Philadelphia VA Medical Center

OBJECTIVE: The Systemic Lupus International Collaborating Clinics (SLICC) group revised and validated the American College of Rheumatology (ACR) systemic lupus erythematosus (SLE) classification criteria in order to improve clinical relevance, meet stringent methodology requirements, and incorporate new knowledge regarding the immunology of SLE. METHODS: The classification criteria were derived from a set of 702 expert-rated patient scenarios. Recursive partitioning was used to derive an initial rule that was simplified and refined based on SLICC physician consensus. The SLICC group validated the classification criteria in a new validation sample of 690 new expert-rated patient scenarios. RESULTS: Seventeen criteria were identified. In the derivation set, the SLICC classification criteria resulted in fewer misclassifications compared with the current ACR classification criteria (49 versus 70; P = 0.0082) and had greater sensitivity (94% versus 86%; P < 0.0001) and equal specificity (92% versus 93%; P = 0.39). In the validation set, the SLICC classification criteria resulted in fewer misclassifications compared with the current ACR classification criteria (62 versus 74; P = 0.24) and had greater sensitivity (97% versus 83%; P < 0.0001) but lower specificity (84% versus 96%; P < 0.0001). CONCLUSION: The new SLICC classification criteria performed well in a large set of patient scenarios rated by experts. According to the SLICC rule for the classification of SLE, the patient must satisfy at least 4 criteria, including at least one clinical criterion and one immunologic criterion OR the patient must have biopsy-proven lupus nephritis in the presence of antinuclear antibodies or anti-double-stranded DNA antibodies.

