Pharmacological and neurosurgical management of cerebral palsy and dystonia: Clinical practice guideline update.

Dystonia, typically characterized by slow repetitive involuntary movements, stiff abnormal postures, and hypertonia, is common among individuals with cerebral palsy (CP). Dystonia can interfere with activities and have considerable impact on motor function, pain/comfort, and ease of caregiving. Although pharmacological and neurosurgical approaches are used clinically in individuals with CP and dystonia that is causing interference, evidence to support these options is limited. This clinical practice guideline update comprises 10 evidence-based recommendations on the use of pharmacological and neurosurgical interventions for individuals with CP and dystonia causing interference, developed by an international expert panel following the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. The recommendations are intended to help inform clinicians in their use of these management options for individuals with CP and dystonia, and to guide a shared decision-making process in selecting a management approach that is aligned with the individual's and the family's values and preferences.

Infectious Diseases Society of America Guidelines on the Diagnosis of COVID-19: Serologic Testing.

BACKGROUND: The role of serologic testing for SARS-CoV-2 has evolved during the pandemic as seroprevalence in global populations has increased. The Infectious Diseases Society of America (IDSA) convened an expert panel to perform a systematic review of the coronavirus disease 2019 (COVID-19) serology literature and construct updated best practice guidance related to SARS-CoV-2 serologic testing. This guideline is an update to the fourth in a series of rapid, frequently updated COVID-19 guidelines developed by IDSA. OBJECTIVE: To develop evidence-based recommendations and identify unmet research needs pertaining to the use of anti-SARS-CoV-2 antibody tests for diagnosis, decisions related to vaccination and administration of monoclonal antibodies or convalescent plasma in immunocompromised patients, and identification of a serologic correlate of immunity. METHODS: A multidisciplinary panel of infectious diseases clinicians, clinical microbiologists and experts in systematic literature reviewed, identified, and prioritized clinical questions related to the use of SARS-CoV-2 serologic tests. Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make testing recommendations. RESULTS: The panel recommends against serologic testing to diagnose SARS-CoV-2 infection in the first two weeks after symptom onset (strong recommendations, low certainty of evidence). Serologic testing should not be used to provide evidence of COVID-19 in symptomatic patients with a high clinical suspicion and repeatedly negative nucleic acid amplification test results (strong recommendation, very low certainty of evidence). Serologic testing may assist with the diagnosis of multisystem inflammatory syndrome in children (strong recommendation, very low certainty of evidence). To seek evidence for prior SARS-CoV-2 infection, the panel suggests testing for IgG, IgG/IgM, or total antibodies to nucleocapsid protein three to five weeks after symptom onset (conditional recommendation, low certainty of evidence). In individuals with previous SARS-CoV-2 infection or vaccination, we suggest against routine serologic testing given no demonstrated benefit to improving patient outcomes (conditional recommendation, very low certainty of evidence.) The panel acknowledges further that a negative spike antibody test may be a useful metric to identify immunocompromised patients who are candidates for immune therapy. CONCLUSIONS: The high seroprevalence of antibodies against SARS-CoV-2 worldwide limits the utility of detecting anti-SARS CoV-2 antibody. The certainty of available evidence supporting the use of serology for diagnosis was graded as very low to low. Future studies should use serologic assays calibrated to a common reference standard.

Certainty of Evidence Assessment in Systematic Reviews Published by High-Impact Sports Science Journals: A Meta-epidemiological Study.

BACKGROUND: Assessing certainty of evidence is a key element of any systematic review. The aim of this meta-epidemiology study was to understand the frequency and ways with which certainty of evidence is assessed in contemporary systematic reviews published in high-impact sports science journals. METHODS: We searched PubMed and relevant journal web sites from 1 August 2016 to 11 October 2022 for systematic reviews published in the top-ten highest-impact journals within the 2020 Journal Citation Report for the Sports Sciences category. Pairs of independent reviewers screened items using a priori established criteria. RESULTS: Of 1250 eligible documents, 258 (20.6%) assessed the certainty of evidence, defined as using two or more distinct domains to provide an overall rating of the trustworthiness of findings across studies. Nine methods were cited for assessing certainty, with the most common being the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach (61.6%). The proportion of systematic reviews assessing certainty of evidence appeared to increase over the 6-year timeframe analyzed. Across all reviews analyzed, a large majority addressed the domains of risk of bias, imprecision, and inconsistency of the results. Other certainty domains including indirectness/applicability were less commonly assessed. DISCUSSION: Only one in five recent contemporary systematic reviews in the field of exercise and sports science assessed certainty of evidence. Organizational and institutional education on methods for assessing evidence may help further increase uptake of these methods and improve both the quality and clinical impact of systematic reviews in the field.

