University of Vermont Medical Center

The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles ("MISEV") guidelines for the field in 2014. We now update these "MISEV2014" guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.

This document has been approved by the AASLD, the Infectious Diseases Society of America, and the American College of Gastroenterology. These recommendations provide a data-supported approach to establishing guidelines. They are based on the following: (1) a formal review and analysis of the recently published world literature on the topic (Medline search up to September 2008); (2) the American College of Physicians' Manual for Assessing Health Practices and Designing Practice Guidelines;1 (3) guideline policies, including the American Association for the Study of Liver Diseases' (AASLD) Policy on the Development and Use of Practice Guidelines and the American Gastroenterological Association's Policy Statement on the Use of Medical Practice Guidelines;2 and (4) the experience of the authors in regard to hepatitis C. Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic and preventive aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies 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 Guidelines).3, 4 AASLD, American Association for the Study of Liver Diseases; ALT, alanine aminotransferase; ANC, absolute neutrophil count; anti-HCV, antibody to HCV; AST, aspartate aminotransferase; CKD, chronic kidney disease; CTP, Child-Turcotte-Pugh; EIA, enzyme immunoassay; ETR, end-of-treatment response; EVR, early virological response; FDA, U.S. Food and Drug Administration; HCV, hepatitis C virus; HIV, human immunodeficiency virus; PCR, polymerase chain reaction; PEG, polyethylene glycol; RVR, rapid virological response; SVR, sustained virological response; ULN, upper limit of normal. The hepatitis C virus (HCV) is a major public health problem and a leading cause of chronic liver disease.5 An estimated 180 million people are infected worldwide.6 In the United States (U.S.), the prevalence of HCV infection between the years 1999 and 2002 was 1.6%, equating to about 4.1 million persons positive for antibody to hepatitis C (anti-HCV), 80% of whom are estimated to be viremic.7 Hepatitis C is the principal cause of death from liver disease and the leading indication for liver transplantation in the U.S.8 Some calculations suggest that mortality related to HCV infection (death from liver failure or hepatocellular carcinoma) will continue to increase over the next two decades.9 The purpose of this document is to provide clinicians with evidence-based approaches to the prevention, diagnosis, and management of HCV infection. The optimal approach to detecting HCV infection is to screen persons for a history of risk of exposure to the virus, and to test selected individuals who have an identifiable risk factor.10 Currently, injection drug use is the primary mode of HCV transmission in the U.S; thus, all persons who use or have used illicit injection drugs in the present or past, even if only once, as well as intranasal drug users who share paraphernalia, should be tested for HCV infection.7, 11, 12 Individuals who have received a blood or blood component transfusion or an organ transplant before 1992 should also be tested. With the introduction of sensitive tests to screen blood donors for HCV antibodies in 1992, transfusion-transmission of HCV has become rare.12, 13 Persons with hemophilia should be tested for HCV infection if blood products were received before 1987, after which time, viral inactivation procedures were implemented.14 Similarly, individuals with unexplained elevations of the aminotransferase levels (alanine and/or aspartate aminotransferase; ALT/AST), those ever on hemodialysis, children born to HCV-infected mothers, or those with human immunodeficiency virus (HIV) infection should be tested for the presence of HCV infection.15-17 Other potential sources of HCV transmission include exposure to an infected sexual partner or multiple sexual partners, exposure among health care workers to HCV-contaminated blood and blood products, and tattooing.12, 15, 18-23 The prevalence of HCV infection is consistently higher among persons with multiple sexual partners, whereas sexual transmission of HCV between monogamous partners is uncommon.11, 18 Thus, although it is prudent to counsel HCV-infected persons to notify their current partners of their HCV status, they should be informed that the risk of sexual transmission is sufficiently low19 that many authorities do not advise the use of barrier protection among monogamous couples.18 Nevertheless, between 1% and 5% of monogamous sexual partners of index HCV cases test positive for anti-HCV. There is no need for HCV-infected persons to limit ordinary household activities except for those that might result in blood exposure, such as sharing a razor or toothbrush. The hepatitis C virus is not transmitted by hugging, kissing, sharing of eating utensils or breastfeeding. Folk medicine practices, including acupuncture and ritual scarification, as well as body piercing, tattooing and commercial barbering are potential modes for transmission of HCV infection when performed without appropriate infection control measures.24-28 Transmission of HCV infection by body piercing is, however, rare and many HCV infected persons who have undergone body piercing acquired their infection by other means.23, 29-33 Therefore, there is no need to routinely test persons who have received tattoos or undergone piercings in the absence of other risk factors, particularly if these procedures have taken place in licensed establishments. Because symptoms are generally absent in individuals with chronic HCV infection, recognition of infection requires risk factor screening, which should be done whenever it is possible to link with appropriate HCV testing and counseling.10 Table 2 outlines the list of persons who should be routinely screened for HCV infection.15 For some groups, such as those with a history of injection drug use or persons with hemophilia, the prevalence of HCV is high (≈90%). For other groups (recipients of blood transfusions prior to 1992), the prevalence is moderate (≈10%). For still others, (persons with needle stick exposure, sexual partners of HCV-infected persons), the prevalence is low (1% to 5%). ○ Persons with HIV infection ○ Persons with hemophilia who received clotting factor concentrates prior to 1987 ○ Persons who have ever been on hemodialysis ○ Persons with unexplained abnormal aminotransferase levels ○ Persons who were notified that they had received blood from a donor who later tested positive for HCV infection ○ Persons who received a transfusion of blood or blood products ○ Persons who received an organ transplant Recommendation 1. As part of a comprehensive health evaluation, all persons should be screened for behaviors that place them at high risk for HCV infection. (Class I, level B). 2. Persons who are at risk should be tested for the presence of HCV infection (Table2) (Class I, level B). Good clinical practice dictates that persons found to be HCV-infected are counseled regarding prevention of spread of the virus to others. Because exposure to infected blood is the primary mode of transmission, it is essential to inform HCV-infected individuals that precautions should be taken to avoid the possibility of exposing others to contact with their blood. This is particularly important for injection drug users who are the leading source of HCV infection, because their transmission route is primarily via sharing of needles and other infected implements. Table 3 outlines the measures to avoid HCV transmission. Recommendation 3. Persons infected with HCV should be counseled on how to avoid HCV transmission to others, as indicated in Table3 (Class I, level C) Two classes of assays are used in the diagnosis and management of HCV infection: serologic assays that detect specific antibody to hepatitis C virus (anti-HCV) and molecular assays that detect viral nucleic acid. These assays have no role in the assessment of disease severity or prognosis. Tests that detect anti-HCV are used both to screen for and to diagnose HCV infection. Anti-HCV can be detected in the serum or plasma using a number of immunoassays. Two enzyme immunoassays (EIAs) are approved by the U.S. Food and Drug Administration (FDA) for clinical use, Abbott HCV EIA 2.0 (Abbott Laboratories, Abbott Park, IL) and ORTHO® HCV Version 3.0 ELISA (Ortho-Clinical Diagnostics, Raritan, NJ), as well as one enhanced chemiluminescence immunoassay (CIA) VITROS® Anti-HCV assay, (Ortho-Clinical Diagnostics, Raritan, NJ). The specificity of current EIAs for anti-HCV is greater than 99%.34 False positive results are more likely to occur when testing is performed among populations where the prevalence of hepatitis C is low. False negative results may occur in the setting of severe immunosuppression such as infection with HIV, solid organ transplant recipients, hypo- or aggammaglobulinemia or in patients on hemodialysis.35-37 The recombinant immunoblot assay, Chiron RIBA HCV 3.0 SIA (Chiron Corporation, Emeryville, CA) is also FDA approved. This assay was originally developed as a more specific, supplemental assay to confirm the results of EIA testing.38, 39 However, specificity is extremely high for third generation EIA results that exceed particular signal/cutoff ratios (e.g., >3.8 for the above mentioned Ortho and Abbott EIA tests). Given the widespread availability of nucleic acid testing, the role for RIBA testing in HCV diagnosis and management has all but disappeared.40, 41 The list of commercial assays available for the detection (qualitative assays) or quantification (quantitative assays) of HCV RNA is shown in Tables 4 and 5. Historically, qualitative assays have been more sensitive than quantitative assays. With the recent availability of real time polymerase chain reaction (PCR)-based assays and transcription-mediated amplification (TMA) assays, with sensitivities of 10-50 IU/mL, there is no longer need for qualitative assays.42, 43 A highly sensitive assay with this lower limit of detection is considered appropriate for monitoring during therapy. All currently available assays have excellent specificity, in the range of 98% to 99%. In 1997, the World Health Organization established the first International standard for HCV RNA nucleic acid technology,44 and the IU rather than viral copies is now the preferred unit to report test results.44, 45 For monitoring purposes, it is important to use the same laboratory test before and during therapy. Genotyping is useful in epidemiological studies and in clinical management for predicting the likelihood of response and determining the optimal duration of therapy. The hepatitis C virus can be classified into at least 6 major genotypes (genotypes 1 to 6) based on a sequence divergence of 30% among isolates.46 Genotype 1 (subtypes 1a and 1b) is the most common in the U.S., followed by genotypes 2 and 3. Less common genotypes (genotypes 4-6) are beginning to be observed more frequently because of the growing cultural diversity within the United States.47 Several commercial assays are available to determine HCV genotypes using direct sequence analysis of the 5′ non-coding region, that include Trugene 5′NC HCV Genotyping kit (Siemens Healthcare Diagnostics Division, Tarrytown, NY), reverse hybridization analysis using genotype specific oligonucleotide probes located in the 5′ non-coding region, INNO-LiPa HCV II, (Innogenetics, Ghent, Belgium), and Versant HCV Genotyping Assay 2.0 (Siemens Healthcare Diagnostics Division, Tarrytown, NY). Incorrect typing among the major genotypes is rare (<3%) and mixed genotypes occur but are uncommon. Occasionally (<5%), tested samples cannot be genotyped. This usually results from low viral levels, issues with the PCR amplification step of the assay, or extreme nucleotide variability within the HCV genome.48 The diagnosis of acute or chronic HCV infection generally requires testing of serum for both antibody to HCV (anti-HCV) and for HCV RNA. A sensitive quantitative HCV RNA assay is recommended for diagnosis because it also provides information on the level of virus which is helpful in management. The differentiation of acute from chronic HCV infection depends on the clinical presentation: namely the presence of symptoms or jaundice, and whether or not there was a prior history of ALT elevation and its duration. After acute exposure, HCV RNA is usually detected in serum before antibody; HCV RNA can be identified as early as 2 weeks following exposure whereas anti-HCV is generally not detectable before 8-12 weeks. These two markers of HCV infection may be present in varying permutations, requiring careful analysis for interpretation (Table 6). One pattern is the identification of both anti-HCV and HCV RNA in a person with recent elevation of the ALT value. This scenario is consistent with either acute HCV infection when there is a recent known risk exposure, with exacerbation of chronic HCV infection, or with an acute hepatitis of another etiology in a patient with chronic HCV infection. Another pattern is the detection of anti-HCV but with a negative test for HCV RNA. This may represent acute HCV infection during a period of transient clearance of HCV RNA, a false positive or negative result or, more commonly, recovery from HCV infection. Re-testing for HCV RNA 4-6 months later is recommended to confirm the resolution of HCV infection. The reverse scenario — a negative anti-HCV test but a positive result for HCV RNA — is compatible with the early stage of acute infection prior to the development of antibody or may represent chronic infection in an immunosuppressed individual. Alternatively, it may represent a false positive HCV RNA result. In all circumstances, re-testing for anti-HCV and HCV RNA in 4-6 months should resolve the issue. Finally, if the patient has raised ALT values but the tests for anti-HCV and HCV RNA are negative, both acute and chronic hepatitis C may be excluded and another diagnosis should be considered. Antibody testing should be repeated in 4-6 months for confirmation purposes. Recommendation 4. Patients suspected of having acute or chronic HCV infection should first be tested for anti-HCV (Class I, Level B.) 5. HCV RNA testing should be performed in: a) Patients with a positive anti-HCV test (Class I, Level B) b) Patients for whom antiviral treatment is being considered, using a sensitive quantitative assay (Class I, Level A) c) Patients with unexplained liver disease whose anti-HCV test is negative and who are immunocompromised or suspected of having acute HCV infection (Class I, Level B). 6. HCV genotyping should be performed in all HCV-infected persons prior to interferon-based treatment in order to plan for the dose and duration of therapy and to estimate the likelihood of response (Class I, Level A) There are three primary reasons for performing a liver biopsy: it provides helpful information on the current status of the liver injury, it identifies features useful in the decision to embark on therapy, and it may reveal advanced fibrosis or cirrhosis that necessitates surveillance for hepatocellular carcinoma (HCC) and/or screening for varices. The biopsy is assessed for grade and stage of the liver injury, but also provides information on other histological features that might have a bearing on liver disease progression.49 The grade defines the extent of necroinflammatory activity, while the stage establishes the extent of fibrosis or the presence of cirrhosis. Several scoring systems have been conceived, the most common being the French METAVIR, the Batts-Ludwig, the International Association for the Study of the Liver (IASL) and the Ishak Scoring systems.50-54 (Table 7). The two more common non-HCV conditions that might affect disease progression and possibly impede treatment response are steatosis49, 55, 56 and excess hepatocellular iron.57 Identifying either of these two features does not preclude initiating treatment, but their presence provides additional information regarding the likelihood of response to treatment.58-60 The liver biopsy has been widely regarded as the "gold standard" for defining the liver disease status, but it has drawbacks that have prompted questions about its value.61, 62 The procedure is not without risks (including pain, bleeding and perforation of other organs),63, 64 it is subject to sampling error,65 it requires special expertise for interpreting the histopathology, it adds cost to medical care, and it is anxiety-provoking for the implicated person. Thus, efforts are underway to seek alternative means of establishing information on the extent of fibrosis by focusing on noninvasive blood marker panels.66 These markers are useful for establishing the two ends of the fibrosis spectrum (minimal fibrosis and cirrhosis) but are less helpful in assessing the mid-ranges of fibrosis or for tracking fibrosis progression.66 The recently developed transient elastography that uses ultrasound and low frequency elastic waves to measure liver elasticity67 has improved the ability to define the extent of fibrosis without a liver biopsy, particularly when combined with other noninvasive markers.68 However, it is not yet ready to replace the liver biopsy since it is not FDA approved, the failure rate is higher in obese patients, and there is now evidence that the transient elastography score can be unexpectedly increased in persons with acute hepatitis who have high necroinflammatory activity but no or minimal fibrosis.69, 70 A liver biopsy may be unnecessary in persons with genotypes 2 and 3 HCV infection, since more than 80% of them achieve a sustained virlogical response (SVR) to standard-of-care treatment. There is, however, an ongoing debate about whether a biopsy is warranted for persons infected with HCV, genotype 1, whose response to such treatment approximates 50% among Caucasians and 30% among African Americans.71-73 Even more uncertain is whether there is need for a liver biopsy in persons infected with the other less common genotypes (4 through 6). Thus, although the liver biopsy was previously regarded as routine for defining the fibrosis stage in persons with genotype 1 infection,62 the issue is now in a state of flux and possible transition. Supporters of a biopsy cite the difficult nature and high cost of current antiviral therapy and are to or treatment if liver minimal to moderate fibrosis stage (Table if the infection is known to have been These individuals are regarded as having liver disease that may not be for their However, treatment is for those with more advanced fibrosis stage (Table be however, that while information from a biopsy is the procedure is not for on treatment. performed and treatment is a common is to the liver biopsy 4 to years later and to treatment should there be evidence of disease The that persons with genotype 1 infection and aminotransferase values not a liver biopsy because they were to have minimal liver and that treatment may be are no longer is now that as many as a of such individuals have and that treatment response is to that of individuals with abnormal serum aminotransferase Therefore, the decision to a liver biopsy should be based on whether treatment is being considered, into the estimated duration of infection and other of liver disease (e.g., the the viral and the to a liver biopsy and to be the biopsy is not performed and treatment not the patient should continue to be at least and a biopsy performed if the aminotransferase values become abnormal and other of liver disease become A liver biopsy should be considered in patients with chronic hepatitis C infection if the patient and health care information regarding fibrosis stage for or to a decision regarding treatment (Class Level B) available noninvasive tests may be useful in defining the presence or absence of advanced fibrosis in persons with chronic hepatitis C infection, but should not replace the liver biopsy in routine clinical practice (Class Level history studies that to of individuals who acute hepatitis C will resolution is more common among infected and than among persons who are when they acute HCV infection has for the infected persons as well as for their the are at risk for progression to cirrhosis and/or the are at risk of the infection through exposure to the The risk of cirrhosis from 5% to over of to studies of and children infected at a and followed for to years report low of 1% to studies of patients to care document higher of to but this may be by to cirrhosis may be in persons who are of who are who are immunosuppressed (e.g., HIV and who more than of although the of with fibrosis progression is Persons with cirrhosis are at risk for the development of over as well as hepatocellular carcinoma (1% to Identifying individuals at risk for disease is the preferred approach is to the of fibrosis on liver biopsy, using a such as the or Persons with no or minimal fibrosis stage and stage have a low risk for and death the next to However, the presence of fibrosis stage Table is an important of progression to cirrhosis and an indication for with HCV can also cause including mixed and is an indication for HCV antiviral therapy of the stage of liver on of Patients with The of therapy is to and death from HCV infection. Because of the of chronic HCV infection over it has been difficult to that therapy of liver treatment are by a virological rather than a clinical can be of serum ALT of HCV RNA from serum by a sensitive and in necroinflammatory score with no in fibrosis Several of virological may to their to treatment. The most important is the sustained virological response as the absence of HCV RNA from serum by a sensitive PCR assay weeks following of therapy (Table This is generally regarded as a although liver has been identified years if cirrhosis at the time of an of virological RVR, rapid virological response of HCV from serum by 4 using a sensitive EVR, early virological response in HCV RNA level to HCV RNA level or HCV RNA negative at treatment SVR, sustained virological response RNA negative weeks after of of HCV RNA in serum after therapy is failure to HCV RNA from serum after weeks of 2 in HCV RNA but still HCV RNA positive at failure to HCV RNA by 2 after of therapy. virus at the of either a or of therapy is to as an end-of-treatment response An does not that an will be but is for it to A rapid virological response as HCV RNA at 4 of treatment, using a sensitive test with a lower limit of detection of IU/mL, a high likelihood of an An early virological response is as a or absence of serum HCV RNA at 12 of therapy with the to achieve an is the most of not an viral is useful for predicting whether or not an is likely to to the of HCV RNA while still on therapy, while virological is the of HCV RNA in serum after treatment is and an was Persons who to serum HCV RNA by at least 2 after weeks of therapy are while those whose HCV RNA levels by but become are to as The currently recommended therapy of chronic HCV infection is the of a and The of this was based the results of three clinical that the of this treatment over standard and not these three of therapy, namely the appropriate dose of the the optimal duration of therapy and the need for a for patients with genotype 1 and genotype 2 and 3 There are two licensed in the United NJ), with a polyethylene to the standard and with a to the standard The of these two of The optimal dose of based on the is to body the dose of used in the was at a of patients with genotype 1 infection that for patients for patients to for patients to and for patients but was more to and in the two U.S. ETR, end-of-treatment response; SVR, sustained virological is at a dose of 180 with to for those who and for those who The the two of an in the more a in the rate as to treatment. A third that the optimal duration of treatment should be based on the viral The established that patients with genotype 1 should be for weeks with standard whereas patients with genotypes 2 and 3 be with low dose for For patients with HCV genotype 4 infection, treatment with for weeks to be the optimal as in a of from another of treatment with a dose of has that weeks duration of therapy is an is these results need to be Patients with genotypes and 6 are in of and to their A recent analysis of the treatment of patients