Potential conflict of interest: Dr. Hwang received grants from Merck and Gilead. Dr. Chang advises Arbutus. Dr. Lok received grants from Gilead and Bristol‐Myers Squibb. Dr. Jonas consults for Gilead and received grants from Bristol‐Myers Squibb and Roche. Dr. Brown consults and received grants from Gilead. Dr. Bzowej received grants from Gilead, Allergan and Cirius. Dr. Terrault received grants from Gilead and Bristol‐Myers Quibb. Dr. Wong is a member of the United States Preventive Services Task Force (USPSTF). This article does not necessarily represent the views and policies of the USPSTF. 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 December 4, 2017. Purpose and Scope of the Guidance This AASLD 2018 Hepatitis B Guidance is intended to complement the AASLD 2016 Practice Guidelines for Treatment of Chronic Hepatitis B1 and update the previous hepatitis B virus (HBV) guidelines from 2009. The 2018 updated guidance on chronic hepatitis B (CHB) includes (1) updates on treatment since the 2016 HBV guidelines (notably the use of tenofovir alafenamide) and guidance on (2) screening, counseling, and prevention; (3) specialized virological and serological tests; (4) monitoring of untreated patients; and (5) treatment of hepatitis B in special populations, including persons with viral coinfections, acute hepatitis B, recipients of immunosuppressive therapy, and transplant recipients. The AASLD 2018 Hepatitis B Guidance provides a data‐supported approach to screening, prevention, diagnosis, and clinical management of patients with hepatitis B. It differs from the published 2016 AASLD guidelines, which conducted systematic reviews and used a multidisciplinary panel of experts to rate the quality (level) of the evidence and the strength of each recommendation using the Grading of Recommendations Assessment, Development and Evaluation system in support of guideline recommendations.1 In contrast, this guidance document was developed by consensus of an expert panel, without formal systematic review or use of the Grading of Recommendations Assessment, Development, and Evaluation system. The 2018 guidance is based upon the following: (1) formal review and analysis of published literature on the topics; (2) World Health Organization guidance on prevention, care, and treatment of CHB5; and (3) the authors’ experience in acute hepatitis B and CHB. Intended for use by health care providers, this guidance identifies preferred approaches to the diagnostic, therapeutic, and preventive aspects of care for patients with CHB. As with clinical practice guidelines, it provides general guidance to optimize the care of the majority of patients and should not replace clinical judgement for a unique patient. This guidance does not seek to dictate a “one size fits all” approach for the management of CHB. Clinical considerations may justify a course of action that differs from this guidance. Interim Data Relevant to the AASLD 2018 Hepatitis B Guidance Since the publication of the 2016 AASLD Hepatitis B Guidelines, tenofovir alafenamide (TAF) has been approved for treatment of CHB in adults. TAF joins the list of preferred HBV therapies, along with entecavir, tenofovir disoproxil fumarate (TDF), and peginterferon (peg‐IFN; Tables 1 and 2)6 (section: Updated Recommendations on the Treatment of Patients With Chronic Hepatitis B). Additionally, studies on the use of TDF for prevention of mother‐to‐child transmission led to TDF being elevated to the level of preferred therapy in this setting (section 1C of Screening, Counseling, and Prevention of Hepatitis B). Table 1 - Approved Antiviral Therapies in Adults and Children Drug Dose in Adultsa Use in Childrena Pregnancy Categoryb Potential Side Effectsb Monitoring on Treatmentc Preferred Peg‐IFN‐α‐2a (adult) IFN‐α‐2b (children) 180 mcg weekly ≥1 year dose: 6 million IU/m2 three times weeklyd C Flu‐like symptoms, fatigue, mood disturbances, cytopenia, autoimmune disorders in adults, anorexia and weight loss in children Complete blood count (monthly to every 3 months) TSH (every 3 months) Clinical monitoring for autoimmune, ischemic, neuropsychiatric, and infectious complications Entecavir 0.5 mg dailye ≥2 years dose: weight‐based to 10‐30 kg; above 30 kg: 0.5 mg dailye C Lactic acidosis (decompensated cirrhosis only) Lactic acid levels if there is clinical concern Test for HIV before treatment initiation Tenofovir dipovoxil fumarate 300 mg daily ≥12 years B Nephropathy, Fanconi syndrome, osteomalacia, lactic acidosis Creatinine clearance at baseline If at risk for renal impairment, creatinine clearance, serum phosphate, urine glucose, and protein at least annually Consider bone density study at baseline and during treatment in patients with history of fracture or risks for osteopenia Lactic acid levels if there is clinical concern Test for HIV before treatment initiation Tenofovir alafenamide 25 mg daily — There are insufficient human data on use during pregnancy to inform a drug‐associated risk of birth defects and miscarriage. Lactic acidosis Lactic acid levels if clinical concern Assess serum creatinine, serum phosphorus, creatinine clearance, urine glucose, and urine protein before initiating and during therapy in all patients as clinically appropriate Test for HIV before treatment initiation Nonpreferred Lamivudine 100 mg daily ≥2 years dose: 3 mg/kg daily to max 100 mg C Pancreatitis Lactic acidosis Amylase if symptoms are present Lactic acid levels if there is clinical concern Test for HIV before treatment initiation Adefovir 10 mg daily ≥12 years C Acute renal failure Fanconi syndrome Lactic acidosis Creatinine clearance at baseline If at risk for renal impairment, creatinine clearance, serum phosphate, urine glucose, and urine protein at least annually Consider bone density study at baseline and during treatment in patients with history of fracture or risks for osteopenia Lactic acid levels if clinical concern Telbivudine 600 mg daily — B Creatine kinase elevation and myopathy Peripheral neuropathy Lactic acidosis Creatine kinase if symptoms are present Clinical evaluation if symptoms are present Lactic acid levels if there is clinical concern aDose adjustments are needed in patients with renal dysfunction.bIn 2015, the U.S. Food and Drug Administration replaced the pregnancy risk designation by letters A, B, C, D, and X with more specific language on pregnancy and This is being in and to TAF includes is not approved for children with chronic hepatitis B, is approved for treatment of chronic hepatitis may using this for children with chronic The of treatment in is is 1 mg daily if the is or if Table - of Approved Antiviral Therapies in Adults with Chronic Hepatitis B and Tenofovir Tenofovir to loss — — loss 3 years 1 Entecavir Tenofovir Tenofovir to loss 6 3 years 6 of of 3 years of years of for for and tenofovir disoproxil for tenofovir for for and tenofovir disoproxil for tenofovir by and for and is a that of to HBV TAF is more TDF in and the to more a to used with and renal and bone 3 of hepatitis B patients with to TAF 25 mg daily or TDF 300 mg daily in a with serum HBV in in loss in and hepatitis B loss in in the TAF and TDF that and serum HBV and and and in TAF and TDF a 3 of patients with to TAF 25 mg daily or TDF 300 mg daily in a in in the TAF and TDF in serum HBV in of TAF patients and of TDF with 1 The approved of TAF is 25 mg with needed creatinine clearance is In 3 TAF TDF in bone density and renal at of In the in the rate was for TAF the was in TDF patients In the in the rate was in TAF the for TDF patients was In and bone density the in bone density for TAF TDF was for patients and in patients In human virus TAF TDF therapy for to that TAF a on bone density and renal with patients on TAF TDF or treatment of renal complications data in patients are with to the on clinical as renal and fracture the of TAF with evidence of led to the preferred HBV for patients studies of from TDF to TAF from the HIV In studies of to a to TAF TDF treatment of an was with in renal the and bone studies that TAF has a TDF and in studies of to 1 Screening, Counseling, and Prevention of Hepatitis B The of the of hepatitis B. Chronic acute is by the of for at least 6 The of with of persons as as to and as In developed the is from or and in with HBV is by and and by by and children in In HBV is transmission the of chronic transmission in the United in children of not appropriate HBV at The majority of children and with CHB in the United States are or HBV the for The risk of chronic HBV acute from in of to in and children to in In persons are more to chronic HBV acute Table 3 at risk for CHB should for HBV and if and to hepatitis B should used for to hepatitis B for as as are for and to from previous HBV HBV does not to Table 3 - at for HBV in of or HBV of and and and and of and of and and and and and and persons not as an in with HBV with immunosuppressive therapy, including to and for or with elevated or of of or with renal including and to with chronic with and of are not in a during the previous 6 evaluation or treatment for a Health care and at risk for to blood or and of for to with or of HBV are the of blood or that of persons with are years of for with are should hepatitis B if Table - of for HBV Test Chronic hepatitis B and management needed HBV management or or immunosuppressive therapy HBV or HBV if if not from of or and not persons may for not may or may not with the on or the risk The of for and for a of to populations, the is previous to HBV the majority of persons from acute HBV in and to been with HBV for before In the the risk of or cirrhosis to HBV is In the persons are at risk of with an rate that to to with chronic HBV with levels more if are if are and are in with of HBV or HIV or hepatitis C virus with more specific may a in persons from with risk for HBV and more may the of HBV during the of acute hepatitis persons should for of to of the risk for HBV for in blood if in Since the the of has to in blood and in with HIV or to or immunosuppressive therapy are at risk for if HBV and should for The majority of for not HBV with specific to or to hepatitis B and HBV with a HBV a HBV does not levels of HBV in blood in an on the and of the used and HBV in the study the of patients an to HBV with the majority a to hepatitis B to persons without HBV for all in Table should HBV to HBV with to levels 3 or data that may the of using an with HBV the of hepatitis B transmission the clinical of the patient. persons are for for are at risk of HBV the risk or immunosuppressive are or in Screening, Counseling, and Prevention of Hepatitis B, all persons are for or without should at risk for HBV in this Guidance on for Hepatitis B should using and is in all persons in with a of persons not as in with HBV persons immunosuppressive therapy, and the in Table persons should for to is not is an in patients HIV are to or and immunosuppressive or renal and in blood if Screening, Counseling, and Prevention of Hepatitis B, B, Patients with chronic HBV should and prevention of transmission as as the of specific been to on the of CHB syndrome and to of more of for and more for are with risk of cirrhosis and the risk of of are the approach is to or with CHB should hepatitis if not persons should transmission to Table of risk of HBV and should if for HBV serological or not been or not the should of HBV from health care to patients has been to in persons with CHB are the for and Prevention that should seek and from an expert review If serum HBV therapy is and of is if serum HBV is to and that Since the U.S. of has that it is for and to are to special to for children in the in and Table - Recommendations for Prevention of of HBV to and Use during if is not or is not or and blood with or Children and Adults in all including not from or and should not from children and and Guidance on of persons should