Indiana University School of Medicine

Potential conflict of interest: Dr. Chalasani consults for and received grants from Eli Lilly. He consults for NuSirt, AbbVie, Afimmune, Tobira, Madrigal, Shire, Cempra, Ardelyx, Axovant, and Amarin. He received grants from Intercept, Gilead, Galectin, and Cumberland. Dr. Younossi consults for Bristol‐Myers Squibb, Gilead, Intercept, Allergan, and GlaxoSmithKline. He advises for Vertex and Janssen. Dr. Brunt advises for Gilead. Dr. Charlton consults for and received grants from Gilead, Intercept, NGM Bio, Genfit, and Novartis. He received grants from Conatus. Dr. Cusi consults for and received grants from Novo Nordisk. He consults for Tobira. He received grants from Cirius, Novartis, Janssen, Zydus, Nordic, and Lilly. Dr. Rinella consults for Intercept, Gilead, Genfit, Novartis, NGM Bio, and Nusirt. She advises for Fibrogen, Immuron, Enanta, and AbbVie. Dr. Harrison consults for Madrigal, NGM Bio, Genfit, Echosens, Prometheus, Cirius, Perspectum, and HistoIndex. He advises for Garland, Intercept, Novartis, and Pfizer. He is on the speakers' bureau for AbbVie, Gilead, and Alexion. Dr. Sanyal consults for and received grants from Salix, Conatus, Galectin, Gilead, malinckrodt, Echosens‐Sandhill, Novartis, and Sequana. He consults for and is employed by Sanyal Bio. He consults for and owns stock in GenFit, Hemoshear, Durect, and Indalo. He consults for Immuron, Intercept, Pfizer, Boehringer Ingleheim, Nimbus, Nitto Denko, Lilly, Novo Nordisk, Fractyl, Allergan, Chemomab, Affimmune, Teva, and Ardelyx. He received grants from Bristol‐Myers Squibb and Merck. He received royalties from UptoDate. He owns stock in Exhalenz, Arkana, and NewCo LLC. The funding for the development of this Practice Guidance was provided by the American Association for the Study of Liver Diseases. This practice guidance was approved by the American Association for the Study of Liver Diseases on June 15, 2017. Preamble This guidance provides a data‐supported approach to the diagnostic, therapeutic, and preventive aspects of nonalcoholic fatty liver disease (NAFLD) care. A “Guidance” document is different from a “Guideline.” Guidelines are developed by a multidisciplinary panel of experts and rate the quality (level) of the evidence and the strength of each recommendation using the Grading of Recommendations, Assessment Development, and Evaluation system. A guidance document is developed by a panel of experts in the topic, and guidance statements, not recommendations, are put forward to help clinicians understand and implement the most recent evidence. This Practice Guidance was commissioned by the American Association for the Study of Liver Diseases (AASLD) and is an update to the Practice Guideline published in 2012 in conjunction with the American Gastroenterology Association and the American College of Gastroenterology (ACG).1 Sections where there have been no notable newer publications are not modified, so some paragraphs remain unchanged. This narrative review and guidance statements are based on the following: (1) a formal review and analysis of the recently published world literature on the topic (Medline search up to August 2016); (2) the American College of Physicians' Manual for Assessing Health Practices and Designing Practice Guidelines2; (3) guideline policies of the AASLD; and (4) the experience of the authors and independent reviewers with regard to NAFLD. This practice guidance is intended for use by physicians and other health professionals. As clinically appropriate, guidance statements should be tailored for individual patients. Specific guidance statements are evidence based whenever possible, and, when such evidence is not available or is inconsistent, guidance statements are made based on the consensus opinion of the authors.3 This is a practice guidance for clinicians rather than a review article, and interested readers can refer to several recent comprehensive reviews.4 Because this guidance document is lengthy, to make it easier for the reader, a list of all guidance statements and recommendations are provided in a tabular form there be (1) evidence of by or and (2) of of such use of a or the of is with such and can be nonalcoholic fatty liver or nonalcoholic is the of evidence of in the form of is the of and with with or this guidance document be to or or of fatty liver of of and the of in from fatty liver to to of evidence of in the form of of the or evidence of The of to and liver is of with and with or This can to liver and liver of with or evidence of or of with no with are with such and of and is a to in liver in with in is A of and and of in the is a of the of in the A have of from are a for of by was a of for of by was the of using and was to be a of for an of of developed by to an rate of The for in the of are A from using of an rate for of the of such this most the of A from an rate of A recent the of from to be the rate from the is to be to the there is a of publications the of in the are in a recent of the of The the of by is The of is from the and the rate is from As the for a liver liver is not in of the there is no of the or of there have been some to the of by The the of in the are in the The of liver for a is to be The of liver a for is from to the of in the and of in of are not in with of the of This and of been this provides a list of the and and and independent of are with and is the most and for NAFLD. the of from to and is with NAFLD. this the of with have is a of in with some have to of have is to the of and this and can in a the of in with or the of in with NAFLD. this and and are in with NAFLD. The of in with been to be a a the based on to and to The rate of was the rate for with the to and to was the rate in the with the was and The of to and the of and of liver disease to with Association of the of or of the (1) than in or than in (2) or (3) than in and than in (4) or or or and or been a for NAFLD. the of in is than in The of and on have the to have a of have a of the of and to be to be is most of the recent the for be by the to the the of the from to and of the have the of with is evidence with with some of are for such and have the following: with have to The most of in with is disease independent of other is the of in the it is the or of with is the of in with with have an a recent and and to be and and and The for and for to be and The most of with is to or are of is the of in the to the of with the the of the of been to a with are have a have and are to from liver than other of from a of from the not have other was with in the of This of in is to most with have is This of with have a of and with the with or in the of in of the for liver disease is of the recent in with a rate of the of in to with a rate of and in with to with a recent of with and a of an of rate not different from with This is with of with with or liver is the of and the of in the are with As of liver disease is the development of The rate was to be of with of the to to liver to and to it is the for in is the of with the and of the of evidence for or recent of of the of in with is A consensus for be in and in a liver to the on and a is of the of in published literature been Guidance or recent on in and on in is a for when with NAFLD. Evaluation of and for other than liver or A recent of with be for based on the the and and for this have not been Guidance with on have or to liver disease or have liver should be have and up with on or and have liver should be for or and for such or for in and can be there should be for with or not with have of the available evidence of and of there are in the and of NAFLD. A analysis using a for in with is not of with available liver can be in with not be to liver or are is experts recently have for for liver disease in with not Guidance for in or is not this of and with of to and of should be a of for and in with such or or can be to or for or of of a of with have a a of with and for and the of liver was and fatty liver was in of of with in the of and the of have been from no in a to in a of an of in using to and and not and, the of and was and Guidance of for is not Evaluation of the The of (1) there is by or (2) there is no (3) there are no for and (4) there are no of of are disease and a with it is to for liver and liver can in with not the of liver of this are and is a of not it can disease the are of was with in a of and are in a with should be in the with in with and the is Liver should be in the of and a to the or of and to in a with NAFLD. of and are in with and are to be an of no liver to a of from the in or in and not with disease or other are should be for the of or and Guidance a with it is to for and with and in the of or a liver should be of in with other of liver disease or to should a for liver of with should the of such or and Assessment of and in The of is is can to liver and liver Liver is the most approach for the of and in with it is is by and and and such and not the of liver in with NAFLD. there been in and for in with is the of this practice of the of and and the and of in with by or by is an for and is in The use of to is a for in an the of in with in is The of is a for the of in with is with of the of an of such and to the of liver with and such and are the for of have been for the of in with This is not available in a The for the of in to Liver and or and The is based on available and and is using the published a of of the an the of for with or A and to a and to the of is an based on and with are with are to have A recent and liver and (1) than other such and and (2) for in with The panel of of of and an of with and for or This panel been recently approved for use in is not available for use in the liver was recently approved by the and for use in and with liver recent the of in with using an on the of in with from the The liver for was with and The for was in of the the on the of using an with in with The rate for in this was The for for and was The recently experience with in with in the using a with an or rate for a liver was is for of in with the by than for or in or for and and have several with and in with for in is not Guidance with the of and can be to for a liver or are clinically for with of or or are clinically for in with NAFLD. to a Liver in Liver the for liver in with NAFLD. is for and some and it should be in the most from and Guidance Liver should be in with are of The of or or liver by or be for are for Liver should be in with in for and the of be a liver of The of are of with the of not by The for of liver in a with or the and on of the is the to from on of and The for have been by the by not with or and or not all for with of or in or and and of have no or of up to is or is and is with and is of in from in in be or in and and be in is readers refer to other recent publications for of of fatty liver disease in and are for of in from the and from the Liver of the and for The was developed a of in from a the the for for use in and from with the of and in with other of liver there is a for and for with based and to the of in and and The by a of was with in and when a a Guidance should a with and with and and A on or be Specific such be The or of should be a to and is of The of should of liver disease the such and with or have from a liver liver disease should be to with and Guidance liver disease should be to with and of and been to with NAFLD. 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Guidance with should not of are to make recommendations with regard to of by with NAFLD. is a and of and for the and a and to and of is there are and of the and and of are not and with have a by and to a of with to be by and the of rather than by the of have evidence of the of with of in with or and A recent analysis of the The and Evaluation and in with to analysis of the The and a of in with in to it is to in with based on to use in with or and several have the of in with liver disease of in liver the of is not in with are not in liver from is in of for are and have with liver or not all and on when this was not a of in liver or liver Guidance with are for and of should be in all with NAFLD. with or are not for liver from can be to in with and be in with should be in with and are are in a a and a in a this was with and This was recently approved by the for with are to in a up to in a recently an for a this was with there was a in Guidance and available in with should not be to and and are and, in is on a to the most for in the with is with an of and to an analysis of the for a of and and with the of when for not to an of or The of on and in the of the of a in of or for not been for and been in a of with been in and and in for The of an to of all to the is is with been an independent of and Because of the of and with and a of is with some of and have all been to be in this As is with a of with is in with with to when is or is with an of disease and in the most for liver in the Because of the of with rate of or of with the is than of are from are for with and and are to other The of is an of and in evidence of is or by for is in of by the of the a rate is than for other than with for than and is in of by the A recent experience of to this from and recommendations for are to for other with and and a and are in the of is by and is in with a of are some to the of patients. and and Guidance with have of should be to clinically or the Guidance to Practice with should be for to the and practice with of should be for to the practice evidence not and for in with evidence not a liver in with or this be on a of Specific to and in be to or to with of in be most for or The of and in are the in with are and with of of in for the in based the of or the for and the and of the A of in and using a of to using the of liver to from The was when for and A recent the of to be in from and in based on This the of in to with with a of with with and with the of was to be with of to in with and or in with so use of the of liver a of with and from of of on the of was in of with liver other than in was the most and was in of the with NAFLD. with the a of and a of of been in of with The of and to was in to a with than to to an and NAFLD. A the of in for of of the and of The the on with received with of the liver developed the was to and the or in of and in not to be and with are on of to the of in is in of of or of by health than of with for with not be and for of by As in with of such and are for and of with of of for in health in for and there are no to with in this the of an for liver disease with and in with and with in the with other the to the of in of fatty or and in are in a of with and, on some liver is to and the of use or is in and for are the no panel of or can and in Guidance with fatty liver are or not should be for of such fatty and in to for of are in with in with or to should a liver to and Because of a of a formal recommendation be made with regard to for in with and A The to a liver in a to the of be the with and the the with an of than or of to of there is an in or of all with to a liver it be to are to have or to with for liver on in of and of have been to for The of the to of with based on of As in development of or to for or disease is of and are can be to in with a of and with is in in with an of of the or of with of a liver a with and the Guidance Liver in with should be in in the is or in there is of or A liver to a of should be on for of with can from in some in of and there is a in This is by or and in the of The and to be different in with Guidance liver should the in with to NAFLD. for are by a of and on to The is to a quality of and and liver and of should be made to from Because most have this is the in with in in and by in most with NAFLD. of the to this using and Because liver not the of the the of on liver not be with to or and not liver in in and the of with and in an or in to on of or the of to aspects of in is are to the of for should with a to quality of and of of American Association and in As in for or have in or liver on and A using in a the of or to in to with the of of was not different the there in and of with to this a no on liver or liver The from the of to this the in of or of was not the a in on to been some to fatty to in a of and to in for in in Guidance and liver in with and should be the of no to with and should not be to or The of a is not to some with of in is be to in and should be with each in

