Saint Louis University Hospital

BACKGROUND: An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab--which blocks cytotoxic T-lymphocyte-associated antigen 4 to potentiate an antitumor T-cell response--administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma. METHODS: A total of 676 HLA-A*0201-positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. RESULTS: The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P=0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P=0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. CONCLUSIONS: Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)

BACKGROUND: Ipilimumab monotherapy (at a dose of 3 mg per kilogram of body weight), as compared with glycoprotein 100, improved overall survival in a phase 3 study involving patients with previously treated metastatic melanoma. We conducted a phase 3 study of ipilimumab (10 mg per kilogram) plus dacarbazine in patients with previously untreated metastatic melanoma. METHODS: We randomly assigned 502 patients with previously untreated metastatic melanoma, in a 1:1 ratio, to ipilimumab (10 mg per kilogram) plus dacarbazine (850 mg per square meter of body-surface area) or dacarbazine (850 mg per square meter) plus placebo, given at weeks 1, 4, 7, and 10, followed by dacarbazine alone every 3 weeks through week 22. Patients with stable disease or an objective response and no dose-limiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy. The primary end point was overall survival. RESULTS: Overall survival was significantly longer in the group receiving ipilimumab plus dacarbazine than in the group receiving dacarbazine plus placebo (11.2 months vs. 9.1 months, with higher survival rates in the ipilimumab-dacarbazine group at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%), and 3 years (20.8% vs. 12.2%) (hazard ratio for death, 0.72; P<0.001). Grade 3 or 4 adverse events occurred in 56.3% of patients treated with ipilimumab plus dacarbazine, as compared with 27.5% treated with dacarbazine and placebo (P<0.001). No drug-related deaths or gastrointestinal perforations occurred in the ipilimumab-dacarbazine group. CONCLUSIONS: Ipilimumab (at a dose of 10 mg per kilogram) in combination with dacarbazine, as compared with dacarbazine plus placebo, improved overall survival in patients with previously untreated metastatic melanoma. The types of adverse events were consistent with those seen in prior studies of ipilimumab; however, the rates of elevated liver-function values were higher and the rates of gastrointestinal events were lower than expected on the basis of prior studies. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00324155.).

RATIONALE: This initiative is focused on building a global consensus around core diagnostic criteria for malnutrition in adults in clinical settings. METHODS: In January 2016, the Global Leadership Initiative on Malnutrition (GLIM) was convened by several of the major global clinical nutrition societies. GLIM appointed a core leadership committee and a supporting working group with representatives bringing additional global diversity and expertise. Empirical consensus was reached through a series of face-to-face meetings, telephone conferences, and e-mail communications. RESULTS: A two-step approach for the malnutrition diagnosis was selected, i.e., first screening to identify "at risk" status by the use of any validated screening tool, and second, assessment for diagnosis and grading the severity of malnutrition. The malnutrition criteria for consideration were retrieved from existing approaches for screening and assessment. Potential criteria were subjected to a ballot among the GLIM core and supporting working group members. The top five ranked criteria included three phenotypic criteria (weight loss, low body mass index, and reduced muscle mass) and two etiologic criteria (reduced food intake or assimilation, and inflammation or disease burden). To diagnose malnutrition at least one phenotypic criterion and one etiologic criterion should be present. Phenotypic metrics for grading severity as Stage 1 (moderate) and Stage 2 (severe) malnutrition are proposed. It is recommended that the etiologic criteria be used to guide intervention and anticipated outcomes. The recommended approach supports classification of malnutrition into four etiology-related diagnosis categories. CONCLUSION: A consensus scheme for diagnosing malnutrition in adults in clinical settings on a global scale is proposed. Next steps are to secure further collaboration and endorsements from leading nutrition professional societies, to identify overlaps with syndromes like cachexia and sarcopenia, and to promote dissemination, validation studies, and feedback. The diagnostic construct should be re-considered every 3-5 years.

BACKGROUND: This initiative aims to build a global consensus around core diagnostic criteria for malnutrition in adults in clinical settings. METHODS: The Global Leadership Initiative on Malnutrition (GLIM) was convened by several of the major global clinical nutrition societies. Empirical consensus was reached through a series of face-to-face meetings, telephone conferences, and e-mail communications. RESULTS: A 2-step approach for the malnutrition diagnosis was selected, that is, first screening to identify at risk status by the use of any validated screening tool, and second, assessment for diagnosis and grading the severity of malnutrition. The malnutrition criteria for consideration were retrieved from existing approaches for screening and assessment. Potential criteria were subjected to a ballot among GLIM participants that selected 3 phenotypic criteria (non-volitional weight loss, low body mass index, and reduced muscle mass) and 2 etiologic criteria (reduced food intake or assimilation, and inflammation or disease burden). To diagnose malnutrition at least 1 phenotypic criterion and 1 etiologic criterion should be present. Phenotypic metrics for grading severity are proposed. It is recommended that the etiologic criteria be used to guide intervention and anticipated outcomes. The recommended approach supports classification of malnutrition into four etiology-related diagnosis categories. CONCLUSIONS: A consensus scheme for diagnosing malnutrition in adults in clinical settings on a global scale is proposed. Next steps are to secure endorsements from leading nutrition professional societies, to identify overlaps with syndromes like cachexia and sarcopenia, and to promote dissemination, validation studies, and feedback. The construct should be re-considered every 3-5 years.

