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Answer questions and earn CME/CNE The revision of the eighth edition of the primary tumor, lymph node, and metastasis (TNM) classification of the American Joint Commission of Cancer (AJCC) for breast cancer was determined by a multidisciplinary team of breast cancer experts. The panel recognized the need to incorporate biologic factors, such as tumor grade, proliferation rate, estrogen and progesterone receptor expression, human epidermal growth factor 2 (HER2) expression, and gene expression prognostic panels into the staging system. AJCC levels of evidence and guidelines for all tumor types were followed as much as possible. The panel felt that, to maintain worldwide value, the tumor staging system should remain based on TNM anatomic factors. However, the recognition of the prognostic influence of grade, hormone receptor expression, and HER2 amplification mandated their inclusion into the staging system. The value of commercially available, gene-based assays was acknowledged and prognostic input added. Tumor biomarkers and low Oncotype DX recurrence scores can alter prognosis and stage. These updates are expected to provide additional precision and flexibility to the staging system and were based on the extent of published information and analysis of large, as yet unpublished databases. The eighth edition of the AJCC TNM staging system, thus, provides a flexible platform for prognostic classification based on traditional anatomic factors, which can be modified and enhanced using patient biomarkers and multifactorial prognostic panel data. The eighth edition remains the worldwide basis for breast cancer staging and will incorporate future online updates to remain timely and relevant. CA Cancer J Clin 2017;67:290-303. © 2017 American Cancer Society.

Idiosyncratic drug-induced liver injury (DILI) is a rare adverse drug reaction and it can lead to jaundice, liver failure, or even death. Antimicrobials and herbal and dietary supplements are among the most common therapeutic classes to cause DILI in the Western world. DILI is a diagnosis of exclusion and thus careful history taking and thorough work-up for competing etiologies are essential for its timely diagnosis. In this ACG Clinical Guideline, the authors present an evidence-based approach to diagnosis and management of DILI with special emphasis on DILI due to herbal and dietary supplements and DILI occurring in individuals with underlying liver disease.

IMPORTANCE: Mammography plays a key role in early breast cancer detection. Single-institution studies have shown that adding tomosynthesis to mammography increases cancer detection and reduces false-positive results. OBJECTIVE: To determine if mammography combined with tomosynthesis is associated with better performance of breast screening programs in the United States. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of screening performance metrics from 13 academic and nonacademic breast centers using mixed models adjusting for site as a random effect. EXPOSURES: Period 1: digital mammography screening examinations 1 year before tomosynthesis implementation (start dates ranged from March 2010 to October 2011 through the date of tomosynthesis implementation); period 2: digital mammography plus tomosynthesis examinations from initiation of tomosynthesis screening (March 2011 to October 2012) through December 31, 2012. MAIN OUTCOMES AND MEASURES: Recall rate for additional imaging, cancer detection rate, and positive predictive values for recall and for biopsy. RESULTS: A total of 454,850 examinations (n=281,187 digital mammography; n=173,663 digital mammography + tomosynthesis) were evaluated. With digital mammography, 29,726 patients were recalled and 5056 biopsies resulted in cancer diagnosis in 1207 patients (n=815 invasive; n=392 in situ). With digital mammography + tomosynthesis, 15,541 patients were recalled and 3285 biopsies resulted in cancer diagnosis in 950 patients (n=707 invasive; n=243 in situ). Model-adjusted rates per 1000 screens were as follows: for recall rate, 107 (95% CI, 89-124) with digital mammography vs 91 (95% CI, 73-108) with digital mammography + tomosynthesis; difference, -16 (95% CI, -18 to -14; P < .001); for biopsies, 18.1 (95% CI, 15.4-20.8) with digital mammography vs 19.3 (95% CI, 16.6-22.1) with digital mammography + tomosynthesis; difference, 1.3 (95% CI, 0.4-2.1; P = .004); for cancer detection, 4.2 (95% CI, 3.8-4.7) with digital mammography vs 5.4 (95% CI, 4.9-6.0) with digital mammography + tomosynthesis; difference, 1.2 (95% CI, 0.8-1.6; P < .001); and for invasive cancer detection, 2.9 (95% CI, 2.5-3.2) with digital mammography vs 4.1 (95% CI, 3.7-4.5) with digital mammography + tomosynthesis; difference, 1.2 (95% CI, 0.8-1.6; P < .001). The in situ cancer detection rate was 1.4 (95% CI, 1.2-1.6) per 1000 screens with both methods. Adding tomosynthesis was associated with an increase in the positive predictive value for recall from 4.3% to 6.4% (difference, 2.1%; 95% CI, 1.7%-2.5%; P < .001) and for biopsy from 24.2% to 29.2% (difference, 5.0%; 95% CI, 3.0%-7.0%; P < .001). CONCLUSIONS AND RELEVANCE: Addition of tomosynthesis to digital mammography was associated with a decrease in recall rate and an increase in cancer detection rate. Further studies are needed to assess the relationship to clinical outcomes.

BACKGROUND: Amantadine hydrochloride is one of the most commonly prescribed medications for patients with prolonged disorders of consciousness after traumatic brain injury. Preliminary studies have suggested that amantadine may promote functional recovery. METHODS: We enrolled 184 patients who were in a vegetative or minimally conscious state 4 to 16 weeks after traumatic brain injury and who were receiving inpatient rehabilitation. Patients were randomly assigned to receive amantadine or placebo for 4 weeks and were followed for 2 weeks after the treatment was discontinued. The rate of functional recovery on the Disability Rating Scale (DRS; range, 0 to 29, with higher scores indicating greater disability) was compared over the 4 weeks of treatment (primary outcome) and during the 2-week washout period with the use of mixed-effects regression models. RESULTS: During the 4-week treatment period, recovery was significantly faster in the amantadine group than in the placebo group, as measured by the DRS score (difference in slope, 0.24 points per week; P=0.007), indicating a benefit with respect to the primary outcome measure. In a prespecified subgroup analysis, the treatment effect was similar for patients in a vegetative state and those in a minimally conscious state. The rate of improvement in the amantadine group slowed during the 2 weeks after treatment (weeks 5 and 6) and was significantly slower than the rate in the placebo group (difference in slope, 0.30 points per week; P=0.02). The overall improvement in DRS scores between baseline and week 6 (2 weeks after treatment was discontinued) was similar in the two groups. There were no significant differences in the incidence of serious adverse events. CONCLUSIONS: Amantadine accelerated the pace of functional recovery during active treatment in patients with post-traumatic disorders of consciousness. (Funded by the National Institute on Disability and Rehabilitation Research; ClinicalTrials.gov number, NCT00970944.).

Herbal and dietary supplements (HDS) are used increasingly both in the United States and worldwide, and HDS-induced liver injury in the United States has increased proportionally. Current challenges in the diagnosis and management of HDS-induced liver injury were the focus of a 2-day research symposium sponsored by the American Association for the Study of Liver Disease and the National Institutes of Health. HDS-induced liver injury now accounts for 20% of cases of hepatotoxicity in the United States based on research data. The major implicated agents include anabolic steroids, green tea extract, and multi-ingredient nutritional supplements. Anabolic steroids marketed as bodybuilding supplements typically induce a prolonged cholestatic but ultimately self-limiting liver injury that has a distinctive serum biochemical as well as histological phenotype. Green tea extract and many other products, in contrast, tend to cause an acute hepatitis-like injury. Currently, however, the majority of cases of HDS-associated liver injury are due to multi-ingredient nutritional supplements, and the component responsible for the toxicity is usually unknown or can only be suspected. HDS-induced liver injury presents many clinical and research challenges in diagnosis, identification of the responsible constituents, treatment, and prevention. Also important are improvements in regulatory oversight of nonprescription products to guarantee their constituents and ensure purity and safety. The confident identification of injurious ingredients within HDS will require strategic alignments among clinicians, chemists, and toxicologists. The ultimate goal should be to prohibit or more closely regulate potentially injurious ingredients and thus promote public safety. (Hepatology 2017;65:363-373).

