15 times the normal range) is relatively limited. Acute viral hepatitis (A-E), ischemic hepatitis or other vascular disorders such as acute venous outflow occlusion (Budd-Chiari), or toxin-mediated hepatitis should be considered. Acute autoimmune hepatitis, hepatic lymphoma or acute biliary occlusion may also present with highly elevated ALT activity. The diagnosis may be made upon historical grounds [ischemic episode, risk factors of acquisition of viral hepatitis, medication or hepatotoxin exposure (e.g., isoniazid) or overdose (e.g., acetaminophen)]. Blood testing (hepatitis and autoimmune serologies) may be helpful where applicable, whereas abdominal imaging may be helpful in other settings (e.g., venous outflow obstruction, biliary obstruction or abnormal lymphadenopathy). NAFLD is probably the most common cause of abnormal ALT values among US adults and may affect up to 3% of the US population.16, 17 Risk factors for NAFLD include obesity, diabetes and hyperlipidemia.18 Elevated ALT may be a component of the metabolic syndrome, the hallmark of which is insulin resistance, manifested by hyperglycemia, hyperlipidemia, abdominal obesity and hypertension. The role of NAFLD as an increasing threat to public health is highlighted by the well-publicized trend in the proportion of overweight or obese Americans.19 Similarly, the prevalence of the metabolic syndrome is also increasing rapidly.20 In these patients, testing for ALT will facilitate timely diagnosis of NAFLD before irreversible fibrosis of the liver is established. Elevated ALT activities may be the only clue to this entity since there are no definitive blood tests to confirm the diagnosis. Furthermore, patients with high ALT among those with the metabolic syndrome may represent a subgroup with a propensity for systemic inflammation that may, in turn, increase the risk of atherosclerosis, leading to coronary artery or cerebrovascular disease.21 Elevated ALT levels may correlate with the severity of NAFLD. In a study in which 233 morbidly obese women were examined, 60% had some degree of hepatic fibrosis, and the majority of these patients had an elevated ALT value. Twenty-eight percent of patients with mild fibrosis and 68% of patients with advanced fibrosis had raised ALT activity. ALT levels were elevated in only 17% of patients without fibrosis.22 These observations are helpful in correlating elevated ALT with severity of liver damage. Therefore, ALT represents an excellent screening test to detect significant NAFLD.23 ALD remains the most common cause of liver-related morbidity and mortality in the United States.24 In alcoholic liver injury, AST activity is characteristically elevated in comparison to ALT activity, although mild elevation of ALT level is common.25 This is thought to be due to the longer half-life of mitochondrial AST released in response to alcohol and the coexistence of deficiency of pyridoxal-6-phosphate in alcoholics, which is a cofactor for the enzymatic activity of ALT.26 History of alcohol use should be ascertained by accurate questioning such as with the CAGE questionnaire27 or the MAST (Michigan alcoholism screening test)28 in all patients with serum aminotransferase elevations. Random blood alcohol level is sometimes useful in distinguishing ALD from NAFLD. The histology of ALD may be indistinguishable from that of NAFLD.29 Chronic HCV infection is the most common chronic blood-borne infection in the United States, affecting approximately 2% of the population.30, 31 However, ALT levels fluctuate in HCV and values may occasionally fall into the normal range.32 Since HCV infection is frequently asymptomatic, ALT elevations noted upon routine blood testing often stimulate the work-up whereby HCV infection is diagnosed. Sixty-nine percent of 248 asymptomatic blood donors who tested positive for HCV antibody had elevated ALT activity.33 Sixty-eight percent of patients positive for HCV RNA had elevated ALT levels, compared with 17% of those without detectable RNA. Patients with severe liver damage on liver biopsy in this cohort had at least 1 elevated ALT determination. Twenty-nine percent of HCV-infected patients with initially normal ALT values, when followed, will develop persistently elevated ALT levels, and 57% will develop transient elevation in ALT activities within 5 years.34 HCV patients with persistently normal ALT levels (at least 2 normal ALT values within 6 months) are more likely to be females35 and tend to have lower necroinflammatory and fibrosis scores on liver biopsy when compared to similar patients with elevated ALT activities.36, 37 Significant fibrosis was found in 8% to 20% of patients with normal ALT levels compared to 60% of patients with elevated ALT activities. While ALT analysis alone may fail to detect a minority of persons infected with HCV, it is most effective in detecting those persons whose liver disease is more severe. Such a characteristic enhances the value of ALT as a screening tool for detection of clinically important liver disease. Moreover, the sensitivity of ALT analysis can be improved with serial measurements and long-term follow-up. Chronic HBV infection, a common etiology of elevated ALT values worldwide, afflicts at least 1.3 million individuals in the United States.38 Certain risk groups, such as individuals born in endemic countries, with a history of injection drug use, or on hemodialysis, may be identified in whom prevalence of HBV infection is particularly high in the United States.39 Chronic HBV infection is also frequently asymptomatic and is sometimes discovered because of an elevated ALT level identified upon routine blood testing. Among HBV patients, the level of ALT is associated with progression of liver disease and development of morbidity. The cumulative risk of development of complications is in patients with ALT values at least 1 to 2 times the upper of normal Among patients who are hepatitis B e ALT is also of the of Thus, in HBV patients, ALT is useful not only in determining the presence of significant liver disease and for also in the in the history of the The use of many has been associated with elevated ALT and are also If elevated ALT levels are should be and ALT levels should be If ALT activity remains elevated, other should be If the medication must be for clinical ALT activity should be If ALT values to increase or are associated with development of symptoms or of hepatic the medication must be hepatitis may also be identified by of mild to moderate elevations of ALT Patients may be asymptomatic or have symptoms such as and the diagnosis is confirmed with testing such as antinuclear antibody and smooth muscle antibody and a liver may be considered. activity an important role in determining and also response in those who Although AST activity has been in these ALT activity is important in these ALT levels may also be elevated in hepatic such as primary biliary cirrhosis or primary elevations in ALT level may be noted in a relatively common of in people of Elevated and serum levels are usually of the gene the although a liver biopsy with remains a useful diagnostic to the extent of liver injury and of Liver biopsy is