prevention of transmission of HBV to and are should not from or practice hepatitis B. and of are to seek and from an expert review panel at should not if serum level may if level is and special are for children in as and are to or use of is in of weight and treatment of including of and are to development of syndrome and Guidance on of and or for is not in patients HIV or are to therapy or immunosuppressive are without are not at risk of transmission of or to are for and are from an with with risk for HBV should the of hepatitis B are for and risk for hepatitis B are not for are HIV or should for with CHB should to with the prevention of mother‐to‐child Hepatitis B and HBV should to Antiviral therapy in the is for with serum HBV of hepatitis with or without the of to been It has been that the in levels of the is to the therapy that has been used to the are and of acute failure been in the therapy from to not in the AASLD guideline recommendation that therapy for prevention of mother‐to‐child transmission at the of or to previous systematic review of therapy in the a in transmission of with or TDF is the preferred to and for with the of TDF treatment in the in risk of mother‐to‐child transmission of hepatitis B with TDF in with a level of HBV kinase levels more in untreated in as clinically studies in the of or data on bone from studies of therapy in a previous study of to bone the study at years of during as the risk of HBV in the is studies including and that the risk of HBV transmission by is more the risk of mother‐to‐child transmission of HBV was in with a level with not the risk of mother‐to‐child transmission the of in not clinical studies support the of during HBV is and during In of the to as without the of has been to and in Chronic HBV does not the of pregnancy the has cirrhosis or care is to the and to that the and HBV of Guidance on of in Pregnancy HBV is in and are not to or with HBV should this as during pregnancy should to care for HBV or for if and of for for HBV therapy should without HBV in the should treatment to mother‐to‐child are not on therapy as as at or should for to 6 for hepatitis and should to for The risk of mother‐to‐child transmission of HBV with should in the risk of in with with cirrhosis should in and with TDF to of as during pregnancy should for HBV or and HBV if is not Recommendations for are in the for and Prevention and on is for at risk of as of of persons with chronic and including with of patients is that in are at a risk of to are not in if the is as studies that serological patients as persons on or with chronic including a is the 10 are to the a of and is are including with on or with use of a of has been to the of patients the level of the of HBV with or without is for of or to or This includes and should of are on the during which is the is to for and for The for and Prevention has updated guidelines for and for health care to is should of may of should and HBV of birth by the for at 1 of The should not before of HBV should used for or 6 Guidance for Prevention of of Hepatitis B With Chronic HBV HBV an and are as a at and 6 or without hepatitis at and to 30 by a at used for the hepatitis and B for a at and 1 has been approved for and of persons are for and should HBV of should and HBV at and the of should at of of persons with chronic HBV chronic and persons with should for to the the of to the a is with a used for including with of is annually for chronic or are not if of to in patients and are and of Chronic Hepatitis B The for CHB and clinical to HBV are in Table The of for at least 6 the of As HBV is not to the are to with chronic and viral clearance, to the development of cirrhosis and CHB is a and with CHB clinical with levels of serum HBV and HBV The levels of serum and HBV as as are of that inform for treatment initiation as as treatment of and levels are needed to treatment Additionally, of using or as are in and with treatment Table 6 - and for Chronic Hepatitis B Chronic Hepatitis B (CHB) present for HBV from to and levels are in and are in CHB. or elevated levels Liver chronic hepatitis with CHB present for levels are million or elevated Liver or and CHB present for HBV in CHB and in CHB or elevated levels Liver or chronic hepatitis with or and with or without CHB present for HBV levels Liver of or levels of HBV loss of HBV in or patients immunosuppressive therapy for a a in HBV to baseline an level of HBV a baseline is and from to for patients Hepatitis times baseline and HBV and hepatitis loss of in a was loss of and of in a was and of in a was loss of in a was with levels and of clinical or evidence of viral in serum HBV from during treatment in a an virological and is for management of persons without cirrhosis are or of for in are to for and for of for of for and 25 for is to management of for in are to for and for of management of a for of for and 25 for is in of the been This to a elevation is the for of in the of treatment that the elevation may to as or 3 in of Chronic Hepatitis B of serum HBV is a in the evaluation of patients with CHB and in the of the of used in clinical practice with a of and a to patients with CHB levels that may from to monitoring of levels is more in and in the for patients with CHB levels and with CHB levels with levels in with CHB in CHB. The is an which the of chronic and been in patients with the of levels in the of of and of treatment HBV of HBV been The of HBV HBV been in the United with A, B, and C being HBV may an in the of as as to is with of and loss with from that HBV B is with at an more a rate of to and a rate of development with from that on in persons with HBV C in with HBV A, B, D, or In a of has been in persons with C or in with the The to led to development of and to and it that from as a for viral levels by in and by of or with The levels of are in patients In and HBV CHB. the of with to levels been with to cirrhosis and clearance in patients with a viral treatment of and provides a at in of for and for the of at that loss or HBV treatment In of the patients with B and C at and treatment of of the patients and of HBV at a treatment as by a level treatment of a in loss of and level with a 3 years or more of Hepatitis B in patients are patients on therapy, the of is virological which is as a in serum HBV from during treatment in a an virological with that during to a in serum HBV that may with in specific in the The and an level Guidance on Use of and is to treatment including initiation of treatment and evaluation of a to in patients is not for the or of patients with CHB. HBV in patients being for therapy, that and B are with of loss C and D, it is not for or of patients with CHB. for viral in patients is not in patients with treatment with on therapy, or experience virological during of Patients on Antiviral Treatment Patients not for therapy monitoring to the for therapy the AASLD 2016 HBV HBV patients should at to monitoring should levels Patients with with levels a to of elevated levels times the of for and for should for Liver should in patients with or elevated in patients been with HBV from a Patients with or or for may used in of to for of Liver are more serum to or in or if levels of as by elevated are HBV patients should with every 3 during the year to that are in the and every If the level monitoring should more In for or evaluation for should that a with HBV may patients in the in which or levels are CHB and In and HBV CHB from CHB with a and of and more of the specific is CHB loss has been to at the rate of this does not at a In a study of patients with CHB in of loss 10 years and to 25 loss in to therapy, being more with with of to cirrhosis or patients of are present or the risk of if loss in patients years or in with cirrhosis or with or hepatitis virus of with of has been This is from in which and are Guidance for Monitoring Patients With Chronic HBV on Treatment that CHB is a persons are not treatment should to an for treatment has patients with should for at to If levels above along with HBV should more should every Patients are with levels and levels times the for for should to years and at a of Liver the of and If the or or or treatment is to are and or If treatment is Patients are with levels and elevated levels times the should to are years and at a of Liver the of and If the or or or treatment is to are and or If treatment is Patients are with and HBV should for and HBV every 3 during the year to CHB. and levels should at to If are a monitoring levels above the along with HBV should more (every In persons with HBV elevated of should not or or autoimmune with CHB should for loss of In persons and monitoring are should if the has a member with or a of years for and years for been with HBV from a for The AASLD 2018 Practice Guidelines on has been the as for and the and of are of The guideline for of persons at risk of with every 6 There was insufficient evidence for or the of every 6 to is not in is or is an is if the risk of is this all patients with cirrhosis patients without and history should with a risk of persons with or HIV and with this there is insufficient evidence to in children in children with cirrhosis or with a member with Guidance for in patients with cirrhosis should with with or without every 6 at risk for or years and years of persons with a member with a history of or persons with should with with or without every 6 There are insufficient data to for in it is to children and with or cirrhosis and with a member with using with or without every 6 persons at risk for are in is not with every 6 should 6 of Chronic HBV in As with with the treatment are to risk of to and including In the viral for by and If is treatment of should If HBV is treatment is by the HBV and levels treatment of virus may to in the of the and monitoring during and treatment is to for viral In the the treatment of for patients with HBV and was and for on the of and HBV with this a in serum HBV an and HBV in patients with HBV before treatment been with and therapy has been to levels in and to with HBV the of and failure are The majority of with elevated HBV and of In patients with cirrhosis or for HBV treatment HBV therapy should with or TAF are the preferred patients with chronic monitoring levels is with for and HBV if levels to or or HBV therapy should if there is evidence of HBV in HBV from for HBV and There are HBV or and approved patients with and more for and review of therapy before initiation of or HBV therapy is with Guidance for Treatment of Patients with HBV and patients should for using the treatment is for patients with HBV treatment is by and levels as the AASLD HBV guidelines for patients are at risk of and with therapy, and monitoring of HBV levels every during treatment and for 3 is in not treatment for patients the AASLD HBV patients with are at risk of with levels should at at the of and during with and for levels or to during treatment or The AASLD 2016 HBV Guidelines of persons at risk for including with HIV persons with and from of Additionally, patients with or HBV levels should for the of to the management of the if there is the to is The is and if this is it should by to of in and has been and the of the quality for by the World Health Organization has led to in Table - at of in with of and with with or HIV with or history of with elevated or with or HBV list is not The of treatment is the of which is by of levels and a in on patients with elevated of HBV and of the for or The of cirrhosis may treatment as is the in HBV are not in patients with or HBV patients with levels may including during treatment of and if the levels treatment with preferred or is of HBV may to which should a on The approved treatment of chronic hepatitis is is the of without in or Treatment as from to the virological The of with does not the of an virological with to of In the study of