There is currently a lack of evidence-based guidelines to guide the pharmacological treatment of neurobehavioral problems that commonly occur after traumatic brain injury (TBI). It was our objective to review the current literature on the pharmacological treatment of neurobehavioral problems after traumatic brain injury in three key areas: aggression, cognitive disorders, and affective disorders/anxiety/ psychosis. Three panels of leading researchers in the field of brain injury were formed to review the current literature on pharmacological treatment for TBI sequelae in the topic areas of affective/anxiety/ psychotic disorders, cognitive disorders, and aggression. A comprehensive Medline literature search was performed by each group to establish the groups of pertinent articles. Additional articles were obtained from bibliography searches of the primary articles. Group members then independently reviewed the articles and established a consensus rating. Despite reviewing a significant number of studies on drug treatment of neurobehavioral sequelae after TBI, the quality of evidence did not support any treatment standards and few guidelines due to a number of recurrent methodological problems. Guidelines were established for the use of methylphenidate in the treatment of deficits in attention and speed of information processing, as well as for the use of beta-blockers for the treatment of aggression following TBI. Options were recommended in the treatment of depression, bipolar disorder/mania, psychosis, aggression, general cognitive functions, and deficits in attention, speed of processing, and memory after TBI. The evidence-based guidelines and options established by this working group may help to guide the pharmacological treatment of the person experiencing neurobehavioral sequelae following TBI. There is a clear need for well-designed randomized controlled trials in the treatment of these common problems after TBI in order to establish definitive treatment standards for this patient population.

To produce a word, the intended word must be selected from a competing set of other words. In other domains where competition affects the selection process, the left inferior frontal gyrus (LIFG) responds to competition among incompatible representations. The aim of this study was to test whether the LIFG is necessary for resolution of competition in word production. Using a methodological approach applying the same rigorous analytic methods to neuropsychological data as is done with neuroimaging data, we compared brain activation patterns in normal speakers (using fMRI) with the results of lesion-deficit correlations in aphasic speakers who performed the same word production task designed to elicit competition during lexical selection. The degree of activation of the LIFG in normal speakers and damage to the LIFG in aphasic speakers was associated with performance on the production task. These convergent findings provide strong support for the hypothesis that the region of cortex commonly known as Broca's area (i.e., the posterior LIFG) serves to bias competitive interactions during language production.

Research on treatment efficacy and effectiveness requires that the treatments of interest be objectively defined. Such definitions are relatively straightforward for pharmacologic and surgical treatments, in which the active ingredients can be specified in terms of chemical structure or anatomic result. Definitions of treatment are more difficult for the many experience-based interventions employed in rehabilitation. This has led to the criticism that much clinical rehabilitation research has characterized the treatments of interest as a "black box," allowing little insight into the active ingredients contained therein. Moreover, rehabilitation care may involve the simultaneous application of multiple different treatments, raising the question of whether to define the individual components or the service delivery system. In this article, we consider how the levels of analysis considered in rehabilitation (disease, impairment, activity, and participation) and the role of theory shape the definition of treatment, and we address the need to develop protocol-based treatments and tools to objectively verify their contents. Rigorous definition of rehabilitation treatments, supported by theory, will facilitate needed efficacy research, will allow replication of that research, and will ultimately foster dissemination of effective treatments into clinical practice.

PURPOSE: Controversy exists regarding the optimal negative margin width for ductal carcinoma in situ (DCIS) treated with breast-conserving surgery and whole-breast irradiation. METHODS: A multidisciplinary consensus panel used a meta-analysis of margin width and ipsilateral breast tumor recurrence (IBTR) from a systematic review of 20 studies including 7,883 patients and other published literature as the evidence base for consensus. RESULTS: Negative margins halve the risk of IBTR compared with positive margins defined as ink on DCIS. A 2-mm margin minimizes the risk of IBTR compared with smaller negative margins. More widely clear margins do not significantly decrease IBTR compared with 2-mm margins. Negative margins narrower than 2 mm alone are not an indication for mastectomy, and factors known to affect rates of IBTR should be considered in determining the need for re-excision. CONCLUSION: Use of a 2-mm margin as the standard for an adequate margin in DCIS treated with whole-breast irradiation is associated with lower rates of IBTR and has the potential to decrease re-excision rates, improve cosmetic outcomes, and decrease health care costs. Clinical judgment should be used in determining the need for further surgery in patients with negative margins narrower than 2 mm.

OBJECTIVE: To evaluate the effects of methylphenidate on a variety of aspects of attention, ranging from laboratory-based impairment measures to caregiver ratings and work productivity, in individuals after traumatic brain injury. DESIGN: A total of 34 adults with moderate to severe traumatic brain injury and attention complaints in the postacute phase of recovery were enrolled in a 6-wk, double-blind, placebo-controlled, repeated crossover study of methylphenidate, administered in a dose of 0.3 mg/kg/dose, twice a day. A wide range of attentional measures was gathered weekly, including computerized and paper-and-pencil tests of attention, videotaped records of individual work in a distracting environment, real-time observational scoring of attentiveness in a classroom environment, and caregiver and clinician rating scales of attentiveness. Participants also attempted to guess their drug condition each week. Data from the first ten participants were used for pilot purposes, to develop attentional factors for composite scoring, and to identify attentional dimensions suggestive of a treatment effect for independent replication. The remaining 24 participants' results were used to confirm potential treatment effects seen in the pilot sample, using Wilcoxon's signed-ranks test on composite factor scores and individual variables. RESULTS: A total of 54 dependent variables were reduced to 13 composite factors and 13 remaining individual variables. Of the 13 attentional factors, five showed suggestive treatment effects in the pilot sample. Of these, three showed statistically significant treatment effects in the replication sample: speed of information processing (effect sizes, -0.06 to 0.48; P < 0.001), attentiveness during individual work tasks (effect sizes, 0.15-0.62; P = 0.01), and caregiver ratings of attention (effect sizes, 0.44-0.50; P = 0.01). Of the individual variables, four showed suggestive treatment effects in the pilot sample, but only one showed significant treatment effects in the replication sample: reaction time before errors in the Sustained Attention to Response Task (effect size, 0.20; P = 0.03). No treatment-related improvement was seen in divided attention, sustained attention, or susceptibility to distraction. None of the variables showed suggestive or definite negative treatment effects. Effect sizes for those performance measures positively affected by methylphenidate were in the small to medium range and included both impairment and activity level measures. Improvements in processing speed did not seem to come at the expense of accuracy. CONCLUSIONS: Methylphenidate, at 0.3 mg/kg/dose, given twice a day to individuals with attentional complaints after traumatic brain injury, seems to have clinically significant positive effects on speed of processing, caregiver ratings of attention, and some aspects of on-task behavior in naturalistic tasks. Further research is needed to identify the optimal dose and to extend these findings to less carefully selected individuals.