For the purposes of classification, it should be specified whether osteoarthritis (OA) of the knee is of unknown origin (idiopathic, primary) or is related to a known medical condition or event (secondary). Clinical criteria for the classification of idiopathic OA of the knee were developed through a multicenter study group. Comparison diagnoses included rheumatoid arthritis and other painful conditions of the knee, exclusive of referred or para-articular pain. Variables from the medical history, physical examination, laboratory tests, and radiographs were used to develop sets of criteria that serve different investigative purposes. In contrast to prior criteria, these proposed criteria utilize classification trees, or algorithms.

BACKGROUND: Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium-glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS: ), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS: The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P = 0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P = 0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P = 0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS: In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years. (Funded by Janssen Research and Development; CREDENCE ClinicalTrials.gov number, NCT02065791.).

INTRODUCTION: The SCARE Guidelines were first published in 2016 and were last updated in 2018. They provide a structure for reporting surgical case reports and are used and endorsed by authors, journal editors and reviewers, in order to increase robustness and transparency in reporting surgical cases. They must be kept up to date in order to drive forwards reporting quality. As such, we have updated these guidelines via a DELPHI consensus exercise. METHODS: The updated guidelines were produced via a DELPHI consensus exercise. Members were invited from the previous DELPHI group, as well as editorial board members and peer reviewers of the International Journal of Surgery Case Reports. The expert group completed an online survey to indicate their agreement with proposed changes to the checklist items. RESULTS: A total of 54 surgical experts agreed to participate and 53 (98%) completed the survey. The responses and suggested modifications were incorporated into the new 2020 guideline. There was a high degree of agreement amongst the SCARE Group, with all modified SCARE items receiving over 70% scores 7-9. CONCLUSION: A DELPHI consensus exercise was completed and an updated and improved SCARE Checklist is now presented.

BACKGROUND: Catheter-related bloodstream infections occurring in the intensive care unit (ICU) are common, costly, and potentially lethal. METHODS: We conducted a collaborative cohort study predominantly in ICUs in Michigan. An evidence-based intervention was used to reduce the incidence of catheter-related bloodstream infections. Multilevel Poisson regression modeling was used to compare infection rates before, during, and up to 18 months after implementation of the study intervention. Rates of infection per 1000 catheter-days were measured at 3-month intervals, according to the guidelines of the National Nosocomial Infections Surveillance System. RESULTS: A total of 108 ICUs agreed to participate in the study, and 103 reported data. The analysis included 1981 ICU-months of data and 375,757 catheter-days. The median rate of catheter-related bloodstream infection per 1000 catheter-days decreased from 2.7 infections at baseline to 0 at 3 months after implementation of the study intervention (P< or =0.002), and the mean rate per 1000 catheter-days decreased from 7.7 at baseline to 1.4 at 16 to 18 months of follow-up (P<0.002). The regression model showed a significant decrease in infection rates from baseline, with incidence-rate ratios continuously decreasing from 0.62 (95% confidence interval [CI], 0.47 to 0.81) at 0 to 3 months after implementation of the intervention to 0.34 (95% CI, 0.23 to 0.50) at 16 to 18 months. CONCLUSIONS: An evidence-based intervention resulted in a large and sustained reduction (up to 66%) in rates of catheter-related bloodstream infection that was maintained throughout the 18-month study period.

BACKGROUND: Depression and anxiety are common in medical patients and are associated with diminished health status and increased health care utilization. This article presents a quantitative review and synthesis of studies correlating medical patients' treatment noncompliance with their anxiety and depression. METHODS: Research on patient adherence catalogued on MEDLINE and PsychLit from January 1, 1968, through March 31, 1998, was examined, and studies were included in this review if they measured patient compliance and depression or anxiety (with n>10); involved a medical regimen recommended by a nonpsychiatrist physician to a patient not being treated for anxiety, depression, or a psychiatric illness; and measured the relationship between patient compliance and patient anxiety and/or depression (or provided data to calculate it). RESULTS: Twelve articles about depression and 13 about anxiety met the inclusion criteria. The associations between anxiety and noncompliance were variable, and their averages were small and nonsignificant. The relationship between depression and noncompliance, however, was substantial and significant, with an odds ratio of 3.03 (95% confidence interval, 1.96-4.89). CONCLUSIONS: Compared with nondepressed patients, the odds are 3 times greater that depressed patients will be noncompliant with medical treatment recommendations. Recommendations for future research include attention to causal inferences and exploration of mechanisms to explain the effects. Evidence of strong covariation of depression and medical noncompliance suggests the importance of recognizing depression as a risk factor for poor outcomes among patients who might not be adhering to medical advice.

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.