Mild cognitive impairment is common in nondemented Parkinson's disease (PD) patients and may be a harbinger of dementia. In view of its importance, the Movement Disorder Society commissioned a task force to delineate diagnostic criteria for mild cognitive impairment in PD. The proposed diagnostic criteria are based on a literature review and expert consensus. This article provides guidelines to characterize the clinical syndrome and methods for its diagnosis. The criteria will require validation, and possibly refinement, as additional research improves our understanding of the epidemiology, presentation, neurobiology, assessment, and long-term course of this clinical syndrome. These diagnostic criteria will support future research efforts to identify at the earliest stage those PD patients at increased risk of progressive cognitive decline and dementia who may benefit from clinical interventions at a predementia stage.

Potential conflict of interest: Dr. Jonas consults and received grants from Gilead. She received grants from Bristol‐Myers Squibb and Roche. Dr. Chang advises Genentech, Alnylam, and Arbutus. Dr. Terrault consults for Bristol‐Myers Squibb and received grants from Gilead. Dr. Bzowej received grants from Gilead, Synageva, and Ocera. The funding for the development of this Practice Guideline was provided by the American Association for the Study of Liver Diseases. This Practice Guideline was approved by the AASLD on August 1, 2015. This Practice Guideline published with accompanying Reviews by Lok et al., Jonas et al., and Brown et al. See Editorial on Page 31 Objectives and Guiding Principles Guiding Principles This document presents official recommendations of the American Association for the Study of Liver Diseases (AASLD) on the treatment of chronic hepatitis B (CHB) virus (HBV) infection in adults and children. Unlike previous AASLD practice guidelines, this guideline was developed in compliance with the Institute of Medicine standards for trustworthy practice guidelines and uses the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach.1 Multiple systematic reviews of the literature were conducted to support the recommendations in this practice guideline. An enhanced understanding of this guideline will be obtained by reading the applicable portions of the systematic reviews. This guideline focuses on using antiviral therapy in chronic HBV infection and does not address other related and important issues, such as screening, prevention, and surveillance. For broader issues related to diagnosis, surveillance, and prevention as well as treatment in special populations (e.g., liver transplant recipients) that are not addressed by this guideline, the previous AASLD guideline2 and recent World Health Organization (WHO) guideline3 are excellent additional resources. Objectives Guideline developers from the AASLD formulated a list of discrete questions that physicians are faced with in daily practice. These questions were: Should adults with immune active CHB be treated with antiviral therapy to decrease liver‐related complications? Should adults with immune‐tolerant infection be treated with antiviral therapy to decrease liver‐related complications? Should antiviral therapy be discontinued in hepatitis B e antigen (HBeAg)‐positive persons who have developed HBeAg seroconversion on therapy? Should antiviral therapy be discontinued in persons with HBeAg‐negative infection with sustained HBV DNA suppression on therapy? In HBV‐monoinfected persons, does entecavir therapy, when compared to tenofovir therapy, have a different impact on renal and bone health? Is there a benefit to adding a second antiviral agent in persons with persistent low levels of viremia while being treated with either tenofovir or entecavir? Should persons with compensated cirrhosis and low levels of viremia be treated with antiviral agents? Should pregnant women who are hepatitis B surface antigen (HBsAg) positive with high viral load receive antiviral treatment in the third trimester to prevent perinatal transmission of HBV? Should children with HBeAg‐positive CHB be treated with antiviral therapy to decrease liver‐related complications? Target Audience This guideline is intended primarily for health care professionals caring for patients with CHB. Additionally, this guideline may assist policy makers in optimizing the care of individuals living with CHB. Background Burden of Disease Globally, an estimated 240 million persons have CHB with a varying prevalence geographically, highest in Africa and Asia.4 In the United States, the National Health and Nutrition Examination Survey (1999 to 2008) identified approximately 704,000 adults with CHB,5 but with adjustments for hepatitis B infection among foreign‐born persons, the upper estimate of CHB in the United States may be as high as 2.2 million.6 Globally, deaths from cirrhosis and hepatocellular carcinoma (HCC) were estimated at 310,000 and 340,000 per year, respectively.7 To reduce the morbidity and mortality of CHB in the United States and worldwide, there is a need for continued efforts to identify infected individuals through targeted screening, prevent new infections through vaccination, and monitor and treat those at risk for complications of their CHB, including surveillance for HCC.8 Natural History in Adults and Children CHB has been traditionally characterized into four phases (Table 1), reflecting the dynamic relationship between viral replication and evolution and the host immune response. These phases are of variable duration and not every person infected with CHB will evolve through all phases. Given the dynamic nature of CHB infection, serial monitoring of HBV DNA and alanine aminotransferase (ALT) levels is important to characterize the phase of infection. A single ALT and HBV DNA level are insufficient to assign phase of infection and/or need for treatment. Of note, some persons will be in the “gray zones,” that their HBV DNA and ALT levels not into the of ALT and HBV DNA levels and/or of liver to the phase of infection. In this HBV DNA levels are ALT levels are for and for and are of or The duration of this phase is but in those who are infected there is an of from immune‐tolerant to the HBeAg‐positive HBeAg‐positive ALT and HBV DNA levels in with liver characterize this of is among those infected at a The of from the HBeAg‐positive to phases is HBeAg The of seroconversion from HBeAg to to HBeAg is per in children of and and among adults to and per year, CHB In this HBV DNA levels are low or ALT levels are and is Liver but variable reflecting previous liver the HBeAg‐positive persons who HBeAg will to in the CHB of have or to HBeAg HBeAg‐negative immune those who from HBeAg to to have ALT and high HBV DNA and of may have of HBV replication and of hepatitis of of persons HBV in the or and liver and with HBeAg‐negative CHB to have HBV DNA levels those with HBeAg‐positive CHB and are to a of CHB ALT HBV DNA HBeAg Liver phase million and HBeAg‐positive phase or CHB phase or but variable HBeAg‐negative immune phase or CHB infection is by of with of to of persons with CHB will will to levels of HBV DNA are in the in the of persons of or antiviral therapy, risk of and of liver‐related complications is adults with CHB, of cirrhosis is and among those with risk of is and risk of is and of cirrhosis and (Table HBV DNA ALT and HBeAg are among the important of risk of to HBV DNA levels HBeAg and cirrhosis are of A of risk has been in adults with HBV DNA levels a HBV DNA level is with of cirrhosis and and and of of in Africa HBV DNA ALT levels to HBeAg seroconversion Development of HBeAg‐negative CHB of cirrhosis HBV DNA ALT to HBeAg seroconversion Development of HBeAg‐negative CHB viral infections and viral infections and and of CHB The of persons with CHB a and with special on risk for and of HBV infection and liver of liver and of HBV and for with hepatitis virus hepatitis virus or virus in those at risk (Table to the nature of CHB, the of high HBV DNA level at a single in is and monitoring of is to need for antiviral The upper of for ALT on are from all including those with liver Evaluation of Examination patients of cirrhosis and risk of including HBV DNA to need for or or patients to other of chronic liver liver HBV in those who have not Liver of the of liver is important in antiviral therapy and need for surveillance. Liver an of the of and other of liver and may be for persons who for treatment. liver is as the to the of and to are of hepatitis B may to of by and different for and on ALT levels have been of such as aminotransferase and have in persons with or on the but in and may be in The of antiviral treatment are to decrease the morbidity and mortality related to CHB. The of a sustained suppression of HBV replication has been with of of HBeAg with or of and in liver the was in treatment of CHB, that of DNA the of in the of in persons with of infection, a risk for of infection. an may be by and sustained HBV DNA suppression and a by of including the The is not an are approved for the treatment of adults with CHB in the United States and approved for the treatment of children with CHB (Table are with therapy with all have an excellent a of persons with CHB, including those with cirrhosis and transplant The in for are For persons with the treatment is For persons with treatment of HBV to be with therapy that HBV have and in Adults and Children in in Potential on million in adults and in children to every monitoring for and complications daily daily to levels daily B and levels or to levels daily daily renal at at risk for renal and at bone at and treatment in persons with of or for levels daily daily B at at risk for renal and at bone at and treatment in persons with of or for levels need to be in persons with renal is not approved for children with CHB, but is approved for treatment of chronic hepatitis may using this for children with chronic The duration of treatment in adults is in adults is daily or or in children and at and For children and at the entecavir and and are to the of therapy (Table are on therapy and therapy The of sustained is but this is with of in Adults CHB and Disease HBV DNA HBeAg HBeAg seroconversion 31 HBV DNA of of of DNA for for entecavir and DNA for for entecavir and by of Guideline Development The questions a for by the guidelines are in CHB therapy treatment of CHB, adults therapy treatment of HBeAg‐positive chronic with HBeAg seroconversion on therapy antiviral therapy antiviral therapy of HBeAg‐negative chronic with viral suppression on antiviral therapy antiviral therapy antiviral therapy of CHB on treatment with therapy bone health CHB on treatment with therapy with persistent viremia therapy or therapy HBV of HBeAg CHB with with HBV DNA therapy treatment women with CHB therapy in third trimester treatment CHB in the HBeAg‐positive CHB, therapy treatment HBeAg of A and the of A of AASLD with an with in systematic reviews to the and the systematic the (Table In this the of in is as or low on the of and risk of and The recommendations on the of of and and and are as to patients with or to the of patients and are with the of are to recommendations to to of the questions are as an to this For the questions with and are The the of Study of of when of when (e.g., (e.g., the low of the of a Recommendation of of and and and of the of Recommendation in this the of and a Health care receive the of The be as a policy in The of in this the of but Health care to patients a that is with their using and is a need for and of of CHB The AASLD antiviral therapy for adults with CHB or HBeAg to decrease the risk of liver‐related of of The AASLD or tenofovir as therapy for adults with CHB. of of CHB is by an of ALT or of HBV DNA or The for ALT in adults is for and for is insufficient for or of ALT other ALT The to treat persons with ALT the but of of liver by or is for persons with CHB and cirrhosis HBV DNA of ALT in the to treat persons with CHB but ALT and HBV DNA is with of of treatment of and may to treatment is a risk for of for treatment of liver of HBV DNA be with and the be as a but not for treatment. of antiviral to of therapy in risk in liver‐related in and entecavir as the important was the of with that need to be in between and tenofovir for therapy of treatment (Table is in persons with and of is not in this A therapy with or of antiviral that is in is (Table HBV A and B are to HBeAg and with is for For persons treated with duration is in and is This treatment duration HBeAg seroconversion of and sustained HBV DNA suppression in of persons who HBeAg to The of and has not of or and is not of therapy for therapy is variable and by HBeAg duration of HBV DNA and of in persons with Evaluation for of using or liver is in treatment including duration of with does not the risk of and surveillance for in persons who are at Background CHB is a dynamic characterized by variable of immune that in the development of liver and liver‐related in a of ALT and HBV DNA levels are of risk of liver a of infection, HBV and HBV and The of HBV therapy is to prevent liver‐related morbidity and in the phases of infection positive and of liver and/or and HBV DNA levels with a risk of liver and and The is in A of were to treatment and of or were and were a of provided in persons with and provided in persons with antiviral compared to treatment and compared therapy to treatment. A to antiviral was not to the of per The of was for low to low to of per was per For the of was