BACKGROUND: Newborn animal studies and pilot studies in humans suggest that mild hypothermia following peripartum hypoxia-ischaemia in newborn infants may reduce neurological sequelae without adverse effects. OBJECTIVES: To determine the effect of therapeutic hypothermia in encephalopathic asphyxiated newborn infants on mortality, long-term neurodevelopmental disability and clinically important side effects. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group as outlined in The Cochrane Library (Issue 2, 2007). Randomised controlled trials evaluating therapeutic hypothermia in term and late preterm newborns with hypoxic ischaemic encephalopathy were identified by searching the Oxford Database of Perinatal Trials, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2007, Issue 2), MEDLINE (1966 to June 2007), previous reviews including cross-references, abstracts, conferences, symposia proceedings, expert informants and journal handsearching. We updated this search in May 2012. SELECTION CRITERIA: We included randomised controlled trials comparing the use of therapeutic hypothermia with standard care in encephalopathic term or late preterm infants with evidence of peripartum asphyxia and without recognisable major congenital anomalies. The primary outcome measure was death or long-term major neurodevelopmental disability. Other outcomes included adverse effects of cooling and 'early' indicators of neurodevelopmental outcome. DATA COLLECTION AND ANALYSIS: Four review authors independently selected, assessed the quality of and extracted data from the included studies. Study authors were contacted for further information. Meta-analyses were performed using risk ratios (RR) and risk differences (RD) for dichotomous data, and weighted mean difference for continuous data with 95% confidence intervals (CI). MAIN RESULTS: We included 11 randomised controlled trials in this updated review, comprising 1505 term and late preterm infants with moderate/severe encephalopathy and evidence of intrapartum asphyxia. Therapeutic hypothermia resulted in a statistically significant and clinically important reduction in the combined outcome of mortality or major neurodevelopmental disability to 18 months of age (typical RR 0.75 (95% CI 0.68 to 0.83); typical RD -0.15, 95% CI -0.20 to -0.10); number needed to treat for an additional beneficial outcome (NNTB) 7 (95% CI 5 to 10) (8 studies, 1344 infants). Cooling also resulted in statistically significant reductions in mortality (typical RR 0.75 (95% CI 0.64 to 0.88), typical RD -0.09 (95% CI -0.13 to -0.04); NNTB 11 (95% CI 8 to 25) (11 studies, 1468 infants) and in neurodevelopmental disability in survivors (typical RR 0.77 (95% CI 0.63 to 0.94), typical RD -0.13 (95% CI -0.19 to -0.07); NNTB 8 (95% CI 5 to 14) (8 studies, 917 infants). Some adverse effects of hypothermia included an increase sinus bradycardia and a significant increase in thrombocytopenia. AUTHORS' CONCLUSIONS: There is evidence from the 11 randomised controlled trials included in this systematic review (N = 1505 infants) that therapeutic hypothermia is beneficial in term and late preterm newborns with hypoxic ischaemic encephalopathy. Cooling reduces mortality without increasing major disability in survivors. The benefits of cooling on survival and neurodevelopment outweigh the short-term adverse effects. Hypothermia should be instituted in term and late preterm infants with moderate-to-severe hypoxic ischaemic encephalopathy if identified before six hours of age. Further trials to determine the appropriate techniques of cooling, including refinement of patient selection, duration of cooling and method of providing therapeutic hypothermia, will refine our understanding of this intervention.

