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.

This AASLD 2018 Hepatitis B Guidance is intended to complement the AASLD 2016 Practice Guidelines for Treatment of Chronic Hepatitis B 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.

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,” meaning that their HBV DNA and ALT levels do not fall into the same phase. Longitudinal follow‐up of ALT and HBV DNA levels and/or assessment of liver histology can serve to clarify the phase of infection. Immune‐tolerant phase: In this highly replicative/low inflammatory phase, HBV DNA levels are elevated, ALT levels are normal (<19 U/L for females and <30 U/L for males), and biopsies are without signs of significant inflammation or fibrosis. The duration of this phase is highly variable, but longest in those who are infected perinatally. With increasing age, there is an increased likelihood of transitioning from immune‐tolerant to the HBeAg‐positive immune‐active phase. HBeAg‐positive immune‐active phase: Elevated ALT and HBV DNA levels in conjunction with liver injury characterize this phase. Median age of onset is 30 years among those infected at a young age. The hallmark of transition from the HBeAg‐positive immune‐active to ‐inactive phases is HBeAg seroconversion. The rate of spontaneous seroconversion from HBeAg to antibody to HBeAg (anti‐HBe) is less than 2% per year in children younger than 3 years of age and increases during puberty and among adults to 8% and 12% per year, respectively. Inactive CHB phase: In this phase, HBV DNA levels are low or undetectable, ALT levels are normal, and anti‐HBe is present. Liver histology shows minimal necroinflammation, but variable fibrosis reflecting previous liver injury during the HBeAg‐positive immune‐active phase. Among persons who undergo spontaneous HBeAg seroconversion, 67%‐80% will continue to remain in the inactive CHB phase. Approximately 4%‐20% of inactive carriers have one or more reversions back to HBeAg positive. HBeAg‐negative immune reactivation phase: Among those who seroconvert from HBeAg to anti‐HBe positive, 10%‐30% continue to have elevated ALT and high HBV DNA levels, and roughly 10%‐20% of inactive carriers may have reactivation of HBV replication and exacerbations of hepatitis after years of quiescence. Most of these persons harbor HBV variants in the precore or core promoter region, and liver histology shows necroinflammation and fibrosis. Persons with HBeAg‐negative CHB tend to have lower serum HBV DNA levels than those with HBeAg‐positive CHB and are more likely to experience a fluctuating course. Table 1 - Phases of CHB Infection ALT HBV DNA HBeAg Liver Histology Immune‐tolerant phase Normal Elevated, typically >1 million IU/mL Positive Minimal inflammation and fibrosis HBeAg‐positive immune‐active phase Elevated Elevated ≥20,000 IU/mL Positive Moderate‐to‐severe inflammation or fibrosis Inactive CHB phase Normal Low or undetectable <2,000 IU/mL Negative Minimal necroinflammation but variable fibrosis HBeAg‐negative immune reactivation phase Elevated Elevated ≥2,000 IU/mL Negative Moderate‐to‐severe inflammation or fibrosis Resolved CHB infection is defined by clearance of HBsAg with acquisition of antibody to HBsAg. Approximately 0.5% of persons with inactive CHB will clear HBsAg yearly; most will develop antibody to HBsAg (anti‐HBs). Low levels of HBV DNA are transiently detected in the serum in the minority of persons achieving seroclearance.10 Clearance of HBsAg, whether spontaneous or after antiviral therapy, reduces risk of hepatic decompensation and improves survival. Risk of liver‐related complications is variable. Among untreated adults with CHB, cumulative 5‐year incidence of cirrhosis is 8%‐20%, and among those with cirrhosis, 5‐year cumulative risk of hepatic decompensation is 20%, and risk of HCC is 2%‐5%.12 Viral, host, and environmental factors influence risks of cirrhosis and HCC13 (Table 2). HBV DNA levels, ALT levels, and HBeAg status are among the most important determinants of risk of progression to cirrhosis,15 whereas HBV DNA levels (>2,000 IU/mL), HBeAg status, and cirrhosis are key predictors of HCC risk.15 A biological gradient of risk has been shown in adults with HBV DNA levels above 2,000 IU/mL; a higher HBV DNA level is associated with progressively higher rates of cirrhosis and HCC.15 Table 2 - Host, Viral/Disease, and Environmental Factors Associated With Cirrhosis and HCC Cirrhosis HCC Host >40 years of age Male sex Immune compromised >40 years of age Male sex Immune compromised Positive family history Born in Sub‐Saharan Africa Viral/disease High serum HBV DNA (>2,000 IU/mL) Elevated ALT levels Prolonged time to HBeAg seroconversion Development of HBeAg‐negative CHB Genotype C Presence of cirrhosis High serum HBV DNA (>2,000 IU/mL) Elevated ALT Prolonged time to HBeAg seroconversion Development of HBeAg‐negative