The Infectious Diseases Society of America Guidelines on the Diagnosis of Coronavirus Disease 2019 (COVID-19): Molecular Diagnostic Testing.

Accurate molecular diagnostic tests are necessary for confirming a diagnosis of coronavirus disease 2019 (COVID-19) and for identifying asymptomatic carriage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The number of available SARS-CoV-2 nucleic acid detection tests continues to increase as does the COVID-19 diagnostic literature. Thus, the Infectious Diseases Society of America (IDSA) developed an evidence-based diagnostic guideline to assist clinicians, clinical laboratorians, patients, and policymakers in decisions related to the optimal use of SARS-CoV-2 nucleic acid amplification tests. In addition, we provide a conceptual framework for understanding molecular diagnostic test performance, discuss nuances of test result interpretation in a variety of practice settings, and highlight important unmet research needs related to COVID-19 diagnostic testing. IDSA convened a multidisciplinary panel of infectious diseases clinicians, clinical microbiologists, and experts in systematic literature review to identify and prioritize clinical questions and outcomes related to the use of SARS-CoV-2 molecular diagnostics. Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make testing recommendations. The panel agreed on 12 diagnostic recommendations. Access to accurate SARS-CoV-2 nucleic acid testing is critical for patient care, hospital infection prevention, and the public health response to COVID-19 infection. Information on the clinical performance of available tests continues to grow, but the quality of evidence of the current literature to support this updated molecular diagnostic guideline remains moderate to very low. Recognizing these limitations, the IDSA panel weighed available diagnostic evidence and recommends nucleic acid testing for all symptomatic individuals suspected of having COVID-19. In addition, testing is suggested for asymptomatic individuals with known or suspected contact with a COVID-19 case when the results will impact isolation/quarantine/personal protective equipment (PPE) usage decisions. Evidence in support of rapid testing and testing of upper respiratory specimens other than nasopharyngeal swabs, which offer logistical advantages, is sufficient to warrant conditional recommendations in favor of these approaches.

GRADE GUIDANCE 38: Updated guidance for rating up certainty of evidence due to a dose-response gradient.

INTRODUCTION: This updated guidance from the Grading of Recommendations Assessment, Development, and Evaluation addresses rating up certainty of evidence due to a dose-response gradient (DRG) observed in synthesis of intervention and exposure studies. STUDY DESIGN AND SETTING: This guidance was developed using iterative discussions and consensus in multiple meetings and was presented to attendees of the Grading of Recommendations Assessment, Development, and Evaluation Working Group meeting for feedback in November 2022 and for final approval in May 2023. RESULTS: The guidance consists of two steps. The first is to determine whether the DRG is credible. We describe five items for assessing credibility: a) is DRG identified using a proper analytical approach; b) is confounding the cause of the DRG; c) is there serious concern about ecological bias; d) is the DRG consistent across studies; and e) is there indirect evidence supporting the DRG. The first two of these items are the most critical. If the DRG was judged to be credible, then the second step is to apply the DRG domain and consider rating up, but only by one level due to the concern about residual confounding. CONCLUSION: Systematic review authors should only rate up certainty in evidence when a DRG is deemed credible.

Adjunctive Vasopressors in Patients with Septic Shock: Protocol for a Systematic Review and Meta-Analysis.

