Citations

Abstract: Background Artificial intelligence (AI)-assisted colonoscopy reduces costs in colorectal cancer screening, but its incremental value relative to non-AI resect-and-discard (RD) strategies for diminutive polyps (≤ 5 mm) remain unclear. We aimed to compare the clinical, economic, and environmental outcomes of AI-assisted and non-AI RD strategies with standard of care (SoC). Methods In our Markov model simulating 6 million individuals aged ≥45 years undergoing screening colonoscopy, 4 strategies were evaluated: SoC, non-AI RD, CADe-assisted RD (CADe-RD), and CADe+CADx-assisted RD (CADe+CADx-RD). The primary outcome was total quality-adjusted life years (QALYs), with secondary outcomes including cost and carbon dioxide (CO₂) emissions. Results Non-AI RD achieved the lowest total cost ($36.6B) and carbon emissions (0.90 million kg CO₂), while yielding the highest QALYs (51.37 million), although differences in QALYs across strategies were small (<0.01%). CADe-RD and CADe+CADx-RD remained cost-saving relative to SoC ($36.9B and $37.4B vs $37.8B, respectively) but were associated with higher costs than non-AI RD. CADe modestly increased adenoma detection without improving QALYs, while the addition of CADx increased costs and emissions and resulted in slightly lower QALYs. Sensitivity analysis showed that CADe+CADx-RD matched or exceeded CADe-RD QALYs only within a limited region of high diagnostic performance. At currently reported CADx performance levels, CADe+CADx-RD yielded lower QALYs and higher costs than CADe-RD. CADe+CADx-RD achieved non-inferiority in QALYs relative to CADe-RD only within a limited region of high diagnostic performance. Conclusions In our non-deterministic model, non-AI RD provided the optimal balance of clinical benefit, cost savings, and lowest environmental impact.

Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C–related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C–attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C–attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.

ABSTRACT Background and Aims It remains unclear whether different factors influence 30‐ and 90‐day readmission rates. We identified predictors of 90‐day mortality in a global cohort of hospitalised patients with cirrhosis. Methods Variables associated with 30‐ and 90‐day post‐discharge readmission, liver transplantation (LT), and mortality were compared in prospectively enrolled, non‐electively hospitalised adult patients with cirrhosis. Results We enrolled 4208 patients from 125 centres across 37 countries. Alcohol‐related liver disease was the most common aetiology of cirrhosis (40%), followed by hepatitis B virus infection (21%); 47% were readmitted, 8% received liver transplantation (LT), and 23% died within 90 days post‐discharge. In multivariable analysis, country income was significantly associated with both 30‐ and 90‐day readmission rates, the receipt of LT, and mortality within 30 and 90 days post‐discharge (all p ‐values < 0.001). Independent predictors of higher rates of 30‐ and 90‐day readmissions, respectively, were disease severity ( p < 0.001, p = 0.003), prior ascites ( p = 0.025, p = 0.016), prior hospitalisation ( p < 0.001), hyponatremia ( p < 0.001, p = 0.008), and in‐hospital vasopressor use ( p = 0.002, p = 0.011). Prior variceal bleeding independently predicted higher 90‐day readmission rates, whereas age, disease severity, mechanical ventilation, and in‐hospital vasopressor use (all, p < 0.001) increased odds of 30‐ and 90‐day post‐discharge death. Additionally, admission ( p = 0.011) and nosocomial ( p = 0.022) infections increased the odds of 90‐day post‐discharge death. Conclusion In a global cohort of hospitalised patients with cirrhosis, patients in high‐income countries exhibited the highest rates of 30‐ and 90‐day readmission, alongside lower mortality rates and a higher incidence of LT. Variables that predict 30‐day readmission also predicted 90‐day readmission. Understanding these disparities is essential for achieving health equity.