INTRODUCTION There are currently more than 1000 prescription medications available for use in the United States and more than 100,000 over‐the‐counter herbal and dietary supplements (HDS) available for purchase in retail stores and online. In addition, the average adult American receives more than six prescription medications per year.1,2 Many of these drugs and HDS products have been implicated as causes of DILI. Furthermore, DILI is a leading reason for regulatory actions regarding drugs in development as well as those in the marketplace.1 Confidently establishing a diagnosis of DILI is difficult because of the need to exclude more common competing causes of liver injury, the protean clinical manifestations from an individual agent, and the lack of a validated diagnostic biomarker.3–5 This guidance was developed with the support and oversight of the American Association for the Study of Liver Diseases Practice Guidelines Committee, who chose to commission a guidance, rather than a guideline, because of the paucity of randomized controlled trials on this topic. This document was developed by consensus of an expert panel and provides guidance statements based on formal review and analysis of the literature on the topics and questions related to the needs of patients with drug and supplement–induced liver injury. The aim of this practice guidance is to provide recommendations regarding the common clinical, laboratory, and histological features seen in patients with DILI based on observational and epidemiological data reported in case series or DILI registries. In addition, expert opinion–based recommendations for patient management, including risk stratification, are provided to assist patients and practitioners. DILI classification DILI can be mechanistically classified as being either direct (i.e., dose‐dependent, intrinsic, and predictable) or idiosyncratic (largely dose‐independent, idiosyncratic, and unpredictable) (Table 1). Direct hepatotoxins such as acetaminophen (APAP) (N‐acetyl‐para‐aminophenol) can cause liver injury in nearly all exposed individuals if a threshold dose or duration is exceeded. In contrast, idiosyncratic hepatotoxins are usually neither dose‐related nor duration‐related but rather occur at varying times during or after drug administration.6 Idiosyncratic DILI is uncommon, with most approved drugs occurring in only 1 in 1000 to 1 in a million exposed individuals. Although most patients do not have rash, eosinophilia, or other hypersensitivity features at presentation, aberrant host immunity is implicated in most instances of idiosyncratic DILI.3 TABLE 1 - Proposed classification of DILI Mechanistic classification Direct hepatotoxicity Idiosyncratic hepatotoxicity Indirect hepatotoxicity Incidence Common Rare Intermediate Dose relatedness Yes No No Predictable Yes No Partially Reproduced in animal models Yes No Not usually Latency Rapid (days) Variable (days to years) Delayed (months) Phenotypes of injury Serum AST, ALT, or ALP elevations, hepatic necrosis, acute fatty liver, nodular regeneration Mixed or cholestatic hepatitis, bland cholestasis, chronic hepatitis Immune‐mediated hepatitis, fatty liver, chronic hepatitis Examples Acetaminophen, niacin, intravenous methotrexate Amoxicillin‐clavulanate, cephalosporins, isoniazid, nitrofurantoin Immune checkpoint inhibitors, anti‐CD20 monoclonal Ab, protein kinase inhibitors Touted mechanism of injury Intrinsic hepatotoxicity that is dose‐dependent Idiosyncratic host metabolic or immune reaction Indirect effect on liver or host immunity Source: Adapted from Björnsson et al.5 A third mechanism of hepatotoxicity is called indirect DILI, which arises when the biological action of the drug affects the host immune system, leading to a secondary form of liver injury. Like idiosyncratic DILI, indirect hepatotoxins are generally independent of the dose of medication administered and have a latency of weeks to months with varying clinical manifestations. Examples of indirect hepatotoxicity include the immune‐mediated hepatitis (IMH) observed with immune checkpoint inhibitors (ICIs) and reactivation of HBV infection following rituximab infusions.7,8 Guidance statements Clinicians should be familiar with the three main types of hepatotoxicity when evaluating patients with suspected DILI. Direct hepatotoxins such as APAP can cause liver injury in nearly all exposed individuals once a threshold dose or duration of use is exceeded. Idiosyncratic DILI is largely independent of the dose and duration of medication use and characterized by a low incidence and variable drug latency and clinical and histological features. Idiosyncratic DILI is believed to arise from an aberrant adaptive host immune response to the drug and/or its metabolite(s). Indirect hepatotoxins are generally independent of the dose administered and have a variable latency and manifestations that arise from the biological action of the drug on the liver and/ or host immune system. Epidemiology of idiosyncratic DILI Idiosyncratic DILI is uncommon, with an estimated annual incidence in the general population of 14 to 19 events per 100,000 inhabitants or 60,000 cases per year in the general US population.9,10 The estimated incidence of idiosyncratic DILI also varies based on the case definition as well as the methods used for case ascertainment. For example, the incidence appears to be higher in exposure‐based studies using electronic medical records (32.8 per 100,000 adult patients who received one of the top implicated drugs in the United States and 40 per 100,000 patients at a pediatric hospital).11,12 The incidence of idiosyncratic DILI is even higher in hospitalized patients, being reported as high as 1.4% among medical inpatients.13–16 Results of ongoing DILI registry studies demonstrate that the spectrum of suspect drugs and demographics of afflicted patients substantially differ among countries and regions.17–24 These observations likely reflect differences in case definitions as well as differences in medication use, health care systems, and sociocultural and medical attributes in the various populations (Table 2). TABLE 2 - Etiologies and outcomes with DILI in different countries Country United States/DILIN, n = 899 Spain, n = 843 Iceland, n = 96 Latin America, n = 311 China, n = 25, 927 India, n = 313/1288 Study design Prospective registry30 Prospective registry29 Prospective, population‐based9 Prospective registry18 Retrospective case series22 Prospective case series21,31 Publication year 2015 2021 2013 2019 2019 2010/2021 Age distribution, years 49 ± 17 54 (11–91) 55¥ (16–91) 50 (11–91) 43% (40–59 years) 39 (12–84)/43 (1–86) % Female 59 48 56 61 49 % and 1 % Liver implicated drug drugs drugs or or immune implicated isoniazid, isoniazid, isoniazid, methotrexate The duration of among Age are as ± or most Liver herbal and dietary case based on the cause of in individual to DILI 1 and The the used in the individual for the Latin to which based on the causes of idiosyncratic DILI Although of medications can cause idiosyncratic DILI, drug are more implicated than For example, and are more implicated than differences among the implicated For HDS products in China, and for of DILI In contrast, HDS products only a of cases in the United and but with an incidence is the most implicated individual in in countries (Table 2). risk of idiosyncratic DILI is by among and Although idiosyncratic DILI is independent of the dose or duration of medication most implicated drugs are at a dose of per than of DILI cases that in liver in the United States by medications with 50 In dose also the risk of idiosyncratic DILI as seen with dose or the with high and in the liver are with an in with a high dose In addition, drugs that form and in in are with DILI risk in of drugs also been with an risk of DILI in and and The of host and and on DILI is not well because of the lack of exposure‐based epidemiological studies to DILI incidence with Although DILI incidence with patient this be in by medication use with differences also with more and A that the DILI incidence was more than 2 times higher in than than 50 differences In addition, to be at risk of and individuals are more to DILI from and case series demonstrate an of with and nitrofurantoin to be with and Liver that is the most common suspect drug among is the leading cause in In addition, more likely to have outcomes and chronic In contrast, more likely to a or liver than the other of the of studies are to these and been with an risk of use, and chronic hepatitis have also been with in the of was not with clinical outcomes in patients in the Prospective Furthermore, are data the of use, and on DILI The mechanism by which chronic liver DILI DILI by been with a dose‐dependent with the of liver than risk host related to and have been reported as DILI (Table A in which been with other appears to be a risk for DILI and with an of studies have also as risk for drugs or HDS In the have low because of the low incidence of DILI in the general but a high likely not in most to DILI, but be in DILI diagnosis and TABLE - with DILI in or and as used in the among the among the provided should be for for of and Phenotypes DILI cases at Liver to the of the based on the reported of Guidance statements The estimated annual incidence of idiosyncratic DILI in the general population is low but higher in exposure‐based studies using electronic medical data and are the most implicated in the DILI series HDS are most implicated in countries and are implicated in countries as The dose of a its and of hepatic the risk of DILI when data to and and as risk for DILI drugs are more likely to cause DILI in individuals are more implicated in such as and are with incidence and of DILI with the of and in DILI is not with liver are at risk of liver injury with drugs In addition, with liver are at risk of outcomes with a DILI A in is a risk drugs and have also been with to individual but the clinical of in DILI diagnosis to be to DILI DILI is largely a clinical diagnosis of on a medical including medication the and of liver and after drug and of other causes of liver The for DILI and and direct and are a of 1). DILI is as one of the or of or ALP if is on at with AST, ALT, or ALP or with AST, ALT, or Although DILI with of to of individuals in the general population have liver because of and other common Proposed diagnostic for patients with suspected DILI. A diagnosis of DILI on of clinical and drug with of other more common causes of liver injury. AST, herbal and dietary of A medication including the use of HDS is in all suspected DILI This should include and of the suspect dose and use of the data (i.e., clinical following drug and (i.e., response to DILI appears months of a drugs have latency In contrast, hypersensitivity can have latency of only Although DILI is to to an agent, is to that to an intravenous agent, such as monoclonal also cause DILI. of medications to the or if cause DILI because of the low dose of medication A clinical of liver injury that been reported for a medication or HDS can be in an is likely the cause of the injury. The of liver injury also the for competing causes of liver 1). In the of injury can be as with a of with a of ALP or These can be more and the as by cases of liver injury, an 2 cases of cholestatic liver injury, and an 2 and a liver injury The is at the of presentation, but the of injury can as the a drug be with more than one clinical causes of liver injury for acute hepatitis is for all patients with suspected DILI including hepatitis A and to exclude acute hepatitis infection 1). In of cases in the analysis of the for of DILI is acute which is reported in developed because of to was in cases in the Although are regarding of the available for acute infection should be in including cases a suspect or in cases with high in patients with suspected DILI should also for hepatitis with for and and are drugs that can an with or are at risk for liver injury, usually characterized by and a in by with or In patients, can be using In cholestatic for is to for In patients with a of than ALT, hepatitis should be if are generally and with high and Furthermore, for in this is patients with suspected DILI should of liver with an to for of or other liver such as or be used to for or drugs have been with clinical and also called such as hepatitis, hepatitis, or These are in