Comparative Efficacy of Advanced Therapies for Management of Moderate-to-Severe Ulcerative Colitis: 2024 American Gastroenterological Association Evidence Synthesis.

BACKGROUND & AIMS: We performed an updated systematic review and network meta-analysis to inform the 2024 American Gastroenterological Association (AGA) Clinical Guidelines on the management of moderate-to-severe ulcerative colitis (UC). METHODS: We searched multiple electronic databases through November 21, 2023, to identify randomized controlled trials in adults with moderate-to-severe UC, comparing different advanced therapies (tumor necrosis factor antagonists, vedolizumab, sphingosine-1-phosphate receptor modulators, interleukin 12/23 or selective interleukin 23 antagonists, and Janus kinase [JAK] inhibitors) against placebo or another active comparator. Our primary outcomes were induction and maintenance of clinical remission, and our secondary outcome was endoscopic improvement. We performed a network meta-analysis using a frequentist approach and applied Grading of Recommendations, Assessment, Development and Evaluation (GRADE) to appraise certainty of evidence. RESULTS: After excluding JAK inhibitors as potential first-line treatment (in accordance with the United States Food and Drug Administration), low-certainty evidence supports clinically important benefit with infliximab, ozanimod, risankizumab, and guselkumab over adalimumab and mirikizumab for achieving remission with induction therapy in biologically naïve patients with moderate-to-severe UC, with risankizumab and ozanimod being ranked the highest for induction of clinical remission. With the inclusion of JAK inhibitors as first-line therapy, upadacitinib was more efficacious compared with all other medications except ozanimod and risankizumab, with low- to moderate-certainty evidence. In patients with prior biologic exposure, upadacitinib, tofacitinib, and ustekinumab were ranked highest for achieving remission. CONCLUSIONS: Using Grading of Recommendations, Assessment, Development and Evaluation to appraise quality of evidence, this updated network meta-analysis will be used to inform comparative efficacy and positioning of advanced therapies for the treatment of biologic-naïve and biologic-exposed patients with moderate-to-severe UC.

Noninvasive liver disease assessment to identify portal hypertension: Systematic and narrative reviews supporting the AASLD Practice Guideline.

BACKGROUND AND AIMS: Portal hypertension is a serious complication of cirrhosis, which leads to life-threatening complications. HVPG, a surrogate of portal pressure, is the reference standard test to assess the severity of portal hypertension. However, since HVPG is limited by its invasiveness and availability, noninvasive liver disease assessments to assess portal pressure, especially clinically significant portal hypertension (CSPH), are needed. APPROACH AND RESULTS: We conducted a systematic review of Ovid MEDLINE(R) Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus from each database's inception to April 22, 2022. We included only studies in English that examined ≥50 patients in single liver disease etiologies, which compared noninvasive tests (blood and/or imaging) to HVPG for predicting clinically significant portal hypertension (CSPH; defined as HVPG ≥ 10 mm Hg) in patients with chronic liver disease. Outcomes included measures of diagnostic test accuracy. Additionally, a narrative review of studies not eligible for the systematic review is also provided. Nine studies with 2492 patients met the inclusion criteria. There was substantial heterogeneity with regard to liver disease studied and cutoff values used to detect CSPH. Blood-based tests, including aspartate-to-platelet ratio index (APRI) (56% sensitivity and 68% specificity) and FIB-4 (54% sensitivity and 73% specificity) had low accuracy measures. Imaging-based tests (transient elastography and shear wave elastography detection of liver stiffness measurement [LSM]) had better accuracy but also had substantial variation; at 15 kPa, TE sensitivity was 90%-96% and specificity was 48%-50%, while at 25 kPa, its sensitivity and specificity were 57%-85% and 82%-93%, respectively. The narrative review suggested that imaging-based tests are the best available noninvasive liver disease assessment to detect CSPH; CSPH is highly unlikely to be present at an LSM ≤15 kPa and likely to be present at an LSM ≥25 kPa. CONCLUSIONS: While imaging-based noninvasive liver disease assessment appeared to have higher accuracy than blood-based tests to detect CSPH, only 9 studies fit the a priori established inclusion criteria for the systematic review. In addition, there was substantial study heterogeneity and variation in cutoffs for LSM to detect CSPH, limiting the ability to establish definitive cutoffs to detect CSPH.