INTRODUCTION: Nosocomial infections (NIs) in cirrhosis are associated with high mortality but could be preventable. Logistic regression (LR) models have failed to identify high-risk patients. We aimed to develop machine learning (ML) models to predict NI. METHODS: The CLEARED consortium consists of prospectively enrolled cirrhosis inpatients from >120 centers. Using day-of-admission clinical data, 3 ML approaches (random forest [RF], extreme gradient boosting, and neural networks [NNs]) were used to predict NI. Data were split 80:20 for training and testing stratified by the outcome. Models were compared using area under the receiver operating characteristic curve (AUC). RESULTS: In total, 8,263 patients (55.90 ± 13.34 years; 64.1% men) from 127 centers in 37 countries were included. NI developed in 869 (10.5%), a median of 6 (4–11) days of postadmission. Major NIs were respiratory (29.6%) and urinary tract infection (15.7%), and spontaneous bacterial peritonitis (13.5%). NIs occurred more frequently in patients from low/low-middle income countries and those with severe liver disease, alcohol etiology, and admission infections. NIs were associated with inpatient mortality (31.9% vs 8.1%, P < 0.001) and liver transplantation (4.8% vs 1.9%, P < 0.001). Although the RF model (AUC 0.69) showed good calibration (Brier score 0.09), outperforming extreme gradient boosting, neural network, and LR models (AUC 0.66 for all; LR comparison P = 0.043), no model achieved AUC ≥0.80 for clinical utility. At 10% predicted probability threshold, the RF model demonstrated only 75.4% sensitivity, 52.9% specificity, and 15.9% positive predictive value (PPV). DISCUSSION: NIs cannot be accurately predicted from day-of-admission data using ML models, even in a large, prospective, global cirrhosis cohort. Every hospitalized patient with cirrhosis should receive protocolized infection control measures.

Background/Aims: Infections with drug-resistant organisms (DROs) are associated with poor outcomes in cirrhosis. Rifaximin, widely used for hepatic encephalopathy (HE), could promote cross-resistance, but data regarding clinical impact are conflicting. Aim: Determine predictors of DROs in a global cirrhosis inpatient cohort focusing on preadmission rifaximin use.Methods: From the global CLEARED consortium, we focused on cirrhosis inpatients with infections on/during admission. Clinical/demographic/medication, especially rifaximin details were recorded. The primary outcome was DRO development. Multivariable regression for DRO including clinical, medications, and country income was performed.Results: 2,949 infected inpatients (55.3 years, 62.9% male) were included. 12.2% of all and 24.4% of culture-positive infections developed DROs; these patients had higher HE (39 vs. 31%, <i>P</i>=0.003), hepatorenal syndrome (25 vs. 19%, <i>P</i>=0.006), lactulose (55 vs. 47%, <i>P</i>=0.008) and rifaximin use (34 vs. 27%, <i>P</i>=0.006) on crude comparisons but country-income distributions were similar. 29.7% were on pre-admission rifaximin, mostly HE-related; they had more advanced cirrhosis and from low/low-middle-income countries. Daptomycin was used in 1.5%, linked with DROs (5.0 vs. 1.0%, <i>P</i><0.0001) without a difference in rifaximin use (1.4 vs.1.7%, <i>P</i>=0.61). On adjusted analysis, MELD-Na (1.03, 95% CI 1.02–1.04, <i>P</i><0.001) increased, whereas male sex (0.73, 95% CI 0.58–0.92, <i>P</i>=0.008) and hepatitis-B (0.65, 95% CI 0.45–0.92, <i>P</i>=0.020) decreased DRO. Rifaximin was not associated with DROs overall (OR 1.07, 95% CI 0.80–1.43, <i>P</i>=0.65) or within income strata (high: 1.07, 95% CI 0.59–1.92, <i>P</i>=0.82, upper-middle: 1.18, 95% CI 0.74–1.85, <i>P</i>=0.49, low/low-middle: 1.04, 95% CI 0.60–1.81, <i>P</i>=0.90) despite sensitivity analyses.Conclusions: In this large global cohort of hospitalized patients with cirrhosis and infections, 12% developed infections involving DROs. 30% had pre-admission rifaximin use which was not linked with daptomycin use or with DRO development on adjusted analysis overall or across country income groups.