BACKGROUND: We conducted a multicenter, randomized trial to compare preoperative chemoradiotherapy followed by surgery with surgery alone in patients with stage I and II squamous-cell cancer of the esophagus. METHODS: The preoperative combined therapy consisted of two one-week courses; each involved radiotherapy, in a dose of 18.5 Gy delivered in five fractions of 3.7 Gy each, and 80 mg of cisplatin per square meter of body-surface area, administered 0 to 2 days before the first day of radiotherapy. The surgical plan included one-stage en bloc esophagectomy and proximal gastrectomy by the abdominal and right thoracic routes, to be performed immediately after randomization in the group assigned to surgery alone and two to four weeks after the completion of preoperative chemoradiotherapy in the group assigned to combined therapy. RESULTS: A total of 297 patients entered the study; 11 were found to be ineligible, and 4 were lost to follow-up. Of the remaining 282, 139 were assigned to surgery alone and 143 to combined therapy. After a median follow-up of 55.2 months, no significant difference in overall survival was observed; the median survival was 18.6 months for both groups. As compared with the group treated with surgery alone, the group treated preoperatively had longer disease-free survival (P=0.003), a longer interval free of local disease (P=0.01), a lower rate of cancer-related deaths (P=0.002), and a higher frequency of curative resection (P=0.017). However, there were more postoperative deaths (P=0.012) in the group treated preoperatively with chemoradiotherapy. Three prognostic factors were found to influence survival in a multivariate analysis: the disease stage, based on computed tomography; the location of the tumor; and whether the surgical resection was curative. CONCLUSIONS: In patients with squamous-cell esophageal cancer, preoperative chemoradiotherapy did not improve overall survival, but it did prolong disease-free survival and survival free of local disease.

BACKGROUND: There is a need for close communication with relatives of patients dying in the intensive care unit (ICU). We evaluated a format that included a proactive end-of-life conference and a brochure to see whether it could lessen the effects of bereavement. METHODS: Family members of 126 patients dying in 22 ICUs in France were randomly assigned to the intervention format or to the customary end-of-life conference. Participants were interviewed by telephone 90 days after the death with the use of the Impact of Event Scale (IES; scores range from 0, indicating no symptoms, to 75, indicating severe symptoms related to post-traumatic stress disorder [PTSD]) and the Hospital Anxiety and Depression Scale (HADS; subscale scores range from 0, indicating no distress, to 21, indicating maximum distress). RESULTS: Participants in the intervention group had longer conferences than those in the control group (median, 30 minutes [interquartile range, 19 to 45] vs. 20 minutes [interquartile range, 15 to 30]; P<0.001) and spent more of the time talking (median, 14 minutes [interquartile range, 8 to 20] vs. 5 minutes [interquartile range, 5 to 10]). On day 90, the 56 participants in the intervention group who responded to the telephone interview had a significantly lower median IES score than the 52 participants in the control group (27 vs. 39, P=0.02) and a lower prevalence of PTSD-related symptoms (45% vs. 69%, P=0.01). The median HADS score was also lower in the intervention group (11, vs. 17 in the control group; P=0.004), and symptoms of both anxiety and depression were less prevalent (anxiety, 45% vs. 67%; P=0.02; depression, 29% vs. 56%; P=0.003). CONCLUSIONS: Providing relatives of patients who are dying in the ICU with a brochure on bereavement and using a proactive communication strategy that includes longer conferences and more time for family members to talk may lessen the burden of bereavement. (ClinicalTrials.gov number, NCT00331877.)

BACKGROUND: The Surviving Sepsis Campaign recommends targeting a mean arterial pressure of at least 65 mm Hg during initial resuscitation of patients with septic shock. However, whether this blood-pressure target is more or less effective than a higher target is unknown. METHODS: In a multicenter, open-label trial, we randomly assigned 776 patients with septic shock to undergo resuscitation with a mean arterial pressure target of either 80 to 85 mm Hg (high-target group) or 65 to 70 mm Hg (low-target group). The primary end point was mortality at day 28. RESULTS: At 28 days, there was no significant between-group difference in mortality, with deaths reported in 142 of 388 patients in the high-target group (36.6%) and 132 of 388 patients in the low-target group (34.0%) (hazard ratio in the high-target group, 1.07; 95% confidence interval [CI], 0.84 to 1.38; P=0.57). There was also no significant difference in mortality at 90 days, with 170 deaths (43.8%) and 164 deaths (42.3%), respectively (hazard ratio, 1.04; 95% CI, 0.83 to 1.30; P=0.74). The occurrence of serious adverse events did not differ significantly between the two groups (74 events [19.1%] and 69 events [17.8%], respectively; P=0.64). However, the incidence of newly diagnosed atrial fibrillation was higher in the high-target group than in the low-target group. Among patients with chronic hypertension, those in the high-target group required less renal-replacement therapy than did those in the low-target group, but such therapy was not associated with a difference in mortality. CONCLUSIONS: Targeting a mean arterial pressure of 80 to 85 mm Hg, as compared with 65 to 70 mm Hg, in patients with septic shock undergoing resuscitation did not result in significant differences in mortality at either 28 or 90 days. (Funded by the French Ministry of Health; SEPSISPAM ClinicalTrials.gov number, NCT01149278.).