BACKGROUND: Acute coronary syndromes arise from coronary atherosclerosis with superimposed thrombosis. Since factor Xa plays a central role in thrombosis, the inhibition of factor Xa with low-dose rivaroxaban might improve cardiovascular outcomes in patients with a recent acute coronary syndrome. METHODS: In this double-blind, placebo-controlled trial, we randomly assigned 15,526 patients with a recent acute coronary syndrome to receive twice-daily doses of either 2.5 mg or 5 mg of rivaroxaban or placebo for a mean of 13 months and up to 31 months. The primary efficacy end point was a composite of death from cardiovascular causes, myocardial infarction, or stroke. RESULTS: Rivaroxaban significantly reduced the primary efficacy end point, as compared with placebo, with respective rates of 8.9% and 10.7% (hazard ratio in the rivaroxaban group, 0.84; 95% confidence interval [CI], 0.74 to 0.96; P=0.008), with significant improvement for both the twice-daily 2.5-mg dose (9.1% vs. 10.7%, P=0.02) and the twice-daily 5-mg dose (8.8% vs. 10.7%, P=0.03). The twice-daily 2.5-mg dose of rivaroxaban reduced the rates of death from cardiovascular causes (2.7% vs. 4.1%, P=0.002) and from any cause (2.9% vs. 4.5%, P=0.002), a survival benefit that was not seen with the twice-daily 5-mg dose. As compared with placebo, rivaroxaban increased the rates of major bleeding not related to coronary-artery bypass grafting (2.1% vs. 0.6%, P<0.001) and intracranial hemorrhage (0.6% vs. 0.2%, P=0.009), without a significant increase in fatal bleeding (0.3% vs. 0.2%, P=0.66) or other adverse events. The twice-daily 2.5-mg dose resulted in fewer fatal bleeding events than the twice-daily 5-mg dose (0.1% vs. 0.4%, P=0.04). CONCLUSIONS: In patients with a recent acute coronary syndrome, rivaroxaban reduced the risk of the composite end point of death from cardiovascular causes, myocardial infarction, or stroke. Rivaroxaban increased the risk of major bleeding and intracranial hemorrhage but not the risk of fatal bleeding. (Funded by Johnson & Johnson and Bayer Healthcare; ATLAS ACS 2-TIMI 51 ClinicalTrials.gov number, NCT00809965.).