in patients with elevated ALT levels, elevated serum and gene of the disease are not usually noted the or in men and the or in It is particularly important to identify patients with early in because liver injury can be with of disease can be if before complications elevations in ALT activity may also identify other less common disorders such as disease and Furthermore, mild elevations of ALT levels are also in the of While ALT is useful as an test in detecting liver disease, its value as a of overall health and is a between ALT activity and when the process not from the The to the between elevated ALT values and mortality risk was based on a cohort of of a health in In this there were individuals of between and in whom and between and were This cohort was up to when were to and of 1 summarizes the impact of levels of ALT on mortality. In of the had ALT whereas only of women had ALT ALT activity, in with higher mortality from all and liver disease. the of ALT was much on mortality. compared to those with ALT men with ALT had times the risk of from liver disease. In women, a similar trend was the number of and in the ALT was the risk in this Risk of to ALT. risk from all of and from liver disease in men and women is In the ALT activity with the risk of cardiovascular mortality as with those with ALT men with ALT had 3 times the risk of from cardiovascular A similar trend was suggested in women, the of cardiovascular was of the in women more A similar analysis has been in on a all who had ALT determined in the were identified and who had in had ALT had within normal and The standardized mortality ratio associated with ALT between 1 and 2 times the was whereas ALT greater than 2 times the was the other ALT less than the was associated with lower risk of than The of ALT being a marker of cardiovascular health has been evaluated by and who the and to correlate ALT activity and risk of coronary artery disease in the general US in the the for the which of lack of or heart and including ALT activity at least of not have hepatitis B or or history of alcohol These included whose ALT was within normal and who had elevated ALT activities. these 2 groups were compared to those with elevated ALT activity had higher cholesterol lower high-density and higher blood and were more likely to be These and other risk factors for coronary artery disease were in a Risk to the risk of coronary artery disease. with elevated ALT levels were to have increase in the risk of coronary artery disease within 10 In women, there was a increase in These that ALT activity is of mortality in the general While mortality may be due to liver disease, it may also be to other risk factors for ALT elevation including obesity, serum and plasma in to alcohol which are to health The cardiovascular mortality risk associated with ALT activity may in part be explained by the metabolic syndrome commonly present in patients with non-alcoholic fatty liver disease. ALT may as a marker of a that is associated with higher cardiovascular risk among individuals with the metabolic The clinical and so suggest that ALT may be useful as a screening test for early detection of asymptomatic liver disease and for other of premature mortality. is as the of disease by or other which can be and A screening test is not to be it is to individuals with a high probability of disease from those with a In a screening test or the most is the by and The the 10 of the to ALT as a screening test for early detection of liver disease in the The primary for which ALT is to is chronic liver disease, which may to liver end-stage liver disease hepatocellular Chronic liver disease is the leading cause of in the United In hepatocellular which in patients with chronic liver disease, is one of the most common the It is that the of and mortality from in the United States has been increasing in the further the of chronic liver disease as a public health of chronic liver disease is with of hepatic fibrosis, leading to although the at which this progression varies by the specific liver disease and by use diagnostic tests to the degree of fibrosis, which has most commonly been a liver although for this assessment are being These the progression of disease in In most chronic liver disease, the disease between the of disease and end-stage liver disease is measured in and This for screening with ALT to detect liver disease in a is as an irreversible Chronic liver disease to effective may be at an early to progression to In such as chronic hepatitis patients with advanced fibrosis have response to than in those with disease. ALT is a test to identify with chronic liver disease in an asymptomatic if not chronic liver disease a component of hepatic inflammation and hepatocellular which ALT is thought to Although high to the diagnostic of ALT in the detection of liver disease in the general population are by or by suggest of ALT as a test to detect chronic liver disease in its early a blood ALT is as as many other such as screening and serum cholesterol Patients with chronic liver disease are commonly in age or and ALT testing before the of life may identify most asymptomatic patients with liver disease. However, further are to at ALT screening must be or to the of a of screening ALT. elevated serum aminotransferase activities 1 of the most common for or study is available to to that may if screening of ALT were to be A diagnostic to identify patients with chronic liver disease that may most from may clinical from such a screening These 2 the and of ALT as a screening its and in general of for morbidity and mortality associated with abnormal ALT, the physical and and of an screening likely the of early diagnosis of chronic liver disease. However, the and of population screening ALT have not been ALT is an part of the evaluation of patients with liver disease. Its as a screening test for liver disease is highlighted by the that most patients with common liver such as viral hepatitis B and and non-alcoholic fatty liver disease have elevated ALT, they remain without symptoms to a Thus, although the and use of ALT analysis may differ specific liver disease ALT is a sensitive test to detect individuals with liver disease. The of ALT activity as an indicator of liver disease has been in which a between ALT and mortality from liver disease. Furthermore, suggest that ALT has a role as a of mortality of liver disease. This is generally construed to NAFLD as a component of the metabolic of insulin resistance, which the development of cardiovascular disease. ALT activity may be important not only as a marker of liver also as an indicator of general although measurement of ALT is commonly as a part of the hepatic the significance of this test may have been In ALT as a screening tool for the found that ALT most of the for a screening However, additional will the and of ALT These include of the for ALT screening and assessment of the impact of its as as its While for these that ALT is an excellent screening test in individuals at risk of liver disease. an abnormal ALT as determined by a normal must an clinical The the Public Policy of AASLD for the to to this document on its The of