and The of the treatment in liver‐related and and of risk and among to of the of the therapy to was with risk in cirrhosis in risk and a risk in and and a risk in the of persons with antiviral therapy risk of and liver but not in mortality In by of therapy, and of cirrhosis and but were with of and The for treatment in a person with is the of liver or as by ALT levels or on and/or active HBV of treatment in adults for ALT to ALT and ALT for is that the ALT levels of adults are for and for using ALT for the to treatment of adults with ALT of the for and for is the ALT in the The HBV DNA levels to are on of with from that the risk of liver‐related complications with HBV DNA levels In systematic liver‐related in persons antiviral therapy by HBV DNA level and in Liver are not to treatment of the of previous to treatment is important in treatment duration of therapy, and does not the ALT and HBV DNA at treatment be A high on and on are with of the with treatment seroconversion and HBV DNA such as may be in cirrhosis have high but are in of or and high ALT levels are with and this to be into in are to risk benefit for persons with ALT and HBV DNA (e.g., for HBeAg positive and for HBeAg who are in the “gray for ALT and HBV DNA for treatment to the of of in treatment are is a need for treatment that the HBV to of Adults CHB The AASLD antiviral therapy for adults with immune‐tolerant CHB. of of be by ALT levels for and for women as The AASLD that ALT levels be at every for adults with immune‐tolerant CHB to monitor for to or CHB. of low of The AASLD antiviral therapy in the of adults of with ALT and HBV DNA and liver or of low of or on liver is a to of antiviral therapy, other of liver are Background Natural have a between HBV DNA levels and the development of and of ALT HBV and HBeAg in This the of adults in the immune‐tolerant phase of infection benefit from antiviral Of note, as In using ALT of for and for and is in the of HBeAg‐positive adults with high HBV DNA In persons who their infection at or in the of from immune‐tolerant to phases is is with of in HBeAg‐positive persons with ALT and The is in of in immune‐tolerant adults with ALT ALT for were with treatment duration of for or for with of HBeAg and seroconversion as the antiviral therapy to treatment were the this The were of different antiviral to antiviral therapy in a of HBeAg and seroconversion of by treatment and all that different from The were and the to persons with ALT were low to low are that antiviral therapy is in of and liver‐related in persons with immune‐tolerant CHB. treatment duration for of HBeAg but not and among including persons with ALT The persons with HBeAg‐positive immune active a for antiviral Given the of of benefit to those with ALT of immune‐tolerant the of antiviral therapy, including antiviral and development of Additionally, there are to a for treatment of immune‐tolerant persons with of the of persons with ALT levels and high HBV DNA levels have and/or on liver the of with for adults with an immune‐tolerant but or antiviral therapy is but the of this is of therapy and are to and of antiviral therapy in adults in the immune‐tolerant phase of CHB, in persons with of of HBeAg to on The AASLD that HBeAg‐positive adults cirrhosis with CHB who to on therapy a of treatment of of The of therapy treatment for at of ALT levels and HBV DNA is not a duration of reduce of an is to treat treatment duration and of treatment of and for health risk for liver and of continued antiviral therapy, with and and for with treatment and and These for HBeAg‐positive adults and with cirrhosis who to on who antiviral therapy be every for at for ALT and The AASLD antiviral therapy for HBeAg‐positive adults with cirrhosis with CHB who to on therapy, on for and there is a for treatment of of with cirrhosis who antiviral therapy be (e.g., for every for ALT and may be in persons who have of there is insufficient to treatment for such Background HBeAg and sustained HBV DNA suppression are of antiviral therapy in HBeAg‐positive persons, those of or seroconversion is the of immune of antiviral therapy, persons with HBeAg‐positive immune active who are treated with antiviral therapy may be to treatment of the of HBeAg treatment with antiviral therapy seroconversion is may be an but may not be for all persons to of and need for is health such as or are different in persons who HBeAg seroconversion compared to those who continued antiviral therapy and is the important of or among HBeAg‐positive persons who antiviral therapy compared to those who continued HBeAg compared continued therapy to a of and of ALT and HBeAg that persons who treatment a of viremia and of ALT of the persons who continued treatment either The second a of ALT of in those who in those who continued antiviral The of HBV DNA was in persons who in those who and that of HBeAg was duration of therapy from HBeAg seroconversion to antiviral treatment was to be and In other of HBeAg seroconversion for entecavir was at and for was at The for antiviral therapy is on the of of therapy in of and with the and with antiviral of antiviral therapy may of and risk of liver in with Additionally, the risk of is in persons who are positive those who were and the risk of cirrhosis is in persons with persistent HBeAg A of has been to reduce the risk of HBeAg the duration of HBeAg seroconversion is for HBeAg‐positive persons who to on health such as or in to the duration of of antiviral therapy in persons cirrhosis and impact of antiviral therapy in persons with of in CHB The AASLD antiviral therapy for adults with HBeAg‐negative CHB, there is a for treatment of of A to therapy for HBeAg‐negative adults cirrhosis of and for health risk for liver and of continued antiviral therapy, with and and for with treatment and and in persons with cirrhosis is not to the for and are may be in persons who have of there is insufficient to treatment for such who antiviral therapy be every for at for ALT and therapy is not for persons cirrhosis who are HBeAg with ALT and viremia chronic hepatitis Background The are in HBV DNA not or viral DNA into the host HBV viremia treatment virus suppression therapy, in some with hepatitis and/or In this antiviral therapy is A previous AASLD hepatitis B practice guideline antiviral therapy for HBeAg‐negative persons was and The is in important such as and among HBeAg‐negative persons who compared to those who continued antiviral were duration of therapy antiviral therapy in HBeAg‐negative an compared treatment duration and were with of viremia in persons treatment viremia in persons with or of four the of treatment in HBeAg‐negative persons with duration of therapy or including and These viremia to level in and ALT in approximately third to of the was in of persons who therapy at of therapy in and in of of therapy in there was in between adults with and in of with cirrhosis in In a from of persons with CHB HBeAg who discontinued therapy from a hepatitis B with the of at 1, and was and there was in the of between persons with and persons with cirrhosis of that virus suppression and ALT may be sustained in of the HBeAg‐negative persons with treatment duration or the of treatment on morbidity and mortality with persistent for and in persons with for treatment of for and Given the health with and antiviral therapy, with duration of are to antiviral therapy be in persons with and treatment for patients on therapy, such as adding or to therapy, are to identify for treatment including levels in the United and and Disease in on Recommendation The AASLD between entecavir and tenofovir of renal and bone of of The not in renal or bone between persons treated with tenofovir or renal such as renal or have been in In persons on renal including and be treatment and (e.g., at and or high risk for renal In the of other risk for there is insufficient for or monitoring of bone in persons on In of renal and/or tenofovir be discontinued and with an with for previous of be on renal and as by Background and tenofovir are approved as for CHB. tenofovir therapy has been with and chronic with and and on from tenofovir therapy in persons has been with bone and there was risk for or with tenofovir therapy in persons in a systematic and of and have been in persons on HBV infection and liver to the of tenofovir a compared to is the for The of renal and bone for to of treatment was low in a recent with and in bone between and from identified a need for in of persons for renal an approximately a and for The of with approved HBV was in of persons with cirrhosis treated with and risk of was with the of for Liver including and The is in The of tenofovir and entecavir was compared in with of per treatment The of adults with cirrhosis in or of tenofovir or entecavir The second of adults on on in renal and in treatment duration was in In the in and/or between the treatment a in of for tenofovir entecavir a in bone in and adults with an treatment duration of additional in of and in of treated with with an additional of renal in A recent of persons with of low risk for renal and bone was a risk for persons on therapy for the risk was low The duration of in of the with to to in low to low of in the for of renal in persons that persons on tenofovir have renal at with treatment duration and are to renal and bone with therapy, in to and to prevent and of on The AASLD that persons with persistent viremia on entecavir or tenofovir of of of The AASLD of in persons with on entecavir or tenofovir either to antiviral with high to or a second antiviral that of of patients is in those with persistent viremia on antiviral viremia has traditionally been as HBV DNA of treatment. This was by of in and an of antiviral therapy with of antiviral and of the of entecavir and persistent viremia is as a in the of HBV DNA and/or to HBV DNA level of is insufficient to for adding a second or to in of in this may not be viral levels are to is by an in HBV DNA by compared to or HBV DNA in persons on therapy with levels be obtained a therapy may assist with A a for to antiviral with high to or adding a second antiviral with a (Table is insufficient to the risk of viral is to be with antiviral therapy compared to the of HBV DNA monitoring has not been monitoring of HBV DNA levels every HBV DNA is and every for of persistent viremia and For persons on treatment with other tenofovir or viral a to antiviral with high to or the of a second antiviral with a (Table for of tenofovir tenofovir entecavir tenofovir tenofovir and entecavir Background all persons viral suppression on entecavir or tenofovir therapy of those treated with of HBeAg‐positive and of HBeAg‐negative viral For those treated with viral suppression were for HBeAg‐positive persons and for HBeAg‐negative For persons on therapy who to an HBV DNA level of therapy, but not for is as to a of therapy is The of adding on an additional antiviral therapy to an to antiviral has not been In on antiviral treatment is with viral and a of and was of to continued among persons with persistent the of was low the of persons with persistent viremia who continued entecavir or tenofovir compared to persons who to with high to or a second antiviral with to viral of persons on with persistent viremia viral or on there was support in of either to a or adding a second antiviral with a In a of persons with entecavir treated with tenofovir or tenofovir and the of viral suppression at was and in the In of persons with treated with tenofovir or tenofovir and entecavir for there was in the of viral suppression between the are of insufficient duration to therapy in of risk for with treatment are to care for persons with persistent viremia or on antiviral is to the health of and adding on antiviral need that a in antiviral therapy, and the of different of Adults and The AASLD that adults with compensated cirrhosis and low levels of viremia be treated with antiviral therapy to reduce the risk of of ALT of of and entecavir are of their and risk of with a low to not be the of to is not in persons with compensated but are treatment is not to persons with compensated cirrhosis and low levels of be for a in HBV DNA and/or be either The ALT level in persons is or the ALT levels the of other for ALT is is a for antiviral does not an of treatment. therapy were monitoring every for at for of viral that to with compensated cirrhosis and high HBV DNA levels are treated per recommendations for HBeAg‐positive and CHB with does not the risk of and surveillance for The AASLD that adults with cirrhosis be treated with antiviral therapy of HBV DNA HBeAg or ALT level to decrease risk of liver‐related of of and tenofovir are is in persons with cirrhosis to for liver is in has been with some and persons with cirrhosis may be at of and is with does not the risk of and surveillance for Background The of HBV treatment is to prevent and liver‐related complications through of sustained suppression of In those with and/or on and/or ALT in with HBV DNA the risk of liver‐related complications is highest and the for treatment be persons with cirrhosis but ALT levels and low levels of viremia are at risk is and have that of hepatitis B in viral load to in with an in at a of per in persons with with a viral load between and to be at the highest there is for using antiviral therapy in persons with cirrhosis and low levels of HBV that and liver‐related or a In of persons with cirrhosis HBV DNA and HBeAg at the developed the other in risk was among patients those with HBV DNA