These recommendations are based on the following: (1) a formal review and analysis of the recently published world literature on the topic [Medline search up to June 2011]; (2) the American College of Physicians' Manual for Assessing Health Practices and Designing Practice Guidelines;1 (3) guideline policies of the three societies approving this document; and (4) the experience of the authors and independent reviewers with regards to NAFLD. Intended for use by physicians and allied health professionals, these recommendations suggest preferred approaches to the diagnostic, therapeutic and preventive aspects of care. They are intended to be flexible and adjustable for individual patients. Specific recommendations are evidence-based wherever possible, and when such evidence is not available or inconsistent, recommendations are made based on the consensus opinion of the authors. To best characterize the evidence cited in support of the recommendations, the AASLD Practice Guidelines Committee has adopted the classification used by the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) workgroup with minor modifications (Table 1).2 The strength of recommendations in the GRADE system is classified as strong (1) or weak (2). The quality of evidence supporting strong or weak recommendations is designated by one of three levels: high (A), moderate (B) or low-quality (C).2 This is a practice guideline for clinicians rather than a review article and interested readers can refer to several comprehensive reviews published recently.3-8 NAFLD, Nonalcoholic Fatty Liver Disease; NAFL,Nonalcoholic Fatty Liver; NASH, Nonalcoholic Steatohepatitis; T2DM, Type 2 Diabetes Mellitus; AST, Aspartate Aminotransferase; ALT, Alanine Aminotransferase; HOMA,Homeostatic Model Assessment; RCT; Randomized Controlled Trial; PIVENS: Pioglitazone versus Vitamin E versus Placebo for the Treatment of Non-diabetic patients with Nonalcoholic steatohepatitis; TONIC; Treatment of Nonalcoholic Fatty Liver Disease in Children; NAS, NAFLD Activity Score; CK18; Cytokeratin 18 Fragments; ELF, Enhanced Liver Fibrosis Panel; TZD; Thiazolidinediones; UDCA: Ursodeoxycholic Acid; ANA; Anti Nuclear Antibody; ASMA: Anti Smooth Muscle Antibody; US; Ultrasound; CT: Computerized Tomography; MR; Magnetic Resonance. The definition of nonalcoholic fatty liver disease (NAFLD) requires that (a) there is evidence of hepatic steatosis, either by imaging or by histology and (b) there are no causes for secondary hepatic fat accumulation such as significant alcohol consumption, use of steatogenic medication or hereditary disorders (Table 2). In the majority of patients, NAFLD is associated with metabolic risk factors such as obesity, diabetes mellitus, and dyslipidemia. NAFLD is histologically further categorized into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH) (Table 3). NAFL is defined as the presence of hepatic steatosis with no evidence of hepatocellular injury in the form of ballooning of the hepatocytes. NASH is defined as the presence of hepatic steatosis and inflammation with hepatocyte injury (ballooning) with or without fibrosis. The incidence of NAFLD has been investigated in a limited number of studies. Two Japanese studies9, 10 reported an incidence rate of 31 and 86 cases of suspected NAFLD per 1,000 person-years respectively, whereas another study from England showed a much lower incidence rate of 29 cases per 100,000 person-years.11 More studies are needed to better understand the incidence of NAFLD across different age, ethnic, and geographic groups. The reported prevalence of NAFLD varies widely depending on the population studied and the definition used. The prevalence of histologically-defined NAFLD was 20% and 51% in two different studies comprised of potential living liver donors.12, 13 The reported prevalence of NAFLD when defined by liver ultrasound ranged between 17% and 46% depending on the population studied.4 In a study consisting of nearly 400 middle aged individuals, the prevalence of NAFLD defined by ultrasonography was 46% and the prevalence of histologically confirmed NASH was 12.2%.14 In the Dallas Heart Study, when assessed by MR spectroscopy the prevalence of NAFLD in the general population was 31%.15 The prevalence of suspected NAFLD when estimated using aminotransferases alone without imaging or histology ranged between 7% and 11%, but aminotransferases can be normal in individuals with NAFLD.4 In summary, estimates of the worldwide prevalence of NAFLD ranges from 6.3% to 33% with a median of 20% in the general population, based on a variety of assessment methods.4 On the other hand, the estimated prevalence of NASH is lower, ranging from 3 to 5%.4 The prevalence of NASH cirrhosis in the general population is not known. Obesity is a common and well documented risk factor for NAFLD. Both excessive BMI and visceral obesity are recognized risk factors for NAFLD. In patients with severe obesity undergoing bariatric surgery, the prevalence of NAFLD can exceed 90% and up to 5% of patients may have unsuspected cirrhosis.4, 16-20 There is a very high prevalence of NAFLD in individuals with type 2 diabetes mellitus (T2DM).4 An ultrasonographic study of patients with T2DM showed a 69% prevalence of NAFLD.21 In another study, 127 of 204 diabetic patients displayed fatty infiltration on ultrasound, and 87% of the patients with fatty infiltration who consented to biopsy had histologic confirmation of NAFLD.22 High serum triglyceride levels and low serum HDL levels are very common in patients with NAFLD. The prevalence of NAFLD in individuals with dyslipidemia attending lipid clinics was estimated to be 50%.23 Age, gender and ethnicity are also associated with a differential prevalence for NAFLD.4 A number of studies have shown that the prevalence of NAFLD increases with age.24-28 The likelihood of disease progression to advanced fibrosis or mortality increases in older patients with NAFLD.29-31 Many recent studies have reported that male gender is a risk factor for fatty liver disease.4 For example, in a study of 26,527 subjects undergoing medical checkups, the prevalence of NAFLD was 31% in men and 16% in women.32 Compared to non-Hispanic whites, Hispanic individuals have significantly higher and non-Hispanic blacks have significantly lower prevalence of NAFLD.15, 33-35 The prevalence of NAFLD in American-Indian and Alaskan-Native populations appears lower, ranging from 0.6% to 2.2%, although the lack of histologic definition makes it likely that is an underestimate.36, 37 There are data to suggest that hypothyroidism, hypopituitarism, hypogonadism, sleep apnea, and polycystic ovary syndrome independent of obesity are important risk factors for the presence of NAFLD (Table 4).3 The evolution of hepatic histologic changes in patients with NAFL and NASH has been investigated by several studies, but these generally included smaller number of patients and had relatively modest duration of follow-up.4, 7 Nonetheless, it is generally agreed that patients with simple steatosis have very slow, if any, histological progression, while patients with NASH can exhibit histological progression to cirrhotic-stage disease.4, 7 The long term outcomes of patients with NAFLD and NASH have been reported in several studies.31, 38-45 Their detailed discussion is beyond the scope of this guideline, but their findings can be summarized as follows; (a) patients with NAFLD have increased overall mortality compared to matched control populations, (b) the most common cause of death in patients with NAFLD, NAFL and NASH is cardiovascular disease, and (c) patients with NASH (but not NAFL) have an increased liver-related mortality rate. Another piece of indirect evidence that supports the progressive nature of NASH is in the features of cryptogenic cirrhosis which is closely related to NAFLD.46, 47 Patients with cryptogenic cirrhosis have disproportionately high prevalence of metabolic risk factors (T2DM, obesity, metabolic syndrome) typical of patients with NAFLD, their liver biopsies frequently show one or more features of NASH, and studies have demonstrated the loss of histological features of NASH with the development of cirrhosis.4, 7, 46, 47 Patients with NAFLD are at increased risk for HCC, but this risk is likely limited to those with advanced fibrosis and cirrhosis.48-53 Several studies investigated the natural history of NASH cirrhosis in comparison to patients with hepatitis C cirrhosis.54-57 One large prospective US-based study55 observed a lower rate of