The Beck Depression Inventory (BDI) is perhaps the most commonly used screening instrument for depression in the general population. We examined the psychometric properties of a Persian-language version of the second edition of this instrument (BDI-II) [Beck et al., 1996] in an Iranian college-student sample. In a sample of 125 student volunteers from two Iranian universities, we compared mean item scores on the BDI-II-Persian with those on the English-language version administered to North American college students, and assessed internal consistency and test-retest reliability of the BDI-II-Persian and its concurrent validity against a measure of negative automatic thoughts in depression, the Automatic Thoughts Questionnaire [Hollon and Kendall, 1980]. We also examined the factor structure of the BDI-II-Persian through comparing the fit of various proposed models to the data using confirmatory factor analysis. The BDI-II-Persian had high internal consistency (Cronbach's alpha=0.87) and acceptable test-retest reliability (r=0.74). The instrument correlated strongly with the Automatic Thoughts Questionnaire. In factor analysis, models with strongly correlated affective-cognitive and somatic-vegetative factors provided a better fit than models with one global factor. These data support the reliability and concurrent validity of the BDI-II-Persian as a measure of depressive symptoms in nonclinical samples.

In this article, we review the existing empirical research on the topic of therapeutic alliance ruptures in psychotherapy. Ruptures in the therapeutic alliance are defined as episodes of tension or breakdown in the collaborative relationship between patient and therapist. Two meta-analyses were conducted. The first reviewed studies examining the relation between rupture-repair episodes and treatment outcome (r = .24, z = 3.06, 95% CI [.09, .39], p = .002, k = 3, N = 148). The second meta-analysis reviewed the research examining the impact on treatment outcome of training therapists in the use of alliance rupture intervention principles (prepost r = .65, z = 5.56, 95% CI [.46, .78], p < .001, k = 8, N = 376). Both meta-analyses provided promising evidence regarding the relevance of alliance rupture-repair processes to therapeutic outcome. The limitations of the research reviewed are discussed as well as practice implications for repairing the inevitable alliance ruptures in psychotherapy.