DILI can with a of clinical and histological from the on host and of TABLE - and histological of idiosyncratic DILI Examples of drugs hepatitis necrosis, with or and hepatitis isoniazid, hepatitis or necrosis, the with and necrosis, Immune checkpoint inhibitors or in or with either or Acetaminophen, hepatitis by hepatitis to chronic hepatitis or hepatitis with hepatitis, or than with with the of hepatitis, inhibitors, inhibitors in and/or with or or injury and Amoxicillin‐clavulanate, cholestatic hepatitis Mixed in and/or with more and injury inhibitors, injury with and liver in the or with to the and Mixed and of and methotrexate of and in a of with necrosis, in of hepatic of and by a either and or and DILI of to chronic hepatitis isoniazid, with of the or to for most common are and and A nodular of liver injury after drug is in DILI of injury after the to the is a of the suspect drug with reported cases in such as The provides a of the clinical features of idiosyncratic DILI to more than 1000 prescription drugs and HDS that are from the In addition, provides a of hepatotoxicity have been to a as 50 or more of liver and approved Guidance statements DILI is as one of the or or ALP if is on with AST, ALT, or ALP or with AST, ALT, or 14 drugs cause liver injury the months of use but have latency or even after drug of a patient with suspected DILI should include a medication and HDS the Idiosyncratic DILI cases should be by the at = and cholestatic which can the of causes of liver injury. causes of liver injury is in all DILI including for hepatitis, metabolic liver and 17 drugs have been with and which be in the for a of the literature on liver injury to 1000 prescription drugs and more than Liver in suspected DILI Although a liver is not to DILI, can be in other causes of liver and in the in a diagnosis of DILI in cases of clinical medications are with histological of liver injury that can be on can also be when the liver or do not with drug or the patient and can be used to the of liver a liver other causes of or that can the clinical or to liver The in the of a liver for a patient with suspected DILI is to the of injury, as are various histological of to of DILI cases with acute liver injury and of which acute or chronic hepatitis with or This histological various of hepatitis, necrosis, and or (Table A diagnostic when to from features observed in such as hepatitis, of an the of and are also observed among DILI cases and in DILI and are not for more and be by cholestasis, a chronic and the hepatitis be by The of in from DILI to as events have been The histological in DILI is injury, with hepatitis and with on liver is not and the of with being in than is an of and liver are in DILI because of and a third of those with of DILI even DILI acute cholestasis, chronic cholestasis, and acute cholestatic In the acute cholestatic bland be the histological and as in and the cholestatic hepatitis is the of by more In chronic cholestasis, the and have injury or to the is common histological manifestations of DILI include fatty liver and be which is related to injury, and or usually not to on nor with and only liver can its DILI in injury to the development of nodular and as and as either acute or chronic appears as and its development is with and histological features and be seen on a liver in a patient with suspected DILI. These include of and of as are in the of or chronic of and is form of DILI seen as with to an adaptive response to drugs and the of DILI and A liver can provide The of and of reaction are with the of and is with These observations also in a of DILI case to chronic DILI is the of liver after months from DILI independent of the of liver injury, the DILI 1 year as the In contrast, a liver chronic liver when is or even on Guidance statements 19 Liver is not to a diagnosis of idiosyncratic DILI but be in DILI cases with a or and in those with diagnostic a is usually not in or A liver can the drugs based on histological and can exclude liver A spectrum of histological been reported in patients with DILI, and a drug be with more than a The of and on a liver in a patient with suspected DILI is with a more those who have or have A liver from a patient with DILI the mechanism of injury, as was seen with the that to and provides an to the that a drug or HDS is the cause of liver injury by the laboratory, and clinical features following and of other more common causes of liver A is to the data and a is that from to of clinical have been developed for DILI and TABLE - in the and to liver injury to to to to liver injury to to to to to to causes of liver injury to to to to or of hepatotoxicity to to to to medication to manifestations to of to to 17 to DILI 17 to from the are and are from and clinical diagnostic not 1 of those 2 (i.e., only or is by in risk not was developed only for drug cases and not for TABLE - Liver expert % 2 likely and but not data support data but with more likely data data Source: Adapted from et be using various with to features from the (Table The also as the for of was in provides a varying from to and the with by injury. The was in and that a from to with the The to the but medications and for manifestations. There are but the of is more with the and the The is not used in clinical practice because was to be to the The is a of the with the of and from to Although the was to be to the in patients, is not currently used of because of the lack of available and The is currently available online. This a of to and at as well as the in independent data The risk and an of competing causes to and diagnostic is and to models include the for by the which have not in DILI or clinical practice because of lack of liver expert The developed by the of DILI that from to (Table of expert include the to for drug and of including liver in to This been to be as as the expert is available in clinical of in DILI There are in DILI with the For example, patients be drugs or HDS products the drugs for In addition, and lack of of HDS chronic liver also is not for by the do not of and with hepatotoxicity to drugs and HDS which to by expert the clinical features of a patient with of the of the suspect other causes of liver regarding the include the of its which developed using a of cases with drug and not by or Furthermore, of other causes of liver injury have been or when the For example, is for for acute or and are data to of risk as in the of the have been in the which by the the for for but the risk of and for all The also provides more guidance in the hepatotoxicity of the suspect drug but is not for use in patients with chronic liver being available is that this electronic provide more and using and data to be in of the the spectrum of DILI from that seen in the United States and (Table or in cases with more than a suspect Furthermore, the not been in liver injury and its and needs to be Guidance statements are three used and its and the and of suspect drug and other drug or HDS an of the laboratory, and histological features at and of competing causes of liver injury. The expert developed by the is used in clinical practice and in but the need for its The and more diagnostic with the but risk of and that are of The is a that more and than but studies are suspect drug is in clinical but when in HDS hepatotoxicity HDS are used the on a For example, more than of the of used dietary supplements in the in a supplements products as well as of different that be and Although have been used for by different for HDS are products that are the of in or of Although most supplements are instances of from individual and products have been including acute liver Epidemiology of HDS use and liver injury American more than on herbal products in on HDS of all cases of liver injury in of products in the United States is are not to that is and only need to to the based on The and provides the regulatory for and in the United The regulatory in as in a For example, in the the of a on the a of use, with of the of injury to a dietary can be reported by and to the US and the These are by the for and when the of a is regulatory actions can be the including of a from the in the most in the diagnosis of liver injury are by to is well that supplements are to or of include and other that are not on the include and usually from the of usually to effect in with the for is the of in products for the of HDS as a of varying leading to latency of to a the of injury can be variable because of the of the the lack of and of liver injury from these over‐the‐counter supplements cause the injury to by patients and HDS and outcomes Many of the most instances of hepatotoxicity from HDS have from products such as and dietary supplements are in that is of that and the such that the with the at be substantially Furthermore, the that supplements implicated in liver injury are The are being to the that from that are or as in (Table TABLE - HDS products and implicated in hepatotoxicity Common or liver reported and or reported and or Mixed one case of reported of hepatotoxicity to of The the of The of the is for its but is likely also for liver injury. cases of liver injury to have been with the most cases being those in which injury following A analysis of cases in the to of the of as being and with a with This risk also been with hepatotoxicity in individuals to a herbal to and studies have that patients with HDS leading to liver are more likely to or to patients with drug This be to of the as the cause of liver injury or of HDS to medical Guidance statements HDS are used with of in the United States and other countries leading to the of and can cause hepatotoxicity that can have variable clinical, laboratory, and histological in the and the which a is the of an individual patient HDS been with hepatotoxicity to in populations and hepatotoxicity in and of idiosyncratic DILI and with idiosyncratic DILI with a drug latency of drugs have an In registry nearly of patients have acute injury, the with either an acute or cholestatic injury (Table 2). a diagnosis of idiosyncratic DILI is the suspect should be patients with acute liver injury need to be for and those with and should be to a liver because of low of drug most patients with DILI to of patients with DILI with be at risk of because of liver or medical studies have also that patients with higher and as well as at are at risk for In addition, have that patients with liver are at risk of hepatic in a of and have been to patients with DILI at risk of hepatic clinical features are with a of such as the of and on liver TABLE - for patients with idiosyncratic DILI Proposed for liver and = for patients and = ALP should be not to cases and = = and a 2 = and used for the for Liver available at DILI is as in liver or the of or histological of ongoing injury months after DILI The incidence of chronic DILI in the was at with and patients with a cholestatic liver injury at being at A of patients (i.e., also of leading to which can be and reported of chronic DILI include hepatic from and to or which to of during (Table of idiosyncratic patients with DILI care is for all patients with acute DILI, including the use of and as with and or for and (Table A of should be in adult patients with in of outcomes in a randomized controlled in patients with randomized of patients with DILI also a of but with outcomes with a of in with for its use in at a dose of 1 of are to patients with immune‐mediated hypersensitivity including the as drug reaction with and In a of (i.e., with be of in patients with features on as well as for patients with DILI from and kinase inhibitors (Table of and DILI but randomized controlled trials are to the dose and TABLE - for patients with idiosyncratic DILI population APAP to 2 per in if to in Prospective data likely patients to if with for duration in studies in hypersensitivity checkpoint with features 1 per of for of for dose and duration not but can be in months with by 50 use cases with 1 for 14 once from other medications and patients or use to with for to a of to in and with acute liver DILI, liver drug reaction with and immune checkpoint not of In to general be for For example, are data clinical with for with to In addition, be of for patients with hepatotoxicity because of its and is a of from that and use been with in patients with following with Guidance statements and with idiosyncratic DILI with an acute