The Addiction Severity Index (ASI) is a clinical/research instrument which has been in wide use during the past 6 years to assess the treatment problems found in alcohol- and drug-abusing patients. In a study of male veterans, a preliminary evaluation of the ASI has indicated reliability and validity. The present report presents an expanded examination of these issues; 181 subjects from three treatment centers were studied. Results of concurrent reliability studies indicate that trained technicians can estimate the severity of patients' treatment problems with an average concordance of .89. Test-retest studies show that the information obtained from the ASI is consistent over a 3-day interval, even with different interviewers. Comparisons of the ASI severity ratings and composite measures with a battery of previously validated tests indicate evidence of concurrent and discriminant validity. The reliability and validity results were consistent across subgroups of patients categorized by age, race, sex, primary drug problem, and treatment center. The authors discuss the strengths and limitations of the instrument based upon 5 years of use. The overall conclusion is that the ASI is a reliable and valid instrument that has a wide range of clinical and research applications, and that it may offer advantages in the examination of important issues such as the prediction of treatment outcome, the comparison of different forms of treatment, and the "matching" of patients to treatments.

BACKGROUND: Despite notable technical advances in therapy for malignant gliomas during the past decade, improved patient survival has not been clearly documented, suggesting that pretreatment prognostic factors influence outcome more than minor modifications in therapy. Age, performance status, and tumor histopathology have been identified as the pretreatment variables most predictive of survival outcome. However, an analysis of the association of survival with both pretreatment characteristics and treatment-related variables is necessary to assure reliable evaluation of new approaches for treatment of malignant glioma. PURPOSE: This study of malignant glioma patients used a non-parametric statistical technique to examine the associations of both pretreatment patient and tumor characteristics and treatment-related variables with survival duration. This technique was used to identify subgroups with survival rates sufficiently different to create improvements in the design and stratification of clinical trials. METHODS: We used a recursive partitioning technique to analyze survival in 1578 patients entered in three Radiation Therapy Oncology Group malignant glioma trials from 1974 to 1989 that used several radiation therapy (RT) regimens with and without chemotherapy or a radiation sensitizer. This approach creates a regression tree according to prognostic variables that classifies patients into homogeneous subsets by survival. Twenty-six pretreatment characteristics and six treatment-related variables were analyzed. RESULTS: The years). Patients younger than 50 years old were categorized by histology (astrocytomas with anaplastic or atypical foci [AAF] versus glioblastoma multiforme [GBM]) and subsequently by normal or abnormal mental status for AAF patients and by performance status for those with GBM. For patients aged 50 years or older, performance status was the most important variable, with normal or abnormal mental status creating the only significant split in the poorer performance status group. Treatment-related variables produced a subgroup showing significant differences only for better performance status GBM patients over age 50 (by extent of surgery and RT dose). Median survival times were 4.7-58.6 months for the 12 subgroups resulting from this analysis, which ranged in size from 32 to 256 patients. CONCLUSIONS: This approach permits examination of the interaction between prognostic variables not possible with other forms of multivariate analysis. IMPLICATIONS: The recursive partitioning technique can be employed to refine the stratification and design of malignant glioma trials.

OBJECTIVE: To develop updated guidelines for the pharmacologic management of rheumatoid arthritis. METHODS: We developed clinically relevant population, intervention, comparator, and outcomes (PICO) questions. After conducting a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to rate the certainty of evidence. A voting panel comprising clinicians and patients achieved consensus on the direction (for or against) and strength (strong or conditional) of recommendations. RESULTS: The guideline addresses treatment with disease-modifying antirheumatic drugs (DMARDs), including conventional synthetic DMARDs, biologic DMARDs, and targeted synthetic DMARDs, use of glucocorticoids, and use of DMARDs in certain high-risk populations (i.e., those with liver disease, heart failure, lymphoproliferative disorders, previous serious infections, and nontuberculous mycobacterial lung disease). The guideline includes 44 recommendations (7 strong and 37 conditional). CONCLUSION: This clinical practice guideline is intended to serve as a tool to support clinician and patient decision-making. Recommendations are not prescriptive, and individual treatment decisions should be made through a shared decision-making process based on patients' values, goals, preferences, and comorbidities.