“…the cause of steatosis, and not the fat accumulation by itself, produces cirrhosis”—Heribert Thaler, 19751 W ith nonalcoholic steatohepatitis (NASH), NASH cirrhosis, and NASH-related hepatocellular carcinoma becoming increasingly prevalent, the need for effective therapies has never been greater. Unfortunately, our understanding of what causes NASH at the molecular level remains mostly speculative, and thus our ability to design clinical trials that test rationally designed therapies is limited. More than a decade has passed since Christopher Day and Oliver James first proposed the oft-cited two-hit hypothesis of nonalcoholic fatty liver disease (NAFLD) to explain the pathogenesis of NASH.2, 3 According to this appealing hypothesis, the accumulation of lipid in the form of triglyceride is needed for the development of NASH and thus constitutes the first “hit” in this disease. The cause of injury in the setting of lipid-loaded hepatocytes was proposed to be oxidant stress leading to lipid peroxidation in the milieu of ample substrate. This second “hit” then triggers the necroinflammatory changes that we recognize histopathologically as NASH. Although this hypothesis has intuitive appeal, emerging data now suggests that in the liver, as in other organs, triglyceride accumulation in the form of lipid droplets truly is just an “innocent bystander” in the processes leading to cellular injury and inflammation,4, 5 an explanation presciently suggested by the eminent Austrian pathologist Heribert Thaler,1 considered by others,6 and acknowledged as a viable alternative by Day and James when they proposed the two-hit hypothesis.3 Convincing evidence for a central role of oxidant stress and lipid peroxidation in causing steatohepatitis has also not been established. A decade of research has confirmed that these processes occur,7 but studies have been unable to prove that oxidant stress or lipid peroxidation are necessary for the development of steatohepatitis in humans. As an alternative hypothesis, emerging evidence now points to metabolites of fatty acids as the real culprits in the hepatocellular injury in NASH, just as they are in other target organs of lipotoxicity (Fig. 1).8-12 Because triglyceride often accumulates as a parallel process during lipotoxic injury, it has been understandably difficult to separate the respective roles of triglyceride and fatty acid metabolites in causing injury and cell death. As with all good hypotheses, the nontriglyceride lipotoxicity hypothesis generates more questions than we can currently answer. Fortunately, it also provides new avenues for investigators to pursue in the search for effective treatments for this common disease. The lipotoxicity model of NASH. Emerging data indicate that metabolites of free fatty acids cause lipotoxic hepatocellular injury manifested as ER stress, inflammation, apoptosis, necrosis, and dysmorphic features such as ballooning and Mallory-Denk body formation. The generation of lipotoxic metabolites of fatty acids typically occurs in parallel with the accumulation of triglyceride droplets (steatosis), resulting in a phenotype recognized as NASH where steatosis and features of cellular injury are present together. A feature of this model that distinguishes it from earlier models of the pathogenesis of NASH is that the accumulation of triglyceride is not needed for the development of NASH and, in fact, it may be protective. A caveat is that steatosis does not “progress” to NASH. Metabolic abnormalities predisposing to lipotoxic injury include an increased supply or impaired disposal of free fatty acids. Insulin resistance plays a central role in these processes by allowing an excessive flow of fatty acids from adipose tissue and also impairing peripheral glucose disposal. Fatty acid disposal in the liver occurs through oxidative pathways and through the formation of triglyceride which is then stored temporarily as lipid droplets or secreted as VLDL. Supply-side salutary processes include reduction of carbohydrate precursors for de novo lipogenesis and prevention of inappropriate lipolysis by improving adipocyte insulin responsiveness. Favorable processes on the disposal side include increasing oxidative pathways (with the caveat that the intracellular antioxidant defenses must be adequate to handle the ROS produced) and increasing formation of triglyceride. Red arrows identify processes that contribute to the flux of fatty acids through hepatocytes, thus promoting lipotoxic injury; green arrows identify processes that eliminate fatty acids and thus reduce lipotoxic injury. Not shown are the mechanistic aspects of injury, repair, and fibrogenesis that ultimately determine whether lipotoxic liver injury leads to cirrhosis. ER, endoplasmic reticulum; IR, insulin resistance; P450, cytochrome P450 mixed function oxidases; ROS, reactive oxygen species; SER, smooth endoplasmic reticulum; VLCFA, very long chain fatty acids; VLDL, very low density lipoprotein. CoA, coenzyme A; CYP, cytochrome P450; DAG, diacylglycerol; DGAT2, diacylglycerol acyltransferase 2; DNL, de novo lipogenesis; ER, endoplasmic reticulum; FABP, fatty acid binding proteins; JNK, c-Jun N-terminal kinase; LPC, lysophosphatidyl choline; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; PPAR, peroxisome proliferator-activated receptor; ROS, reactive oxygen species; SCD-1, stearoyl-CoA desaturase-1; SREBP-1c, sterol regulatory element binding protein 1c; VLDL, very low density lipoprotein. Lipotoxicity is a term coined by Unger 15 years ago to describe the toxic effects of excessive free fatty acids on pancreatic beta cell survival.13 The term has never been formally defined but has been used variably to describe cellular injury and death caused by free fatty acids, their metabolites, and even triglyceride, although triglyceride is generally found to be relatively inert.8, 14 Because a wide variety of metabolites can be derived from fatty acids having varying chain lengths and varying degrees and locations of desaturation, not to mention cis versus trans configuration of double bonds, the number of permutations of fatty acid metabolites is enormous, making the identification of lipotoxic species challenging.15 Identifying important fatty acid derivatives remains an area of intense lipidomic study to understand lipotoxic diseases of the heart, pancreatic islets, and vasculature, as well as the liver.10, 12, 16-21 Shown in Fig. 2 are a few of the many putative mediators of nontriglyceride lipotoxicity. We should anticipate that as lipidomic studies advance and new metabolites are discovered, this list will appear quite naïve in retrospect. Possible fatty acid–derived mediators of lipotoxicity. Currently available data suggest that fatty acid metabolites participate in lipotoxic liver injury recognized as NASH. The reintroduction of diacylglycerol from triglyceride may play an important role in regulating the exposure of cells to these intermediaries and is highly regulated by a family of proteins.41, 67, 125 The tissue specificity and regulation of these pathways has been reviewed.66, 69, 70, 72 ACSL, acyl-CoA synthase; AGPAT, acyl-glycerolphosphate acyltransferase; ATGL, adipose triglyceride lipase; CPT, choline phosphotransferase; DAGK, diacylglycerol kinase; DGATs, diacylglycerol acyltransferases; GPAT, glycerol monophosphate acyltransferase; HSL, hormone-sensitive lipase; LPAAT, lysophosphatidic acid acyltransferase; LPAP, lysophosphatidic acid phosphatase; LysoPLD, lysophospholipase D; MAGK, monoacylglycerol kinase; MGL, monoacylglycerol lipase; MOGAT, monoacylglycerol acyltransferase; PLA, phospholipase A; PLD, phospholipase D. The accumulation of triglyceride as lipid droplets was once thought to be the underlying cause of insulin resistance in muscle, liver, and other tissues, but data now indicate that accumulation of lipid droplets is a parallel phenomenon and not the cause of altered insulin signaling pathways.12, 14, 22-24 Similarly, the data implicating triglyceride stored within hepatocyte lipid droplets as a cause of liver injury in human studies and animal models mostly demonstrate an the than triglyceride accumulation is not have suggested that triglyceride flow by of the during hepatocyte although this has been triglyceride does to injury during and during The accumulation of lipid droplets has been with increased of endoplasmic stress, although the role of this cellular in NASH is diacylglycerol acyltransferase 2 the triglyceride have increased triglyceride accumulation and of endoplasmic a of endoplasmic these not in the pathways of c-Jun N-terminal and that are typically in insulin resistance and in the fatty triglyceride accumulation but not lipotoxic injury caused by fatty acid exposure in cell and in the that to the role of triglyceride versus fatty acid–derived triglyceride precursors have been relatively in nontriglyceride lipotoxic injury. has been of of oxidative disposal pathways that can reduce the of fatty acids and the of evidence has also lipid accumulation from injury. triglyceride very low density by the triglyceride protein caused impaired of triglyceride, leading to triglyceride not appear to cause liver A has from studies that the formation of lipid droplets may be a that lipotoxicity from other fatty acid–derived 12, studies of lipotoxicity this in and a of triglyceride formation has been in pancreatic and of triglyceride as fat droplets is a the fatty acids in triglyceride must be at and the cell is unable to handle through other the stored triglyceride as a of lipotoxic fatty acids are highly to As a free fatty acids are with to and intracellular fatty acids are to fatty acid binding within cells that have for fatty acid hepatocytes, and of fatty acid in does not the flux through the but in with NASH, the flux of fatty acids through the liver is Because fatty acids are to the are mostly a function of and not of is through the have confirmed that the intracellular fatty acid is in the even with increased in the as with that of fatty acid in hepatocytes are to be with the increased of fatty acids to and that process is the other of in cells and of liver steatosis in the liver and liver cell that the role of this in lipotoxicity. as the intracellular for of fatty acids to that as and the the the more can be A study of in the of with NASH to with fatty liver but the of which remains Because fatty acids can be to many it has been difficult to prove whether free fatty acids or their metabolites are for the cellular injury in fatty acids can as for leading to a of study that or of function of can steatohepatitis in Fatty acids are also of leading to inappropriate of and causing of As for peroxisome proliferator-activated and fatty acids also effects that play and roles in of and as an and lipotoxicity by promoting the disposal of fatty acids through oxidative and data that fatty acids cause lipotoxic injury, other studies have shown that the formation of A is a in the development of fatty lipotoxicity. in liver cells and pancreatic have shown that acyl-CoA with lipotoxicity caused by fatty other metabolites of fatty acids need to be considered as more causes of lipotoxic liver injury. are fatty acid metabolites that thought to play a role in lipotoxic cellular and are increased in fatty liver lipotoxicity has been shown in pancreatic but studies that in other cell not fatty injury. the of with the not lipotoxicity in cell and not to be in lipotoxic cell death in cells their these will be to human liver disease remains to be but studies are now to other lipid species as more species are of protein a of for cellular signaling the of species is regulated to the of in and as for the formation of triglyceride and in species have been as a to lipidomic of liver from with with or steatohepatitis found although than was found in the increased may increased of fatty acids through the liver, but may not be to the cellular injury of studies of the role of in promoting steatohepatitis are needed to their role in lipotoxic liver injury. or is a of cell and lipid and it is a necessary of for formation and of fatty acid from the on the glycerol generates lysophosphatidyl choline a that has been in cellular injury as well as study found that be an important of lipotoxicity in this in liver from a of with found to be increased and in to disease A role of in lipotoxic liver injury was then human liver cell hepatocytes in and in the lipotoxic injury to on an with of through species can be through the of phospholipase on and of phospholipase shown to lipotoxicity in cell Although this important study it provides evidence for the of of fatty lipotoxicity. A wide variety of other metabolites of free fatty acids, and play a role in the lipotoxicity caused by excessive exposure to free fatty acids. lysophosphatidic acid species are that through a family of and acid species or and they also with a number of intracellular signaling regulating fat are a process of lipotoxic metabolites from free fatty acids is or that this by increasing the flux of fatty acids through the liver, through increased supply or impaired disposal of fatty acids, lipotoxicity. of the pathways that lipotoxic from fatty acids or of pathways that of also be to lipotoxicity. Because the understanding of lipotoxicity is just emerging and the mediators at the molecular level are currently data that of the role of such pathways in lipotoxicity. on that lipotoxic liver injury have been in cell and animal but evidence in human disease is limited. The of studies are The of fatty acid exposure and triglyceride accumulation and disposal have been for more than The of free fatty acids are adipocyte triglyceride lipolysis with of free fatty acids the or hepatocyte de novo lipogenesis the formation of new fatty acids from and acids as (Fig. tissue lipolysis is the of fatty acids to the liver, in with NASH, may contribute to of the fatty to the free fatty acid include of chain fatty acids from the and of and for of the triglyceride in are not a of fat for the This is important when treatments for NASH, to reduce triglyceride not have a on the The role of the supply side of fatty acid to the liver, through excessive peripheral lipolysis or excessive in the development of NASH has been well of triglyceride stored in adipose tissue with the of fatty acids the is regulated by the of and and is more than regulation of the hormone-sensitive as was once thought The process is by lipid and of adipocyte monophosphate Insulin is a of the of fatty acids from adipose tissue triglyceride and, as insulin resistance at the level of adipose tissue is for inappropriate lipolysis that leads to lipotoxic fatty acids are from adipose they can be in the liver to as triglyceride to the this has been proposed to play a role in it Although the has been that fatty acids by adipocyte are and to other tissues, data now also suggest that oxidative pathways within also be an important a role in and although this to be acids can also with adipose tissue to by adipose through the to monophosphate acids to and The of peripheral lipolysis on the liver can be by fatty acid is well recognized that adipocyte such as occurs during can more fatty acids to the liver than the liver can studies the of on liver but studies have also shown that the of such peripheral lipolysis on the liver can be by oxidative by of from the effects of excessive fatty acid but at the of effects of fatty acids on other will steatosis, but with impaired are to liver and the that has a in fat fatty acid or in that even to and are that need in clinical with to and the common that all The de novo of fatty acids is a of carbohydrate to the liver from and impaired peripheral glucose disposal. that include excessive carbohydrate in the form of may be common causes of the supply side of the fatty acid through the to fatty acid from the for this and thus provides an of as the for in have confirmed the of in and a study in has now with more fatty acids triglyceride, a of fatty acids must to fatty acids the of the glycerol is with an fatty The stearoyl-CoA effects this and is to the formation of triglyceride in the of adequate fatty acids. studies have shown that of triglyceride but at the of increased Similarly, excessive with a in but in caused liver injury but triglyceride accumulation in studies to the evidence that triglyceride formation is a than a cause of injury. studies shown that is often by in oxidative that as long as alternative pathways of fatty acid disposal are lipotoxic injury can be novo lipogenesis can also be by in sterol regulatory element binding protein the for the of for of in animal models has been as a to lipotoxic liver is by acids through the a for as a of inappropriate lipogenesis and of such as and with intracellular of fatty acids from the triglyceride by is a relatively to the fatty acid flux through the recognized and quite by is the role of in fatty acids from triglyceride within hepatocyte lipid this process play a role in the of hepatocyte lipid lipolysis is also by and of these as a of the generation of fatty acids has been understanding the effects of intracellular is by the in the effects of or are the liver, adipose or with acid in and in the that at the level of the liver play a role in this increased supply of fatty acids not be a disposal pathways are of disposal is to fat to and through As an important antioxidant must be to handle reactive oxygen species such as and that are in as are from to oxygen as fatty acids are Not the liver is with is present in in hepatocytes and hepatocyte and lipid and is a for the to eliminate reactive during oxidative of has not been shown to in that this is of the of ROS to during increased oxidative of fatty and studies have shown that this can be resulting in cell death and fatty acids to the liver are not needed as a of and are from to the formation of triglyceride. in the fatty acids are used as a of through to and fatty acids to oxidative pathways versus triglyceride formation is pancreatic glucose and to fatty acid the liver, is but peripheral lipolysis in adipose tissue to fatty acids to the liver, then this the disposal pathways at a and may to lipotoxicity. the to in NAFLD, a central role of in lipotoxic liver whether or is often with the steatohepatitis that these is to altered in the liver or is the of such as muscle, adipose or other peripheral has not been established. for have been shown to impaired function and are to The that or to and in is a second of oxidative fatty acid that be when are The role of fatty acid in NASH was difficult to understand in the of the the of ROS was a central role in causing NASH. of the in to cause NASH, and was found to be in which oxygen is to to oxygen to are well with to handle and ROS that are by such as pathways as a for human NASH has with mixed a available in has been shown to be in human studies of other have not been in clinical of in the or the role of in to in fatty acid and the of shown in human The oxidative smooth ER cytochrome P450 a of free fatty acids. This is of fatty acids such as chain and fatty acids with of or of double of fatty acids by leads to acids that are by of has been in NASH. Although thought to be a of ROS has not found this to be the of the oxidative and are regulated by the thus as a for a of species and, as a with the this to fatty acid the is also a for species but the formation and or of fatty acids as triglyceride. The accumulation of triglyceride as lipid droplets in NASH is by a of and that this predisposing to lipotoxic injury and in insulin signaling in cell and in animal human data has been difficult to of VLDL, the of and is not with liver that may be necessary for liver disease to in this This was also suggested to be the in the which and fatty liver steatohepatitis when studies have insulin resistance in the pathogenesis of As our understanding of insulin resistance has questions have which are important for the development of NASH. our of a common has been that NASH is a disease of the liver, insulin resistance in the liver must be of insulin to cause or lipotoxic liver injury in Because insulin pathways in the liver, even that insulin resistance be an that excessive de novo lipogenesis from data demonstrate that insulin resistance at the level of adipose tissue is the for the development of lipotoxic have shown that adipose tissue insulin resistance may be a target of of in adipose tissue may be a of adipose tissue insulin and of the or in have been shown to reduce inappropriate lipolysis and the in animal Because insulin resistance is to NASH, insulin may be an important in therapies for NASH. insulin can be the of glucose as the or the Insulin more with to NASH and the role of adipose insulin resistance be an of adipose insulin to insulin adipose insulin can be the of insulin free fatty acid to the a that be in studies of NASH and in the of with NASH. accumulation in the liver was once thought to insulin signaling and be a cause of insulin resistance in the liver and data have shown that triglyceride does not insulin signaling just as it does not cause lipotoxic injury; it is a of the increased supply of fatty acids or their impaired disposal leading to lipotoxic cell stress and in the insulin signaling that in A of the understanding of the of lipotoxic hepatocellular injury and the resulting to injury that leads to the phenotype of NASH has been 14 stress but role in cell injury and death has not been it plays a role in lipotoxic injury to be the of data for ROS as a to liver injury in all with a of oxidant stress may be important in insulin and studies have shown that excessive can contribute to insulin cell death to be central to the pathogenesis of lipotoxic injury in the as it is in other and of and may be of this is in understanding the of the liver to lipotoxic injury in animal models of NASH with the of the signaling as a leading from injury to The lipotoxicity model of NASH an it does not a number of other to the phenotype of liver injury recognized as NASH. impaired of excessive accumulation of in cell and with impaired flow or and such as or and are to be important to varying degrees in but are not for in this This the that what is currently recognized as NASH on a liver a of with a common The hypothesis that NASH is caused by nontriglyceride lipotoxicity has important lipotoxicity occurs of triglyceride then are have lipotoxic liver injury but not have triglyceride This triglyceride is impaired and the flux of fatty acids to the liver is not by oxidative disposal. lipotoxic liver injury present with liver and a inflammation, Mallory-Denk and but ballooning be present in such is Although a common is that cells are studies suggest that what is as ballooning on accumulation of very triglyceride droplets that are from during for A study liver but changes in liver fat of may be an of such A second caveat is that steatosis does not “progress” to NASH. Although studies this the of steatosis to steatohepatitis has in our of the of intuitive of of in the setting of steatosis or steatohepatitis found on a when steatosis was on an earlier relatively be by the of lipotoxic injury not by our relatively of cells or Mallory-Denk or lipotoxic injury in to such as in The in that a the that human NASH be more on this than is currently This hypothesis is by data in and in the study of with liver caused by triglyceride accumulation does not appear to cause liver injury, liver fat can be a of excessive fatty acid from peripheral adipose tissue and thus as a of peripheral insulin has been to the of treatments that peripheral by their effects on is when this the of steatosis not with the of steatohepatitis in changes in steatosis with in of injury in a clinical an to the formation of triglyceride, this fat accumulation in the liver, to lipotoxic injury. an of putative of is needed in steatosis as a for flux of fatty acids through the liver and of the lipotoxicity. the has with of an for the liver abnormalities in with flux of fatty acids through the liver and lipotoxic liver The term is but is a disease as not this it is to the steatosis is not to the pathogenesis of injury, then the need for a is more lipotoxic liver injury is not in form or but is and it from the that triglyceride can cause lipotoxic injury. it is a lipotoxic liver injury should with the caveat that triglyceride is generally and not a to lipotoxicity. and be considered by investigators in the in to a new not for lipotoxic liver injury but also for steatosis or injury NAFLD, a of A body of evidence now to the causes of NASH. thought to be a disease caused by triglyceride accumulation in hepatocytes with oxidant stress and lipid peroxidation causing and new data from animal studies and a number of human studies now evidence that triglyceride accumulation does not cause insulin resistance or cellular injury in the The lipotoxic liver injury hypothesis for the pathogenesis of NASH suggests that we need to our on the of fatty acids to the liver or in the This can be by improving insulin at the level of adipose tissue to inappropriate peripheral lipolysis and by de novo lipogenesis in the are the for de novo and carbohydrate through changes and increasing glucose through important of and prevention of lipotoxic liver injury, a disease NASH. to for this to the many investigators in the of lipotoxicity to the not