Background: Over one-third of patients with septic shock have adjunctive vasopressors added to first-line vasopressors. However, no randomized trial has detected improved mortality with adjunctive vasopressors. Published systematic reviews and meta-analysis have sought to inform the use of adjunctive vasopressors, yet each published review has limitations that hinder its interpretation. This review aims to overcome the limitations of previous reviews by systematically synthesizing the direct evidence for adjunctive vasopressor therapy use in adult patients with septic shock. Methods: We will conduct a systematic review and meta-analysis of randomized controlled trials evaluating adjunctive vasopressors (vasopressin analogues, angiotensin II, hydroxocobalamin, methylene blue, and catecholamine analogues) in adult patients with septic shock. Relevant studies will be identified through comprehensive searches of MEDLINE, Embase, CENTRAL, and reference lists of previous systematic reviews. Only randomized trials comparing adjunctive vasopressors (>75% of subjects on vasopressors at enrollment) to standard care vasopressors in adults with septic shock (>75% of subjects having septic shock) will be included. Titles and abstracts will be screened, full-text articles assessed for eligibility, and data extracted from included studies. Outcomes of interest include short-term mortality, intermediate-term mortality, kidney replacement therapy, digital/peripheral ischemia, and venous thromboembolism. Pairwise meta-analysis using a random-effects model will be utilized to estimate the risk ratio for the outcomes. Risk of bias will be adjudicated with the Cochrane Risk of Bias 2 tool, and GRADE will be used to rate the certainty of the body of evidence. Discussion: Although adjunctive vasopressors are commonly used in patients with septic shock their effect on patient-important outcomes is unclear. This study is planned to use rigorous systematic review methodology, including strict adhere to established guidelines, in order to overcome limitations of previously-published reviews and inform clinical practice and treatment guidelines for the use of adjunctive vasopressors in adults with septic shock. Systematic review registration: PROSPERO CRD4202327984.

Different meta-analysis methods can change judgements about imprecision of effect estimates: a meta-epidemiological study.

OBJECTIVES: To empirically evaluate five commonly used meta-analysis methods and their impact on imprecision judgements about effect estimates. The two fixed-effect model methods were the inverse variance method based on normal distribution and the Mantel-Haenszel method. The three random-effects model methods were the DerSimonian and Laird, the Hartung-Knapp-Sidik-Jonkman and the profile likelihood approaches. DESIGN: Meta-epidemiological study. SETTING: Meta-analyses published between 2007 and 2019 in the 10 general medical journals with the highest impact factors that evaluated a medication or device for chronic medical conditions and included at least 5 randomised trials. MAIN OUTCOME MEASURES: Discordance in the judgements of imprecision of effect estimates based on two definitions: when either boundary of 95% CI of the OR changed by more than 15% or changed in relation to the null. RESULTS: We analysed 88 meta-analyses including 1114 trials with an average of 12.60 trials per meta-analysis and average I2 of 26% (range: 0%-96%). The profile likelihood failed to converge in three meta-analyses (3%). Discordance in imprecision judgements based on the two definitions, respectively, occurred between the fixed normal distribution and fixed Mantel-Haenszel method (8% and 2%), between the DerSimonian and Laird and Hartung-Knapp-Sidik-Jonkman methods (19% and 10%), between the DerSimonian and Laird and profile likelihood methods (9% and 5%), and between the Hartung-Knapp-Sidik-Jonkman and profile likelihood methods (5% and 13%). Discordance was greater when fewer studies and greater heterogeneity was present. CONCLUSION: Empirical evaluation of studies of chronic medical conditions showed that conclusions about the precision of the estimates of the efficacy of a drug or device frequently changed when different pooling methods were used, particularly when the number of studies within a meta-analysis was small and statistical heterogeneity was substantial. Sensitivity analyses using more than one method may need to be considered in these two scenarios.

Testing guidelines during times of crisis: challenges and limitations of developing rapid and living guidelines.