BACKGROUND: The effects of a carbohydrate-restricted diet on weight loss and risk factors for atherosclerosis have been incompletely assessed. METHODS: We randomly assigned 132 severely obese subjects (including 77 blacks and 23 women) with a mean body-mass index of 43 and a high prevalence of diabetes (39 percent) or the metabolic syndrome (43 percent) to a carbohydrate-restricted (low-carbohydrate) diet or a calorie- and fat-restricted (low-fat) diet. RESULTS: Seventy-nine subjects completed the six-month study. An analysis including all subjects, with the last observation carried forward for those who dropped out, showed that subjects on the low-carbohydrate diet lost more weight than those on the low-fat diet (mean [+/-SD], -5.8+/-8.6 kg vs. -1.9+/-4.2 kg; P=0.002) and had greater decreases in triglyceride levels (mean, -20+/-43 percent vs. -4+/-31 percent; P=0.001), irrespective of the use or nonuse of hypoglycemic or lipid-lowering medications. Insulin sensitivity, measured only in subjects without diabetes, also improved more among subjects on the low-carbohydrate diet (6+/-9 percent vs. -3+/-8 percent, P=0.01). The amount of weight lost (P<0.001) and assignment to the low-carbohydrate diet (P=0.01) were independent predictors of improvement in triglyceride levels and insulin sensitivity. CONCLUSIONS: Severely obese subjects with a high prevalence of diabetes or the metabolic syndrome lost more weight during six months on a carbohydrate-restricted diet than on a calorie- and fat-restricted diet, with a relative improvement in insulin sensitivity and triglyceride levels, even after adjustment for the amount of weight lost. This finding should be interpreted with caution, given the small magnitude of overall and between-group differences in weight loss in these markedly obese subjects and the short duration of the study. Future studies evaluating long-term cardiovascular outcomes are needed before a carbohydrate-restricted diet can be endorsed.

OBJECTIVE: To develop updated guidelines for the pharmacologic management of rheumatoid arthritis. METHODS: We developed clinically relevant population, intervention, comparator, and outcomes (PICO) questions. After conducting a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to rate the certainty of evidence. A voting panel comprising clinicians and patients achieved consensus on the direction (for or against) and strength (strong or conditional) of recommendations. RESULTS: The guideline addresses treatment with disease-modifying antirheumatic drugs (DMARDs), including conventional synthetic DMARDs, biologic DMARDs, and targeted synthetic DMARDs, use of glucocorticoids, and use of DMARDs in certain high-risk populations (i.e., those with liver disease, heart failure, lymphoproliferative disorders, previous serious infections, and nontuberculous mycobacterial lung disease). The guideline includes 44 recommendations (7 strong and 37 conditional). CONCLUSION: This clinical practice guideline is intended to serve as a tool to support clinician and patient decision-making. Recommendations are not prescriptive, and individual treatment decisions should be made through a shared decision-making process based on patients' values, goals, preferences, and comorbidities.

OBJECTIVE: To update evidence-based medicine recommendations for treating nonmotor symptoms in Parkinson's disease (PD). BACKGROUND: The International Parkinson and Movement Disorder Society Evidence-Based Medicine Committee's recommendations for treatments of PD were first published in 2002, updated in 2011, and now updated again through December 31, 2016. METHODS: Level I studies testing pharmacological, surgical, or nonpharmacological interventions for the treatment of nonmotor symptoms in PD were reviewed. Criteria for inclusion and quality scoring were as previously reported. The disorders covered were a range of neuropsychiatric symptoms, autonomic dysfunction, disorders of sleep and wakefulness, pain, fatigue, impaired olfaction, and ophthalmologic dysfunction. Clinical efficacy, implications for clinical practice, and safety conclusions are reported. RESULTS: A total of 37 new studies qualified for review. There were no randomized controlled trials that met inclusion criteria for the treatment of anxiety disorders, rapid eye movement sleep behavior disorder, excessive sweating, impaired olfaction, or ophthalmologic dysfunction. We identified clinically useful or possibly useful interventions for the treatment of depression, apathy, impulse control and related disorders, dementia, psychosis, insomnia, daytime sleepiness, drooling, orthostatic hypotension, gastrointestinal dysfunction, urinary dysfunction, erectile dysfunction, fatigue, and pain. There were no clinically useful interventions identified to treat non-dementia-level cognitive impairment. CONCLUSIONS: The evidence base for treating a range of nonmotor symptoms in PD has grown substantially in recent years. However, treatment options overall remain limited given the high prevalence and adverse impact of these disorders, so the development and testing of new treatments for nonmotor symptoms in PD remains a top priority. © 2019 International Parkinson and Movement Disorder Society.

Subthalamic nucleus (STN) deep brain stimulation (DBS) is currently the most common therapeutic surgical procedure for patients with Parkinson's disease (PD) who have failed medical management. However, a recent summary of clinical evidence on the effectiveness of STN DBS is lacking. We report the results of such a systematic review and meta-analysis. A comprehensive review of the literature using Medline and Ovid databases from 1993 until 2004 was conducted. Estimates of change in absolute Unified Parkinson's Disease Rating Scale (UPDRS) scores after surgery were generated using random-effects models. Sources of heterogeneity were explored with meta-regression models, and the possibility of publication bias was evaluated. Patient demographics, reduction in medication requirements, change in dyskinesia, daily offs, quality of life, and a ratio of postoperative improvement from stimulation compared to preoperative improvement by medication from each study were tabulated and average scores were calculated. Adverse effects from each study were summarized. Thirty-seven cohorts were included in the review. Twenty-two studies with estimates of standard errors were included in the meta-analysis. The estimated decreases in absolute UPDRS II (activities of daily living) and III (motor) scores after surgery in the stimulation ON/medication off state compared to preoperative medication off state were 13.35 (95% CI: 10.85-15.85; 50%) and 27.55 (95% CI: 24.23-30.87; 52%), respectively. Average reduction in L-dopa equivalents following surgery was 55.9% (95% CI: 50%-61.8%). Average reduction in dyskinesia following surgery was 69.1% (95% CI: 62.0%-76.2%). Average reduction in daily off periods was 68.2% (95% CI: 57.6%-78.9%). Average improvement in quality of life using PDQ-39 was 34.5% +/- 15.3%. Univariable regression showed improvements in UPDRS III scores were significantly greater in studies with higher baseline UPDRS III off scores, increasing disease duration prior to surgery, earlier year of publication, and higher baseline L-dopa responsiveness. Average baseline UPDRS III off scores were significantly lower (i.e., suggesting milder disease) in later than in earlier studies. In multivariable regression, L-dopa responsiveness, higher baseline motor scores, and disease duration were independent predictors of greater change in motor score. No evidence of publication bias in the available literature was found. The most common serious adverse event related to surgery was intracranial hemorrhage in 3.9% of patients. Psychiatric sequelae were common. Synthesis of the available literature indicates that STN DBS improves motor activity and activities of daily living in advanced PD. Differences between available studies likely reflect differences in patient populations and follow-up periods. These data provide an estimate of the magnitude of the treatment effects and emphasize the need for controlled and randomized studies.

Abstract Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40–50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes 1 . Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel 2 ) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10–20% (14–24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.