decompensation and mortality in patients with NASH cirrhosis as compared to patients with hepatitis C cirrhosis. However, a more recent international study56 of 247 NAFLD patients with advanced fibrosis and cirrhosis followed over a mean duration of 85.6 ± 54.5 months showed an overall 10-year survival of 81.5% that was not different from matched patients with hepatitis C cirrhosis. Importantly, both studies have shown that patients with NASH cirrhosis are at significantly lower risk for HCC than patients with hepatitis C cirrhosis.55, 56 By definition, NAFLD indicates the lack of any evidence of ongoing or recent consumption of significant quantities of alcohol. However, the precise definition of significant alcohol consumption in patients with suspected NAFLD is uncertain. A recent consensus meeting58 concluded that, for NASH clinical trials candidate eligibility purposes, significant alcohol consumption be defined as >21 drinks per week in men and >14 drinks per week in women over a 2-year period prior to baseline liver histology. Furthermore, this group recommended that validated questionnaires should be used to quantify the amount of alcohol consumption in the context of clinical trials. The definition of significant alcohol consumption in the published NAFLD literature has been inconsistent and ranged from > 1 alcoholic drink (∼ 10 grams of alcohol per one drink unit) per day to > 40 grams per day, and published studies have not always used gender-specific definitions.59 If self-reported alcohol consumption details are not consistent with clinical suspicion when evaluating a patient with suspected NAFLD, confirmation with a family member or a close friend should be considered. Recommendation 1. Ongoing or recent alcohol consumption > 21 drinks on average per week in men and > 14 drinks on average per week in women is a reasonable definition for significant alcohol consumption when evaluating patients with suspected NAFLD in clinical practice. (Strength – 2, Quality - C) Some patients undergoing thoracic and abdominal imaging for reasons other than liver symptoms, signs or biochemistry may demonstrate unsuspected hepatic steatosis. While this phenomenon is not uncommon in clinical practice, studies have not systematically examined the characteristics or natural history of NAFLD in this patient population. Recommendations 2. When patients with unsuspected hepatic steatosis detected on imaging have symptoms or signs attributable to liver disease or have abnormal liver biochemistries, they should be evaluated as though they have suspected NAFLD and worked-up accordingly. (Strength – 1, Evidence -A) 3. In patients with unsuspected hepatic steatosis detected on imaging who lack any liver-related symptoms or signs and have normal liver biochemistries, it is reasonable to assess for metabolic risk factors (e.g., obesity, glucose intolerance, dyslipidemia) and alternate causes for hepatic steatosis such as significant alcohol consumption or medications. (Strength – 1, Evidence -A) 4. In patients with unsuspected hepatic steatosis detected on imaging who are asymptomatic and have normal liver biochemistries, a liver biopsy cannot be recommended. (Strength – 1, Evidence -B) It can be argued that there should be systematic screening for NAFLD, at least among higher-risk individuals attending diabetes and obesity clinics. However, at present there are significant gaps in our knowledge regarding the diagnosis, natural history, and treatment of NAFLD. As liver biochemistries can be within normal ranges in patients with NAFLD and NASH, they may not be sufficiently sensitive to serve as screening tests, whereas liver ultrasound is potentially more sensitive but it is expensive and cumbersome as a screening test. Recommendation 5. Screening for NAFLD in adults attending primary care clinics or high-risk groups attending diabetes or obesity clinics is not advised at this time due to uncertainties surrounding diagnostic tests and treatment options, along with lack of knowledge related to the long-term benefits and cost-effectiveness of screening. (Strength – 1, Evidence -B) Anecdotal experience and some published studies suggest familial clustering and heritability of NAFLD,60-63 but conclusive studies are lacking. In a retrospective cohort study, Willner et al. observed that 18% of patients with NASH have a similarly affected first degree relative.61 A small familial aggregation study observed that patients with NAFLD have a significantly higher number of first degree relatives with cirrhosis and a trend towards familial clustering of NAFLD or cryptogenic cirrhosis than matched healthy controls.62 In another familial aggregation study63 of overweight children with and without NAFLD, after adjusting for age, gender, race, and BMI, the heritability of MR-measured liver fat fraction was 0.386, and fatty liver was present in 18% of family members of children with NAFLD despite normal ALT and lack of obesity. Recommendation 6. Systematic screening of family members for NAFLD is currently not recommended. (Strength – 1, Evidence - B) The diagnosis of NAFLD requires that (a) there is hepatic steatosis by imaging or histology, (b) there is no significant alcohol consumption, (c) there are no competing etiologies for hepatic steatosis, and (d) there are no co-existing causes for chronic liver disease. Common alternative causes of hepatic steatosis are significant alcohol consumption, hepatitis C, medications, parenteral nutrition, Wilson's disease, and severe malnutrition (Table 2). When evaluating a patient with newly suspected NAFLD, it is important to exclude co-existing etiologies for chronic liver disease including hemochromatosis, autoimmune liver disease, chronic viral hepatitis, and Wilson's disease.3 Mildly elevated serum ferritin is common in patients with NAFLD and it does not necessarily indicate increased iron stores.3, 64 Elevated serum ferritin and transferrin saturation in patients with suspected NAFLD should lead to testing for genetic hemochromatosis. Mutations in the HFE gene occur with variable frequency in patients with NAFLD and their clinical significance is unclear.64 One should consider a liver biopsy to assess hepatic iron concentration and to exclude significant hepatic injury and fibrosis in a patient with suspected NAFLD with elevated serum ferritin and a homozygote or compound heterozygote C282Y mutation in the HFE gene.65 Elevated serum autoantibodies are common in patients with NAFLD and are generally considered to be an epiphenomenon.3 In a recently published large study from the NASH Clinical Research Network, positive serum autoantibodies, defined as ANA > 1:160 or ASMA >1:40 were present in 21% of patients with well-phenotyped NAFLD and were not associated with more advanced histologic features.66 Recommendations 7. When evaluating a patient with suspected NAFLD, it is essential to exclude competing etiologies for steatosis and co-existing common chronic liver disease. (Strength – 1, Evidence - A) 8. Persistently high serum ferritin and increased iron saturation, especially in the context of homozygote or heterozygote C282Y HFE mutations may warrant a liver biopsy. (Strength – 1, Evidence - B) 9. High serum titers of autoantibodies in association with other features suggestive of autoimmune liver disease (very high aminotransferases, high globulin) should prompt a more complete work-up for autoimmune liver disease. (Strength – 1, Evidence - B) The natural history of NAFLD is fairly dichotomous – NAFL is generally benign whereas NASH can progress to cirrhosis, liver failure, and liver cancer. Existing dogma posits that liver biopsy is the most reliable approach for identifying the presence of steatohepatitis and fibrosis in patients with NAFLD, but it is generally acknowledged that biopsy is limited by cost, sampling error, and procedure-related morbidity and mortality. Serum aminotransferase levels and imaging tests such as ultrasound, CT, and MR do not reliably assess steatohepatitis and fibrosis in patients with NAFLD. Therefore, there has been significant interest in developing clinical prediction rules and non-invasive biomarkers for identifying steatohepatitis in patients with NAFLD,7 but their detailed discussion is beyond the scope of this practice guideline. The presence of metabolic syndrome is a strong predictor for the presence of steatohepatitis in patients with NAFLD3, 7, 67-69 and may be used to best identify patients with persistently abnormal liver biochemistries who would benefit