BACKGROUND: The start of the COVID-19 pandemic presented a situation in which there was an urgent need for decision-making that relates to diagnosis, but the evidence was lacking, of low certainty or constantly changing. Rapid and living guideline development methods were needed and had to be applied to rigorous guideline approaches, such as the Grading of Recommendations Assessment, Development, and Evaluation approach. OBJECTIVES: To describe the process of developing rapid diagnosis guidelines when there is limited and imperfect available data at the time of crisis. SOURCES: Case example from four Infectious Disease Society of America COVID-19 diagnostic guidelines. CONTENT: As the world was experiencing panic with COVID-19, there were serious doubts about the feasibility of following a rigorous process for guideline development when timeliness was of extreme value. The Infectious Disease Society of America guideline panels supported by several methodologists strongly believed that at times of crisis, it is more important than ever to follow a rigorous process. The panel adopted a rapid and living systematic review methodology and applied the Grading of Recommendations Assessment, Development and Evaluation approach to four diagnosis guidelines despite the challenges of scarce and dynamic evidence. We describe the methodological details of the rapid and living approach (data extraction, meta-analysis, Evidence to Decision framework, and recommendation development), the challenge of resources, the challenge of scarce evidence, the challenge of rapidly changing evidence, as well as 'wins' from the Infectious Disease Society of America experience. IMPLICATIONS: Mitigation of pandemics relies on rapid and accurate diagnosis, which is challenged by many knowledge gaps. This necessitates emerging evidence is rapidly incorporated in a living fashion with several decisional and contextual factors to ensure the best public health strategies and care for patients. This process must be systematic and transparent for developing trustworthy guidelines and should be supported by all stakeholders, including researchers, editors, publishers, professional societies, and policymakers.

Increasing liver stiffness is associated with higher incidence of hepatocellular carcinoma in hepatitis C infection and non-alcoholic fatty liver disease-A population-based study.

BACKGROUND & AIMS: Both non-alcoholic fatty liver disease (NAFLD) and hepatitis C virus (HCV) infection commonly result in hepatic fibrosis and may lead to cirrhosis. This study aims to determine the incidence of HCC in patients with HCV or NAFLD complicated by advanced fibrosis, inferred from measurements of liver stiffness. METHODS: Using Veterans Affairs (VA) Informatics and Computing Infrastructure (VINCI), we identified a nationwide cohort of patients with an existing diagnosis of HCV or NAFLD with liver transient elastography (TE) testing from 2015 to 2019. HCC cases, along with a random sample of non-HCC patients, were identified and validated, leading to calculation of incidence rates for HCC after adjustment for confounders. RESULTS: 26,161 patients carried a diagnosis of HCV and 13,629 were diagnosed with NAFLD at the time of testing. In those with HCV, rates of HCC increased with liver stiffness with incidences of 0.28 (95% CI 0.24, 0.34), 0.93 (95% CI 0.72, 1.17), 1.28 (95% CI 0.89, 1.79), and 2.79 (95% CI 2.47, 3.14)/100,000 person years for TE score ranges <9.5 kPa, 9.5-12.5 kPa, 12.5-14.5 kPa and >14.5 kPa, respectively, after a median follow-up of 2.3 years. HCC incidence also increased with higher TE liver stiffness measures in NAFLD after a median follow-up of 1.1 years. CONCLUSION: In this retrospective cohort, the incidence of HCC in HCV and NAFLD increases with higher TE liver stiffness measures, confirming that advanced fibrosis portends risk in viral and non-viral fibrotic liver diseases. Additional comparative studies are needed to determine the optimal cut point of TE liver stiffness to inform HCC screening guidelines and approaches.

The Infectious Diseases Society of America Guidelines on the Diagnosis of COVID-19: Antigen Testing.