Abstract In this systematic review, we aimed to assess the sensitivity of serum immunofixation (SIFE), urine immunofixation (UIFE), and serum free light chain (sFLC) in detecting plasma cell dyscrasia associated with light chain (AL) amyloidosis. We searched the literature using PubMed, Embase, and CENTRAL databases since inception through March 2024. We included studies reporting the diagnostic accuracy of immunofixation and/or sFLC in patients with AL amyloidosis. We used the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach to assess the certainty of the evidence and QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies-2) to assess the risk of bias. After deduplication, 29 237 records were screened, and 44 studies (n = 18 071) were included. For the meta-analysis, 28 studies reported sensitivity for SIFE (n = 3390), 24 studies for UIFE (n = 2830), 19 studies for SIFE and UIFE (n = 2819), 21 studies for sFLC ratio (n = 3678), 6 studies for SIFE and sFLC ratio (n = 372), 3 studies for UIFE and sFLC ratio (n = 242), and 10 studies for all 3 tests (n = 1430). Pooled sensitivities were as follows: SIFE, 0.68 (95% confidence interval [CI], 0.62-0.73); UIFE, 0.77 (95% CI, 0.72-0.81); SIFE and UIFE, 0.89 (95% CI, 0.84-0.93); and sFLC ratio, 0.82 (95% CI, 0.78-0.86). When SIFE, UIFE, and sFLC ratio were combined, the sensitivity reached 0.99 (95% CI, 0.96-1.00). The high sensitivity of combining SIFE, UIFE, and sFLC ratio supports their use as a reliable initial testing strategy to raise suspicion for AL amyloidosis and guide decisions regarding future diagnostic modalities.

Abstract Introduction Revascularization to prevent limb loss is not feasible or represents a very high risk in a significant proportion of patients with chronic limb-threatening ischaemia (CLTI). No standard definition currently exists to define this population of patients. The aim of this study was to develop a consensus-based, multidomain definition to improve clinical assessment and reporting of studies in people with ‘no option’ (NO) or ‘poor option’ (PO) CLTI. Methods A modified Delphi process was conducted with 164 specialists from 30 countries. Two iterative survey rounds were used to reach consensus, defined as ≥70% agreement with a score of ≥7 on a nine-point scale. Results Some 164 international vascular specialists participated in the study, averaging 19 years of experience. A multidomain framework including arterial disease anatomy, biology, risk, function, and context (ABRFC) achieved 83% consensus. A ‘desert foot’ was defined as the absence of distal arterial revascularization targets on advanced non-invasive imaging, invasive digital subtraction angiography, and at least one failed endovascular revascularization attempt (81.6% agreement). Inadequate autogenous bypass conduit was defined as the lack of usable autologous vein across all four limbs (85% agreement). Patients were classified as NO for revascularization if they present with ‘desert foot’, prohibitive medical risk, a non-functional limb, or in those patients who refused arterial revascularization. PO revascularization patients combined factors such as severe infection, lack of autologous vein, or treatment non-compliance (72.1% agreement). Conclusion This consensus study established a structured, expert-validated definition of no option or poor option for revascularisation of patients with CLTI. The multidomain ABRFC framework provides a foundation for standardized clinical assessment, trial design, and future guideline development.

Abstract Systemic amyloidosis is a rare, multisystem disorder that is often challenging to diagnose due to vague and nonspecific symptoms that frequently overlap with other disorders. By the time patients are diagnosed, irreversible organ impairment from amyloid deposition occurrs, contributing to substantial morbidity and mortality. Although developing the American Society of Hematology (ASH) guidelines on systemic amyloidosis, we identified a critical knowledge gap in the recognition of the clinical presentation of its most common subtypes. Therefore, we conducted a scoping review of 117 studies following PRISMA-ScR (Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews) guidelines to identify clinical “red flags” for light chain (AL) and transthyretin (ATTR; wild-type [ATTRwt] and hereditary [ATTRv]) amyloidosis. Studies were identified from the comprehensive systematic review through the ASH amyloidosis diagnosis guideline panel, data mining, and gray literature review. Data were extracted and synthesized by systems to characterize the earliest and most frequently overlooked clinical red flags for the different types of amyloidosis. Shortness of breath and fatigue, the earliest symptoms of AL amyloidosis, contrast with the carpal tunnel syndrome occurring years before ATTRwt cardiac amyloidosis is diagnosed. Weight loss, unexplained abdominal pain, and early satiety were overlooked red flags for AL amyloidosis, compared to the preceding arrhythmias often missed in evaluation for ATTRwt amyloidosis. Sensory loss was the predominant neuropathic presentation for AL amyloidosis compared to the painful length-dependent neuropathy of ATTRv amyloidosis. Awareness of the early symptoms and distinct patterns across subtypes can enhance cross-specialty awareness and support earlier diagnosis and intervention of AL and ATTR amyloidosis.