diagnostically and prognostically from a liver biopsy. There has been intense interest in non-invasive methods to identify advanced fibrosis in patients with NAFLD7;these include the NAFLD Fibrosis Score70, Enhanced Liver Fibrosis (ELF) panel70 and transient elastography. The NAFLD Fibrosis Score is based on six readily available variables (age, BMI, hyperglycemia, platelet count, albumin, AST/ALT ratio) and it is calculated using the published formula (http://nafldscore.com). In a meta-analysis of 13 studies consisting of 3,064 patients,7 NAFLD Fibrosis Score has an AUROC of 0.85 for predicting advanced fibrosis (i.e., bridging fibrosis or cirrhosis) and a score < −1.455 had 90% sensitivity and 60% specificity to exclude advanced fibrosis whereas a score > 0.676 had 67% sensitivity and 97% specificity to identify the presence of advanced fibrosis. The ELF panel consists of plasma levels of three matrix turnover proteins (hyaluronic acid, TIMP-1, and PIIINP) had an AUROC of 0.90 with 80% sensitivity and 90% specificity for detecting advanced fibrosis.71 Circulating levels of cytokeratin-18 (CK18) fragments have been investigated extensively as novel biomarkers for the presence of steatohepatitis in patients with NAFLD.7, 72 Wieckowska et al., measured CK18 fragments in plasma that had been obtained from 44 consecutive patients with suspected NAFLD at the time of liver biopsy, and correlated the findings with hepatic immunohistochemistry data.70 Plasma CK18 fragments were markedly increased in patients with NASH compared with patients with simple steatosis or normal biopsies (median 765.7 U/L versus 202.4 U/L or 215.5 U/L, respectively; P < 0.001), and independently predicted NASH (OR 1.95; 95% CI 1.18-3.22 for every 50 U/L increase). This observation was reproduced in several subsequent studies and a recent meta-analysis estimated that plasma CK18 levels have a sensitivity of 78%, specificity of 87%, and an area under the receiver operating curve (AUROC) of 0.82 (95% CI: 0.78-0.88) for steatohepatitis in patients with NAFLD.7 Although these are very encouraging results, currently this assay is not commercially available. Furthermore, as each study utilized a study-specific cut-off value, there is not an established cut-off value for identifying steatohepatitis. Transient elastography, which measures liver stiffness non-invasively, has been successful in identifying advanced fibrosis in patients with hepatitis B and hepatitis C. Although a recent meta-analysis showed high sensitivity and specificity for identifying fibrosis in NAFLD,7 it has a high failure rate in individuals with a higher BMI. Furthermore, it is not commercially available in the United States. Other imaging tools such as MR elastography, although commercially available in the United States, is rarely used in clinical practice. A major limitation of these prediction models and biomarkers is that they have largely been investigated in cross-sectional studies and thus their utility in monitoring disease natural history, predicting outcomes or response to therapeutic intervention is unknown. Recommendations 10. As the metabolic syndrome predicts the presence of steatohepatitis in patients with NAFLD, presence can be used to patients for a liver biopsy. (Strength – 1, Evidence - B) NAFLD Fibrosis Score is a for identifying NAFLD patients with higher likelihood of bridging fibrosis cirrhosis. (Strength – 1, Evidence - B) Although CK18 is a for identifying it is to in clinical practice. (Strength – 1, Evidence - B) Liver biopsy the for liver histology in patients with NAFLD. However, it is expensive and some morbidity and very mortality it should be in those who would benefit the most from diagnostic, therapeutic and Recommendations Liver biopsy should be considered in patients with NAFLD who are at increased risk to have steatohepatitis and advanced fibrosis. (Strength – 1, Evidence - B) The presence of metabolic syndrome and the NAFLD Fibrosis Score may be used for identifying patients who are at risk for steatohepatitis and advanced fibrosis. (Strength – 1, Evidence - B) Liver biopsy should be considered in patients with suspected NAFLD in competing etiologies for hepatic steatosis and co-existing chronic liver cannot be without a liver biopsy. (Strength – 1, Evidence - B) The of patients with NAFLD consists of liver disease as well as the associated metabolic such as obesity, and As patients with NAFLD without steatohepatitis have from a liver at liver disease should be limited to those with Many studies indicate that may aminotransferases and hepatic steatosis when measured either by or MR imaging and In a meta-analysis of and clinical studies between most studies reported in aminotransferases and hepatic steatosis by ultrasound across a of of different and high low high fat However, these studies were as a of largely and using histology as the primary More recent studies also showed an in aminotransferases and hepatic steatosis on histology with in with was investigated in two trials. In the study by et ALT and steatosis by but on liver histology not be evaluated the majority of patients not a liver biopsy. However, in the study by et not or liver histology. The best evidence for loss as a to liver histology in NASH from a that 31 with NASH to changes and a week of moderate for versus The had loss in the alone and to an in steatosis, and but not fibrosis. Importantly, with 7% loss had significant in steatosis, and NAFLD Activity Score There was a in the study by et who > 5% steatosis, whereas individuals with loss had significant in steatosis, and A number of recent studies used MR spectroscopy to assess changes in hepatic fat in response to The from these studies using a variety of either by or in with different have reported a significant in liver fat by an average of from 20% to The degree of hepatic fat was to the of the intervention and generally a loss between to The of without on hepatic steatosis was investigated in studies using MR of a week of over a period of to In but one liver fat without a significant in Recommendations loss generally hepatic steatosis, either by alone or in with increased (Strength – 1, Evidence - A) of at least of appears to steatosis, but a loss to may be needed to (Strength – 1, Evidence - B) alone in adults with NAFLD may hepatic steatosis but to other aspects of liver histology unknown. (Strength – 1, Evidence - B) Several studies investigated the of on aminotransferases and liver histology in patients with studies demonstrated a in and but no significant in liver An consisting of patients with NASH either 2 E or loss for more with than with E or However, there was a modest in hepatic steatosis and inflammation in the of patients undergoing liver biopsies with In a study in patients, NASH in of patients, although of the study was by a significant loss in the more than 10 et reported a lack of in a control of with a and intervention in both groups. Other studies also to show major benefit for on hepatic or liver A recent concluded that months of intervention not aminotransferases or liver histology, compared with intervention independently of or the presence of Recommendation has no significant on liver histology and is not recommended as a treatment for liver disease in adults with (Strength – 1, Evidence - A) Several studies investigated the of and on aminotransferases and liver histology in adults with In an in subjects with NASH, aminotransferases and hepatic steatosis, ballooning and inflammation but not fibrosis. in a subsequent et observed that aminotransferases and hepatic steatosis, but not or fibrosis and also showed et a of in patients with NASH who had glucose or Although there was a significant ± with it significantly aminotransferases, steatosis, and The with in compared to of patients and there was a trend towards in fibrosis among patients to et a of intervention with either or for months in a of patients with While steatosis not significantly compared to hepatocellular injury and fibrosis The study is a large that 247 patients with NASH to E or for The primary was an in 2 with at least 1 in hepatocellular ballooning and in either the inflammation or steatosis and no in the fibrosis It was in in the group compared to in the group and in the E group this study of two primary and E a of was considered to be significant a Therefore, although there were histological benefits associated with this study concluded that not the primary However, of NASH, a secondary was in significantly higher number of