BACKGROUND: Immunoassays designed to detect SARS-CoV-2 protein antigens (Ag) are commonly used to diagnose COVID-19. The most widely used tests are lateral flow assays that generate results in approximately 15 minutes for diagnosis at the point-of-care. Higher throughput, laboratory-based SARS-CoV-2 Ag assays have also been developed. The number of commercially available SARS-CoV-2 Ag detection tests has increased rapidly, as has the COVID-19 diagnostic literature. The Infectious Diseases Society of America (IDSA) convened an expert panel to perform a systematic review of the literature and develop best practice guidance related to SARS-CoV-2 Ag testing. This guideline is an update to the third in a series of frequently updated COVID-19 diagnostic guidelines developed by the IDSA. OBJECTIVE: The IDSA's goal was to develop evidence-based recommendations or suggestions that assist clinicians, clinical laboratories, patients, public health authorities, administrators and policymakers in decisions related to the optimal use of SARS-CoV-2 Ag tests in both medical and non-medical settings. METHODS: A multidisciplinary panel of infectious diseases clinicians, clinical microbiologists and experts in systematic literature review identified and prioritized clinical questions related to the use of SARS-CoV-2 Ag tests. A review of relevant, peer-reviewed published literature was conducted through April 1, 2022. Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make testing recommendations. RESULTS: The panel made ten diagnostic recommendations. These recommendations address Ag testing in symptomatic and asymptomatic individuals and assess single versus repeat testing strategies. CONCLUSIONS: U.S. Food and Drug Administration (FDA) SARS-CoV-2 Ag tests with Emergency Use Authorization (EUA) have high specificity and low to moderate sensitivity compared to nucleic acid amplification testing (NAAT). Ag test sensitivity is dependent on the presence or absence of symptoms, and in symptomatic patients, on timing of testing after symptom onset. In contrast, Ag tests have high specificity, and, in most cases, positive Ag results can be acted upon without confirmation. Results of point-of-care testing are comparable to those of laboratory-based testing, and observed or unobserved self-collection of specimens for testing yields similar results. Modeling suggests that repeat Ag testing increases sensitivity compared to testing once, but no empirical data were available to inform this question. Based on these observations, rapid RT-PCR or laboratory-based NAAT remains the testing method of choice for diagnosing SARS-CoV-2 infection. However, when timely molecular testing is not readily available or is logistically infeasible, Ag testing helps identify individuals with SARS-CoV-2 infection. Data were insufficient to make a recommendation about the utility of Ag testing to guide release of patients with COVID-19 from isolation. The overall quality of available evidence supporting use of Ag testing was graded as very low to moderate.

Evidence-Based Cognitive Endoscopy Simulators: Do They Exist? A Systematic Search and Evaluation of Existing Platforms.

BACKGROUND: The development of guidelines by gastroenterology societies increasingly stresses evidence-based endoscopic practice. AIMS: We performed a systematic assessment to determine whether endoscopic video teaching platforms incorporate evidence-based educational strategies and methods in order to disseminate guideline-based endoscopic management strategies. METHODS: Platforms with a video component were systematically identified using the Google search engine, Apple and Android application stores, and searching four major gastroenterology society websites and three known platforms, to identify all relevant platforms. Two video samples from each teaching platform were reviewed independently by two authors and assessed for use of a priori defined principles of evidence-based medicine, as determined by consensus agreement and for the use of simulation. RESULTS: Fourteen platforms were included in the final analysis, and two videos from each were analyzed. One of the 14 platforms used simulation and incorporated evidence-based medicine principles consistently. Nine of the 14 platforms were not transparent in regard to citation. None of the platforms consistently cited the certainty of evidence or explained how evidence was selected. CONCLUSIONS: Education of guideline-based endoscopic management strategies using principles of evidence-based medicine is under-utilized in endoscopic videos. In addition, the use of cognitive simulation is absent in this arena. There is a paucity of evidence-based cognitive endoscopy simulators designed for fellows that incorporate systematic evaluation, and efforts should be made to create this platform.

Accuracy of Ultrasound Elastography and Fibrosis-4 Index (FIB-4) in Ruling Out Cirrhosis in Obese Non-Alcoholic Fatty Liver Disease (NAFLD) Patients.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of advanced liver disease in the USA. Liver biopsy, the gold standard diagnostic test for evaluating liver fibrosis, is associated with significant risk and expense. The accuracy of ultrasound elastography and Fibrosis-4 index (FIB-4) in the obese NAFLD population is unknown. We aimed to compare the accuracy of ultrasound elastography and FIB-4 to liver biopsy in ruling out cirrhosis in NAFLD patients at a tertiary, transplant referral center in the US. METHODS: We retrospectively evaluated 93 patients with a mean age of 53 years (SD: 13 years) who underwent liver ultrasound elastography and liver biopsy, and additionally calculated their FIB-4 at the time of biopsy. We compared the liver stiffness measurement (LSM) obtained from ultrasound elastography and FIB-4 with the pathology results for ruling out cirrhosis. RESULTS: 85% of the patients were white, 53% were female, average BMI was 34.7 (SD: 6.7), 52% had diabetes, and 53% had hypertension. For biopsy-proven cirrhosis (prevalence 15%), a cut-off value of 12.5 kilopascals (kPa) for F4 had a sensitivity of 92% and a specificity of 54%. Values below this threshold excluded cirrhosis with 98% certainty. Compared to FIB-4, ultrasound elastography showed higher accuracy in ruling out cirrhosis (92% vs. 80% sensitivity, 98% vs. 95% negative predictive value (NPV), respectively). CONCLUSION: To our knowledge, this is the first study in a tertiary transplant referral center in the USA to show that ultrasound elastography was superior to FIB-4 and can be used as a reliable screening test to rule out cirrhosis in obese NAFLD patients at a 12.5 kPa cut-off. Therefore, helping to avoid the risk and expense associated with liver biopsy.

Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19.

BACKGROUND: There are many pharmacologic therapies that are being used or considered for treatment of coronavirus disease 2019 (COVID-19), with rapidly changing efficacy and safety evidence from trials. OBJECTIVE: Develop evidence-based, rapid, living guidelines intended to support patients, clinicians, and other healthcare professionals in their decisions about treatment and management of patients with COVID-19. METHODS: In March 2020, the Infectious Diseases Society of America (IDSA) formed a multidisciplinary guideline panel of infectious disease clinicians, pharmacists, and methodologists with varied areas of expertise to regularly review the evidence and make recommendations about the treatment and management of persons with COVID-19. The process used a living guideline approach and followed a rapid recommendation development checklist. The panel prioritized questions and outcomes. A systematic review of the peer-reviewed and grey literature was conducted at regular intervals. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the certainty of evidence and make recommendations. RESULTS: Based on the most recent search conducted on May 31, 2022, the IDSA guideline panel has made 30 recommendations for the treatment and management of the following groups/populations: pre- and post-exposure prophylaxis, ambulatory with mild-to-moderate disease, hospitalized with mild-to-moderate, severe but not critical, and critical disease. As these are living guidelines, the most recent recommendations can be found online at: https://idsociety.org/COVID19guidelines. CONCLUSIONS: At the inception of its work, the panel has expressed the overarching goal that patients be recruited into ongoing trials. Since then, many trials were done which provided much needed evidence for COVID-19 therapies. There still remain many unanswered questions as the pandemic evolved which we hope future trials can answer.

During HCV DAA Therapy Plasma Mip1B, IP10, and miRNA Profile Are Distinctly Associated with Subsequent Diagnosis of Hepatocellular Carcinoma: A Pilot Study.

Background: Hepatitis C virus (HCV) therapy lowers risk of hepatocellular carcinoma (HCC). Little is known about factors driving/preceding HCC in treated persons. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) regulate host response and pathogenesis of disease. We investigated plasma levels of these RNAs and select serum markers before, during, and after HCV therapy, preceding HCC. Methods: Of 187 DAA treated HCV patients where therapy oriented longitudinal sampling was performed at a time without HCC diagnosis, 9 were subsequently diagnosed with HCC within 2 years of therapy. They were matched with 7 patients not diagnosed with HCC over the same time period. RNASeq was performed on plasma, and serum was assessed for biomarkers of inflammation by ELISA. Results: HCC diagnosis was 19 months (6-28) after therapy start in the HCC group. 73 and 63 miRs were differentially expressed at baseline (before DAA therapy) and 12 weeks after DAA therapy comparing HCC and non-HCC groups. Several lncRNA- showed differential expression as well. Several miRNA suppressors of cancer-related pathways, lncRNA- and mRNA-derived stabilized short RNAs were consistently absent in the plasma of patients who developed HCC. Serum IP10, and MCP-1 level was higher in the HCC group 12 weeks after therapy, and distinct miRNAs correlated with IP10 and MCP-1. Finally, in a focused analysis of 8 miRNAs best associated with HCC we observed expression of mi576 and mi-5189 correlation with expression of a select group of PBMC mRNA. Conclusions: These results are consistent with complex interplay between RNA-mediated host immune regulation and cancer suppression, strikingly skewed 12 weeks following therapy, prior to HCC diagnosis.

Transient elastography score is elevated during rheumatoid factor-positive chronic hepatitis C virus infection and rheumatoid factor decline is highly variable over the course of direct-acting antiviral therapy.