Background Light chain (AL) amyloidosis is a rare disease caused by the misfolding of immunoglobulin light chains produced by a plasma cell dyscrasia. Patients can present with involvement of many organs, including the heart, kidneys, liver, nerves, and other sites, resulting in a high symptom burden. Timely and accurate diagnosis is important to prevent organ failure and improve patient survival. Objective These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients and clinicians in the timely and effective diagnosis of AL amyloidosis. Methods ASH formed a multidisciplinary guideline panel that included 22 individuals representing various medical specialties (academic and community hematology, nephrology, neurology, cardiology, internal medicine, and pathology) as well as 1 patient representative. The group was balanced to minimize potential bias from conflicts of interest. The University of Kansas Medical Center supported the guideline development process, including updating or performing systematic evidence reviews (up to 6 March 2023). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE evidence-to-decision frameworks, to assess evidence and make recommendations, which were subject to public comment. Results The panel agreed on 12 recommendations. Conclusions The use of serum immunofixation, urine immunofixation, and serum free light chains enhances the clinical suspicion of AL amyloidosis. The diagnosis of AL amyloidosis can be made effectively through surrogate biopsies, which require both a bone marrow biopsy and fat-pad sampling; however, target organ biopsies may be favored in certain clinical situations.

Abstract Introduction Cannabidiol has been shown to exert significant anti-inflammatory effects and has demonstrated efficacy in murine models of autoimmune myocarditis, pericarditis, and heart failure. The ARCHER Study assessed whether a pharmaceutically produced cannabidiol formulation showed beneficial effects on cardiac magnetic resonance (CMR) endpoints known to predict prognosis in this patient population. Methods In a multicentre international double-blind placebo-controlled phase 2 study, we randomly assigned 109 patients within 10 days of CMR confirmed diagnosis of acute myocarditis to 12 weeks of pharmaceutically produced oral cannabidiol (active) or placebo. Dose was titrated up to 10 mg/kg of body weight twice daily. Primary endpoints were the difference in extracellular volume (ECV) and global longitudinal strain (GLS) measured by CMR at week 12. Other CMR endpoints included left-ventricular ejection fraction (LVEF), LV mass, intracellular volume (ICV), LV end-diastolic and end-systolic volumes (LVEDV, LVESV), and left-atrial end-systolic volume (LAESV). Results All randomized patients (56 active/53 placebo) completed the study with no loss to follow-up. Study drug appeared safe and well tolerated. Baseline mean ECV 38.9 ± 10.9 ml, GLS −15.3 ± 3.6%, and LVEF 60.6 ± 9.9% were consistent with mild to moderate myocarditis and predominantly intact LV function. Week 12 mean ECV was 33.6 ml in the active group and 37.3 ml in the placebo group, a difference of −3.7 ml, confidence interval (CI): −7.4 to 0.1; P = .0538; GLS was −16.0% in the active group and −15.9% in the placebo group, difference of −0.1, CI: −1.2 to 1.1; P = .90. Left ventricular mass was significantly reduced in the active group at 121.1 g compared to placebo 130.3 g, a difference of −9.2, CI: −16.4 to −2.1; P = .0117. In terms of remodelling, LAESV was significantly reduced in the active group (−8.1 ml; P = .0376) while the reduction in LVEDV failed to reach significance (−7.4 ml; P = .098). Conclusion In mild-to-moderate acute myocarditis, treatment with pharmaceutically manufactured cannabidiol was not associated with a statistically significant change in myocardial ECV or GLS, although a trend towards reduction in ECV was observed. In addition, improvement in other potential markers of myocardial recovery, including a significant reduction in LV mass, was seen in the active treatment group. Further investigation of the therapeutic potential of this therapy in inflammatory cardiac conditions is warranted.