Imaging-based noninvasive liver disease assessment for staging liver fibrosis in chronic liver disease: A systematic review supporting the AASLD Practice Guideline.

BACKGROUND AND AIMS: Transient elastography (TE), shear wave elastography, and/or magnetic resonance elastography (MRE), each providing liver stiffness measurement (LSM), are the most studied imaging-based noninvasive liver disease assessment (NILDA) techniques. To support the American Association for the Study of Liver Diseases guidelines on NILDA, we summarized the evidence on the accuracy of these LSM methods to stage liver fibrosis (F). APPROACH AND RESULTS: A comprehensive search for studies assessing LSM by TE, shear wave elastography, or MRE for the identification of significant fibrosis (F2-4), advanced fibrosis (F3-4), or cirrhosis (F4), using histopathology as the standard of reference by liver disease etiology in adults or children from inception to April 2022 was performed. We excluded studies with <50 patients with a single disease entity and mixed liver disease etiologies (with the exception of HCV/HIV coinfection). Out of 9447 studies, 240 with 61,193 patients were included in this systematic review. In adults, sensitivities for the identification of F2-4 ranged from 51% to 95%, for F3-4 from 70% to 100%, and for F4 from 60% to 100% across all techniques/diseases, whereas specificities ranged from 36% to 100%, 74% to 100%, and 67% to 99%, respectively. The largest body of evidence available was for TE; MRE appeared to be the most accurate method. Imaging-based NILDA outperformed blood-based NILDA in most comparisons, particularly for the identification of F3-4/F4. In the pediatric population, imaging-based NILDA is likely as accurate as in adults. CONCLUSIONS: LSM from TE, shear wave elastography, and MRE shows acceptable to outstanding accuracy for the detection of liver fibrosis across various liver disease etiologies. Accuracy increased from F2-4 to F3-4 and was the highest for F4. Further research is needed to better standardize the use of imaging-based NILDA, particularly in pediatric liver diseases.

Rifampin Based Therapy for Patients With Staphylococcus aureus Native Vertebral Osteomyelitis: A Systematic Review and Meta-analysis.

BACKGROUND: Native vertebral osteomyelitis (NVO) caused by Staphylococcus aureus is associated with high risk of treatment failure and increased morbidity. The role of rifampin-based therapy for the treatment of this condition is controversial. The goal of this systematic review and meta-analysis is to explore the efficacy and safety of rifampin-based therapy for the treatment of S. aureus NVO. METHODS: We searched Cochrane, Embase, Medline, Scopus, and Web of Science databases for studies published up to May 2023, focusing on adults with NVO treated with or without rifampin-containing regimens. A random-effects model meta-analysis estimated relative risks and risk difference with 95% confidence intervals (CI). RESULTS: Thirteen studies (2 randomized controlled trials and 11 comparative cohort studies), comprising 244 patients with S. aureus NVO who received rifampin and 435 who did not, were analyzed. Meta-analysis showed that rifampin-based regimens were associated with lower risk of clinical failure (risk difference, -14%; 95% CI, -19% to -8%; P < .001; I2 = 0%; relative risk, 0.58; 95% CI, .37-.92, P = .02, I2 = 21%). Only 1 study reported on adverse events. All studies had a high or uncertain risk of bias, and the certainty of evidence was rated as very low. CONCLUSIONS: Adjunctive rifampin therapy might be associated with lower risk of S. aureus NVO treatment failure; however, the low certainty of evidence precludes drawing definitive conclusions that would alter clinical practice. A randomized trial is necessary to corroborate these findings.

The Infectious Diseases Society of America Guidelines on the Diagnosis of COVID-19: Molecular Diagnostic Testing (December 2023).

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.

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.

Causally interpretable meta-analysis combining aggregate and individual participant data.

Recent work in causally-interpretable meta-analysis (CIMA) has bridged the gap between traditional meta-analysis and causal inference. While traditional meta-analysis results generally do not apply to any well-defined population, CIMA approaches specify a target population to which meta-analytic treatment effect estimates are transported. While theoretically attractive, these approaches currently have some practical limitations. Most assume that all studies in the meta-analysis have individual participant data (IPD), which is rare in practice because most trials share only aggregate data. We propose a method to perform CIMA using a combination of aggregate data and IPD. This method borrows information from studies with IPD to augment the aggregate data and create aggregate-matched synthetic IPD (AMSIPD), which can be used readily in the existing CIMA framework. By allowing use of both aggregate data and IPD, the method opens CIMA to more applications and can avoid biases arising from using only studies with IPD. We present a case study and simulations showing the AMSIPD approach is promising and merits further investigation as an advancement of CIMA.