BACKGROUND: In acquired thrombotic thrombocytopenic purpura (TTP), an immune-mediated deficiency of the von Willebrand factor-cleaving protease ADAMTS13 allows unrestrained adhesion of von Willebrand factor multimers to platelets and microthrombosis, which result in thrombocytopenia, hemolytic anemia, and tissue ischemia. Caplacizumab, an anti-von Willebrand factor humanized, bivalent variable-domain-only immunoglobulin fragment, inhibits interaction between von Willebrand factor multimers and platelets. METHODS: In this double-blind, controlled trial, we randomly assigned 145 patients with TTP to receive caplacizumab (10-mg intravenous loading bolus, followed by 10 mg daily subcutaneously) or placebo during plasma exchange and for 30 days thereafter. The primary outcome was the time to normalization of the platelet count, with discontinuation of daily plasma exchange within 5 days thereafter. Key secondary outcomes included a composite of TTP-related death, recurrence of TTP, or a thromboembolic event during the trial treatment period; recurrence of TTP at any time during the trial; refractory TTP; and normalization of organ-damage markers. RESULTS: The median time to normalization of the platelet count was shorter with caplacizumab than with placebo (2.69 days [95% confidence interval {CI}, 1.89 to 2.83] vs. 2.88 days [95% CI, 2.68 to 3.56], P=0.01), and patients who received caplacizumab were 1.55 times as likely to have a normalization of the platelet count as those who received placebo. The percentage of patients with a composite outcome event was 74% lower with caplacizumab than with placebo (12% vs. 49%, P<0.001). The percentage of patients who had a recurrence of TTP at any time during the trial was 67% lower with caplacizumab than with placebo (12% vs. 38%, P<0.001). Refractory disease developed in no patients in the caplacizumab group and in three patients in the placebo group. Patients who received caplacizumab needed less plasma exchange and had a shorter hospitalization than those who received placebo. The most common adverse event was mucocutaneous bleeding, which was reported in 65% of the patients in the caplacizumab group and in 48% in the placebo group. During the trial treatment period, three patients in the placebo group died. One patient in the caplacizumab group died from cerebral ischemia after the end of the treatment period. CONCLUSIONS: Among patients with TTP, treatment with caplacizumab was associated with faster normalization of the platelet count; a lower incidence of a composite of TTP-related death, recurrence of TTP, or a thromboembolic event during the treatment period; and a lower rate of recurrence of TTP during the trial than placebo. (Funded by Ablynx; HERCULES ClinicalTrials.gov number, NCT02553317 .).