The upcoming 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours is part of an effort to hierarchically catalogue human cancers arising in various organ systems within a single relational database. This paper summarizes the new WHO classification scheme for myeloid and histiocytic/dendritic neoplasms and provides an overview of the principles and rationale underpinning changes from the prior edition. The definition and diagnosis of disease types continues to be based on multiple clinicopathologic parameters, but with refinement of diagnostic criteria and emphasis on therapeutically and/or prognostically actionable biomarkers. While a genetic basis for defining diseases is sought where possible, the classification strives to keep practical worldwide applicability in perspective. The result is an enhanced, contemporary, evidence-based classification of myeloid and histiocytic/dendritic neoplasms, rooted in molecular biology and an organizational structure that permits future scalability as new discoveries continue to inexorably inform future editions.

Insulin resistance plays an important role in the pathophysiology of diabetes and is associated with obesity and other cardiovascular risk factors. The "gold standard" glucose clamp and minimal model analysis are two established methods for determining insulin sensitivity in vivo, but neither is easily implemented in large studies. Thus, it is of interest to develop a simple, accurate method for assessing insulin sensitivity that is useful for clinical investigations. We performed both hyperinsulinemic isoglycemic glucose clamp and insulin-modified frequently sampled iv glucose tolerance tests on 28 nonobese, 13 obese, and 15 type 2 diabetic subjects. We obtained correlations between indexes of insulin sensitivity from glucose clamp studies (SI(Clamp)) and minimal model analysis (SI(MM)) that were comparable to previous reports (r = 0.57). We performed a sensitivity analysis on our data and discovered that physiological steady state values [i.e. fasting insulin (I(0)) and glucose (G(0))] contain critical information about insulin sensitivity. We defined a quantitative insulin sensitivity check index (QUICKI = 1/[log(I(0)) + log(G(0))]) that has substantially better correlation with SI(Clamp) (r = 0.78) than the correlation we observed between SI(MM) and SI(Clamp). Moreover, we observed a comparable overall correlation between QUICKI and SI(Clamp) in a totally independent group of 21 obese and 14 nonobese subjects from another institution. We conclude that QUICKI is an index of insulin sensitivity obtained from a fasting blood sample that may be useful for clinical research.