BACKGROUND: Elevated rheumatoid factor (RF) levels and systemic immune activation are highly prevalent during chronic hepatitis C virus (HCV) infection. Direct-acting antiviral (DAA) therapy has been associated with normalization of various soluble immune activation parameters. Whether the RF levels relate to soluble immune activation markers during chronic HCV infection, and over what time frame RF levels normalize during and after DAA treatment is unknown and was investigated here. METHODS: In a longitudinal study, plasma and serum was obtained from HCV infected RF positive (RF+) and RF negative (RF-) participants. The levels of RF, HCV RNA and soluble markers of inflammation were determined before (week 0), during (weeks 4, 8 and 12) and after (week 24) treatment with HCV DAA therapy. In a subset of RF+ participants, the analysis was extended to over 70 weeks after therapy initiation. Hepatic and other clinical parameters were determined at baseline (week 0) in all participants. RESULTS: Before therapy, transient elastography (TE) score was greater in RF+ compared to RF- HCV infected participants, while the systemic levels of soluble inflammatory markers were comparable. Following DAA therapy initiation, HCV RNA levels became undetectable within 4 weeks in both the RF+ and RF- groups. RF levels declined in the first 6 months in most RF+ persons but most commonly remained positive. The levels of some soluble inflammatory markers declined, mainly within 4 weeks of DAA therapy start, in both the RF+ and RF- groups. The baseline (week 0) TE score correlated with RF levels before, during and after DAA therapy, while plasma IL-18 levels correlated with RF level after DAA therapy. CONCLUSION: During chronic HCV infection, TE score is elevated in RF+ HCV infected individuals and factors other than HCV viremia (including liver stiffness or fibrosis and select markers of inflammation) likely contribute to persistence of RF after treatment of HCV with DAA.

AGA Clinical Practice Guideline on Systemic Therapy for Hepatocellular Carcinoma.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC), the most common primary liver cancer, remains a deadly cancer, with an incidence that has tripled in the United States since 1980. In recent years, new systemic therapies for HCC have been approved and a critical assessment of the existing data is necessary to balance benefits and harms and inform the development of evidence-based guidelines. METHODS: The American Gastroenterological Association formed a multidisciplinary group consisting of a Technical Review Panel and a Guideline Panel. The Technical Review Panel prioritized clinical questions and outcomes according to their importance for clinicians and patients and conducted an evidence review of systemic therapies in patients with advanced-stage HCC. The Grading of Recommendations Assessment, Development and Evaluation framework was used to assess evidence. The Guideline Panel reviewed the evidence and used the Evidence-to-Decision Framework to develop recommendations. RESULTS: The Panel reviewed the evidence, summarized in the Technical Review, for the following medications approved by the US Food and Drug Administration for HCC: first-line therapies: bevacizumab+atezolizumab, sorafenib, and lenvatinib; second-line therapies: cabozantinib, pembrolizumab, ramucirumab, and regorafenib; and other agents: bevacizumab, nivolumab, and nivolumab+ipilimumab. CONCLUSIONS: The Panel agreed on 11 recommendations focused on systemic therapy for HCC in patients who are not eligible for locoregional therapy or resection, those with metastatic disease and preserved liver function, those with poor liver function, and those on systemic therapy as adjuvant therapy.

Lessons Learned from Coronavirus Disease 2019 (COVID-19) Therapies: Critical Perspectives From the Infectious Diseases Society of America (IDSA) COVID-19 Treatment Guideline Panel.

Despite the challenges of the pandemic, there has been substantial progress with coronavirus disease 2019 (COVID-19) therapies. Pivotal COVID-19 trials like SOLIDARITY, RECOVERY, and ACCT-1 were rapidly conducted and data disseminated to support effective therapies. However, critical shortcomings remain on trial conduct, dissemination and interpretation of study results, and regulatory guidance in pandemic settings. The lessons that we learned have implications for both the current pandemic and future emerging infectious diseases. There is a need for establishing and standardizing clinical meaningful outcomes in therapeutic trials and for targeting defined populations and phenotypes that will most benefit from specific therapies. Standardized processes should be established for rapid and critical data review and dissemination to ensure scientific integrity. Clarity around the evidence standards needed for issuance of both emergency use authorization (EUA) and biologic license application (BLA) should be established and an infrastructure for executing rapid trials in epidemic settings maintained.