Meaningful speech, as exemplified in object naming, calls on knowledge of the mappings between word meanings and phonological forms. Phonological errors in naming (e.g. GHOST named as 'goath') are commonly seen in persisting post-stroke aphasia and are thought to signal impairment in retrieval of phonological form information. We performed a voxel-based lesion-symptom mapping analysis of 1718 phonological naming errors collected from 106 individuals with diverse profiles of aphasia. Voxels in which lesion status correlated with phonological error rates localized to dorsal stream areas, in keeping with classical and contemporary brain-language models. Within the dorsal stream, the critical voxels were concentrated in premotor cortex, pre- and postcentral gyri and supramarginal gyrus with minimal extension into auditory-related posterior temporal and temporo-parietal cortices. This challenges the popular notion that error-free phonological retrieval requires guidance from sensory traces stored in posterior auditory regions and points instead to sensory-motor processes located further anterior in the dorsal stream. In a separate analysis, we compared the lesion maps for phonological and semantic errors and determined that there was no spatial overlap, demonstrating that the brain segregates phonological and semantic retrieval operations in word production.

Medical Writings: Book Notes20 April 2004Applied Longitudinal Data Analysis for Epidemiology: A Practical GuideLeonard E. Braitman, PhDLeonard E. Braitman, PhDFrom Albert Einstein Healthcare Network, Philadelphia, Pennsylvania.For the Longitudinal Data Study Group; e-mail, .Search for more papers by this authorEmail the corresponding author at [email protected]Author, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-140-8-200404200-00042 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Twisk JW. 301 pages. New York: Cambridge Univ Pr; 2003. ISBN 0521525802. $40.00. Order phone 845-353-7500.Field of medicine: Epidemiology and biostatistics.Format: Softcover book.Audience: Physician researchers, epidemiologists, and analysts of biomedical data.Purpose: To provide a cogent nontechnical introduction to the analysis of clinical and epidemiologic longitudinal studies.Content: In longitudinal studies, “the outcome variable is measured in the same individual on several different occasions” so that the development of a certain outcome can be studied over time and be related to development of other variables. The book's chapters on continuous, binary, and categorical and count outcomes begin ... Author, Article, and Disclosure InformationAffiliations: From Albert Einstein Healthcare Network, Philadelphia, Pennsylvania.For the Longitudinal Data Study Group; e-mail, [email protected]net. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 20 April 2004Volume 140, Issue 8Page: 676KeywordsComputer softwareComputersEpidemiologyHealth careLongitudinal studiesMarkov modelsRegression analysisSoftware toolsStatistical dataStatistical methods ePublished: 20 April 2004 Issue Published: 20 April 2004 Copyright & PermissionsCopyright © 2004 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...

Drug-induced liver injury is one of the more challenging forms of liver disease, both in diagnosis and management. Several hundred drugs, nutritional supplements, and herbal medications have been implicated in causing liver injury. Their clinical presentation can be highly variable and mimic almost any form of liver disease. The literature on drug-induced liver injury is large, but spread among many journals in many different specialties and languages. Excellent textbooks are available, but they are rapidly out-of-date and not always easily accessed. Drug-induced liver injury is also a challenging area of research, in that most cases are unpredictable, idiosyncratic, and rare and thus difficult to study. As a consequence, there have been few advances in the understanding, control, or prevention of drug-induced liver injury in the last 50 years. DILIN, Drug-Induced Liver Injury Network; NIDDK, National Institute of Diabetes and Digestive and Kidney Diseases; NLM, National Library of Medicine. As a part of a long-term initiative in promoting basic and clinical research on drug-induced liver injury, the Liver Disease Research Branch of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in collaboration with the National Library of Medicine (NLM) has created the LiverTox website (www.livertox.nih.gov) (Fig. 1). LiverTox is a multilayered, informational, and interactive website with comprehensive and evidence-based information on drug, dietary supplement, and herbal-induced liver injury that is freely accessible to physicians, researchers, and the public. The website is particularly designed for use by physicians and healthcare professionals who might rarely see patients with drug-induced liver injury, including family practitioners, internists, pediatricians, psychiatrists, surgeons, specialists, and subspecialists in all areas of medicine. The website will also be helpful to hepatologists and experts in hepatotoxicity by providing a complete and accurate summary of information about the clinical features of liver injury for each medication, along with a complete and annotated list of references. Finally, LiverTox will be helpful to patients seeking information on liver injury due to drugs. The LiverTox website. LiverTox consists of three major components: (1) an introductory and background section, (2) separate records on the hepatotoxicity of individual drugs, and (3) an interactive section that allows for submission and assessment of cases. The introductory and background section includes an overview and detailed discussion of the problem of drug-induced liver injury: its frequency, major causes, epidemiology, natural history, diagnosis, and management. The section provides a description of the principal clinical and histologic patterns of liver injury (phenotypes), standardized definitions of terms used, and discussion of methods to diagnose and judge severity and causality in drug-induced liver injury. This section includes specific and detailed information about formal causality assessment instruments such as the Roussel Uclaf Causality Assessment Method (RUCAM), the Maria and Victorino Clinical Scale (M&V), the Naranjo Adverse Drug Reaction Probability Scale, and the Drug Induced-Liver Injury Network (DILIN) Causality Process. The website provides printable copies of the actual instruments, discussion of their relative strengths and weaknesses, and detailed instructions on their completion (manual of operations). The bulk of the LiverTox website consists of individual records on ∼650 different medications, dietary supplements, and herbals. The specific agents are searchable using both generic and trade names. The agents discussed include all of the major known causes of drug-induced liver injury as well as the most commonly used medications in the United States (prescription and nonprescription and whether or not they cause liver injury). Limited numbers of the many drugs, herbals, and nutritional supplements available only outside of the United States are discussed in LiverTox based upon whether they have been implicated in cases of hepatotoxicity. Each drug record is a concise summary (200-400 words) about the drug class, mechanism of action, indications, dose-regimens, frequency of use, and common side effects. This introduction is followed by a concise description of the hepatotoxicity associated with the agent, including its frequency, clinical patterns, and course followed by a brief overview of the known or suspected mechanisms of injury from the medication. A final paragraph summarizes the prognosis and outcome of liver injury from the agent and gives a brief discussion of management. This overview is followed by one to four actual case reports taken from the published literature or from the DILIN Network. The drug record also includes chemical information with the drug structure and specific Internet links to the approved product labeling (package insert). Each drug record concludes with a comprehensive list of scientific articles and publications on hepatotoxicity of the medication prepared by the NLM and annotated by NIDDK staff. The final component of LiverTox is an interactive section that allows clinicians to submit a case report or to make suggestions and comments about the website. Submission of a case requires registration and assignment of a password. The submission uses a highly structured method with cues to enter the specific information necessary to fully assess the liver injury and judge severity and causality. Information sought includes the name of the drug, dates it was started and stopped, dates of onset of the drug-induced liver injury, pertinent demographic and medical history, initial and serial laboratory tests, and specialized testing and imaging results. The LiverTox website then produces a computer-generated history, a table of serial laboratory results, a graphic display of the course of the illness, and calculations of latency, time to recovery, severity, causality (RUCAM score), and data completeness. The submission can also generate an official MedWatch report, if requested, so as to include the case in the official Food and Drug Administration's (FDA) Adverse Event Reporting System (AERS). Unlike the typical MedWatch report, however, submissions made through LiverTox will be specific for liver-related adverse events and will provide all of the information necessary to adequately assess liver-related adverse drug events. The submitted cases will be maintained in a searchable database available to the registrants for analysis. This database will provide a means of monitoring the frequency and secular trends in the incidence of drug induced-liver injury and permits analysis of clinical features and outcomes of the submitted cases. Finally, LiverTox allows for submission of comments regarding the content of the website which will aid in the updating and improvement in the information provided. LiverTox became available online in April 2012 and was released officially as of October 1, 2012. At the time of release, the text of LiverTox contained over one million words, provided information on more than 650 medications, and included over 12,000 annotated references. LiverTox is a work-in-progress and will continue to add new drug records, references, and information in the years ahead. Comments about the accuracy and completeness of LiverTox and suggestions for improvement are welcomed. The creators of LiverTox hope that the website will be a practical and widely used tool for improving diagnosis, management, prevention, and treatment of drug-induced liver disease. The ultimate purpose of LiverTox is to provide a stimulus and structured basis for future clinical and basic research into this important but often neglected cause of liver disease.