Clinical presentation and outcomes in patients with antiphospholipid syndrome-associated adrenal hemorrhage. A multicenter cohort study and systematic literature review.

BACKGROUND: Adrenal hemorrhage (AH) can occur in patients with antiphospholipid Syndrome (APS). We aimed to characterize the clinical manifestations, treatments, and outcomes of patients presenting with APS-associated AH (APS-AH) through a retrospective cohort and a systematic literature review (SLR). METHODS: We performed a mixed-source approach combining a multicenter cohort with an SLR of patients with incident APS-AH. We included patients from Mayo Clinic and published cases with persistent positivity for antiphospholipid antibodies and presenting with AH, demonstrated by imaging or biopsy. We extracted demographics, clinical characteristics, laboratory findings, treatment strategies, and outcomes (primary adrenal insufficiency and mortality). We used Kaplan-Meier and Cox models for survival analysis. RESULTS: We included 256 patients in total, 61 (24%) from Mayo Clinic and 195 (76%) from the SLR. The mean age was 46.8 (SD 15.2) years, and 45% were female. 69% of patients had bilateral adrenal involvement and 64% presented adrenal insufficiency. The most common symptoms at presentation were abdominal pain in 79%, and nausea and vomiting 46%. Hyponatremia (77%) was the most common electrolyte abnormality. Factors associated with primary adrenal insufficiency were bilateral adrenal involvement at initial imaging (OR 3.73, CI; 95%, 1.47-9.46) and anticardiolipin IgG positivity (OR 3.80, CI; 95%, 1.30-11.09). The survival rate at five years was 82%. History of stroke was associated with 3.6-fold increase in mortality (HR 3.62, 95% CI; 1.33-9.85). CONCLUSION: AH is a severe manifestation of APS with increased mortality. Most patients developed permanent primary adrenal insufficiency, particularly those positive for anticardiolipin IgG and bilateral adrenal involvement.

American Gastroenterological Association-American College of Gastroenterology Clinical Practice Guideline: Pharmacological Management of Chronic Idiopathic Constipation.

INTRODUCTION: Chronic idiopathic constipation (CIC) is a common disorder associated with significant impairment in quality of life. This clinical practice guideline, jointly developed by the American Gastroenterological Association and the American College of Gastroenterology, aims to inform clinicians and patients by providing evidence-based practice recommendations for the pharmacological treatment of CIC in adults. METHODS: The American Gastroenterological Association and the American College of Gastroenterology formed a multidisciplinary guideline panel that conducted systematic reviews of the following agents: fiber, osmotic laxatives (polyethylene glycol, magnesium oxide, lactulose), stimulant laxatives (bisacodyl, sodium picosulfate, senna), secretagogues (lubiprostone, linaclotide, plecanatide), and serotonin type 4 agonist (prucalopride). The panel prioritized clinical questions and outcomes and used the Grading of Recommendations Assessment, Development, and Evaluation framework to assess the certainty of evidence for each intervention. The Evidence to Decision framework was used to develop clinical recommendations based on the balance between the desirable and undesirable effects, patient values, costs, and health equity considerations. RESULTS: The panel agreed on 10 recommendations for the pharmacological management of CIC in adults. Based on available evidence, the panel made strong recommendations for the use of polyethylene glycol, sodium picosulfate, linaclotide, plecanatide, and prucalopride for CIC in adults. Conditional recommendations were made for the use of fiber, lactulose, senna, magnesium oxide, and lubiprostone. DISCUSSION: This document provides a comprehensive outline of the various over-the-counter and prescription pharmacological agents available for the treatment of CIC. The guidelines are meant to provide a framework for approaching the management of CIC; clinical providers should engage in shared decision making based on patient preferences as well as medication cost and availability. Limitations and gaps in the evidence are highlighted to help guide future research opportunities and enhance the care of patients with chronic constipation.