CHB Genotype C Environmental Concurrent viral infections (HCV, HIV, and HDV) Heavy alcohol use Metabolic syndrome (obesity, diabetes) Concurrent viral infections (HCV, HIV, and HDV) Heavy alcohol use Metabolic syndrome (obesity, diabetes) Aflatoxin Smoking Diagnosis, Staging and Monitoring of Persons With CHB The initial evaluation of persons with CHB should include a thorough history and physical examination, with special emphasis on risk factors for coinfection, alcohol use, and family history of HBV infection and liver cancer. Laboratory tests should include assessment of liver disease activity and function, markers of HBV replication, and tests for coinfection with hepatitis C virus (HCV), hepatitis delta virus (HDV), or human immunodeficiency virus (HIV) in those at risk (Table 3). Owing to the fluctuating nature of CHB, the accuracy of one high HBV DNA level at a single time point in predicting prognosis is poor and regular monitoring of disease status is imperative to determine need for antiviral therapy. The upper limits of normal (ULNs) for ALT values based on healthy subjects are lower than laboratory values derived from all populations, including those with subclinical liver disease.19 Table 3 - Initial Evaluation of HBsAg‐Positive Patient History/Physical Examination Routine Laboratory Tests Serology/Virology Imaging/Staging Studies All patients Symptoms/signs of cirrhosis Alcohol and metabolic risk factors Family history of HCC Vaccination status CBC including platelet count, AST, ALT, total bilirubin, alkaline phosphatase, albumin, INR HBeAg/anti‐HBe HBV DNA quantitation Anti‐HAV to determine need for vaccination Abdominal ultrasound Vibration‐controlled transient elastography or serum fibrosis panel (APRI, FIB‐4, or FIbroTest) Select patients Tests to rule out other causes of chronic liver diseases if elevated liver test(s) AFP, GGT HBV genotype Anti‐HDV Anti‐HCV Anti‐HIV in those who have not undergone one‐time screening (ages 13‐64) Liver biopsy Abbreviation:s INR, international normalized ratio; GGT, gamma‐glutamyl transpeptidase. Determination of the stage of liver disease is important in guiding antiviral therapy decisions and need for surveillance. Liver biopsy provides an assessment of the severity of necroinflammation and fibrosis, rules out other causes of liver disease, and may be especially useful for persons who lack clear‐cut indications for treatment. Whereas liver biopsy is regarded as the best method to assess the severity of inflammatory activity and fibrosis, noninvasive methods to assess fibrosis severity are also useful. Acute‐on‐chronic exacerbations of hepatitis B may lead to overestimation of fibrosis stage by noninvasive tests, and different cutoffs for significant and advanced fibrosis depending on ALT levels have been proposed.20 Serum markers of fibrosis, such as aspartate aminotransferase (AST)‐to‐platelet ratio index (APRI), FIB‐4, FibroTest, and vibration‐controlled transient elastography, have only moderate accuracy in identifying persons with significant fibrosis (fibrosis stage 2 or greater on the Metavir scale), but good diagnostic accuracy in excluding advanced fibrosis21 and may be useful aids in decision making. Antiviral Therapy The goals of antiviral treatment are to decrease the morbidity and mortality related to CHB. The achievement of a sustained suppression of HBV replication has been associated with normalization of serum ALT, loss of HBeAg with or without detection of (anti‐HBe), and improvement in liver histology. Historically, the term “cure” was avoided in treatment of CHB, given that persistence of covalently closed circular DNA (cccDNA), the transcriptional template of HBV,23 in the nucleus of hepatocytes, even in persons with serological markers of resolved infection, poses a lifelong risk for reactivation of infection. However, an immunological cure may be defined by HBsAg loss and sustained HBV DNA suppression and a virological cure defined by eradication of virus, including the cccDNA form. The latter is not currently an attainable goal. There are six therapeutic agents approved for the treatment of adults with CHB in the United States and five therapeutic agents approved for the treatment of children with CHB (Table 4). Side effects are more frequent with interferon (IFN) therapy than with nucleos(t)ide analogs (NAs) therapy. Overall, all NAs have an excellent safety profile across a wide spectrum of persons with CHB, including those with decompensated cirrhosis and transplant recipients.25 The side effects listed in Table 4 for NAs are infrequent. For persons with HDV coinfection, the only effective treatment is pegylated interferon (Peg‐IFN). For persons with HIV coinfection, treatment of HBV needs to be coordinated with HIV therapy given that several HBV drugs have anti‐HIV activity (tenofovir, entecavir, lamivudine, and telbivudine).26 Table 4 - Approved Antiviral Therapies in Adults and Children Drug Dose in Adultsa Use in Childrena Pregnancy Category Potential Side Effectsb Monitoring on Treatmentb Peg‐IFN‐2a(adult) IFN‐α‐2b (children) 180 μg weekly ≥1 year Dose: 6 million IU/m2 TIWc C Flu‐like symptoms, fatigue, mood disturbances, cytopenias, autoimmune disorders in adults Anorexia and weight loss in children CBC (monthly to every 3 months) TSH (every 3 months) Clinical monitoring for autoimmune, ischemic, neuropsychiatric, and infectious complications Lamivudine 100 mg daily ≥2 years Dose: 3 mg/kg daily to max 100 mg C Pancreatitis Lactic acidosis Amylase if symptoms Lactic acid levels if clinical concern Telbivudine 600 mg daily — B Creatine kinase elevations and myopathy Peripheral neuropathy Lactic acidosis Creatine kinase if symptoms Cinical evaluation if symptoms Lactic acid levels if clinical concern Entecavir 0.5 or 1.0 mg dailyd ≥2 years Dose: weight‐based to 10‐30 kg; above 30 kg 0.5 mg daily[Link] C Lactic acidosis Lactic acid levels if clinical concern Adefovir 10 mg daily ≥12 years 10 mg daily C Acute renal failure Fanconi syndrome Nephrogenic diabetes insipidus 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 persons with history of fracture or risks for osteopenia Lactic acid levels if clinical concern Tenofovir 300 mg daily ≥12 years 300 mg daily 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 persons with history of fracture or risks for osteopenia Lactic acid levels if clinical concern aDoses need to be adjusted in persons with renal dysfunction.bPer package insert.cPeg‐IFN‐α‐2a is not approved for children with CHB, but is approved for treatment of chronic hepatitis C. Providers may consider using this drug for children with chronic HBV. The duration of treatment indicated in adults is 48 weeks.dEntecavir dose in adults is 1 mg daily if lamivudine or telbivudine experienced or decompensated cirrhosis.Entecavir doses in treatment‐naïve children older than 2 and at least 10 kg are: 0.15 mg (10‐11 kg), 0.2 mg (>11‐14 kg), 0.25 mg (>14‐17 kg), 0.3 mg (>17‐20 kg), 0.35 mg (>20‐23 kg), 0.4 mg (>23‐26 kg), 0.45 mg (>26‐30 kg), and 0.5 mg (>30 kg). For treatment‐experienced children older than 2 and at least 10 kg, the entecavir doses are: 0.30 mg (10‐11 kg), 0.4 mg (>11‐14 kg), 0.5 mg (>14‐17 kg), 0.6 mg (>17‐20 kg), 0.7 mg (>20‐23 kg), 0.8 mg (>23‐26 kg), 0.9 mg (>26‐30 kg), and 1.0 mg (>30 kg).Abbreviations: CBC, complete blood counts; TSH, thyroid‐stimulating hormone. Biochemical, serological, virological, and histological endpoints are used to assess the success of therapy (Table 5). Assessments are performed on continuous therapy (NAs)27 and after therapy discontinuation (Peg‐IFN).2 The best predictor of sustained remission off‐treatment is HBsAg loss, but this is infrequently achieved with current therapies. Table 5 - Efficacy of Approved Preferred Antiviral Therapies in Adults With Treatment‐Naïve CHB and Immune Active Disease (Not Head‐to‐Head Comparisons) Peg‐IFNa (%) Entecavirb (%) Tenofovirb (%) HBeAg‐Positive HBV DNA suppressionc 30‐42 (<2,000‐40,000 IU/mL) 8‐14 (<80 IU/mL) 61 (<50‐60 IU/mL) 76 (<60 IU/mL) HBeAg loss 32‐36 22‐25 — HBeAg seroconversion 29‐36 21‐22 21 Normalization ALT[Link] 34‐52 68‐81 68 HBsAg loss 2‐7 (6 mos post‐treatment) 11 (at 3 yrs post‐treatment) 2‐3 (1 yr) 4‐5 (2 yrs) 3 (1 yr) 8 (3 yrs) (References) 31 36 30 HBeAg‐Negative HBV DNA suppressiond 43 (<4,000 IU/mL) 19 (<80 IU/mL) 90‐91 93 Normalization ALT[Link] 59 78‐88 76 HBsAg loss (%) 4 (6 mos post‐treatment) 6 (at 3 yrs post‐treatment) 0‐1 (1 yr) 0 (1 yr) (References) 40 42 39 aAssessed 6 months after completion of 12 months of therapy.bAssessed after 2‐3 years of continuous therapy.cHBV DNA <2,000‐40,000 IU/mL for Peg‐IFN; <60 IU/mL for entecavir and tenofovir.dHBV DNA <20,000 IU/mL for Peg‐IFN; <60 IU/mL for entecavir and tenofovir.ALT normalization defined by laboratory normal. Methods of Guideline Development The specific questions specified a priori for evaluation by the guidelines committee are shown in Table 6. Table 6 - Clinical Questions Evaluated Question Population Intervention Comparison Outcome(s) 1 Immune‐active CHB Antiviral therapy No treatment Cirrhosis, decompensation, HCC, death, loss of HBsAg 2 Immune‐tolerant CHB, adults Antiviral therapy No treatment Cirrhosis, decompensation, HCC, death, loss of HBsAg 3 HBeAg‐positive immune‐active chronic hepatitis, with HBeAg seroconversion on therapy Continued antiviral therapy Stopping antiviral therapy Cirrhosis, HCC, reactivation, seroreversion, decompensation, loss of HBsAg 4 HBeAg‐negative immune‐active chronic hepatitis, with viral suppression on antiviral therapy Continued antiviral therapy Stopping antiviral therapy Reactivation, decompensation, loss of HBsAg 5 CHB on treatment with oral therapy Tenofovir Entecavir Renal function, hypophosphatemia, bone health 6 CHB on treatment