OBJECTIVE: To determine patient, institution, and machine characteristics that contribute to variation in radiation doses used for computed tomography (CT). DESIGN: Prospective cohort study. SETTING: Data were assembled and analyzed from the University of California San Francisco CT International Dose Registry. PARTICIPANTS: Standardized data from over 2.0 million CT examinations of adults who underwent CT between November 2015 and August 2017 from 151 institutions, across seven countries (Switzerland, Netherlands, Germany, United Kingdom, United States, Israel, and Japan). MAIN OUTCOME MEASURES: Mean effective doses and proportions of high dose examinations for abdomen, chest, combined chest and abdomen, and head CT were determined by patient characteristics (sex, age, and size), type of institution (trauma center, care provision 24 hours per day and seven days per week, academic, private), institutional practice volume, machine factors (manufacturer, model), country, and how scanners were used, before and after adjustment for patient characteristics, using hierarchical linear and logistic regression. High dose examinations were defined as CT scans with doses above the 75th percentile defined during a baseline period. RESULTS: The mean effective dose and proportion of high dose examinations varied substantially across institutions. The doses varied modestly (10-30%) by type of institution and machine characteristics after adjusting for patient characteristics. By contrast, even after adjusting for patient characteristics, wide variations in radiation doses across countries persisted, with a fourfold range in mean effective dose for abdomen CT examinations (7.0-25.7 mSv) and a 17-fold range in proportion of high dose examinations (4-69%). Similar variation across countries was observed for chest (mean effective dose 1.7-6.4 mSv, proportion of high dose examinations 1-26%) and combined chest and abdomen CT (10.0-37.9 mSv, 2-78%). Doses for head CT varied less (1.4-1.9 mSv, 8-27%). In multivariable models, the dose variation across countries was primarily attributable to institutional decisions regarding technical parameters (that is, how the scanners were used). CONCLUSIONS: CT protocols and radiation doses vary greatly across countries and are primarily attributable to local choices regarding technical parameters, rather than patient, institution, or machine characteristics. These findings suggest that the optimization of doses to a consistent standard should be possible. STUDY REGISTRATION: Clinicaltrials.gov NCT03000751.

Abbreviated Breast MRI vs Digital Breast Tomosynthesis for Breast Cancer Detection in Women With Dense Breasts

PURPOSE: To investigate differences in attitudes, preferences, and behaviors regarding end of life in terminally ill patients and their designated family caregivers. PATIENTS AND METHODS: 68 African-American and white patients with stage III-B or IV lung or stage IV colon cancer and 68 patient-designated family caregivers interviewed between December 1999 and May 2001. RESULTS: White patients were more likely to have a durable power of attorney (34% v 8%, P =.01) and were more likely to have a living will (LW; 41% v 11%, P =.004) than were African-American patients. More African-American than white patients desired the use of life-sustaining measures (cardiopulmonary resusitation [CPR], mechanical ventilation, tube feeding) in their current condition (all P >.12). In a near-death condition, African-American patients were more likely than white patients to desire each of the life-sustaining measures (all P <.004). There was no patient-caregiver agreement beyond chance regarding preferences for initiation of CPR, tube feeding, or mechanical ventilation in the patient's current condition or in the near-death condition. In the near-death condition in patients without LWs, there was disagreement in 46% of patient-caregiver pairs about CPR, in 50% about mechanical ventilation, and in 43% about tube feeding. CONCLUSION: Although most patients and families endorse the primacy of the patient in decisions at end of life, the majority do not take supporting actions. Disagreements between patients and families about the use of life-sustaining measures in patients without LWs may result in patients' preferences being superseded at end of life.

BACKGROUND: Although studies have reported ethnic differences in approaches to end of life, the role of spiritual beliefs is less well understood. PURPOSE: This study investigated differences between African American and White patients with cancer in their use of spirituality to cope with their cancer and examined the role of spiritual coping in preferences at end-of-life. METHODS: The authors analyzed data from interviews with 68 African American and White patients with an advanced stage of lung or colon cancer between December 1999 and June 2001. RESULTS: Similar high percentages of African American and White patients reported being "moderately to very spiritual" and "moderately to very religious." African American patients were more likely to report using spirituality to cope with their cancer as compared to their White counterparts (p = .002). Patients who reported belief in divine intervention were less likely to have a living will (p = .007). Belief in divine intervention, turning to higher power for strength, support and guidance, and using spirituality to cope with cancer were associated with preference for cardiopulmonary resuscitation, mechanical ventilation, and hospitalization in a near-death scenario. CONCLUSIONS: It was found that patients with cancer who used spiritual coping to a greater extent were less likely to have a living will and more likely to desire life-sustaining measures. If efforts aimed at improving end-of-life care are to be successful, they must take into account the complex interplay of ethnicity and spirituality as they shape patients' views and preferences around end of life.