Home and Community-Based Services: A Systematic Review and Evidence Map.

BACKGROUND: Many adults aged 60 years or older have functional limitations and require home and community-based services (HCBS) to support their independence and delay the transition to an institutionalized setting. This systematic review provides an evidence map of the existing literature on HCBS identifying evidence gaps for policy and research. METHODS: A comprehensive literature search of multiple databases including Medline, Embase, and Scopus was conducted through December 7, 2023. Interviews with various stakeholders were conducted to solicit additional perspectives. Narrative and thematic synthesis was conducted to evaluate HCBS in terms of populations, interventions, outcomes, person-centeredness, and relevant quality measures. RESULTS: We identified 27 primary studies and 29 quality measures. Populations of HCBS studies can be categorized as those with functional disability, cognitive impairment, high-risk/frail conditions, and disease-specific conditions (Parkinson's disease, Alzheimer's disease, and post-stroke). HCBS interventions targeted optimization of person-centered planning, nonpharmacological approaches for dementia care, physical rehabilitation, self-directed home care, geriatric resources for practical support at home, and interdisciplinary care coordination for high-risk conditions. Person-centered planning and self-direction of HCBS services were not explicitly described in many studies and very few studies focused on addressing health-related social needs, whereas the majority reported primary clinical outcomes. Numerous quality measures exist for HCBS, some of which were validated, addressed multiple person-centered domains, and may apply across various conditions and populations. Key challenges in the literature on HCBS include limited number of randomized trials, inadequate descriptions of interventions to determine person-centeredness, limited information on facilitators and barriers, and limited information on workforce challenges in recruiting, retaining, and training personnel delivering HCBS. DISCUSSION: This evidence map describes the current state of HCBS and identifies evidence gaps for future research and policy decisions.

Measuring Documentation Burden in Healthcare.

BACKGROUND: The enactment of the Health Information Technology for Economic and Clinical Health Act and the wide adoption of electronic health record (EHR) systems have ushered in increasing documentation burden, frequently cited as a key factor affecting the work experience of healthcare professionals and a contributor to burnout. This systematic review aims to identify and characterize measures of documentation burden. METHODS: We integrated discussions with Key Informants and a comprehensive search of the literature, including MEDLINE, Embase, Scopus, and gray literature published between 2010 and 2023. Data were narratively and thematically synthesized. RESULTS: We identified 135 articles about measuring documentation burden. We classified measures into 11 categories: overall time spent in EHR, activities related to clinical documentation, inbox management, time spent in clinical review, time spent in orders, work outside work/after hours, administrative tasks (billing and insurance related), fragmentation of workflow, measures of efficiency, EHR activity rate, and usability. The most common source of data for most measures was EHR usage logs. Direct tracking such as through time-motion analysis was fairly uncommon. Measures were developed and applied across various settings and populations, with physicians and nurses in the USA being the most frequently represented healthcare professionals. Evidence of validity of these measures was limited and incomplete. Data on the appropriateness of measures in terms of scalability, feasibility, or equity across various contexts were limited. The physician perspective was the most robustly captured and prominently focused on increased stress and burnout. DISCUSSION: Numerous measures for documentation burden are available and have been tested in a variety of settings and contexts. However, most are one-dimensional, do not capture various domains of this construct, and lack robust validity evidence. This report serves as a call to action highlighting an urgent need for measure development that represents diverse clinical contexts and support future interventions.

Estimating reference intervals from an IPD meta-analysis using quantile regression.

BACKGROUND: Reference intervals, which define an interval in which a specific proportion of measurements from a healthy population are expected to fall, are commonly used in medical practice. Synthesizing information from multiple studies through meta-analysis can provide a more precise and representative reference interval than one derived from a single study. However, the current approaches for estimating the reference interval from a meta-analysis mainly rely on aggregate data and require parametric distributional assumptions that cannot always be checked. METHODS: With the availability of individual participant data (IPD), non-parametric methods can be used to estimate reference intervals without any distributional assumptions. Furthermore, patient-level covariates can be introduced to estimate personalized reference intervals that may be more applicable to specific patients. This paper introduces quantile regression as a method to estimate the reference interval from an IPD meta-analysis under the fixed effects model. RESULTS: We compared several non-parametric bootstrap methods through simulation studies to account for within-study correlation. Under fixed effects model, we recommend keeping the studies fixed and only randomly sampling subjects with replacement within each study. CONCLUSION: We proposed to use the quantile regression in the IPD meta-analysis to estimate the reference interval. Based on the simulation results, we identify an optimal bootstrap strategy for estimating the uncertainty of the estimated reference interval. An example of liver stiffness measurements, a clinically important diagnostic test without explicitly established reference range in children, is provided to demonstrate the use of quantile regression in estimating both overall and subject-specific reference intervals.