Nonalcoholic steatohepatitis (NASH) is a significant form of chronic liver disease in adults and children. The natural history of NASH ranges from indolent to end-stage liver disease. Current studies are focusing on identification of histologic and/or clinical markers of progression. NASH may be an underlying cause of cryptogenic cirrhosis, and the lesions of NASH may recur in allograft livers. An expanding array of clinical conditions and pathogenetic mechanisms have been identified, but many cases remain "idiopathic"; lack of significant alcohol use is, by definition, common to all cases. Neither clinical evaluation nor laboratory values can ensure either the diagnosis or the exclusion of NASH, and liver biopsy interpretation continues to be considered the "gold standard" for diagnosis. The lesions in NASH are similar but not identical to those of alcoholic steatohepatitis; exact, specific histologic criteria for the diagnosis are currently under discussion. The lesions most commonly accepted for NASH include steatosis, hepatocyte ballooning degeneration, mild diffuse lobular mixed acute and chronic inflammation, and perivenular, perisinusoidal collagen deposition. Zone 3 accentuation may be detected. Mallory's hyaline, vacuolated nuclei in periportal hepatocytes, lobular lipogranulomas, and PAS-diastase-resistant Kupffer cells are common. In biopsy specimens from children, portal inflammation may be more prominent than in adults. Progression of fibrosis may result in bridging septa and cirrhosis. The lesions of steatohepatitis may be noted concurrently with other forms of chronic liver disease. A histological "grading and staging" system has been developed to reflect the unique features of steatohepatitis, gradations of severity and fibrosis, and to promote uniform reporting of the histopathology.