Palliative care is defined as multidisciplinary, specialized medical care that addresses the physical, spiritual, and psychosocial needs of patients with serious illness and their caregivers.[1, 2] The benefits of palliative care are increasingly recognized across disease states and for patients with decompensated cirrhosis (DC).[3-5] This American Association for the Study of Liver Diseases (AASLD) guidance to providing palliative care for patients with cirrhosis was developed with the support and oversight of the AASLD Practice Guidelines Committee. The AASLD Practice Guidelines Committee chose to commission a guidance, rather than a guideline, because of the paucity of randomized controlled trials (RCTs) on this topic. AASLD guidelines are supported by systematic reviews of the literature, formal ratings of evidence quality and strength of recommendations, and, if appropriate, meta-analysis of results using the Grading of Recommendations Assessment Development and Evaluation system. In contrast, this document was developed by consensus of an expert panel and provides guidance statements based on formal review and analysis of the literature on the topics and questions related to the palliative care needs of patients with cirrhosis and their caregivers. Although palliative care can be considered regardless of the stage of cirrhosis, this guidance document predominantly addresses issues pertinent to adult patients with DC because this group bears considerable physical, psychosocial, and financial burden. We specifically focus on topics that are not covered in existing AASLD practice guidelines/guidance documents and thus refer the readers to the AASLD practice guidelines for specific recommendations for the diagnosis and management of ascites, hepatic encephalopathy (HE), hepatocellular carcinoma (HCC), and portal hypertension.[6-9] In addition, the complex palliative care needs for patients with HCC are not specifically addressed by this guidance, but are addressed by other guidelines.[10, 11] Palliative care can be provided at any stage of a serious illness and concurrently with disease-directed and curative treatments (including organ transplants). Over the past decade, the body of evidence supporting early palliative care has expanded to include persons with nonmalignant conditions, such as cirrhosis.[3, 4] Palliative care takes a comprehensive, person-centered approach to care, focusing on the aspects of care most important to patients and their families/informal caregivers. Because of this comprehensive scope, management typically relies on a team, including physicians, nurses, chaplains, social workers, and other providers. Table 1 illustrates the conceptual distinctions between primary and specialty palliative care. Specialty palliative care refers to care delivered by specialists with advanced palliative care skills such as board-certified palliative care physicians or palliative-certified nurses, social workers, pharmacists, and chaplains.[12] However, primary palliative care describes care aligned with the principles of palliative care (e.g., person-centered, communication-focused symptom management) that can be delivered by any medical professional.[12] The National Consensus Project for Quality Palliative Care defined eight core domains of high-quality palliative care around which this guidance is framed (Figure 1).[13, 14] Although all eight domains can apply to patients with DC, their relative importance may vary across the illness trajectory.[5, 15] Advance care planning (ACP) is a component of palliative care that involves the iterative and longitudinal process of medical decision making for patients and their families over the course of their illness trajectory.[16, 17] ACP includes identifying surrogate decision makers, illness education and prognostic disclosure, and formal documentation of goals for medical and end-of-life care (EoLC) through advance directives that center on the goals, values, and preferences of patients and their families.[17] Hospice is EoLC focused on allowing people in the last phases of incurable disease to live as fully and comfortably as possible.[14] Hospice is different than palliative care in that it focuses exclusively on comfort, rather than disease-directed curative treatment, and includes only persons with a life expectancy measured in months. In the USA, the hospice benefit is provided under Medicare Part A, and patients must have a defined, time-limited prognosis (certified by one or more physicians as ≤6 months).[18] DC is in many cases incurable, and life expectancy, which can be predicted with models such as the Model for End-Stage Liver Disease (MELD) and Child-Pugh-Turcotte scores, may be well below 6 months.[6, 19-21] Because of the poor prognosis of DC, many patients with DC qualify for hospice benefits, which can help support patients and their caregivers. Attention to patients' families and support persons, herein called caregivers, is a core value and component of palliative care (Figure 1). Caregivers are discussed in The National Consensus Project under the heading of clinical implications. Throughout this document, we address the role of caregivers in each aspect of palliative care. Caregivers of patients with DC often face under-recognized psychological, physical, and financial burdens.[22-27] Their symptoms include stress, anxiety, depression, insomnia, decreased health-related quality of life (HRQoL), and worse physical health.[23, 25-27] Psychological symptom burden among caregivers is associated with patients' alcohol use, encephalopathy, ascites, liver disease (LD) severity, repeated hospitalizations, prognostic uncertainty, and lack of information.[25-29] Caregivers of patients with DC report feeling unprepared to provide physical care, medication management, and transportation to their loved ones and often experience significant financial burdens.[23-25, 27, 30-32] Importantly, the financial, social, and psychological burdens of cirrhosis experienced by caregivers can continue to impact caregivers after patients die. As such, support for caregivers of patients with cirrhosis should start early and extend through the bereavement period. This support can include inquiring about how they are doing during a medical visit, acknowledging the challenges of caregiving, and referring to services for support. Hepatology providers should assess caregivers' goals and consider their needs. Being knowledgeable about and providing a list of ancillary services to caregivers is something that can occur in hepatology. Services of interest to caregivers may include pastoral care or spiritual support, mental health resources, bereavement support, grief counseling, caregiver support websites, and peer support groups. Cirrhosis is associated with poor HRQoL attributable to multiple physical, cognitive, psychological, and social stressors that are challenging to manage.[30, 33, 34] Although the prognosis for patients with DC is variable, with a 5-year mortality ranging from 20% to 80% across studies, the overall disease trajectory is progressive, with declining health and increasing symptom burden and frequent hospitalizations at the end of life.[19, 35-37] Though liver transplantation (LT) can be curative, few patients are ever waitlisted for or receive LT.[38] Palliative care needs of patients with cirrhosis and their caregivers are frequently underaddressed.[39] Only 11% of patients with cirrhosis receive specialty palliative care or hospice care referrals, and consultation often occurs very late in the disease course.[40-44] Consequently, patients with cirrhosis receive EoLC that is more resource intensive and invasive than that of patients with other serious, life-limiting illnesses.[27, 44, 45] There are several barriers to palliative care implementation that have been identified specifically in hepatology. These barriers include a shortage of specialty palliative care providers, absence of evidence-based referral criteria, lack of role clarity between specialists, stigma that palliative care is synonymous with "giving up" on curative treatments, lack of provider training, competing demands on providers' time, and prognostic uncertainty.[22, 27, 41, 46-50] In addition, many of the symptoms experienced by persons with DC are highly liver specific and managed longitudinally by liver teams. This is in contrast to oncology practice models in which palliative care teams frequently have a key role managing malignant pain syndromes throughout the disease course.[51] Transplant evaluation and listing may also present a unique barrier to palliative care for patients with cirrhosis, related to the perceived incompatibility of transplantation and palliative care. One study found that patients with cirrhosis undergoing transplant evaluation received lower-quality EoLC.[52] Similarly, a qualitative study of 42 patients and 46 clinicians found that transplant teams avoided discussing nonaggressive treatment options with patients, leading caregivers to feel unprepared to support their loved ones at the end of life.[53] Finally, hepatology training does not routinely include palliative care training, and palliative care competencies for hepatologists have not been developed. Despite these barriers, hepatology clinicians, especially those with a longitudinal relationship with patients and families, can play a key role in delivering primary palliative care to address patients' and caregivers' needs. Some elements of primary palliative care that could be provided as part of routine hepatology care include evaluating and managing symptoms, identifying and documenting surrogate decision makers, eliciting patient preferences about treatment and aligning care plans with these preferences, providing counseling about what to expect in the future, and referring patients for social services to increase support in the community. A growing body of evidence supports the integration of curative and palliative care approaches for patients with DC (Table 2).[54-57] Observational studies have demonstrated reduced resource use, decreased symptoms, and improved HRQoL for patients with cirrhosis who receive palliative care services.[50, 58, 59] A single-arm, single-center study found that outpatient specialty palliative care referral for all patients undergoing LT evaluation resulted in improved physical and psychological symptom scores.[54] Likewise, an outpatient primary palliative care intervention led by hepatology nurses with palliative care and communication training was feasible and acceptable to recently discharged patients and their health care teams.[57] The intervention was associated with improved HRQoL, care coordination, coping, and anticipatory planning. Two studies that examined inpatient palliative care also had favorable findings. A specialty palliative care intervention in a single academic surgical intensive care was associated with earlier consensus around goals of care, reduced length of stay, and earlier provision of comfort-focused care without any change in mortality.[55] Caregivers also reported having more time to say goodbye.[55] This intervention included early consultation with an interdisciplinary palliative care team, who provided a comprehensive evaluation within 24 h of admission, including discussion of prognosis, caregiver support, ACP, and symptom assessment. The palliative care team then participated in daily rounds and conducted a caregiver meeting within 72 h of admission. To the best of our knowledge, Shinall et al. conducted the only RCT of a palliative care intervention in inpatients with cirrhosis. The intervention included patients with a life expectancy <12 months and involved an inpatient specialty palliative care consultation and monthly postdischarge follow-up with the palliative care team, who reviewed medications, symptoms, and goals of care.[56] The comparison group received usual care that included palliative care at the discretion of the hepatologist (19% received palliative care), and results were analyzed on an intention-to-treat basis. Although this trial was prematurely terminated because of low enrollment, patients in the intervention group had significantly reduced readmission rates and more days alive outside of the hospital as compared with patients in the control group.[56] The researchers cited barriers to enrollment including patients and family feeling overwhelmed at the time of index hospitalization, concerns about whether insurance would cover palliative care, challenges with identifying caregivers, and a narrow screen-in to enrollment window.[56] Few interventions have included caregivers of patients with cirrhosis. A randomized trial of a cognitive behavior-based coping intervention delivered by trained nurses or social workers by telephone (as compared with LD education as an attention control) did not significantly impact mental health or HRQoL for patients or caregivers.[60] However, a mindfulness-based stress reduction and supportive group therapy intervention was associated with improved patient and caregiver mental health symptoms and HRQoL.[61] More trials are needed to understand how to best help caregivers of patients with cirrhosis. Although these early data generally support the effectiveness of palliative care interventions for patients with cirrhosis and their caregivers, larger trials are needed to further characterize the optimal timing and content of these interventions. Conducting palliative care trials in this population is especially challenging for several reasons. Such trials are resource and time intensive; the population is heterogeneous (in terms of illness severity, trajectory, and treatments) with considerable prognostic uncertainty; trials require rigorous, potentially intrusive study monitoring; and there is limited interest in the topic from commercial sources, among others. The ongoing PAL LIVER trial, funded by the Patient-Centered Outcomes Research Institute, is recruiting patients with advanced liver disease and their caregivers from 18 clinical centers in the United States, comparing the effectiveness of palliative care delivered by specialists versus trained hepatologists for improving patients' HRQoL, symptoms, caregiver burden, and health care use.[62] PAL LIVER and other studies are needed to establish which palliative outcomes matter most to patients and their caregivers. As cirrhosis-specific data accumulate, trials of palliative care in other similar populations may help to inform care. Over the past decade, several landmark studies have assessed the impact of multicomponent, interdisciplinary palliative care interventions in patients with advanced heart, lung, renal, and hematological diseases across multiple domains of palliative care (Table S1).[13, 14] Palliative care interventions have improved physical (e.g., fatigue, pain), psychological (e.g., depression, anxiety, and mood), social, spiritual, EoLC, ACP, caregivers' quality of life, and cost-effectiveness of care.[63-77] However, evidence for improvement in religious, existential, and cultural aspects of care remains limited.[14] In general, interventions with a comprehensive evaluation by palliative care specialists, including nurses, social workers, or physicians, were associated with improved quality of care and symptom management. ACP is a proactive, ongoing, collaborative process of decision making about health care preferences, goals, and values in the context of a life-limiting illness.[16, 17] Decisions around life-sustaining treatments, completing advance directives, and identifying surrogate decision makers are all part of ACP, which is based on continuous assessment and documentation of patients' personal values, preferences, and caregiver input.[14, 17] Written documentation (such as advance directives) can help ensure that these values and preferences are respected across clinical teams and health care settings. ACP interventions are also associated with greater concordance between patient preferences and care delivery, completion of advance directives, and improved end-of-life management.[78] Thus, facilitating ACP is an important component of caring for persons with DC. Table 3 outlines key ACP definitions, and Figure 2 illustrates key components of ACP, including assessing patients' capacity and willingness to engage in ACP, identifying surrogate decision makers who should be present for conversations, and eliciting and documenting preferences.[14, 17, 79] It is critical to document this information early in the trajectory of cirrhosis, before the onset of encephalopathy, for example. It is also notable that a person who is present at an outpatient appointment or at the hospital bedside may not be the person that local surrogacy laws identify as a default surrogate or the person that the patient wants to be making decisions on their behalf. Ideally, clinicians with a continuity relationship with a patient and an understanding of their prognosis should regularly engage in conversations regarding prognosis and goals of care.[14] Unfortunately, these conversations often do not occur until the end of life for patients with DC.[36, 43, 48, 53, 59, 80-83] Insufficient and delayed discussions likely contribute to receipt of high-intensity EoLC.[84] Conversely, early palliative care referral has been associated with higher rates of goals-of-care discussions in retrospective cohort studies.[58, 59] One pilot trial found that provider education and standardized documentation were associated with a 23% increase in advance directive completion and a 51% increase in goals-of-care conversations.[85] Similarly, specialty palliative care consultation with transplant evaluation led to early identification of surrogate decision-maker and ACP documentation.[54] In a single-site pilot RCT, a 5-min ACP video decision support tool for transplant-ineligible patients with DC significantly improved their knowledge about EoLC, informed their preferences for resuscitation and intubation, and was highly acceptable to patients (Table 2).[86] An expert panel, supported by modified Delphi methods, provided guidance on the timing of ACP in patients with DC.[87] They recommended that advance directives should be completed as early in the course of cirrhosis as possible and preferably before hepatic decompensation and potentially loss of decision-making capacity. Similarly, goals-of-care discussions, with or without the support of specialty palliative care services, should be prioritized when LT is being considered or if death is anticipated within 6 months.[87, 88] Resources that can support hepatologists in leading ACP include patient-facing visual aids, communication training, and goals-of-care communication training workshops and webinars (Table S2).[16, 89-95] Communication skills are a key component of ACP and palliative care. Uncertainty of the illness trajectory in cirrhosis complicates communication about prognosis. Furthermore, care preferences can fluctuate with a patient's changing clinical status. Clinicians may struggle to effectively communicate the complexity and uncertainty associated with the fluctuating and unpredictable clinical course—indeed, 80% of respondents in a large survey of hepatologists felt that the communication training they had received (in this study, around end-of-life communication) was inadequate.[48] Patients and families struggle to get the information they need or desire, particularly in the setting of critical illness.[84] Several published communication frameworks may be well suited to address the unpredictability associated with cirrhosis (Figure 3).[89-95] Although communication training is associated with improved person-centered outcomes, more work is needed to tailor approaches to training and communication in hepatology settings.[90] The medical team should also ensure that communication occurs in the language preferred by patients and families using a professional medical interpreter, if the preferred language is different than that of the provider.[96] Psychosocial, spiritual, and cultural aspects of care are understudied in all patient populations, despite being important to patients.[44] In general, an interdisciplinary, person-centered approach is recommended when addressing these potentially sensitive topics, and it is important to be aware of the local supportive care resources through ongoing conversations with social work, pharmacy, patient navigation, chaplaincy, spiritual care, and pastoral care, where available.[14] A key component of person-centered palliative care is assessing patient and caregiver psychosocial needs across social determinants of health, including financial stability, employment, food insecurity, housing, transportation, and access for necessary equipment/supplies.[14] Assessing financial burden is also important for patients with DC, who often report high rates of cost-related nonadherence to medications and food insecurity.[31, 97, 98] The question "Are you having difficulty paying for your medical care?" is an effective early screen for financial burden and engaging social work and pharmacy services to help support patients and their families in mitigating financial stress.[31, 97, 98] Cirrhosis carries a significant financial burden for patients and families. Patients with DC require a high number of informal caregiving hours each week compared with persons with other illnesses, which can lead to difficulty maintaining employment for family caregivers.[31] Patients differ in their beliefs and approaches to ACP, palliative care, and death and dying related to their spiritual and cultural frames of reference.[20] The limited relevant spirituality research in cirrhosis includes two qualitative studies that identified spirituality as a key determinant of HRQoL and perceptions of medical care.[99, 100] General palliative care guidelines recommend routinely evaluating the spiritual and cultural needs of patients and their families through understanding their preferred communication preferences, values, of spiritual and approaches to death and medical chaplaincy, and spiritual care providers as in the care of patients and families may in providing sensitive palliative care that also their spiritual beliefs and and can also help to support caregivers during the time of Although and spiritual care providers are not across health care patients and their families to include or spiritual from the to in their care can be in work has demonstrated and in palliative care and pain More work is needed to the to which these in health care access versus cultural or in preferences for care. However, a understanding of patients' spiritual and cultural needs may ACP and palliative care to patients with DC from management is a core component of caring for patients with DC, who from often on a systematic the most frequently reported symptoms are pain psychological symptoms anxiety, and Because often not all symptoms can be addressed in a single clinical it is important to an approach to and Although a review of outcomes and is of for this the approach to addressing symptoms may include to questions about or Several such have been in palliative care, including the Assessment of Care and the Assessment Clinicians should assess symptom severity, and and the impact of to the are experienced through the cognitive and of the patient and must be in the context of the symptom ratings should be relative to past ratings from the person over Because clinicians may be with the management of symptoms, particularly at the end of life, a team approach and early to palliative care, social work, and other services are important in providing comprehensive palliative care to patients and In the we the most symptoms and their such as physical therapy and cognitive should be when that these can address multiple symptoms with can be challenging in patients with cirrhosis, a approach is generally Table of and of medications for palliative care of patients with The of pain in persons with cirrhosis can be and Cirrhosis can lead to or pain through ascites, and hepatic or because of of of pain can but the most are (e.g., and (e.g., Table the approach to pain management for patients with cirrhosis, which can be and The in addressing pain is to assess and (e.g., ascites, local and The of pain also the pain is more to therapy than pain management often involves including management, physical and As such, pain (e.g., pain to management, of or with associated may require consultation with palliative care specialists or in pain management. approaches to pain management have not been specifically in patients with cirrhosis, but pain cognitive and physical and therapy are and in other populations for the management of approaches have been in cirrhosis, but is for pain and in Although there are data about the of in patients with cirrhosis, studies of that is likely in patients with and a review the benefits of for cirrhosis more Similarly, can be for limited such as physical therapy remains Because of hepatic and the of encephalopathy, and are generally preferred for management of pain in patients with are generally for These can include as discussed or or Although there are data supporting the of in patients with cirrhosis, they are generally considered and have demonstrated in other are to a of and for (e.g., and pain (e.g., are effective and have limited likely in persons with to 2 daily as 6 as is generally and should be the therapy for pain in this However, patients should be informed that other and may include which the daily are among the most medications in patients with studies the impact of in patients with cirrhosis attributable to of and One trial of patients with cirrhosis demonstrated that of of or was associated with significantly of and of and Thus, should be avoided in patients with cirrhosis. Although has been