What Free Flaps Are Surgeons Using for Palatal Fistula Repair in Patients with Cleft Palate? A Systematic Review.

OBJECTIVE: Recalcitrant palatal fistulas in patients with cleft palate history sometimes require free flap reconstruction. This study reviews the literature on described flaps and outcomes. DESIGN: A systematic review was conducted per the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. SETTING: All study designs were included. Non-English articles were excluded. PATIENTS AND PARTICIPANTS: Patients with a history of cleft palate who underwent free flap reconstruction for a oronasal fistula. INTERVENTIONS: Free tissue transfer for a palatal fistula repair. MAIN OUTCOMEE MEASURES: Information regarding defect and flap characteristics were reviewed. Surgical outcomes such as flap loss rates, rates of recurrent fistula formation, and speech outcomes were also obtained. RESULTS: Our search returned 894 articles, of which 23 were included. All studies were retrospective case series and reports. A total of 65 patients were described with an average age of 19.3 (range 3-55) years and a median fistula size of 8.00 cm2 (range 2.54 cm2 - 24 cm2). The most common flap was the radial forearm flap (n = 37). Nine patients (13.8%) had recurrent fistula formation with surgical revision successful in all cases in which the patient returned to the operating room. There were two partial flap losses and no total flap losses. Speech outcomes showed improvement in 27 patients across 10 studies. CONCLUSIONS: Palatal fistula repair with free tissue transfer is safe with an acceptable risk profile and low flap loss rate. Early recurrence due to partial flap necrosis and dehiscence are successfully managed with flap readvancement.

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.

Clinical features, risk factors, and outcomes of diffuse alveolar hemorrhage in antiphospholipid syndrome: A mixed-method approach combining a multicenter cohort with a systematic literature review.

BACKGROUND: Antiphospholipid syndrome (APS) is a systemic autoimmune disease clinically associated with thrombotic and obstetric events. Additional manifestations have been associated with APS, like diffuse alveolar hemorrhage (DAH). We aimed to summarize all the evidence available to describe the presenting clinical features, their prognostic factors, and short- and long-term outcomes. METHODS: We performed a mixed-method approach combining a multicenter cohort with a systematic literature review (SLR) of patients with incident APS-associated DAH. We described their clinical features, treatments, prognostic factors, and outcomes (relapse, mortality, and requirement of mechanical ventilation [MV]). Kaplan-Meier methods were used to estimate relapse and mortality rates, and Cox and logistic regression models were used to assess the factors associated as appropriate. RESULTS: We included 219 patients with incident APS-associated DAH (61 from Mayo Clinic and 158 from SLR). The median age was 39.5 years, 51% were female, 29% had systemic lupus erythematosus, and 34% presented with catastrophic APS (CAPS). 74% of patients had a history of thrombotic events, and 26% of women had a history of pregnancy morbidity; half of the patients had a history of thrombocytopenia, and a third had valvulopathy. Before DAH, 55% of the patients were anticoagulated. At DAH onset, 65% of patients presented hemoptysis. The relapse rate was 47% at six months and 52% at one year. Triple positivity (HR 4.22, 95% CI 1.14-15.59) was associated with relapse at six months. The estimated mortality at one and five years was 30.3% and 45.8%. Factors associated with mortality were severe thrombocytopenia (< 50 K/µL) (HR 3.10, 95% CI 1.39-6.92), valve vegetations (HR 3.22, 95% CI 1.14-9.07), CAPS (HR 3.80, 95% CI 1.84-7.87), and requirement of MV (HR 2.22, 95% CI 1.03-4.80). Forty-two percent of patients required MV on the incident DAH episode. Patients presenting with severe thrombocytopenia (OR 6.42, 95% CI 1.77-23.30) or CAPS (OR 4.30, 95% CI 1.65-11.16) were more likely to require MV. CONCLUSION: APS-associated DAH is associated with high morbidity and mortality, particularly when presenting with triple positivity, thrombocytopenia, valvular involvement, and CAPS.