with oral therapy with persistent viremia Continue therapy Change or switch therapy HBV resistance, clinical flare, decompensation, loss of HBeAg 7 CHB with cirrhosis, with HBV DNA <2,000 IU/mL Antiviral therapy No treatment Decompensation, HCC, death 8 Pregnant women with CHB Antiviral therapy in third trimester No treatment CHB in the infant, safety HBeAg‐positive CHB, Antiviral therapy No treatment Cirrhosis, decompensation, HCC, death, HBeAg seroconversion, loss of HBsAg A and the of A of AASLD with an with in systematic reviews to the these key and the systematic the (Table In this the of in is as or low based on the of and risk of and The based recommendations on the of of and values and and clinical are as to most patients with minimal or to the of patients values and are with the of are to recommendations to to five of the key questions are as an to this For the questions with and are after Table 7 - The the of Study Initial of of when Risk of when High (e.g., (e.g., Dose gradient Low All the low of the of a Recommendation of of and Patient values and and of the of Recommendation Most in this the of and only a Health care Most should receive the of The can be as a policy in most The of in this the of but Health care to patients a decision that is with their values using decision aids and decision making. There is a need for and of of Persons With CHB The AASLD antiviral therapy for adults with immune‐active CHB or HBeAg to decrease the risk of liver‐related of of The AASLD entecavir, or tenofovir as initial therapy for adults with immune‐active CHB. of Low of Immune‐active CHB is defined by an of ALT or of significant histological disease elevated HBV DNA above 2,000 IU/mL or above IU/mL The for ALT in healthy adults is 30 U/L for and 19 U/L for There is insufficient for or use of ALT other than ALT ≥2 The decision to treat persons with ALT above the but of severity of liver disease by biopsy or noninvasive Therapy is for persons with immune‐active CHB and cirrhosis if HBV DNA of ALT factors in the decision to treat persons with immune‐active CHB but ALT and HBV DNA are: age is associated with higher likelihood of significant histological Family history of HCC treatment of and HBsAg may months to years after treatment discontinuation is a risk for drug Presence of for treatment of liver disease severity of HBV DNA should be with immune‐active disease and the cutoffs should be as a but not for treatment. of antiviral to of one therapy in achieving risk in liver‐related However, in and entecavir as the most important was the lack of with factors that need to be in between entecavir, and tenofovir for therapy of treatment side effects (Table 4). is in persons with autoimmune disease, disease, cytopenias, disease, and decompensated history of lamivudine is not in this Family A therapy with or use of oral antiviral that is in is best (Table 4). HBV A and B are more likely to HBeAg and HBsAg loss with than is for For persons treated with 48 duration is used in most and is This treatment duration HBeAg seroconversion rates of and sustained off‐treatment HBV DNA suppression <2,000 IU/mL in of persons who HBeAg to anti‐HBe The of and NAs has not higher rates of off‐treatment serological or virological and is not of therapy for therapy is variable and by HBeAg status, duration of HBV DNA and of All NAs dose in persons with creatinine clearance Evaluation for stage of disease using noninvasive methods or liver biopsy is useful in guiding treatment decisions including duration of therapy. with does not the risk of HCC, and surveillance for HCC should continue in persons who are at Background CHB is a dynamic disease characterized by variable of immune activity that in the development of cirrhosis, liver and liver‐related death in a of Elevated serum ALT and HBV DNA levels are of risk of liver factors include older age, a family history of HCC, alcohol use, HIV infection, HBV genotype and HBV precore and core promoter The of HBV therapy is to prevent liver‐related morbidity and Persons in the immune‐active phases of infection positive and elevated ALT, histological of liver injury inflammation and/or and elevated HBV DNA levels with a greater risk of liver disease and associated and The profile is in Table A total of 42 were to treatment and of cirrhosis, HCC, decompensation, or were and were a total of provided in persons with cirrhosis, and provided in persons with decompensated specific antiviral compared to treatment and compared therapy to treatment. A to antiviral was not to the of per The of was higher for low to low to of per was lower than per For specific the of was and highly variable. The of the treatment in liver‐related cirrhosis, decompensation, HCC, and and of risk across and among to of the lower of the Antiviral therapy to was associated with significant risk in cirrhosis in risk and a risk in HCC and