RATIONALE: Burnout syndrome (BOS) associated with stress has been documented in health care professionals in many specialties. The intensive care unit (ICU) is a highly stressful environment. Little is known about BOS in critical care nursing staff. OBJECTIVES: To identify determinants of BOS in critical care nurses. METHODS: We conducted a questionnaire survey in France. Among 278 ICUs contacted for the study, 165 (59.4%) included 2,525 nursing staff members, of whom 2,392 returned questionnaires with complete Maslach Burnout Inventory data. MEASUREMENTS AND MAIN RESULTS: Of the 2,392 respondents (82% female), 80% were nurses, 15% nursing assistants, and 5% head nurses. Severe BOS-related symptoms were identified in 790 (33%) respondents. By multivariate analysis, four domains were associated with severe BOS: (1) personal characteristics, such as age (odds ratio [OR], 0.97/yr; confidence interval [CI], 0.96-0.99; p=0.0008); (2) organizational factors, such as ability to choose days off (OR, 0.69; CI, 0.52-0.91; p=0.009) or participation in an ICU research group (OR, 0.74; CI, 0.56-0.97; p=0.03); (3) quality of working relations (1-10 scale), such as conflicts with patients (OR, 1.96; CI, 1.16-1.30; p=0.01), relationship with head nurse (OR, 0.92/point; CI, 0.86-0.98; p=0.02) or physicians (OR, 0.81; CI, 0.74-0.87; p=0.0001); and (4) end-of-life related factors, such as caring for a dying patient (OR, 1.39; CI, 1.04-1.85; p=0.02), and number of decisions to forego life-sustaining treatments in the last week (OR, 1.14; CI, 1.01-1.29; p=0.04). CONCLUSION: One-third of ICU nursing staff had severe BOS. Areas for improvement identified in our study include conflict prevention, participation in ICU research groups, and better management of end-of-life care. Interventional studies are needed to investigate these potentially preventive strategies.