HCV, hepatitis C virus; ALT, alanine aminotransferase; AST, aspartate aminotransferase; HIV, human immunodeficiency virus; anti-HCV, HCV antibody; RNA, ribonucleic acid; PCR, polymerase chain reaction; TMA, transcription-mediated amplification; FDA, Food and Drug Administration; HCC, hepatocellular carcinoma; SVR, sustained virologic response; EVR, early virologic response; ETR, end of treatment response; peginterferon, pegylated interferon; G-CSF, granulocyte colony-stimulating factor; HAART, highly active antiretroviral therapy; ddI, didanosine; GM-CSF, granulocyte-macrophage colony-stimulating factor. These recommendations provide a data-supported approach. They are based on the following: (1) a formal review and analysis of the recently published world literature on the topic (Medline search); (2) the American College of Physicians' Manual for Assessing Health Practices and Designing Practice Guidelines1 ; (3) guideline policies, including the American Association for the Study of Liver Diseases' (AASLD) Policy on the Development and Use of Practice Guidelines and the American Gastroenterological Association's Policy Statement on the Use of Medical Practice Guidelines2; the guideline procedures of the Infectious Diseases Society of America3; and (4) the experience of the authors in the specified topic. These recommendations are fully endorsed by the AASLD, the Infectious Diseases Society of America, and the American College of Gastroenterology. Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic and preventive aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case. Specific recommendations are based on relevant published information. In an attempt to characterize the quality of evidence supporting recommendations, the Practice Guidelines Committee of the AASLD requires a category to be assigned and reported with each recommendation (Table 1). The hepatitis C virus (HCV) is a major public health problem and a leading cause of chronic liver disease. In the United States, the Centers for Disease Control and Prevention estimates that there are more than 2.7 million people with ongoing HCV infection.5 HCV is the leading cause of death from liver disease in the United States.6 The purpose of this article is to provide clinicians with approaches to the diagnosis, management, and prevention of HCV infection. The optimal methods of detecting HCV infection are to screen populations for history of risk and to test selected individuals with an identifiable risk factor. With careful questioning, an HCV risk factor can be identified in more than 90% of cases.7 The primary source of HCV transmission is HCV-infected blood or blood products. In the United States, injection drug use is the chief mode of transmission, and anyone who has ever injected illicit drugs should be tested.5, 7 Persons should also be tested if they received a blood or blood component transfusion or organ transplant before 1992, when sensitive tests were first used to screen donors for HCV antibodies. Since that time, HCV infection is rarely transmitted by transfusion.8 Other potential sources of HCV transmission include exposure to an infected sexual partner or multiple sexual partners, frequent exposure to infected blood among health care workers, and perinatal exposure.9-11 Although HCV prevalence rates are consistently higher in persons with multiple sexual partners, sexual transmission of HCV between monogamous partners is rare.7 Thus, while it is common to counsel HCV-infected persons to notify their current partners of their HCV status, they should be told that the risk of sexual transmission is sufficiently low12 that many authorities do not advise use of barrier precautions (i.e., latex condoms). Testing of sexual partners, therefore, is done chiefly for reassurance. There is no need to curtail ordinary household activities except those that might result in blood exposure, such as sharing a razor or toothbrush. HCV is not transmitted by hugging and the sharing of eating utensils. Although a monogamous sexual relationship carries a low risk of transmission of HCV infection, as noted above, the risk is higher in persons involved with multiple sexual partners. Persons with hemophilia should be tested for HCV infection if blood products were received before 1987, when viral inactivation procedures were implemented. It is also advisable to test persons for HCV infection if they have evidence of otherwise unexplained elevations of aminotransferase levels (alanine and/or aspartate aminotransferases; ALT /AST), have ever been on hemodialysis, or have human immunodeficiency virus (HIV) infection.10 Other situations that have been suggested to carry a risk for HCV transmission include certain folk medicine practices (acupuncture, ritual scarification), body piercing, tattooing, and even commercial barbering.13-17 Some studies of HCV infection have reported associations with commercial tattooing, suggesting possible acquisition of HCV infection in this setting.18-20 Most studies of body piercing have not differentiated between ear piercing and piercing of other body parts. As a result of discrepancies in study design, definitive conclusions regarding risks associated with these forms of percutaneous exposures are problematic, although the risk, if present, is likely to be low. Thus, there is no need to routinely test persons who have received tattoos or undergone piercing, particularly if these procedures have taken place in licensed establishments. Table 2, adapted from recommendations published by the Centers for Disease Control, Atlanta, Georgia,10 outlines the list of persons who should be routinely tested for HCV infection. For some of these categories (e.g., injection drug users, persons with hemophilia), the HCV prevalence is high (≈90%); for others (e.g., recipients of blood transfusions prior to 1992), the prevalence is moderate (≈10%). For still others (e.g., persons exposed by needle stick, sexual partners of HCV-infected persons), it is quite low (2%-5%). 1. Persons who should be tested for HCV infection are listed in Table 2(Grade, III). Persons found to be HCV-infected need to be counseled regarding prevention of spread of the virus to others. Good clinical practice dictates that all persons identified as infected with HCV be informed that transmission to others occurs through contact with their blood and that they should therefore take precautions against the possibility of such exposure. Although this advice applies to all HCV-infected persons, it has particular importance for injection drug users who are the leading source of HCV infections. Circumstances requiring counseling are shown in Table 3. 2. Persons infected with HCV should be counseled on how to avoid HCV transmission to others, as indicated in Table 3(Grade, III). Utilizing the tests described in Table 4, several strategies can be employed to detect HCV infection. In clinical practice, the usual approach is to test initially for antibodies to HCV (anti-HCV), then to use HCV ribonucleic acid (RNA) to document viremia. Because most persons with ongoing HCV infection have HCV RNA levels in the range of the quantitative assays and because the quantity of HCV RNA is useful to know before providing and monitoring HCV treatment,21 many experts routinely obtain quantitative rather than qualitative HCV RNA tests to confirm the presence of viremia.22 However, quantitative HCV RNA tests are generally not as sensitive; therefore, some experts prefer a qualitative HCV RNA test either as the primary test or to confirm a positive HCV antibody result in patients with a negative result by quantitative assay.23, 24 A negative sensitive RNA test in a person with HCV antibodies most likely indicates that the HCV infection has resolved. Other interpretations are that the anti-HCV immunoassay is falsely positive, the HCV RNA test is falsely negative, or rarely, that a person has intermittent or low-level viremia. The recombinant immunoblot assay has limited usefulness in clinical practice but may establish the cause of a positive anti-HCV immunoassay in a person with undetectable HCV RNA.24 A negative immunoblot result indicates that a positive anti-HCV immunoassay result represented a false positive result and that no further testing is needed. A positive immunoblot result followed by two or more instances in which HCV RNA cannot be detected using a licensed, qualitative assay suggest that HCV infection has resolved and no further HCV testing is indicated. There are instances in which a negative anti-HCV does not exclude HCV infection in patients with suspected liver disease. These include acute HCV infection or immunosuppressed states. HCV RNA testing can be used to establish acute HCV infection after an exposure because HCV RNA can be detected in 1 to 2 weeks, while antibodies to HCV are detectable an average of 8 weeks later.25-27 HCV RNA testing can also be used to test for HCV infection in persons with negative HCV antibody results who are known to have conditions associated with diminished antibody production, such as HIV infection and chronic hemodialysis.23 HCV RNA can be detected in the blood using amplification techniques such as polymerase chain reaction (PCR) or transcription-mediated amplification (TMA).28 The Food and Drug Administration (FDA) has approved 2 PCR-based tests for qualitative detection of HCV RNA: (1) Amplicor Hepatitis C Virus Test, version 2.0, and (2) Cobas Amplicor Hepatitis C Virus Test, version 2.0 (Roche Molecular Systems, Branchburg, NJ), which have lower limits of detection of approximately 50 IU/mL. Other commercially available nonapproved assays are used by some diagnostic laboratories. Quantitative assays (Table 4) ascertain the quantity of HCV RNA in blood using either target amplification (PCR, TMA) or signal amplification techniques (branched DNA assay). The level of HCV RNA in blood helps in predicting the likelihood of response to treatment, and the change in the level of HCV RNA during treatment can be used to monitor response. The results should be reported in international units to standardize data,29 although the dynamic ranges differ and the results can be difficult to compare between assays, as noted in Table 4. Because a change in the HCV RNA level is used to monitor treatment response, it is important at the outset of treatment to obtain the actual level rather than simply a report indicating that the level exceeds an upper limit of detection, since HCV RNA levels sometimes are above the linear range of currently available assays. In addition, the same quantitative test should be used while on therapy to avoid confusion. The only quantitative test that has currently received FDA approval is Versant HCV RNA version 3.0 (Bayer Diagnostics, Tarrytown, NY) (Table 4). There are 6 major HCV genotypes.30 Although genotype does not predict the outcome of infection, it does predict the likelihood of treatment response, and, in many cases, determines the duration of treatment.31-33 Genotyping can be performed by direct sequence analysis, by reverse hybridization to genotype-specific oligonucleotide probes, or by the use of restriction fragment length polymorphism. Two tests, not yet FDA approved, are currently available for clinical use: (1) the Trugene HCV 5'NC Genotyping Kit (Visible Genetics, Toronto, Canada), which is based on direct sequencing followed by comparison with a reference sequence database, and (2) the line-probe assay (Inno LiPA HCV II, Innogenetics, Ghent, Belgium), which is based on reverse hybridization of PCR amplicons on a nitrocellulose strip coated with genotype-specific oligonucleotide probes.34-36 Once the genotype is identified, the test need not be repeated. Current commercial tests fail to identify the genotype in a small proportion (<3 %) of HCV-positive persons,37 and a similarly low proportion (1%-4%) may display mixed genotypes.37, 38 3. Patients suspected of having chronic HCV infection should be tested for HCV antibodies. (Grade, II-2) 4. HCV RNA testing should be performed in (a) patients with a positive anti-HCV test (Grade, II-2); (b) patients for whom antiviral treatment is being considered, using a quantitative assay (Grade, II-2); (c) patients with unexplained liver disease whose anti-HCV test is negative and who are immune-compromised or suspected of having acute HCV infection (Grade, II-2). 5. HCV genotype should be determined in all HCV-infected persons prior to treatment in order to determine the duration of therapy and likelihood of response (Grade, I). The role of liver biopsy in the management of patients with chronic hepatitis C is currently being debated. In the initial treatment trials of hepatitis C, a liver biopsy was regarded as an important parameter in helping to guide management and treatment, particularly at a time when response to treatment was low. More recently, with the improvement of treatment effectiveness, the value of the liver biopsy has been questioned because of the potential risks of the procedure and the concern of sampling error.39 This has prompted some to challenge the need for biopsy and to suggest that the procedure may not be necessary as a prelude to treatment. However, since current therapy is effective in clearing virus in only about one half of those treated, and since treatment is associated with costs and adverse events, there are likely many individuals in whom therapy can be safely deferred. The liver biopsy furnishes information about the staging of fibrosis and the degree of hepatic inflammation, histopathological features that are helpful to both the patient and the provider for predicting the natural history of disease and thus the relative urgency of therapy.40-42 Three scoring systems for defining the degree of inflammation (grading) and the extent of fibrosis (staging) have been devised, 2 of which—the Metavir scoring system43 and the Ishak grading system44—have received the greatest attention. The components of these systems are shown in Table 5. Using the degree of fibrosis as one component of the basis for therapy, treatment is generally advised if the liver biopsy displays a Metavir score of ≥ 2 or an Ishak score of ≥ 3. Some experts, in considering the need for treatment, also assess the intensity of liver inflammation. However, there are no established guidelines for how to combine the degrees of liver fibrosis and inflammation. Moreover, measurement of liver fibrosis, and especially liver inflammation, can be compromised by sampling error and by difficulties in the histopathologic interpretation. In most studies, the extent of liver fibrosis is an independent predictor of treatment response. Patients with milder degrees of fibrosis generally respond more favorably to treatment than do patients with more advanced fibrosis (bridging fibrosis or cirrhosis).45, 46 However, the need for treatment in such patients is lower than it is for those with advanced fibrosis. The cost-effectiveness of treating patients with no liver fibrosis has been questioned, since the prognosis even without therapy is excellent, further underscoring the importance of accurately staging the severity of liver disease.47 Clinical, laboratory and radiological findings can identify many patients with cirrhosis, but not those with lesser degrees of fibrosis.48 Thus, in persons without strong clinical evidence of cirrhosis, a liver biopsy is useful in providing information about the extent of liver damage associated with chronic infection, the feature that remains the best predictor of prognosis. Although liver fibrosis markers are commercially available, they are currently insufficiently accurate to support their routine use.49 Until sensitive serum markers can be developed that will define all stages of fibrosis and mirror the information derived from liver biopsy, the procedure remains the only means of defining the severity of damage from HCV infection in many patients. After weighing the risks, benefits and costs of existing HCV treatments and of liver biopsy, most experienced clinicians routinely obtain a liver biopsy in patients with HCV genotype-1 infection to guide recommendations for treatment. Patients infected with HCV genotypes 2 and 3, however, have a high likelihood of response and, therefore, some advocate treating all such patients regardless of severity of liver disease without resorting to liver biopsy. For patients with no or little fibrosis (i.e., Metavir score <2 or Ishak score <3), in whom treatment is often deferred, liver biopsy can be used to monitor progression of liver disease. An interval of 4 to 5 years between biopsies may be needed to measure change in such patients.50 Although the spectrum of liver fibrosis tends to be worse in persons with elevated blood levels of aminotransferases than in those with normal aminotransferase levels,51 14% to 24% of persons with persistently normal values have more-than-portal fibrosis on liver biopsy. These persons may have progressive liver disease over time despite persistence of normal aminotransferase values.51, 52 In individuals with normal aminotransferase values and extensive hepatic fibrosis (bridging fibrosis or cirrhosis), treatment should be considered, and liver biopsy is the only available method to obtain the necessary information to guide this decision. In patients with chronic infection and clinical signs of advanced cirrhosis, liver biopsy may add little to the clinical impression and may be riskier than in healthier patients. 6. Regardless of the level of ALT, a liver biopsy should be done when the results will influence whether treatment is recommended, but a biopsy is not mandatory in order to initiate therapy (Grade, III). 7. A liver biopsy may be obtained to provide information on prognosis (Grade, III). Natural history studies indicate that 55% to 85% of persons who develop acute hepatitis C will remain HCV-infected. Among these individuals, 5% to 20% are reported to develop cirrhosis over periods of approximately 20 to 25 years.53, 54 The higher percentage figure of 20% may not reflect the cirrhosis rate in the general population of HCV-infected persons because these data originate largely from studies in tertiary-care settings, and hence may represent referral bias. Persons with HCV-related cirrhosis are at risk for developing end-stage liver disease (a risk of approximately 30% over 10 years) as well as hepatocellular carcinoma (HCC) (a risk of approximately 1% to 2% per year).55 The 15% to 45% of persons with acute hepatitis C who do recover (HCV RNA not detected in their blood) are not subject to long-term complications and do not need treatment. In general clinical practice, however, acute hepatitis C is uncommonly recognized; the majority of patients already have chronic hepatitis C. In persons with persistent infection, evolution to cirrhosis is the primary concern, usually requiring the passage of 2 or more decades, and occurring more often in persons infected at older ages (particularly men), those who drink more than 50 grams of alcohol each day, those who are obese or have substantial hepatic steatosis, and those with HIV coinfection.56-58 More-than-portal fibrosis on liver biopsy (Metavir ≥2 or Ishak ≥3) is an important predictor of future progression of liver disease and the need for HCV treatment.40, 41, 57 Infection with HCV can also be associated with a variety of extra-hepatic manifestations, chief of which is the induction of abnormal circulating proteins called cryoglobulins. The pathologic consequence, termed mixed cryoglobulinemia, is the development of vasculitis, which is associated with certain skin manifestations and internal organ damage that predominantly the The presence of is an for HCV antiviral therapy, regardless of the of liver disease. The of treatment is to complications of HCV this is by of infection. treatment are by the results of HCV RNA Infection is when there is a sustained virologic response as the of HCV RNA in serum by a sensitive test at the end of treatment and 6 Persons who an have a in the HCV RNA level in some studies as a or of HCV RNA weeks therapy, to as an early virologic response of detectable virus at of treatment is to as end of treatment response A patient is to have when HCV RNA undetectable on treatment but is detected after of treatment. Persons in whom HCV RNA levels remain on treatment are while those whose HCV RNA levels (e.g., by but are to as in liver including improvement in fibrosis, has been in patients or pegylated in with particularly in those with an to There have been substantial in the of HCV treatment and there are currently several treatments approved by the FDA (Table In clinical the rates have been with the of of and which the current of care. in therapy of chronic hepatitis C. interferon; pegylated interferon; are by of the to thus and the half of the There are 2 licensed products in the United States, the and the Because of their half they can be by injection In higher rates have been with the of of than with by injection a with or used In these was by was FDA and with of was as a of with a higher of if and if In a of was used with either or the of Since the 2 have not been in a using their relative cannot be However, there were of treatment response and adverse It should be noted that data to be useful for treatment recommendations were not for both forms of For the of the study was the only one of that a treatment duration of 6 is for persons infected with HCV genotypes 2 or recommendations have been to both response rates to and response to genotype and HCV RNA are shown in and 4. The likelihood of an can be by patient as well as by the In all treatment studies, genotype is the predictor of response. In the studies of and rates were higher in patients who or HCV lower HCV RNA levels lower body and of fibrosis and In persons who were with with the independent associated with an genotype than and body than The majority of patients in the first 2 trials who were infected with genotype 2 or 3, but a small were infected with genotypes 4, and 6. In these 2 in patients with genotype-1 were to while the response rates in those with genotype 2 or were to In the study that the data were further by genotype and viral Persons with genotype 1 and a high viral to who received the of and an of the rate among those with genotype 1 and a low viral who were with the same was In in persons with genotypes 2 and and a high viral who were and the rate was while those with genotypes 2 and and a low viral who were similarly an of virologic response rates with and therapy for weeks to genotype and viral virologic response rates with or and to virologic response rates in recipients of and 2 of for 24 or In American patients with genotype-1 infection, rates are lower than in although estimates are not currently available for the of and In the study of with the of an based on the was at as an at from of the HCV RNA of patients with an an among those who not have an EVR, to develop an data were noted in the study that used with Among persons who an EVR, an of those who not have an EVR, developed an The optimal treatment duration and were in a in which all persons received at a of while patients in the 4 received either 24 or weeks of at of either or the of or were not only the HCV but also the viral or 2 of those with genotype 1. In patients with genotype 1 with low-level the was in those who received the higher and who were for weeks This was also optimal for patients with genotype 1 and a high viral an In in patients with genotype 2 or 3, regardless of the viral no were detected with the 4 treatment suggesting that at a of for 24 weeks is associated with such as and and and skin fibrosis and and to with than with associated with such as or Because of the concern of from the use of it is that persons who the drug use methods both during treatment and for a of 6 after treatment. reported in with the use of and include and such as and granulocyte colony-stimulating factor have been used to the adverse of and However, currently there are data to their routine use as a means to avoid or and in clinical to be more in the initial weeks of treatment and often can be with such as or such as and, Current recommendations for treatment of persons with chronic hepatitis C are derived from data in the trials