Abstract Learning Objectives After completing this course, the reader will be able to: Explain the effect of hypoxia on resistance to treatment. Describe the causes of tumor hypoxia. Characterize cellular response to hypoxia. Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com Hypoxia is a characteristic feature of locally advanced solid tumors resulting from an imbalance between oxygen (O2) supply and consumption. Major causative factors of tumor hypoxia are abnormal structure and function of the microvessels supplying the tumor, increased diffusion distances between the nutritive blood vessels and the tumor cells, and reduced O2 transport capacity of the blood due to the presence of disease- or treatment-related anemia. Tumor hypoxia is a therapeutic concern since it can reduce the effectiveness of radiotherapy, some O2-dependent cytotoxic agents, and photodynamic therapy. Tumor hypoxia can also negatively impact therapeutic outcome by inducing changes in the proteome and genome of neoplastic cells that further survival and malignant progression by enabling the cells to overcome nutritive deprivation or to escape their hostile environment. The selection and clonal expansion of these favorably altered cells further aggravate tumor hypoxia and support a vicious circle of increasing hypoxia and malignant progression while concurrently promoting the development of more treatment-resistant disease. This pattern of malignant progression, coupled with the demonstration of a relationship between falling hemoglobin level and worsening tumor oxygenation, highlights the need for effective treatment of anemia as one approach for correcting anemic hypoxia in tumors, and in so doing, possibly improving therapeutic response.

The work of liver stem cell biologists, largely carried out in rodent models, has now started to manifest in human investigations and applications. We can now recognize complex regenerative processes in tissue specimens that had only been suspected for decades, but we also struggle to describe what we see in human tissues in a way that takes into account the findings from the animal investigations, using a language derived from species not, in fact, so much like our own. This international group of liver pathologists and hepatologists, most of whom are actively engaged in both clinical work and scientific research, seeks to arrive at a consensus on nomenclature for normal human livers and human reactive lesions that can facilitate more rapid advancement of our field.

TRANSCRIPTION FACTORS play a major role in differentiation in a number of cell types, including the various hematopoietic lineages.[1-4][1] In the hematopoietic system, stem cells undergo a process of commitment to multipotential progenitors, which in turn give rise to mature blood cells. Although a

BACKGROUND: Video games have become extensively integrated into popular culture. Anecdotal observations of young surgeons suggest that video game play contributes to performance excellence in laparoscopic surgery. Training benefits for surgeons who play video games should be quantifiable. HYPOTHESIS: There is a potential link between video game play and laparoscopic surgical skill and suturing. DESIGN: Cross-sectional analysis of the performance of surgical residents and attending physicians participating in the Rosser Top Gun Laparoscopic Skills and Suturing Program (Top Gun). Three different video game exercises were performed, and surveys were completed to assess past experience with video games and current level of play, and each subject's level of surgical training, number of laparoscopic cases performed, and number of years in medical practice. SETTING: Academic medical center and surgical training program. PARTICIPANTS: Thirty-three residents and attending physicians participating in Top Gun from May 10 to August 24, 2002. MAIN OUTCOME MEASURES: The primary outcome measures were compared between participants' laparoscopic skills and suturing capability, video game scores, and video game experience. RESULTS: Past video game play in excess of 3 h/wk correlated with 37% fewer errors (P<.02) and 27% faster completion (P<.03). Overall Top Gun score (time and errors) was 33% better (P<.005) for video game players and 42% better (P<.01) if they played more than 3 h/wk. Current video game players made 32% fewer errors (P=.04), performed 24% faster (P<.04), and scored 26% better overall (time and errors) (P<.005) than their nonplaying colleagues. When comparing demonstrated video gaming skills, those in the top tertile made 47% fewer errors, performed 39% faster, and scored 41% better (P<.001 for all) on the overall Top Gun score. Regression analysis also indicated that video game skill and past video game experience are significant predictors of demonstrated laparoscopic skills. CONCLUSIONS: Video game skill correlates with laparoscopic surgical skills. Training curricula that include video games may help thin the technical interface between surgeons and screen-mediated applications, such as laparoscopic surgery. Video games may be a practical teaching tool to help train surgeons.