American Gastroenterological Association-American College of Gastroenterology Clinical Practice Guideline: Pharmacological Management of Chronic Idiopathic Constipation.

INTRODUCTION: Chronic idiopathic constipation (CIC) is a common disorder associated with significant impairment in quality of life. This clinical practice guideline, jointly developed by the American Gastroenterological Association and the American College of Gastroenterology, aims to inform clinicians and patients by providing evidence-based practice recommendations for the pharmacological treatment of CIC in adults. METHODS: The American Gastroenterological Association and the American College of Gastroenterology formed a multidisciplinary guideline panel that conducted systematic reviews of the following agents: fiber, osmotic laxatives (polyethylene glycol, magnesium oxide, lactulose), stimulant laxatives (bisacodyl, sodium picosulfate, senna), secretagogues (lubiprostone, linaclotide, plecanatide), and serotonin type 4 agonist (prucalopride). The panel prioritized clinical questions and outcomes and used the Grading of Recommendations Assessment, Development, and Evaluation framework to assess the certainty of evidence for each intervention. The Evidence to Decision framework was used to develop clinical recommendations based on the balance between the desirable and undesirable effects, patient values, costs, and health equity considerations. RESULTS: The panel agreed on 10 recommendations for the pharmacological management of CIC in adults. Based on available evidence, the panel made strong recommendations for the use of polyethylene glycol, sodium picosulfate, linaclotide, plecanatide, and prucalopride for CIC in adults. Conditional recommendations were made for the use of fiber, lactulose, senna, magnesium oxide, and lubiprostone. DISCUSSION: This document provides a comprehensive outline of the various over-the-counter and prescription pharmacological agents available for the treatment of CIC. The guidelines are meant to provide a framework for approaching the management of CIC; clinical providers should engage in shared decision making based on patient preferences as well as medication cost and availability. Limitations and gaps in the evidence are highlighted to help guide future research opportunities and enhance the care of patients with chronic constipation.

A systematic review supporting the Society for Vascular Surgery guidelines on the management of heritable aortopathies.

BACKGROUND: To support the development of clinical practice guidelines on the management of patients with genetic aortopathies and arteriopathies, a writing committee from the Society for Vascular Surgery has commissioned this systematic review. METHODS: We conducted a systematic review and searched multiple databases for studies addressing six questions identified by the Society for Vascular Surgery guideline committee about evaluating and managing patients with genetic aortopathies and arteriopathies. Studies were selected and appraised by pairs of independent reviewers. RESULTS: We included 12 studies in this systematic review. We did not identify studies about the long-term outcomes of endovascular repair for aortic aneurysm in patients with heritable aortopathy or about new aortic events in pregnant women with a history of aortic dissection (AD) or aneurysm. A small case series demonstrated a 100% survival rate and 100% aortic intervention-free survival at 15 months (range, 7-28 months) after endograft repair for type B AD. A positive genetic diagnosis was discovered in 36% of patients with aortic aneurysms and dissections who had no risk factors for hereditary aortopathies, and these patients had a mortality rate of 11% at a median follow-up duration of 5 months. Black patients had lower 30-day mortality than White patients (5.6% vs 9.0%, respectively), but they had a higher overall aortic reintervention rate at 30 days after AD repair (47% vs 27%, respectively). Aortic reinterventions owing to aneurysmal expansion and endoleak at 30 days were higher in Black patients than White patients. The certainty of evidence was judged to be very low across all the outcomes evaluated in this systematic review. CONCLUSIONS: The available evidence suggests high survival after thoracic endovascular aortic repair for type B AD in young patients with heritable aortopathies, but with limited long-term follow-up. Genetic testing in patients with acute aortic aneurysms and dissections had a high yield. It was positive for most patients with risk factors for hereditary aortopathies and in more than one-third for all other patients, and was associated with new aortic events within 15 years.

Assessing the robustness of results from clinical trials and meta-analyses with the fragility index.