To evaluate the dynamic range of tissue imaged by elastography, the mechanical behavior of breast and prostate tissue samples subject to compression loading has been investigated. A model for the loading was validated and used to guide the experimental design for data collection. The model allowed the use of small samples that could be considered homogeneous; this assumption was confirmed by histological analysis. The samples were tested at three strain rates to evaluate the viscoelastic nature of the material and determine the validity of modeling the tissue as an elastic material for the strain rates of interest. For loading frequencies above 1 Hz, the storage modulus accounted for over 93 percent of the complex modulus. The data show that breast fat tissue has a constant modulus over the strain range tested while the other tissues have a modulus that is dependent on the strain level. The fibrous tissue samples from the breast were found to be 1 to 2 orders of magnitude stiffer than fat tissue. Normal glandular breast tissue was found to have an elastic modulus similar to that of fat at low strain levels, but the modulus of the glandular tissue increased by an order of magnitude above fat at high strain levels. Carcinomas from the breast were stiffer than the other tissues at the higher strain level; intraductal in situ carcinomas were like fat at the low strain level and much stiffer than glandular tissue at the high strain level. Infiltrating ductal carcinomas were much stiffer than any of the other breast tissues. Normal prostate tissue has a modulus that is lower than the modulus of the prostate cancers tested. Tissue from prostate with benign prostatic hyperplasia (BPH) had modulus values significantly lower than normal tissue. There was a constant but not significant difference in the modulus of tissues taken from the anterior and posterior portions of the gland.

OBJECTIVE: To describe the relapse curve and rate of long-term prolonged abstinence among smokers who try to quit without treatment. METHOD: Systematic literature review. DATA SOURCES: Cochrane Reviews, Dissertation Abstracts, Excerpt Medica, Medline, Psych Abstracts and US Center for Disease Control databases plus bibliographies of articles and requests of scientists. STUDY SELECTION: Prospective studies of self-quitters or studies that included a no-treatment control group. DATA EXTRACTION: Two reviewers independently extracted data in a non-blind manner. DATA SYNTHESIS: The number of studies was too small and the data too heterogeneous for meta-analysis or other statistical techniques. RESULTS: There is a paucity of studies reporting relapse curves of self-quitters. The existing eight relapse curves from two studies of self-quitters and five no-treatment control groups indicate most relapse occurs in the first 8 days. These relapse curves were heterogeneous even when the final outcome was made similar. In terms of prolonged abstinence rates, a prior summary of 10 self-quitting studies, two other studies of self-quitters and three no-treatment control groups indicate 3-5% of self-quitters achieve prolonged abstinence for 6-12 month after a given quit attempt. CONCLUSIONS: More reports of relapse curves of self-quitters are needed. Smoking cessation interventions should focus on the first week of abstinence. Interventions that produce abstinence rates of 5-10% may be effective. Cessation studies should report relapse curves.

Contrast medium-induced acute kidney injury (CI-AKI) is a predominant cause of hospital-acquired renal insufficiency. With an increasing number of contrast medium-enhanced radiological procedures being performed in a rapidly increasing ageing population in the Western world, it is imperative that more attention is given to understand the aetiology of CI-AKI to devise novel diagnostic methods and to formulate effective prophylactic and therapeutic regimens to reduce its incidence and its associated morbidity and mortality. This article presents high-yield information on the above-mentioned aspects of CI-AKI, primarily based on results of randomised controlled trials, meta-analyses, systematic reviews and international consensus guidelines.

Importance: More than 100 million units of blood are collected worldwide each year, yet the indication for red blood cell (RBC) transfusion and the optimal length of RBC storage prior to transfusion are uncertain. Objective: To provide recommendations for the target hemoglobin level for RBC transfusion among hospitalized adult patients who are hemodynamically stable and the length of time RBCs should be stored prior to transfusion. Evidence Review: Reference librarians conducted a literature search for randomized clinical trials (RCTs) evaluating hemoglobin thresholds for RBC transfusion (1950-May 2016) and RBC storage duration (1948-May 2016) without language restrictions. The results were summarized using the Grading of Recommendations Assessment, Development and Evaluation method. For RBC transfusion thresholds, 31 RCTs included 12 587 participants and compared restrictive thresholds (transfusion not indicated until the hemoglobin level is 7-8 g/dL) with liberal thresholds (transfusion not indicated until the hemoglobin level is 9-10 g/dL). The summary estimates across trials demonstrated that restrictive RBC transfusion thresholds were not associated with higher rates of adverse clinical outcomes, including 30-day mortality, myocardial infarction, cerebrovascular accident, rebleeding, pneumonia, or thromboembolism. For RBC storage duration, 13 RCTs included 5515 participants randomly allocated to receive fresher blood or standard-issue blood. These RCTs demonstrated that fresher blood did not improve clinical outcomes. Findings: It is good practice to consider the hemoglobin level, the overall clinical context, patient preferences, and alternative therapies when making transfusion decisions regarding an individual patient. Recommendation 1: a restrictive RBC transfusion threshold in which the transfusion is not indicated until the hemoglobin level is 7 g/dL is recommended for hospitalized adult patients who are hemodynamically stable, including critically ill patients, rather than when the hemoglobin level is 10 g/dL (strong recommendation, moderate quality evidence). A restrictive RBC transfusion threshold of 8 g/dL is recommended for patients undergoing orthopedic surgery, cardiac surgery, and those with preexisting cardiovascular disease (strong recommendation, moderate quality evidence). The restrictive transfusion threshold of 7 g/dL is likely comparable with 8 g/dL, but RCT evidence is not available for all patient categories. These recommendations do not apply to patients with acute coronary syndrome, severe thrombocytopenia (patients treated for hematological or oncological reasons who are at risk of bleeding), and chronic transfusion-dependent anemia (not recommended due to insufficient evidence). Recommendation 2: patients, including neonates, should receive RBC units selected at any point within their licensed dating period (standard issue) rather than limiting patients to transfusion of only fresh (storage length: <10 days) RBC units (strong recommendation, moderate quality evidence). Conclusions and Relevance: Research in RBC transfusion medicine has significantly advanced the science in recent years and provides high-quality evidence to inform guidelines. A restrictive transfusion threshold is safe in most clinical settings and the current blood banking practices of using standard-issue blood should be continued.

These recommendations provide a data-supported approach to establishing guidelines. They are based on the following: (1) a

Abstract Background. —Under the auspices of the College of American Pathologists, a multidisciplinary group of clinicians, pathologists, and statisticians considered prognostic and predictive factors in breast cancer and stratified them into categories reflecting the strength of published evidence. Materials and Methods. —Factors were ranked according to previously established College of American Pathologists categorical rankings: category I, factors proven to be of prognostic import and useful in clinical patient management; category II, factors that had been extensively studied biologically and clinically, but whose import remains to be validated in statistically robust studies; and category III, all other factors not sufficiently studied to demonstrate their prognostic value. Factors in categories I and II were considered with respect to variations in methods of analysis, interpretation of findings, reporting of data, and statistical evaluation. For each factor, detailed recommendations for improvement were made. Recommendations were based on the following aims: (1) increasing uniformity and completeness of pathologic evaluation of tumor specimens, (2) enhancing the quality of data collected about existing prognostic factors, and (3) improving patient care. Results and Conclusions. —Factors ranked in category I included TNM staging information, histologic grade, histologic type, mitotic figure counts, and hormone receptor status. Category II factors included c- erb B-2 (Her2- neu ), proliferation markers, lymphatic and vascular channel invasion, and p53. Factors in category III included DNA ploidy analysis, microvessel density, epidermal growth factor receptor, transforming growth factor-α, bcl-2, pS2, and cathepsin D. This report constitutes a detailed outline of the findings and recommendations of the consensus conference group, organized according to structural guidelines as defined.

AIMS: To systematically investigate the effectiveness of voucher-based reinforcement therapy for the treatment of substance use disorders. METHODS: Effect sizes and 95% confidence intervals were calculated for studies published between January 1991 and March 2004 that utilized voucher-based reinforcement therapy (VBRT) or related monetary-based incentives to treat substance use disorders (SUDs). FINDINGS: Thirty studies involved interventions targeting abstinence from drug use using experimental designs where effects on treatment outcome could be attributed to the VBRT intervention. The estimated average effect size (r) for those studies was 0.32 (95% CI 0.26-0.38). Analyses of variables thought to moderate VBRT effect sizes revealed that more immediate voucher delivery and greater monetary value of the voucher were associated with larger effect sizes. Additional studies were identified wherein VBRT was used to target clinic attendance (n = 6) or medication compliance (n = 4). VBRT studies targeting attendance produced average effect sizes of 0.15 (95% CI 0.02-0.28), while those that targeted medication compliance produced an average effect of 0.32 (95% CI 0.15-0.47). No significant moderators were identified for these 10 studies. CONCLUSIONS: Overall, VBRT generated significantly better outcomes than did control treatments. These results further support the efficacy of VBRT, quantify the magnitude of its effects, identify significant moderators and suggest potential directions for future research.