Because depression and painful symptoms commonly occur together, we conducted a literature review to determine the prevalence of both conditions and the effects of comorbidity on diagnosis, clinical outcomes, and treatment. The prevalences of pain in depressed cohorts and depression in pain cohorts are higher than when these conditions are individually examined. The presence of pain negatively affects the recognition and treatment of depression. When pain is moderate to severe, impairs function, and/or is refractory to treatment, it is associated with more depressive symptoms and worse depression outcomes (eg, lower quality of life, decreased work function, and increased health care utilization). Similarly, depression in patients with pain is associated with more pain complaints and greater impairment. Depression and pain share biological pathways and neurotransmitters, which has implications for the treatment of both concurrently. A model that incorporates assessment and treatment of depression and pain simultaneously is necessary for improved outcomes.

Increasing evidence in both experimental and clinical studies suggests that oxidative stress plays a major role in the pathogenesis of both types of diabetes mellitus. Free radicals are formed disproportionately in diabetes by glucose oxidation, nonenzymatic glycation of proteins, and the subsequent oxidative degradation of glycated proteins. Abnormally high levels of free radicals and the simultaneous decline of antioxidant defense mechanisms can lead to damage of cellular organelles and enzymes, increased lipid peroxidation, and development of insulin resistance. These consequences of oxidative stress can promote the development of complications of diabetes mellitus. Changes in oxidative stress biomarkers, including superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase, glutathione levels, vitamins, lipid peroxidation, nitrite concentration, nonenzymatic glycosylated proteins, and hyperglycemia in diabetes, and their consequences, are discussed in this review. In vivo studies of the effects of various conventional and alternative drugs on these biomarkers are surveyed. There is a need to continue to explore the relationship between free radicals, diabetes, and its complications, and to elucidate the mechanisms by which increased oxidative stress accelerates the development of diabetic complications, in an effort to expand treatment options.

There is increasing evidence that subjective cognitive decline (SCD) in individuals with unimpaired performance on cognitive tests may represent the first symptomatic manifestation of Alzheimer's disease (AD). The research on SCD in early AD, however, is limited by the absence of common standards. The working group of the Subjective Cognitive Decline Initiative (SCD-I) addressed this deficiency by reaching consensus on terminology and on a conceptual framework for research on SCD in AD. In this publication, research criteria for SCD in pre-mild cognitive impairment (MCI) are presented. In addition, a list of core features proposed for reporting in SCD studies is provided, which will enable comparability of research across different settings. Finally, a set of features is presented, which in accordance with current knowledge, increases the likelihood of the presence of preclinical AD in individuals with SCD. This list is referred to as SCD plus.

BACKGROUND: Chemotherapy combinations that include an alkylating agent and a platinum coordination complex have high response rates in women with advanced ovarian cancer. Such combinations provide long-term control of disease in few patients, however. We compared two combinations, cisplatin and cyclophosphamide and cisplatin and paclitaxel, in women with ovarian cancer. METHODS: We randomly assigned 410 women with advanced ovarian cancer and residual masses larger than 1 cm after initial surgery to receive cisplatin (75 mg per square meter of body-surface area) with either cyclophosphamide (750 mg per square meter) or paclitaxel (135 mg per square meter over 24 hours). RESULTS: Three hundred eighty-six women met all the eligibility criteria. Known prognostic factors were similar in the two treatment groups. Alopecia, neutropenia, fever, and allergic reactions were reported more frequently in the cisplatin-paclitaxel group. Among 216 women with measurable disease, 73 percent in the cisplatin-paclitaxel group responded to therapy, as compared with 60 percent in the cisplatin-cyclophosphamide group (P = 0.01). The frequency of surgically verified complete response was similar in the two groups. Progression-free survival was significantly longer (P < 0.001) in the cisplatin-paclitaxel group than in the cisplatin-cyclophosphamide group (median, 18 vs. 13 months). Survival was also significantly longer (P < 0.001) in the cisplatin-paclitaxel group (median, 38 vs. 24 months). CONCLUSIONS: Incorporating paclitaxel into first-line therapy improves the duration of progression-free survival and of overall survival in women with incompletely resected stage III and stage IV ovarian cancer.