Several pathologic conditions may manifest as an osteochondral lesion of the knee that consists of a localized abnormality involving subchondral marrow, subchondral bone, and articular cartilage. Although understanding of these conditions has evolved substantially with the use of high-spatial-resolution MRI and histologic correlation, it is impeded by inconsistent terminology and ambiguous abbreviations. Common entities include acute traumatic osteochondral injuries, subchondral insufficiency fracture, so-called spontaneous osteonecrosis of the knee, avascular necrosis, osteochondritis dissecans, and localized osteochondral abnormalities in osteoarthritis. Patient demographics, the clinical presentation, and the role of trauma are critical for differential diagnosis. A localized osteochondral defect can be created acutely or can develop as an end result of several chronic conditions. MRI features that aid in diagnosis include the location and extent of bone marrow edema, the presence of a fracture line, a hypointense area immediately subjacent to the subchondral bone plate, and deformity of the subchondral bone plate. These findings are essential in diagnosis of acute traumatic injuries, subchondral insufficiency fracture, and its potentially irreversible form, spontaneous osteonecrosis of the knee. If the lesion consists of a subchondral region demarcated from the surrounding bone, the demarcation should be examined for completeness and the presence of a “double-line sign” that is seen in avascular necrosis or findings of instability, which are important for proper evaluation of osteochondritis dissecans. Subchondral bone plate collapse, demonstrated by the presence of a depression or a fluid-filled cleft, can be seen in advanced stages of both avascular necrosis and subchondral insufficiency fracture, indicating irreversibility. Once the diagnosis is established, it is important to report pertinent MRI findings that may guide treatment of each condition. ©RSNA, 2018 An earlier incorrect version of this article appeared online. This article was corrected on August 23, 2018.