Abstract In October 2022, these guidelines were reviewed by an expert work group convened by ASH. Review included limited searches for new evidence and discussion of the search results. Following this review, the ASH Committee on Quality agreed to continue monitoring the supporting evidence rather than revise or retire these guidelines at this time. Limited searches and expert review will be repeated annually going forward until these guidelines are revised or retired. Background: Venous thromboembolism (VTE) is the third most common vascular disease. Medical inpatients, long-term care residents, persons with minor injuries, and long-distance travelers are at increased risk. Objective: These evidence-based guidelines from the American Society of Hematology (ASH) intend to support patients, clinicians, and others in decisions about preventing VTE in these groups. Methods: ASH formed a multidisciplinary guideline panel balanced to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline-development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and adult patients. The Grading of Recommendations Assessment, Development and Evaluation approach was used to assess evidence and make recommendations, which were subject to public comment. Results: The panel agreed on 19 recommendations for acutely ill and critically ill medical inpatients, people in long-term care facilities, outpatients with minor injuries, and long-distance travelers. Conclusions: Strong recommendations included provision of pharmacological VTE prophylaxis in acutely or critically ill inpatients at acceptable bleeding risk, use of mechanical prophylaxis when bleeding risk is unacceptable, against the use of direct oral anticoagulants during hospitalization, and against extending pharmacological prophylaxis after hospital discharge. Conditional recommendations included not to use VTE prophylaxis routinely in long-term care patients or outpatients with minor VTE risk factors. The panel conditionally recommended use of graduated compression stockings or low-molecular-weight heparin in long-distance travelers only if they are at high risk for VTE.

BACKGROUND: Medical care for very low birth weight (VLBW) infants and their mothers has changed dramatically during the 1990s, yet it is unclear how these changes have affected mortality and morbidity. OBJECTIVE: We used the Vermont Oxford Network Database to identify trends in clinical practice and patient outcomes for VLBW infants born from 1991 to 1999. METHODS: Logistic regression was used to evaluate temporal trends in practices and outcomes while adjusting for patient characteristics and accounting for clustering of cases within hospitals. RESULTS: There were 118 448 infants 501 to 1500 g from 362 neonatal intensive care units enrolled in the Network Database from 1991 to 1999. Prenatal care, cesarean section, multiple births, antenatal steroids, and 1-minute Apgar scores increased during this period, as did the use of nasal continuous positive airway pressure, high-frequency ventilation, surfactant, and postnatal steroids. The proportion of white infants decreased; the proportions of Hispanic infants and those of other races increased. The crude and adjusted rates of mortality, pneumothorax, intraventricular hemorrhage (IVH), and severe IVH declined from 1991 to 1995, whereas from 1995 to 1999, the rates of mortality, IVH, and severe IVH did not change significantly, and pneumothorax increased. CONCLUSIONS: There have been major changes in both obstetric and neonatal care during the 1990s. These changes were associated with decreases in mortality and morbidity for VLBW infants during the first half of the decade. However, since 1995, no additional improvements in mortality or morbidity have been seen, ending a decades-long trend of improving outcomes for these infants.

BACKGROUND: Accurate risk stratification is crucial for effective treatment planning after myocardial infarction (MI). Previous studies suggest that the peri-infarct border zone may be an important arrhythmogenic substrate. In this pilot study, we tested the hypothesis that the extent of the peri-infarct zone quantified by contrast-enhanced cardiac magnetic resonance (CMR) is an independent predictor of post-MI mortality. METHODS AND RESULTS: We studied 144 patients with documented coronary artery disease and abnormal myocardial delayed enhancement (MDE) consistent with MI. A computer-assisted, semiautomatic algorithm quantified the total infarct size and divided it into the core and peri-infarct regions based on signal-intensity thresholds (>3 SDs and 2 to 3 SDs above remote normal myocardium, respectively). The peri-infarct zone was normalized as a percentage of the total infarct size (%MDE(periphery)). After a median follow-up of 2.4 years, 29 (20%) patients died. Patients with an above-median %MDE(periphery) were at higher risk for death compared with those with a below-median %MDE(periphery) (28% versus 13%, log-rank P<0.01). Multivariable analysis showed that left ventricular systolic volume index and %MDE(periphery) were the strongest predictors of all-cause mortality (adjusted hazard ratio [HR] for %MDE(periphery), 1.45 per 10% increase; P=0.002) and cardiovascular mortality (adjusted HR, 1.51 per 10% increase; P=0.009). Similarly, after adjusting for age and left ventricular ejection fraction, %MDE(periphery) maintained strong and independent associations with all-cause mortality (adjusted HR, 1.42; P=0.005) and cardiovascular mortality (adjusted HR, 1.49; P=0.01). CONCLUSIONS: In patients with a prior MI, the extent of the peri-infarct zone characterized by CMR provides incremental prognostic value beyond left ventricular systolic volume index or ejection fraction. Infarct characteristics by CMR may prove to be a unique and valuable noninvasive predictor of post-MI mortality.

BACKGROUND: Olfactory dysfunction is an increasingly recognised condition, associated with reduced quality of life and major health outcomes such as neurodegeneration and death. However, translational research in this field is limited by heterogeneity in methodological approach, including definitions of impairment, improvement and appropriate assessment techniques. Accordingly, effective treatments for smell loss are limited. In an effort to encourage high quality and comparable work in this field, among others, we propose the following ideas and recommendations. Whilst the full set of recommendations are outlined in the main document, points include the following: - Patients with suspected olfactory loss should undergo a full examination of the head and neck, including rigid nasal endoscopy with small diameter endoscopes. - Subjective olfactory assessment should not be undertaken in isolation, given its poor reliability. - Psychophysical assessment tools used in clinical and research settings should include reliable and validated tests of odour threshold, and/or one of odour identification or discrimination. - Comprehensive chemosensory assessment should include gustatory screening. - Smell training can be helpful in patients with olfactory loss of several aetiologies. CONCLUSIONS: We hope the current manuscript will encourage clinicians and researchers to adopt a common language, and in so doing, increase the methodological quality, consistency and generalisability of work in this field.