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 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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Atrial fibrillation (AF) affects more than 33 million individuals worldwide1 and has a complex heritability2. 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. This large, multi-ethnic genome-wide association study identifies 97 loci significantly associated with atrial fibrillation. These loci are enriched for genes involved in cardiac development, electrophysiology, structure and contractile function.

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.

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.

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.

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.

Abstract 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 ≥8.0 mg/dl) and gout with normal or impaired (serum creatinine level &gt;1.5 to ≤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 ≤ 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 &lt;6.0 mg/dl compared with allopurinol (22%) and placebo (0%). A significantly ( P &lt; 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 &lt;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.

photocatalysis-induced reactive oxygen species (ROS) generation. Nanotechnology tools to inactivate SARS-CoV-2 in patients could also be explored. In this case, nanomaterials could be used to deliver drugs to the pulmonary system to inhibit interaction between angiotensin-converting enzyme 2 (ACE2) receptors and viral S protein. Moreover, the concept of "nanoimmunity by design" can help us to design materials for immune modulation, either stimulating or suppressing the immune response, which would find applications in the context of vaccine development for SARS-CoV-2 or in counteracting the cytokine storm, respectively. In addition to disease prevention and therapeutic potential, nanotechnology has important roles in diagnostics, with potential to support the development of simple, fast, and cost-effective nanotechnology-based assays to monitor the presence of SARS-CoV-2 and related biomarkers. In summary, nanotechnology is critical in counteracting COVID-19 and will be vital when preparing for future pandemics.

Abstract Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry 1,2 . Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated ( P &lt; 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis 3 , and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN ) and variants (such as at GRK5 and NOS3 ). Using a three-pronged approach 4 , we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry 5 . Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.