Few surveys have been performed to define the characteristics and impact of breakthrough pain in the cancer population. In this cross-sectional survey of inpatients with cancer, patients responded to a structured interview (the Breakthrough Pain Questionnaire) designed to characterize breakthrough pain, and also completed measures of pain and mood (Memorial Pain Assessment Card (MPAC)), pain-related interference in function (Brief Pain Inventory (BPI)), depressed mood (Beck Depression Inventory (BDI)), and anxiety (Beck Anxiety Inventory (BAI)). Of 178 eligible patients, 164 (92.2%) met the criteria for controlled background pain. The median age was 50.6 years (range 26 to 77 years), 52% were men, and 80.6% were Caucasian. Tumor diagnoses were mixed, 75% had metastatic disease, 65% had pain caused directly by the neoplasm, and a majority had mixed nociceptive-neuropathic pain. The median Karnofsky Performance Status score was 60 (range 40 to 90). Eighty-four (51.2%) patients had experienced breakthrough pain during the previous day. The median number of episodes was six (range 1 to 60) and the median interval from onset to peak was 3 min (range 1 s to 30 min). Although almost two-thirds (61.7%) could identify precipitants (movement 20.4%; end-of-dose failure 13.2%), pain was unpredictable in a large majority (78.2%). Patients with breakthrough pain had more intense (P < 0.001) and more frequent (P < 0.01) background pain than patients without breakthrough pain. Breakthrough pain was also associated with greater pain-related functional impairment (difference in mean BPI. P < 0.001), worse mood (mood VAS, P < 0.05; BDI, P < 0.001), and more anxiety (BAI, P < 0.001). Multivariate analysis confirmed that breakthrough pain independently contributed to impaired functioning and psychological distress. These data confirm that cancer-related breakthrough pain is a prevalent and heterogeneous phenomenon. The presence of breakthrough pain is a marker of a generally more severe pain syndrome, and is associated with both pain-related functional impairment and psychological distress. The findings suggest the need for further studies of breakthrough pain and more effective therapeutic strategies.

OBJECTIVES: The American College of Critical Care Medicine provided 2002 and 2007 guidelines for hemodynamic support of newborn and pediatric septic shock. Provide the 2014 update of the 2007 American College of Critical Care Medicine "Clinical Guidelines for Hemodynamic Support of Neonates and Children with Septic Shock." DESIGN: Society of Critical Care Medicine members were identified from general solicitation at Society of Critical Care Medicine Educational and Scientific Symposia (2006-2014). The PubMed/Medline/Embase literature (2006-14) was searched by the Society of Critical Care Medicine librarian using the keywords: sepsis, septicemia, septic shock, endotoxemia, persistent pulmonary hypertension, nitric oxide, extracorporeal membrane oxygenation, and American College of Critical Care Medicine guidelines in the newborn and pediatric age groups. MEASUREMENTS AND MAIN RESULTS: The 2002 and 2007 guidelines were widely disseminated, translated into Spanish and Portuguese, and incorporated into Society of Critical Care Medicine and American Heart Association/Pediatric Advanced Life Support sanctioned recommendations. The review of new literature highlights two tertiary pediatric centers that implemented quality improvement initiatives to improve early septic shock recognition and first-hour compliance to these guidelines. Improved compliance reduced hospital mortality from 4% to 2%. Analysis of Global Sepsis Initiative data in resource rich developed and developing nations further showed improved hospital mortality with compliance to first-hour and stabilization guideline recommendations. CONCLUSIONS: The major new recommendation in the 2014 update is consideration of institution-specific use of 1) a "recognition bundle" containing a trigger tool for rapid identification of patients with septic shock, 2) a "resuscitation and stabilization bundle" to help adherence to best practice principles, and 3) a "performance bundle" to identify and overcome perceived barriers to the pursuit of best practice principles.