The Eastern Association for the Surgery of Trauma (EAST) has taken a leadership role in the development of evidenced-based practice guidelines for trauma. 1 These original guidelines were developed by interested trauma surgeons in 1997 for the EAST Web site (http://www.east.org), where a brief summary of four guidelines was published. A revised, complete, and significantly edited practice management guidelines for the prevention of venous thromboembolism in trauma patients is presented herein. The step-by-step process of practice management guideline development, as outlined by the Agency for Health Care Policy and Research (AHCPR), has been used as the methodology for the development of these guidelines. 2 Briefly, the first step in guideline development is a classification of scientific evidence. A Class I study is a prospective, randomized controlled trial. A Class II study is a clinical study with prospectively collected data or large retrospective analyses with reliable data. A Class III study is retrospective data, expert opinion, or a case report. Once the evidence is classified, it can be used to make recommendations. A Level I recommendation is convincingly justifiable on the basis of the scientific information alone. Usually, such a recommendation is made on the basis of a preponderance of Class I data, but some strong Class II data can be used. A Level II recommendation means the recommendation is reasonably justifiable, usually on the basis of a preponderance of Class II data. If there are not enough Class I data to support a Level I recommendation, they may be used to support a Level II recommendation. A Level III recommendation is generally only supported by Class III data. These practice guidelines address eight different areas of practice management as they relate to the prevention and diagnosis of venous thromboembolism in trauma patients. There are few Level I recommendations because there is a paucity of Class I data in the area of trauma literature. We believe it is important to highlight areas where future investigation may bring about definitive Level I recommendations. RISK FACTORS FOR VENOUS THROMBOEMBOLISM AFTER INJURY I. Statement of the Problem A number of factors have been reported to increase the risk of venous thromboembolism (VTE) after injury. Because VTE prophylaxis is associated with complications, it is essential to identify subgroups of trauma patients in whom the benefit of VTE prophylaxis will outweigh the risk of its administration. This is important because the benefits from the different methods of prophylaxis are still unclear when compared with no prophylaxis. Because the literature is inconsistent, a systematic review is needed to produce the best available evidence. Below, we describe the results of a meta-analysis of the existing literature. The reader needs to remember the limitations of meta-analysis. In addition, the fact that a risk factor was not identified as significant in meta-analysis does not mean that this factor must be ignored. Absence of proof does not equal proof of absence. It only means that enough evidence does not exist and that further studies of high quality are needed. II. Process Three literature databases were searched (MEDLINE, EMBASE, and Cochrane Controlled Trials Register) for articles reporting risk factors of VTE. All articles were reviewed by two independent reviewers and a third reviewer in cases of disagreement. The review was prepared against predetermined screening criteria, and the articles were given a numerical quality score. From an initial broad research that identified 4,093 relevant titles, 73 articles met all the inclusion criteria and were finally accepted for meta-analysis. Pooled effect sizes (odds ratio [OR] and their 95% confidence intervals [CIs]) were estimated by the DerSimonian and Laird random-effects model. Shrinkage graphs were produced to display the effect size of each study and to compare with the overall model estimate. The heterogeneity among studies was tested by the Q statistic and p value for the χ2 test of heterogeneity. A level of significance at p < 0.05 was used for all comparisons. To include a risk factor for meta-analysis, three or more studies reported on the risk factor. Risk factors identified only in one or two studies were not included. The risk factors identified were treated as either dichotomous or continuous variables as appropriate. For instance, if three or more studies provided data on the incidence of VTE in patients who were older or younger than 55 years old, then the risk factor was "age > 55," a dichotomous variable. On the other hand, if three or more studies provided data on the age of patients with or without VTE by using only a mean and SD, the risk factor was simply "age," a continuous variable (Table 1).Table 1: Studies Reporting on Risk Factors of Venous Thromboembolism in Trauma PatientsIII. Recommendations Level I: Patients with spinal cord injuries or spinal fractures are at high-risk for venous thromboembolism after trauma. 2–12 Level II: 1. Older age is an increased factor for venous thromboembolism, but it is not clear at what exact age the risk increases substantially. 4,5,9,11,13,14 2. Increasing Injury Severity Score (ISS) and blood transfusion appear to increase the risk of venous thromboembolism, but this association is still unclear. 3,5,8,9,14,15 3. Traditional risk factors such as long bone fractures, 3–6,9–13,15–17 pelvic fractures, 3–5,9–12,15,18 or head injuries, 3–9,15 although significantly associated with a high risk of venous thromboembolisms in single-institution studies, were not found to be powerful risk factors on meta-analysis. IV. Scientific Foundation Risk factors As Dichotomous Variables The following variables were reported in three or more studies and were included in the meta-analysis: gender, 3,13,18,19 head injury, 3–9,15 long bone fracture, 3–6,9–13,16,17,19 pelvic fracture, 3–5,9–12,15 spinal fracture, 3–12 and spinal cord injury. 4,9–12 A number of studies included age as a risk factor, but the different cut-off points used in each study (age > 30, 40, 50, 55, etc.) did not allow an analysis of this variable. The only risk factors found to place the patient at higher risk for development of deep venous thrombosis (DVT) were spinal fractures (OR, 2.260; 95%; CI, 1.415–3.610) and, even greater, spinal cord injury (OR, 3.017; 95% CI, 1.794–5.381). No significant heterogeneity was reported among studies on the different risk factors. Although long bone fractures were not found to bear statistical significance on meta-analysis, at least one high-quality study 17 with a valid regression model and an adequate sample size found long bone fractures to be a significant risk factor for venous thromboembolism. Risk Factors As Continuous Variables Three continuous variables (i.e., age, 5,9,11,13,14 ISS, 3,5,9,11,14,15 and units of blood transfused 3,14,15) were reported in more than three studies and were included in the meta-analysis. Compared with patients without DVT, patients with DVT were significantly older (8.133 ± 1.504 [95% CI, 5.115–11.141]) years and had a significantly higher ISS (1.430 ± 0.747 [95% CI, 0.000–2.924]). The statistical difference in ISS was marginal, as shown by the lower limit of the 95% CI, and had minimal clinical significance. The difference of blood transfused between patients with and without DVT was not statistically significant (1.882 ± 2.815; 95% CI, −3.637–7.401), and no heterogeneity was reported among these studies. V. Summary The existing evidence supports the presence of two risk factors of posttraumatic VTE: spinal fractures and spinal cord injuries. Older age was an additional risk factor, but it was not clear at what exact age the risk increases substantially. Inadequate literature evidence exists to support that other frequently reported risk factors, such as long bone fractures, pelvic fractures, or head injuries, really increase the risk for VTE. However, a need exists for additional research in this area. In particular, adequate sized prospective studies should reevaluate the role of long bone fracture, pelvic fractures, head injuries, as well as specific age, blood transfusion, and ISS thresholds. V. Future Investigation Adequately sized studies should reevaluate the role of long bone fracture, pelvic fractures, and head injuries, as well as age, blood transfusion, and ISS thresholds and their association with the development of VTE after trauma. Large databases could be used to quantify risk using logistic regression profiles and could be the basis of specific prevention strategies. THE USE OF LOW-DOSE HEPARIN FOR DVT/PE PROPHYLAXIS I. Statement of the Problem The fact that DVT and pulmonary embolism (PE) occur after trauma is incontrovertible. The optimal mode of prophylaxis has yet to be determined. Low-dose heparin (LDH), given in doses of 5,000 units subcutaneously two or three times daily, represents one pharmacologic treatment modality for prophylaxis against DVT/PE. In contrast, LDH has not been shown to be particularly effective in preventing VTE in trauma patients. Three recent prospective trials demonstrated that LDH was no better in preventing DVT than no prophylaxis at all in patients with an ISS > 9. Sample sizes in these studies were small, and hence a type II statistical error cannot be excluded. The results of LDH use in trauma, with regard to PE, are even more vague. II. Process A MEDLINE review from 1966 to the present revealed several hundred articles related to the use of LDH in medical and general surgical patients. Only the nine articles related to the use of LDH in trauma patients were used for the following recommendations (Table 2).Table 2: Lose-Dose HeparinIII. Recommendations Level I: A Level I recommendation on this topic cannot be supported because of insufficient data. Level II: Little evidence exist to support the benefit of LDH as a sole agent for prophylaxis in the trauma patient at high-risk for VTE. 3,7,10,14,20–22 Level III: For patients in whom bleeding could exacerbate injuries (such as those with intracranial hemorrhage, incomplete spinal cord injuries, intraocular injuries, severe pelvic or lower extremity injuries with traumatic hemorrhage, and intra-abdominal solid organ injuries being managed nonoperatively), the safety of LDH has not been established, and an individual decision should be made when considering anticoagulant prophylaxis. IV. Scientific Foundation Heparin is a naturally occurring polysaccharide varying in molecular weight from 2,000 to 40,000. LDH augments the activity of antithrombin III, a potent, naturally occurring inhibitor of activated factor X (Xa) and thrombin, which produces interruption of both the intrinsic and extrinsic pathways. Low-dose heparin causes only minimal or no change in conventional clotting tests, such as the partial thromboplastin time. Studies on the use of LDH in trauma patients are inconclusive. In addition, many of these studies are single-institution studies with small sample sizes and lack randomization. These studies are summarized in Table 2. 7,20,21 Studies with larger sample sizes and randomization will be discussed herein. 3,5,10,14,17,22 Knudson et al. 3 reported on 251 patients in a cohort study who received LDH, a pneumatic compression device (PCD), or no prophylaxis. These authors failed to show any effectiveness with prophylaxis in most trauma patients, except in the subgroup of patients with neurotrauma in which PCD was more effective in preventing DVT than control. Upchurch et al. 14 compared 66 intensive care unit (ICU)-dependent trauma patients who received either LDH or no VTE prophylaxis. No significance difference was seen in VTE rates between the two groups. In this same study, the authors performed a meta-analysis of the current literature concerning the use of LDH in 1,102 trauma patients. This meta-analysis demonstrated no benefit of LDH as prophylaxis compared with no prophylaxis (10% vs. 7%;p = 0.771). Geerts et al. 17 randomized 344 trauma patients to receive low-molecular-weight heparin (LMWH) or LDH and found significantly fewer DVTs with LMWH than with LDH (31% vs. 44%, p = 0.014 for all DVT; and 15% vs. 6%, p = 0.012 for proximal DVT). This study had no control group. However, when compared with the predicted DVT rate if the study patients had not received prophylaxis, the risk reduction for LDH was only 19% for DVT and only 12% for proximal DVT, whereas the comparative risk reductions for LMWH were 43% and 65%, respectively. Napolitano et al. 10 used a serial ultrasound screening protocol for DVT in 437 patients who were given four types of prophylaxis (LDH, PCD, LDH and PCD, and no prophylaxis) according to their attending surgeon's preference. No significant difference was seen in DVT rates between groups (8.6%, 11.6%, 8.0%, and 11.9%, respectively). Velmahos et al. 5 looked at the use of LDH and PCD or PCD alone in 200 critically injured patients who were then followed with biweekly Doppler examinations to detect proximal lower extremity DVT. The incidence of DVT was 13% overall, and no difference was seen between the two groups. The majority (58%) of DVT developed in the first 2 weeks. In a meta-analysis conducted under the auspices of the Agency for Healthcare Research and Quality, Velmahos and colleagues 22 looked at all randomized controlled and nonrandomized studies on the use of LDH in trauma patients. The four randomized controlled studies on the use of LDH in trauma patients showed no difference in the incidence of DVT between those receiving LDH versus no prophylaxis (OR, 0.965; 95% CI, 0.360–2.965; vs. OR, 1.33; 95% CI, 0.360–2.965). V. Summary In summary, to date, LDH has very little proven efficacy in the prevention of VTE after trauma. Most studies on the use of LDH in trauma patients suffer from severe methodologic errors, poor study design, and small sample size, suggesting the possibility of a type II statistical error. VI. Future Investigation Enough accumulated data do not exist to support the use of LDH in a trial in high-risk trauma patients. Future studies should focus on the potential benefit of more efficacious agents such as low-molecular-weight heparin. THE ROLE OF ARTERIOVENOUS FOOT PUMPS IN THE PROPHYLAXIS OF DVT/PE IN THE TRAUMA PATIENT I. Statement of the Problem In 1983, Gardner and Fox 23 discovered a venous pump on the sole of the foot that consists of a plexus of veins that fills by gravity and empties on weightbearing, thus increasing femoral blood flow without muscular assistance. A mechanical device, the arteriovenous (A-V) foot pump, has been developed to mimic this effect of weightbearing. The major advantage of this system is that it only requires access to the foot, which enables its use in patients with Jones dressings, casts, or externally fixed limbs that previously were unsuitable for a PCD. One study has shown that the pulsatile action of the A-V foot pump increased venous blood flow velocity in the popliteal vein by 250%. 24 II. Process With the recent clinical introduction of the A-V foot pump, there is a paucity of relevant literature related to this subject. A MEDLINE review dating back to 1980 revealed 12 articles on A-V foot pumps, with 8 articles specifically related to the use of A-V foot pumps in the trauma patient. These eight studies were the basis for the recommendations below (Table 3).Table 3: A-V Foot PumpsIII. Recommendations Level I: A Level I recommendation for this topic cannot be supported because of insufficient data. Level II: A Level II recommendation for this topic cannot be supported because of insufficient data. Level III: A-V foot pumps may be used as a substitute for pneumatic compression devices in those high-risk trauma patients who cannot wear PCDs because of external fixators or casts and cannot be anticoagulated because of their injuries. It should be noted that in trauma patients, A-V foot pumps have not been shown to be as efficacious as PCDs and are associated with some significant complications. 12,25,26 IV. Scientific Foundation Most of the studies involving the use of A-V foot pumps are found in the orthopedic literature, and many of these series involve small numbers of patients. Although little has been documented on the effects of A-V footpumps on DVT in trauma patients, other beneficial effects have been observed. In 71 patients who had operations or casts for traumatic lower extremity injuries, Gardner and Fox 27 showed a significant decrease in pain, swelling, and measurement of compartment pressures in the affected extremities with the use of the A-V foot pumps. In the discussion to this article, the authors hypothesized that the increased blood flow seen with the pumps was because of hyperemia mediated by endothelial-derived relaxing factor (now thought to be nitric oxide) that was liberated by the endothelium secondary to sudden pressure changes, which could have been caused by the A-V pumps. This endothelial-derived relaxing factor release could encourage the opening of critically closed capillaries, enabling reabsorption of fluid, hence the decrease in compartment pressures. In addition, reports have been documented of A-V foot pumps improving arterial blood flow with the relief of ischemic rest pain. 28,29 In addition to preventing VTE, all of these proposed foot pump mechanisms of action may be potentially beneficial in healing extremity injuries. In a recent prospective randomized study by Knudson et al., 12 A-V foot pumps were one arm of a number of prophylactic measures (LMWH and PCDs were the other arms) used to prevent DVT in high-risk trauma patients. Of 372 patients enrolled in the study, the DVT rate was 5.7% for the A-V foot pumps, 2.5% for the PCDs, and 0.8% for the low-molecular-weight heparin as determined on follow-up serial duplex ultrasound. Of note, in 8 of 53 patients who wore foot pumps, severe skin changes, including blistering and wound problems, occurred. This required three patients to be removed early from the study. Spain et al. 25 compared the use of A-V foot pumps to PCDs in injured patients. In this nonrandomized study, patients who could not receive a PCD because of lower extremity injuries were in A-V foot pumps. no significant difference was seen in DVT rates between the two with PCDs at and A-V foot pumps at The authors of this study that A-V foot pumps were a to PCDs when lower extremity fractures the use of et al. performed a randomized prospective trial A-V foot pumps with PCDs in high-risk orthopedic patients and followed with serial ultrasound. In patients, the overall incidence of DVT was in those with A-V foot pumps and in those with analysis of such a study was by the heterogeneity of the two groups and the fact that a number of patients received either or In study by et al. in a trauma of and patients, the A-V foot pumps were found to be and only of the a to that reported by et al. for V. Summary Only one clinical series in trauma patients A-V foot pumps with other of DVT prophylaxis. The results from this series were not definitive in of benefits of A-V foot pumps preventing DVT. However, a use of A-V foot pumps may exist in the high-risk trauma patient who has a to heparin because of injuries or who cannot have PCDs on lower extremities secondary to external fixators or large VI. Future randomized studies are needed A-V foot pumps to prophylactic measures in trauma patients at high risk for the development of DVT. THE USE OF IN THE OF DVT/PE I. Statement of the Problem The role of PCDs for prophylaxis against DVT has been and used in general patients, orthopedic patients, and trauma patients. the risk factor of PCDs have been shown to increase mean and femoral venous blood in the lower In addition, PCDs have been shown to have a effect on the that to the increases of inhibitor and the of In a number of prospective randomized studies, PCDs have been shown to the incidence of both DVT and the use of PCDs include the by which PCDs the efficacy of PCDs on the extremities or a lower extremity compared with both lower the of risk in PCDs and the of PCD that PCDs should be with this practice has not been used. of PCDs have been noted in case reports and have been associated with of the lower extremity which should be II. Process A MEDLINE from to the present produced a large number of articles on this articles to thromboembolism prevention were of these articles were to the following guidelines (Table Recommendations Level I: A Level I recommendation on this topic cannot be supported because of insufficient data. Level II: A Level II recommendation on this topic cannot be supported because of insufficient data. Level III: In a meta-analysis of studies on the benefit of PCDs in trauma patients, no benefit of the use of PCDs no prophylaxis was 22 In the of patients, PCDs may have some benefit in studies. IV. Scientific Foundation The factors that are to the basis of the of venous are of blood flow in the injury the of the and Scientific and clinical of PCDs that the of the effect on DVT prophylaxis from their to increase mean and femoral vein velocity and the and et al. venous velocity at the femoral vein using Doppler ultrasound in patients and in control In the control was increased from a mean velocity of at rest to with PCDs and with In patients, the was from a velocity of to In both of these the were statistically significant when compared with and were not further by the use of of blood flow velocity and of the PCDs revealed a association with and increased that a mechanical effect from of the Studies have in effects of In a study, et al. showed that times were not as a for study on in inhibitor and demonstrated a significant increase in an decrease in in patients pneumatic compression and a and role of PCDs in the of and found that activity to of This to have important clinical in that PCDs must be to in A recent study documented patients in whom PCDs have been but who than of the the which their important in the study by et al. was that there to be an decrease in activity when blood was in from the area of PCD This difference in and effects has important on the of PCDs on the to prevent DVT in the A paucity of studies exists specifically the use of PCDs in trauma patients with injuries. In a prospective study by Knudson et al., trauma patients received either PCDs and or This study showed a 12% rate of VTE in the PCD versus in the LDH which was not significantly This study did not that either of prevention or was better than no prophylaxis. et al. conducted a prospective, nonrandomized study of trauma patients with an ISS > who received either PCDs, LDH, or no prophylaxis, and who serial ultrasound screening for DVT at 5 and 10 after demonstrated a VTE rate of in the in the PCD and in the LDH group. No statistically significant difference was noted in VTE rates in the prophylaxis but a significant difference was seen in those who received prophylaxis versus no prophylaxis < and spinal patients, two to benefit from prophylaxis. risk reduction of VTE with prophylaxis was from to in patients and to in spinal patients. However, the of this study in that patients to receive no prophylaxis were to receive some of prophylaxis at the of the attending This may have the DVT rates for each prophylactic modality In a prospective Knudson et al. 3 compared PCD, LDH, and no prophylaxis. LDH PCD to any to trauma patients with injuries, except in the specific subgroup of patients with neurotrauma in which PCD was more effective in preventing DVT than control = In to the study by Knudson et al., et al., in a nonrandomized prospective study, looked at the incidence of VTE in a of patients with < patients received PCDs and did not because of lower extremity the receiving PCDs, four developed and developed DVT. In the not receiving prophylaxis, two developed and two developed DVT. Although the study was small, the in this study the efficacy of PCD even in severe patients. In a of orthopedic trauma patients with and pelvic fractures, PCDs were found to significantly those who had no prophylaxis vs. = In subgroup PCDs were only effective in the not in those with pelvic devices appear to be with minimal cases of pressure from a PCD have been and compartment have been reported with A potential of PCDs is intracranial pressure in patients with severe head injury. This was by et al. in 24 patients of who had and pressure after and of pneumatic The authors found no significant increase in or with the use of PCDs at any and that PCDs can be used in patients. In an evidenced-based meta-analysis by the Agency of Healthcare Research and on the incidence of DVT after trauma, Velmahos et al. 22 found that PCDs no benefit no prophylaxis in both randomized control studies (OR, 95% CI, and in nonrandomized controlled studies (OR, 95% CI, In study, Velmahos et al. 5 compared PCD, LDH, and a of PCD and LDH in a prospective study of 200 critically injured patients followed by Doppler ultrasound to detect proximal DVT. In all three the proximal DVT rate was the authors to any of the three prophylactic were in the high-risk patient. V. Summary studies the effectiveness of PCDs in trauma patients are Although the exact of action of PCDs is their effect is to be on a of factors is well and the system is these mechanisms are better and to specific the use of PCDs are VI. Future Investigation studies need to be performed specifically to the use of PCDs in trauma patients at risk for VTE. the efficacy of using the device on one lower extremity