BACKGROUND: Hypothermia is protective against brain injury after asphyxiation in animal models. However, the safety and effectiveness of hypothermia in term infants with encephalopathy is uncertain. METHODS: We conducted a randomized trial of hypothermia in infants with a gestational age of at least 36 weeks who were admitted to the hospital at or before six hours of age with either severe acidosis or perinatal complications and resuscitation at birth and who had moderate or severe encephalopathy. Infants were randomly assigned to usual care (control group) or whole-body cooling to an esophageal temperature of 33.5 degrees C for 72 hours, followed by slow rewarming (hypothermia group). Neurodevelopmental outcome was assessed at 18 to 22 months of age. The primary outcome was a combined end point of death or moderate or severe disability. RESULTS: Of 239 eligible infants, 102 were assigned to the hypothermia group and 106 to the control group. Adverse events were similar in the two groups during the 72 hours of cooling. Primary outcome data were available for 205 infants. Death or moderate or severe disability occurred in 45 of 102 infants (44 percent) in the hypothermia group and 64 of 103 infants (62 percent) in the control group (risk ratio, 0.72; 95 percent confidence interval, 0.54 to 0.95; P=0.01). Twenty-four infants (24 percent) in the hypothermia group and 38 (37 percent) in the control group died (risk ratio, 0.68; 95 percent confidence interval, 0.44 to 1.05; P=0.08). There was no increase in major disability among survivors; the rate of cerebral palsy was 15 of 77 (19 percent) in the hypothermia group as compared with 19 of 64 (30 percent) in the control group (risk ratio, 0.68; 95 percent confidence interval, 0.38 to 1.22; P=0.20). CONCLUSIONS: Whole-body hypothermia reduces the risk of death or disability in infants with moderate or severe hypoxic-ischemic encephalopathy.

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favor of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panelists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms "nonalcoholic" and "fatty" were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease. There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction-associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and nonstigmatising, and can improve awareness and patient identification.

IMPORTANCE: Extremely preterm infants contribute disproportionately to neonatal morbidity and mortality. OBJECTIVE: To review 20-year trends in maternal/neonatal care, complications, and mortality among extremely preterm infants born at Neonatal Research Network centers. DESIGN, SETTING, PARTICIPANTS: Prospective registry of 34,636 infants, 22 to 28 weeks' gestation, birth weight of 401 to 1500 g, and born at 26 network centers between 1993 and 2012. EXPOSURES: Extremely preterm birth. MAIN OUTCOMES AND MEASURES: Maternal/neonatal care, morbidities, and survival. Major morbidities, reported for infants who survived more than 12 hours, were severe necrotizing enterocolitis, infection, bronchopulmonary dysplasia, severe intracranial hemorrhage, cystic periventricular leukomalacia, and/or severe retinopathy of prematurity. Regression models assessed yearly changes and were adjusted for study center, race/ethnicity, gestational age, birth weight for gestational age, and sex. RESULTS: Use of antenatal corticosteroids increased from 1993 to 2012 (24% [348 of 1431 infants]) to 87% (1674 of 1919 infants]; P < .001), as did cesarean delivery (44% [625 of 1431 births] to 64% [1227 of 1921]; P < .001). Delivery room intubation decreased from 80% (1144 of 1433 infants) in 1993 to 65% (1253 of 1922) in 2012 (P < .001). After increasing in the 1990s, postnatal steroid use declined to 8% (141 of 1757 infants) in 2004 (P < .001), with no significant change thereafter. Although most infants were ventilated, continuous positive airway pressure without ventilation increased from 7% (120 of 1666 infants) in 2002 to 11% (190 of 1756 infants) in 2012 (P < .001). Despite no improvement from 1993 to 2004, rates of late-onset sepsis declined between 2005 and 2012 for infants of each gestational age (median, 26 weeks [37% {109 of 296} to 27% {85 of 320}]; adjusted relative risk [RR], 0.93 [95% CI, 0.92-0.94]). Rates of other morbidities declined, but bronchopulmonary dysplasia increased between 2009 and 2012 for infants at 26 to 27 weeks' gestation (26 weeks, 50% [130 of 258] to 55% [164 of 297]; P < .001). Survival increased between 2009 and 2012 for infants at 23 weeks' gestation (27% [41 of 152] to 33% [50 of 150]; adjusted RR, 1.09 [95% CI, 1.05-1.14]) and 24 weeks (63% [156 of 248] to 65% [174 of 269]; adjusted RR, 1.05 [95% CI, 1.03-1.07]), with smaller relative increases for infants at 25 and 27 weeks' gestation, and no change for infants at 22, 26, and 28 weeks' gestation. Survival without major morbidity increased approximately 2% per year for infants at 25 to 28 weeks' gestation, with no change for infants at 22 to 24 weeks' gestation. CONCLUSIONS AND RELEVANCE: Among extremely preterm infants born at US academic centers over the last 20 years, changes in maternal and infant care practices and modest reductions in several morbidities were observed, although bronchopulmonary dysplasia increased. Survival increased most markedly for infants born at 23 and 24 weeks' gestation and survival without major morbidity increased for infants aged 25 to 28 weeks. These findings may be valuable in counseling families and developing novel interventions. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00063063.

Epstein, Jonathan I MD; Allsbrook, William C Jr MD; Amin, Mahul B MD; Egevad, Lars L MD, PhD and the ISUP Grading Committee Author Information

Publicado também em: https://repositorio.unifesp.br/handle/11600/53933

Clinical criteria for the classification of patients with hip pain associated with osteoarthritis (OA) were developed through a multicenter study. Data from 201 patients who had experienced hip pain for most days of the prior month were analyzed. The comparison group of patients had other causes of hip pain, such as rheumatoid arthritis or spondylarthropathy. Variables from the medical history, physical examination, laboratory tests, and radiographs were used to develop different sets of criteria to serve different investigative purposes. Multivariate methods included the traditional "number of criteria present" format and "classification tree" techniques. Clinical criteria: A classification tree was developed, without radiographs, for clinical and laboratory criteria or for clinical criteria alone. A patient was classified as having hip OA if pain was present in combination with either 1) hip internal rotation greater than or equal to 15 degrees, pain present on internal rotation of the hip, morning stiffness of the hip for less than or equal to 60 minutes, and age greater than 50 years, or 2) hip internal rotation less than 15 degrees and an erythrocyte sedimentation rate (ESR) less than or equal to 45 mm/hour; if no ESR was obtained, hip flexion less than or equal to 115 degrees was substituted (sensitivity 86%; specificity 75%). Clinical plus radiographic criteria: The traditional format combined pain with at least 2 of the following 3 criteria: osteophytes (femoral or acetabular), joint space narrowing (superior, axial, and/or medial), and ESR less than 20 mm/hour (sensitivity 89%; specificity 91%). The radiographic presence of osteophytes best separated OA patients and controls by the classification tree method (sensitivity 89%; specificity 91%). The "number of criteria present" format yielded criteria and levels of sensitivity and specificity similar to those of the classification tree for the combined clinical and radiographic criteria set. For the clinical criteria set, the classification tree provided much greater specificity. The value of the radiographic presence of an osteophyte in separating patients with OA of the hip from those with hip pain of other causes is emphasized.