The fragility index has been increasingly used to assess the robustness of the results of clinical trials since 2014. It aims at finding the smallest number of event changes that could alter originally statistically significant results. Despite its popularity, some researchers have expressed several concerns about the validity and usefulness of the fragility index. It offers a comprehensive review of the fragility index's rationale, calculation, software, and interpretation, with emphasis on application to studies in obstetrics and gynecology. This article presents the fragility index in the settings of individual clinical trials, standard pairwise meta-analyses, and network meta-analyses. Moreover, this article provides worked examples to demonstrate how the fragility index can be appropriately calculated and interpreted. In addition, the limitations of the traditional fragility index and some solutions proposed in the literature to address these limitations were reviewed. In summary, the fragility index is recommended to be used as a supplemental measure in the reporting of clinical trials and a tool to communicate the robustness of trial results to clinicians. Other considerations that can aid in the fragility index's interpretation include the loss to follow-up and the likelihood of data modifications that achieve the loss of statistical significance.

The association of sensitivity and specificity with disease prevalence: analysis of 6909 studies of diagnostic test accuracy.

BACKGROUND: Sensitivity and specificity are characteristics of a diagnostic test and are not expected to change as the prevalence of the target condition changes. We sought to evaluate the association between prevalence and changes in sensitivity and specificity. METHODS: We retrieved data from meta-analyses of diagnostic test accuracy published in the Cochrane Database of Systematic Reviews (2003-2020). We used mixed-effects random-intercept linear regression models to evaluate the association between prevalence and logit-transformed sensitivity and specificity. The model evaluated all meta-analyses as nested within each systematic review. RESULTS: We analyzed 6909 diagnostic test accuracy studies from 552 meta-analyses that were included in 92 systematic reviews. For sensitivity, compared with the lowest quartile of prevalence, the second, third and fourth quartiles were associated with significantly higher odds of identifying a true positive case (odds ratio [OR] 1.17, 95% confidence interval [CI] 1.09-1.26; OR 1.32, 95% CI 1.23-1.41; OR 1.47, 95% CI 1.37-1.58; respectively). For specificity, compared with the lowest quartile of prevalence, the second, third and fourth quartiles were associated with significantly lower odds of identifying a true negative case (OR 0.74, 95% CI 0.69-0.80; OR 0.65, 95% CI 0.60-0.70; OR 0.47, 95% CI 0.44-0.51; respectively). Pooled regression coefficients from bivariate models conducted within each meta-analysis showed that prevalence was positively associated with sensitivity and negatively associated with specificity. Findings were consistent across subgroups. INTERPRETATION: In this large sample of diagnostic studies, higher prevalence was associated with higher estimated sensitivity and lower estimated specificity. Clinicians should consider the implications of disease prevalence and spectrum when interpreting the results from studies of diagnostic test accuracy.

A Framework for the Development of Living Practice Guidelines in Health Care.

BACKGROUND: Living practice guidelines are increasingly being used to ensure that recommendations are responsive to rapidly emerging evidence. OBJECTIVE: To develop a framework that characterizes the processes of development of living practice guidelines in health care. DESIGN: First, 3 background reviews were conducted: a scoping review of methods papers, a review of handbooks of guideline-producing organizations, and an analytic review of selected living practice guidelines. Second, the core team drafted the first version of the framework. Finally, the core team refined the framework through an online survey and online discussions with a multidisciplinary international group of stakeholders. SETTING: International. PARTICIPANTS: Multidisciplinary group of 51 persons who have experience with guidelines. MEASUREMENTS: Not applicable. RESULTS: A major principle of the framework is that the unit of update in a living guideline is the individual recommendation. In addition to providing definitions, the framework addresses several processes. The planning process should address the organization's adoption of the living methodology as well as each specific guideline project. The production process consists of initiation, maintenance, and retirement phases. The reporting should cover the evidence surveillance time stamp, the outcome of reassessment of the body of evidence (when applicable), and the outcome of revisiting a recommendation (when applicable). The dissemination process may necessitate the use of different venues, including one for formal publication. LIMITATION: This study does not provide detailed or practical guidance for how the described concepts would be best implemented. CONCLUSION: The framework will help guideline developers in planning, producing, reporting, and disseminating living guideline projects. It will also help research methodologists study the processes of living guidelines. PRIMARY FUNDING SOURCE: None.