UNLABELLED: Previous controlled trials are inconclusive regarding the efficacy of ursodeoxycholic acid (UDCA) for treating primary sclerosing cholangitis (PSC). One hundred fifty adult patients with PSC were enrolled in a long-term, randomized, double-blind controlled trial of high-dose UDCA (28-30 mg/kg/day) versus placebo. Liver biopsy and cholangiography were performed before randomization and after 5 years. The primary outcome measures were development of cirrhosis, varices, cholangiocarcinoma, liver transplantation, or death. The study was terminated after 6 years due to futility. At enrollment, the UDCA (n = 76) and placebo (n = 74) groups were similar with respect to sex, age, duration of disease, serum aspartate aminotransferase and alkaline phosphatase levels, liver histology, and Mayo risk score. During therapy, aspartate aminotransferase and alkaline phosphatase levels decreased more in the UDCA group than the placebo group (P < 0.01), but improvements in liver tests were not associated with decreased endpoints. By the end of the study, 30 patients in the UDCA group (39%) versus 19 patients in the placebo group (26%) had reached one of the pre-established clinical endpoints. After adjustment for baseline stratification characteristics, the risk of a primary endpoint was 2.3 times greater for patients on UDCA than for those on placebo (P < 0.01) and 2.1 times greater for death, transplantation, or minimal listing criteria (P = 0.038). Serious adverse events were more common in the UDCA group than the placebo group (63% versus 37% [P < 0.01]). CONCLUSION: Long-term, high-dose UDCA therapy is associated with improvement in serum liver tests in PSC but does not improve survival and was associated with higher rates of serious adverse events.

AIM: The prevalence of airway obstruction varies widely with the definition used. OBJECTIVES: To study differences in the prevalence of airway obstruction when applying four international guidelines to three population samples using four regression equations. METHODS: We collected predicted values for forced expiratory volume in 1 s/forced vital capacity (FEV(1)/FVC) and its lower limit of normal (LLN) from the literature. FEV(1)/FVC from 40 646 adults (including 13 136 asymptomatic never smokers) aged 17-90+years were available from American, English and Dutch population based surveys. The prevalence of airway obstruction was determined by the LLN for FEV(1)/FVC, and by using the Global Initiative for Chronic Obstructive Lung Disease (GOLD), American Thoracic Society/European Respiratory Society (ATS/ERS) or British Thoracic Society (BTS) guidelines, initially in the healthy subgroup and then in the entire population. RESULTS: The LLN for FEV(1)/FVC varied between prediction equations (57 available for men and 55 for women), and demonstrated marked negative age dependency. Median age at which the LLN fell below 0.70 in healthy subjects was 42 and 48 years in men and women, respectively. When applying the reference equations (Health Survey for England 1995-1996, National Health and Nutrition Examination Survey (NHANES) III, European Community for Coal and Steel (ECCS)/ERS and a Dutch population study) to the selected population samples, the prevalence of airway obstruction in healthy never smokers aged over 60 years varied for each guideline: 17-45% of men and 7-26% of women for GOLD; 0-18% of men and 0-16% of women for ATS/ERS; and 0-9% of men and 0-11% of women for BTS. GOLD guidelines caused false positive rates of up to 60% when applied to entire populations. CONCLUSIONS: Airway obstruction should be defined by FEV(1)/FVC and FEV(1) being below the LLN using appropriate reference equations.

RATIONALE: Many sources of conflict exist in intensive care units (ICUs). Few studies recorded the prevalence, characteristics, and risk factors for conflicts in ICUs. OBJECTIVES: To record the prevalence, characteristics, and risk factors for conflicts in ICUs. METHODS: One-day cross-sectional survey of ICU clinicians. Data on perceived conflicts in the week before the survey day were obtained from 7,498 ICU staff members (323 ICUs in 24 countries). MEASUREMENTS AND MAIN RESULTS: Conflicts were perceived by 5,268 (71.6%) respondents. Nurse-physician conflicts were the most common (32.6%), followed by conflicts among nurses (27.3%) and staff-relative conflicts (26.6%). The most common conflict-causing behaviors were personal animosity, mistrust, and communication gaps. During end-of-life care, the main sources of perceived conflict were lack of psychological support, absence of staff meetings, and problems with the decision-making process. Conflicts perceived as severe were reported by 3,974 (53%) respondents. Job strain was significantly associated with perceiving conflicts and with greater severity of perceived conflicts. Multivariate analysis identified 15 factors associated with perceived conflicts, of which 6 were potential targets for future intervention: staff working more than 40 h/wk, more than 15 ICU beds, caring for dying patients or providing pre- and postmortem care within the last week, symptom control not ensured jointly by physicians and nurses, and no routine unit-level meetings. CONCLUSIONS: Over 70% of ICU workers reported perceived conflicts, which were often considered severe and were significantly associated with job strain. Workload, inadequate communication, and end-of-life care emerged as important potential targets for improvement.