BACKGROUND: Health care organizations face pressures from patients to improve the quality of care and clinical outcomes, as well as pressures from managed care to do so more efficiently. Coordination, the management of task interdependencies, is one way that health care organizations have attempted to meet these conflicting demands. OBJECTIVES: The objectives of this study were to introduce the concept of relational coordination and to determine its impact on the quality of care, postoperative pain and functioning, and the length of stay for patients undergoing an elective surgical procedure. Relational coordination comprises frequent, timely, accurate communication, as well as problem-solving, shared goals, shared knowledge, and mutual respect among health care providers. RESEARCH DESIGN: Relational coordination was measured by a cross-sectional questionnaire of health care providers. Quality of care was measured by a cross-sectional postoperative questionnaire of total hip and knee arthroplasty patients. On the same questionnaire, postoperative pain and functioning were measured by the WOMAC osteoarthritis instrument. Length of stay was measured from individual patient hospital records. SUBJECTS: The subjects for this study were 338 care providers and 878 patients who completed questionnaires from 9 hospitals in Boston, MA, New York, NY, and Dallas, TX, between July and December 1997. MEASURES: Quality of care, postoperative pain and functioning, and length of acute hospital stay. RESULTS: Relational coordination varied significantly between sites, ranging from 3.86 to 4.22 (P <0.001). Quality of care was significantly improved by relational coordination (P <0.001) and each of its dimensions. Postoperative pain was significantly reduced by relational coordination (P = 0.041), whereas postoperative functioning was significantly improved by several dimensions of relational coordination, including the frequency of communication (P = 0.044), the strength of shared goals (P = 0.035), and the degree of mutual respect (P = 0.030) among care providers. Length of stay was significantly shortened (53.77%, P <0.001) by relational coordination and each of its dimensions. CONCLUSIONS: Relational coordination across health care providers is associated with improved quality of care, reduced postoperative pain, and decreased lengths of hospital stay for patients undergoing total joint arthroplasty. These findings support the design of formal practices to strengthen communication and relationships among key caregivers on surgical units.

Opioids have been regarded for millennia as among the most effective drugs for the treatment of pain. Their use in the management of acute severe pain and chronic pain related to advanced medical illness is considered the standard of care in most of the world. In contrast, the long-term administration of an opioid for the treatment of chronic noncancer pain continues to be controversial. Concerns related to effectiveness, safety, and abuse liability have evolved over decades, sometimes driving a more restrictive perspective and sometimes leading to a greater willingness to endorse this treatment. The past several decades in the United States have been characterized by attitudes that have shifted repeatedly in response to clinical and epidemiological observations, and events in the legal and regulatory communities. The interface between the legitimate medical use of opioids to provide analgesia and the phenomena associated with abuse and addiction continues to challenge the clinical community, leading to uncertainty about the appropriate role of these drugs in the treatment of pain. This narrative review briefly describes the neurobiology of opioids and then focuses on the complex issues at this interface between analgesia and abuse, including terminology, clinical challenges, and the potential for new agents, such as buprenorphine, to influence practice.

The optimal assessment of cancer pain includes a detailed description of pain characteristics and classification by both syndrome and likely mechanisms. In the clinical setting, the interpretation of this information is aided by knowledge of the available clinical experiences on these aspects of the pain. Unfortunately, existing data are limited. There have been few large surveys of cancer pain characteristics and syndromes, and comparative data from patients in different parts of the world are entirely lacking. To better define the characteristics of cancer pain syndromes the Task Force on Cancer Pain of the International Association for the Study of Pain (IASP) conducted a prospective, cross-sectional, international, multicenter survey of pain specialists and their patients. From a total of 100 clinicians who described themselves as cancer pain practitioners in the IASP membership directory, 51 agreed to participate in the survey and a total of 58 provided data. These clinicians resided in 24 countries and evaluated a total of 1095 patients with severe cancer pain mostly requiring opioid medication, using a combination of patient-rated and observer-rated measures. The patient-rated scales comprised a pain intensity measure chosen from the brief pain inventory. The observer-rated information included demographic and tumor-related data, and responses on checklists of pain syndromes and pathophysiologies. Patients were heterogeneous in terms of demographics and tumor-related information. More than 76% had a Kamofsky performance status score < or = 70. Almost one-quarter of the patients experienced two or more pains. A large majority of the patients (92.5%) had one or more pains caused directly by the cancer; 20.8% of patients had one or more pains caused by cancer therapies. The average (SD) duration of pain was 5.9 (10.5) months. Approximately two-thirds of patients (66.7%) reported that the worst pain intensity during the day prior to the survey was > or = 7 on a 10-point numeric scale. The factors that were univariately associated with higher pain intensity included the presence of breakthrough pain, somatic pain or neuropathic pain, age younger than 60 years, and lower performance status score. A multivariate model suggested that the presence of breakthrough pain, somatic pain, and lower performance status were the most important predictors of intense pain. Pains that were inferred by the treating clinician to be nociceptive and due to somatic injury occurred in 71.6% of the patients. Pains labeled nociceptive visceral were noted in 34.7% and pains inferred to have neuropathic mechanisms occurred in 39.7%. In a broad classification, the major pain syndromes comprised bone or joint lesions (41.7% of patients), visceral lesions (28.1%), soft tissue infiltration (28.3%), and peripheral nerve injuries (27.8%). Twenty-two types of pain syndromes were most prevalent. Large differences in the diagnosis of breakthrough pain by clinicians of different countries suggest that this phenomenon is either defined or recognized differently across countries. These data confirm, in segment of the cancer population experiencing severe pain, in different parts of the world, that cancer pain characteristics, syndromes and pathophysiologies are very heterogeneous. Predictors of worsening pain can be identified. The data provide a useful context for the interpretation of pain-related information acquired in both clinical and research settings. They suggest the need for future studies and the potential usefulness of a written checklist for cancer pain syndromes and pathophysiologies.