OBJECTIVE: To assess the efficacy and safety of anifrolumab, a type I interferon (IFN) receptor antagonist, in a phase IIb, randomized, double-blind, placebo-controlled study of adults with moderate-to-severe systemic lupus erythematosus (SLE). METHODS: Patients (n = 305) were randomized to receive intravenous anifrolumab (300 mg or 1,000 mg) or placebo, in addition to standard therapy, every 4 weeks for 48 weeks. Randomization was stratified by SLE Disease Activity Index 2000 score (<10 or ≥10), oral corticosteroid dosage (<10 or ≥10 mg/day), and type I IFN gene signature test status (high or low) based on a 4-gene expression assay. The primary end point was the percentage of patients achieving an SLE Responder Index (SRI[4]) response at week 24 with sustained reduction of oral corticosteroids (<10 mg/day and less than or equal to the dose at week 1 from week 12 through 24). Other end points (including SRI[4], British Isles Lupus Assessment Group [BILAG]-based Composite Lupus Assessment [BICLA], modified SRI[6], and major clinical response) were assessed at week 52. The primary end point was analyzed in the modified intent-to-treat (ITT) population and type I IFN-high subpopulation. The study result was considered positive if the primary end point was met in either of the 2 study populations. The Type I error rate was controlled at 0.10 (2-sided), within each of the 2 study populations for the primary end point analysis. RESULTS: The primary end point was met by more patients treated with anifrolumab (34.3% of 99 for 300 mg and 28.8% of 104 for 1,000 mg) than placebo (17.6% of 102) (P = 0.014 for 300 mg and P = 0.063 for 1,000 mg, versus placebo), with greater effect size in patients with a high IFN signature at baseline (13.2% in placebo-treated patients versus 36.0% [P = 0.004] and 28.2% [P = 0.029]) in patients treated with anifrolumab 300 mg and 1,000 mg, respectively. At week 52, patients treated with anifrolumab achieved greater responses in SRI(4) (40.2% versus 62.6% [P < 0.001] and 53.8% [P = 0.043] with placebo, anifrolumab 300 mg, and anifrolumab 1,000 mg, respectively), BICLA (25.7% versus 53.5% [P < 0.001] and 41.2% [P = 0.018], respectively), modified SRI(6) (28.4% versus 49.5% [P = 0.002] and 44.7% [P = 0.015], respectively), major clinical response (BILAG 2004 C or better in all organ domains from week 24 through week 52) (6.9% versus 19.2% [P = 0.012] and 17.3% [P = 0.025], respectively), and several other global and organ-specific end points. Herpes zoster was more frequent in the anifrolumab-treated patients (2.0% with placebo treatment versus 5.1% and 9.5% with anifrolumab 300 mg and 1,000 mg, respectively), as were cases reported as influenza (2.0% versus 6.1% and 7.6%, respectively), in the anifrolumab treatment groups. Incidence of serious adverse events was similar between groups (18.8% versus 16.2% and 17.1%, respectively). CONCLUSION: Anifrolumab substantially reduced disease activity compared with placebo across multiple clinical end points in the patients with moderate-to-severe SLE.

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. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

The mammalian intestinal tract is colonized by trillions of beneficial commensal bacteria that are anatomically restricted to specific niches. However, the mechanisms that regulate anatomical containment remain unclear. Here, we show that interleukin-22 (IL-22)-producing innate lymphoid cells (ILCs) are present in intestinal tissues of healthy mammals. Depletion of ILCs resulted in peripheral dissemination of commensal bacteria and systemic inflammation, which was prevented by administration of IL-22. Disseminating bacteria were identified as Alcaligenes species originating from host lymphoid tissues. Alcaligenes was sufficient to promote systemic inflammation after ILC depletion in mice, and Alcaligenes-specific systemic immune responses were associated with Crohn's disease and progressive hepatitis C virus infection in patients. Collectively, these data indicate that ILCs regulate selective containment of lymphoid-resident bacteria to prevent systemic inflammation associated with chronic diseases.

OBJECTIVE: To develop and validate new classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIM) and their major subgroups. METHODS: Candidate variables were assembled from published criteria and expert opinion using consensus methodology. Data were collected from 47 rheumatology, dermatology, neurology, and pediatric clinics worldwide. Several statistical methods were utilized to derive the classification criteria. RESULTS: Based on data from 976 IIM patients (74% adults; 26% children) and 624 non-IIM patients with mimicking conditions (82% adults; 18% children), new criteria were derived. Each item is assigned a weighted score. The total score corresponds to a probability of having IIM. Subclassification is performed using a classification tree. A probability cutoff of 55%, corresponding to a score of 5.5 (6.7 with muscle biopsy) "probable IIM," had best sensitivity/specificity (87%/82% without biopsies, 93%/88% with biopsies) and is recommended as a minimum to classify a patient as having IIM. A probability of ≥90%, corresponding to a score of ≥7.5 (≥8.7 with muscle biopsy), corresponds to "definite IIM." A probability of <50%, corresponding to a score of <5.3 (<6.5 with muscle biopsy), rules out IIM, leaving a probability of ≥50-<55% as "possible IIM." CONCLUSION: The European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for IIM have been endorsed by international rheumatology, dermatology, neurology, and pediatric groups. They employ easily accessible and operationally defined elements, and have been partially validated. They allow classification of "definite," "probable," and "possible" IIM, in addition to the major subgroups of IIM, including juvenile IIM. They generally perform better than existing criteria.

Underlying differences in device accuracy may be compounded in these measures.Our study is limited by being conducted with young, healthy volunteers in a controlled setting with a convenience sample of a small number of applications and devices.Results should be confirmed in other settings and with other devices.Increased physical activity facilitated by these devices could lead to clinical benefits not realized by low adoption of pedometers.Our findings may help reinforce individuals' trust in using smartphone applications and wearable devices to track health behaviors, which could have important implications for strategies to improve population health.

INTRODUCTION: Increasing evidence suggests a role for the gut microbiome in central nervous system disorders and a specific role for the gut-brain axis in neurodegeneration. Bile acids (BAs), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signaling functions and seem dysregulated in Alzheimer's disease (AD). METHODS: Serum levels of 15 primary and secondary BAs and their conjugated forms were measured in 1464 subjects including 370 cognitively normal older adults, 284 with early mild cognitive impairment, 505 with late mild cognitive impairment, and 305 AD cases enrolled in the AD Neuroimaging Initiative. We assessed associations of BA profiles including selected ratios with diagnosis, cognition, and AD-related genetic variants, adjusting for confounders and multiple testing. RESULTS: In AD compared to cognitively normal older adults, we observed significantly lower serum concentrations of a primary BA (cholic acid [CA]) and increased levels of the bacterially produced, secondary BA, deoxycholic acid, and its glycine and taurine conjugated forms. An increased ratio of deoxycholic acid:CA, which reflects 7α-dehydroxylation of CA by gut bacteria, strongly associated with cognitive decline, a finding replicated in serum and brain samples in the Rush Religious Orders and Memory and Aging Project. Several genetic variants in immune response-related genes implicated in AD showed associations with BA profiles. DISCUSSION: We report for the first time an association between altered BA profile, genetic variants implicated in AD, and cognitive changes in disease using a large multicenter study. These findings warrant further investigation of gut dysbiosis and possible role of gut-liver-brain axis in the pathogenesis of AD.

OBJECTIVE: To compare the urate-lowering efficacy and safety of febuxostat, allopurinol, and placebo in a large group of subjects with hyperuricemia and gout, including persons with impaired renal function. METHODS: Subjects (n = 1,072) with hyperuricemia (serum urate level > or = 8.0 mg/dl) and gout with normal or impaired (serum creatinine level >1.5 to < or = 2.0 mg/dl) renal function were randomized to receive once-daily febuxostat (80 mg, 120 mg, or 240 mg), allopurinol (300 or 100 mg, based on renal function), or placebo for 28 weeks. RESULTS: Significantly (P < or = 0.05) higher percentages of subjects treated with febuxostat 80 mg (48%), 120 mg (65%), and 240 mg (69%) attained the primary end point of last 3 monthly serum urate levels <6.0 mg/dl compared with allopurinol (22%) and placebo (0%). A significantly (P < 0.05) higher percentage of subjects with impaired renal function treated with febuxostat 80 mg (4 [44%] of 9), 120 mg (5 [45%] of 11), and 240 mg (3 [60%] of 5) achieved the primary end point compared with those treated with 100 mg of allopurinol (0 [0%] of 10). Proportions of subjects experiencing any adverse event or serious adverse event were similar across groups, although diarrhea and dizziness were more frequent in the febuxostat 240 mg group. The primary reasons for withdrawal were similar across groups except for gout flares, which were more frequent with febuxostat than with allopurinol. CONCLUSION: At all doses studied, febuxostat more effectively lowered and maintained serum urate levels <6.0 mg/dl than did allopurinol (300 or 100 mg) or placebo in subjects with hyperuricemia and gout, including those with mild to moderately impaired renal function.