Allogeneic hematopoietic stem-cell transplantation (HSCT) is the only curative treatment for sickle cell disease (SCD); nevertheless, its use has been limited by the risk of transplantation-related mortality (TRM). Between November 1988 and December 2004, 87 consecutive patients with severe SCD ranging from 2 to 22 years of age received transplants in France. Cerebral vasculopathy was the principal indication for transplantation (55 patients). All the patients received grafts from a sibling donor after a myeloablative conditioning regimen (CR). The only change in the CR during the study period was the introduction of antithymocyte globulin (ATG) in March 1992. The rejection rate was 22.6% before the use of ATG but 3% thereafter. With a median follow-up of 6 years (range, 2.0 to 17.9 years), the overall and event-free survival (EFS) rates were 93.1% and 86.1%, respectively. Graft versus host disease (GVHD) was the main cause of TRM. Importantly, cord blood transplant recipients did not develop GVHD. No new ischemic lesions were detected after engraftment, and cerebral velocities were significantly reduced. The outcome improved significantly with time: the EFS rate among the 44 patients receiving transplants after January 2000 was 95.3%. These results indicate that HLA-identical sibling HSCT after myeloablative conditioning with ATG should be considered as a standard of care for SCD children who are at high risk for stroke.

The evaluation of 73 appendiceal lesions fulfilling the criteria of so-called “mucocele” showed that they comprise 3. distinctive clinicopathologic entities: 1) Focal or diffuse mucosal hyperplasia, with no epithelial atypia and mild distention of the lumen (18 cases). The microscopic pattern is highly reminiscent of the colonic hyperplastic polyp. This is a benign lesion, almost always a pathologic finding in appendices removed incidentally. Of the 18 cases classified as such, 5 were associated with adenocarcinoma of the large bowel, and 1 with ovarian mucinous cystoma; 2) Mutinous cystadenoma, exhibiting some degree of epithelial atypia and marked distention of the lumen (46 cases). Four of these were associated with ovarian mucinous cystoma and 9 with adenocarcinoma of the large bowel. In 10 cases, variable amounts of acellular mucus were present in the periappendiceal region and occasionally free in the peritoneal cavity. In 3 of these cases the mucus most probably originated from a coexistent ovarian tumor. Of the followed patients, none died as a consequence of the appendiceal cystadenoma. Simple excision of the lesion was curative in every case; and 3) Mucinous cystadenocarcinoma (9 cases). This group was distinguished from the previous one by the presence of stromal invasion by glands and/or epithelial cells in the peritoneal implants. Six were associated with peritoneal involvement (so-called pseudomyxoma peritonei); in 2 others, the lesion was limited to the appendix, and in the remainder there was direct extension into the urinary bladder. Of the 6 patients with peritoneal extension, 4 died as a result of the disease 2-11 years after the original surgery, 1 was lost to followup, and the sixth case is a recent observation. The 2 patients with localized tumor were alive and well 2 and 19 years after treatment, respectively. The patient with direct extension into the urinary bladder was alive and well 7 years after an anterior pelvic exenteration. On the basis of these findings we suggest that most instances of so-called “mucocele” should be regarded as mucinous neoplasms, analogous in many aspects to the epithelial tumors of the colon, with peculiarities probably due to the anatomical characteristics of the organ in which they arise.

Neurogenic orthostatic hypotension (nOH) is common in patients with neurodegenerative disorders such as Parkinson's disease, multiple system atrophy, pure autonomic failure, dementia with Lewy bodies, and peripheral neuropathies including amyloid or diabetic neuropathy. Due to the frequency of nOH in the aging population, clinicians need to be well informed about its diagnosis and management. To date, studies of nOH have used different outcome measures and various methods of diagnosis, thereby preventing the generation of evidence-based guidelines to direct clinicians towards 'best practices' when treating patients with nOH and associated supine hypertension. To address these issues, the American Autonomic Society and the National Parkinson Foundation initiated a project to develop a statement of recommendations beginning with a consensus panel meeting in Boston on November 7, 2015, with continued communications and contributions to the recommendations through October of 2016. This paper summarizes the panel members' discussions held during the initial meeting along with continued deliberations among the panel members and provides essential recommendations based upon best available evidence as well as expert opinion for the (1) screening, (2) diagnosis, (3) treatment of nOH, and (4) diagnosis and treatment of associated supine hypertension.

The patients' blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract.

Laparoscopic cholecystectomy uses carbon dioxide, a highly diffusable gas, for insufflation. With extended periods of insufflation, patient arterial carbon dioxide levels may be adversely altered. Patients were selected for laparoscopic cholecystectomy using the same criteria as for open cholecystectomy. Twenty patients (group 1) had normal preoperative cardiopulmonary status (American Society of Anesthesiologists class I), while 10 patients (group 2) had previously diagnosed cardiac or pulmonary disease (class II or III). Demographic, hemodynamic, arterial blood gas, and ventilatory data were collected before peritoneal insufflation and at intervals during surgery. Patients with preoperative cardiopulmonary disease demonstrated significant increases in arterial carbon dioxide levels and decreases in pH during carbon dioxide insufflation compared with patients without underlying disease. Results of concurrent noninvasive methods of assessing changes in partial arterial pressures of carbon dioxide (end-tidal carbon dioxide measured with mass spectrographic techniques) may be misleading and misinterpreted because changes in partial arterial pressures of carbon dioxide are typically much smaller than changes in arterial blood levels and, unlike arterial gas measurements, do not indicate the true level of arterial hypercarbia. During laparoscopic cholecystectomy, patients with chronic cardiopulmonary disease may require careful intraoperative arterial blood gas monitoring of absorbed carbon dioxide.

Ethnic minorities currently compose approximately one third of the population of the United States. The U.S. model of health care, which values autonomy in medical decision making, is not easily applied to members of some racial or ethnic groups. Cultural factors strongly influence patients' reactions to serious illness and decisions about end-of-life care. Research has identified three basic dimensions in end-of-life treatment that vary culturally: communication of "bad news"; locus of decision making; and attitudes toward advance directives and end-of-life care. In contrast to the emphasis on "truth telling" in the United States, it is not uncommon for health care professionals outside the United States to conceal serious diagnoses from patients, because disclosure of serious illness may be viewed as disrespectful, impolite, or even harmful to the patient. Similarly, with regard to decision making, the U.S. emphasis on patient autonomy may contrast with preferences for more family-based, physician-based, or shared physician- and family-based decision making among some cultures. Finally, survey data suggest lower rates of advance directive completion among patients of specific ethnic backgrounds, which may reflect distrust of the U.S. health care system, current health care disparities, cultural perspectives on death and suffering, and family dynamics. By paying attention to the patient's values, spirituality, and relationship dynamics, the family physician can elicit and follow cultural preferences.