Rafferty, Janice M.D.; Shellito, Paul M.D.; Hyman, Neil H. M.D.; Buie, W. Donald M.D. and the Standards Committee of The American Society of Colon and Rectal Surgeons Author Information

BACKGROUND: Salvage radiation therapy is often necessary in men who have undergone radical prostatectomy and have evidence of prostate-cancer recurrence signaled by a persistently or recurrently elevated prostate-specific antigen (PSA) level. Whether antiandrogen therapy with radiation therapy will further improve cancer control and prolong overall survival is unknown. METHODS: In a double-blind, placebo-controlled trial conducted from 1998 through 2003, we assigned 760 eligible patients who had undergone prostatectomy with a lymphadenectomy and had disease, as assessed on pathological testing, with a tumor stage of T2 (confined to the prostate but with a positive surgical margin) or T3 (with histologic extension beyond the prostatic capsule), no nodal involvement, and a detectable PSA level of 0.2 to 4.0 ng per milliliter to undergo radiation therapy and receive either antiandrogen therapy (24 months of bicalutamide at a dose of 150 mg daily) or daily placebo tablets during and after radiation therapy. The primary end point was the rate of overall survival. RESULTS: The median follow-up among the surviving patients was 13 years. The actuarial rate of overall survival at 12 years was 76.3% in the bicalutamide group, as compared with 71.3% in the placebo group (hazard ratio for death, 0.77; 95% confidence interval, 0.59 to 0.99; P=0.04). The 12-year incidence of death from prostate cancer, as assessed by means of central review, was 5.8% in the bicalutamide group, as compared with 13.4% in the placebo group (P<0.001). The cumulative incidence of metastatic prostate cancer at 12 years was 14.5% in the bicalutamide group, as compared with 23.0% in the placebo group (P=0.005). The incidence of late adverse events associated with radiation therapy was similar in the two groups. Gynecomastia was recorded in 69.7% of the patients in the bicalutamide group, as compared with 10.9% of those in the placebo group (P<0.001). CONCLUSIONS: The addition of 24 months of antiandrogen therapy with daily bicalutamide to salvage radiation therapy resulted in significantly higher rates of long-term overall survival and lower incidences of metastatic prostate cancer and death from prostate cancer than radiation therapy plus placebo. (Funded by the National Cancer Institute and AstraZeneca; RTOG 9601 ClinicalTrials.gov number, NCT00002874 .).

BACKGROUND: Surfactant therapy is effective in improving the outcome of very preterm infants. Trials have studied a wide variety of surfactant preparations used either to prevent or treat respiratory distress syndrome (RDS). In animal models, prophylactic surfactant leads to more homogeneous distribution and less evidence of lung damage. However, administration requires intubation and treatment of infants who will not go on to develop RDS. This is of particular concern with the advent of improved approaches to providing continuous distending pressure, particularly in the form of nasal continuous positive airway pressure (CPAP). OBJECTIVES: To compare the effect of prophylactic surfactant administration to surfactant treatment of established RDS in very preterm infants at risk of RDS. SEARCH METHODS: We updated the search of the Cochrane Central Register of Controlled Trials (The Cochrane Library), MEDLINE, EMBASE, CINAHL, and clinical trials.gov register in December 13, 2011. SELECTION CRITERIA: Randomized and quasi-randomized controlled trials that compared the effects of prophylactic surfactant administration to surfactant treatment of established RDS in preterm infants at risk of RDS. DATA COLLECTION AND ANALYSIS: Data regarding clinical outcomes were extracted from the reports of the clinical trials by the reviewers. Data analysis was done in accordance with the standards of the Cochrane Neonatal Review Group. MAIN RESULTS: Eleven studies were identified that met inclusion criteria [nine without routine application of continuous positive air way pressure (CPAP) in the selective treatment group; two with routine application of CPAP in the selective treatment group]The meta-analysis of studies conducted prior to the routine application of CPAP demonstrated a decrease in the risk of air leak and neonatal mortality associated with prophylactic administration of surfactant. However, the analyses of studies that allowed for routine stabilization on CPAP demonstrated a decrease in the risk of chronic lung disease or death in infants stabilized on CPAP. When all studies were evaluated together, the benefits of prophylactic surfactant could no longer be demonstrated. AUTHORS' CONCLUSIONS: Although the early trials of prophylactic surfactant administration to infants judged to be at risk of developing RDS compared to selective use of surfactant in infants with established RDS demonstrated a decreased risk of air leak and mortality, recent large trials that reflect current practice (including greater utilization of maternal steroids and routine post delivery stabilization on CPAP) do not support these differences and demonstrate less risk of chronic lung disease or death when using early stabilization on CPAP with selective surfactant administration to infants requiring intubation.