BACKGROUND: Patients with human immunodeficiency virus (HIV) infection are at increased risk for bacterial pneumonia in addition to opportunistic infection. However, the risk factors for bacterial pneumonia and its incidence in this population are not well defined. METHODS: In a multicenter, prospective, observational study, we monitored 1130 HIV-positive and 167 HIV-negative participating adults for up to 64 months for pulmonary disease. The HIV-positive group comprised 814 homosexual or bisexual men, 261 injection-drug users, and 55 female partners of HIV-infected men. RESULTS: There were 237 episodes of bacterial pneumonia among the HIV-positive participants (rate, 5.5 per 100 person-years), as compared with 6 episodes among the HIV-negative participants (rate, 0.9 per 100 person-years; P < 0.001). The rate of bacterial pneumonia increased with decreasing CD4 lymphocyte counts (2.3, 6.8, and 10.8 episodes per 100 person-years in the strata with more than 500, 200 to 500, and fewer than 200 cells per cubic millimeter, respectively; P < or = 0.022 for each comparison). Injection-drug users had a higher rate of bacterial pneumonia than did homosexual or bisexual men or female partners. In the stratum with the fewest CD4 lymphocytes, cigarette smoking was associated with an increased rate of pneumonia. Mortality was almost four times higher among participants with an episode of pneumonia than among the others. Prophylaxis with trimethoprim-sulfamethoxazole was associated with a 67 percent reduction in confirmed episodes of bacterial pneumonia (P = 0.007). CONCLUSIONS: Bacterial pneumonia is more frequent in HIV-positive persons than in seronegative controls, and the risk is highest among those with CD4 lymphocyte counts below 200 per cubic millimeter and among injection-drug users.

The assessment of extra-, intracellular and total body water (ECW, ICW, TBW) is important in many clinical situations. Bioimpedance spectroscopy (BIS) has advantages over dilution methods in terms of usability and reproducibility, but a careful analysis reveals systematic deviations in extremes of body composition and morbid states. Recent publications stress the need to set up and validate BIS equations in a wide variety of healthy subjects and patients with fluid imbalance. This paper presents two new equations for determination of ECW and ICW (referred to as body composition spectroscopy, BCS) based on Hanai mixture theory but corrected for body mass index (BMI). The equations were set up by means of cross validation using data of 152 subjects (120 healthy subjects, 32 dialysis patients) from three different centers. Validation was performed against bromide/deuterium dilution (NaBr, D2O) for ECW/TBW and total body potassium (TBK) for ICW. Agreement between BCS and the references (all subjects) was -0.4 +/- 1.4 L (mean +/- SD) for ECW, 0.2 +/- 2.0 L for ICW and -0.2 +/- 2.3 L for TBW. The ECW agreement between three independent reference methods (NaBr versus D2O-TBK) was -0.1 +/- 1.8 L for 74 subjects from two centers. Comparing the new BCS equations with the standard Hanai approach revealed an improvement in SEE for ICW and TBW by 0.6 L (24%) for all subjects, and by 1.2 L (48%) for 24 subjects with extreme BMIs (<20 and >30). BCS may be an appropriate method for body fluid volume determination over a wide range of body compositions in different states of health and disease.