Lipoprotein subclasses are associated with Hepatic steatosis: insights from the prospective multicenter imaging study for the evaluation of chest pain (PROMISE) clinical trial.

Objectives: To determine the relationship between lipoprotein particle size/number with hepatic steatosis (HS), given its association with traditional lipoproteins and coronary atherosclerosis. Methods: Individuals with available CT data and blood samples enrolled in the PROMISE trial were studied. HS was defined based on CT attenuation. Lipoprotein particle size/number were measured by nuclear magnetic resonance spectroscopy. Principal components analysis (PCA) was used for dimensionality reduction. The association of PCA factors and individual lipoprotein particle size/number with HS were assessed in multivariable regression models. Associations were validated in an independent cohort of 59 individuals with histopathology defined HS. Results: Individuals with HS (n=410/1,509) vs those without (n=1,099/1,509), were younger (59±8 vs 61±8 years) and less often females (47.6 % vs 55.9 %). All PCA factors were associated with HS: factor 1 (OR:1.36, 95 %CI:1.21-1.53), factor 3 (OR:1.75, 95 %CI:1.53-2.02) and factor 4 (OR:1.49; 95 %CI:1.32-1.68) were weighted heavily with small low density lipoprotein (LDL) and triglyceride-rich (TRL) particles, while factor 2 (OR:0.86, 95 %CI:0.77-0.97) and factor 5 (OR:0.74, 95 %CI:0.65-0.84) were heavily loaded with high density lipoprotein (HDL) and larger LDL particles. These observations were confirmed with the analysis of individual lipoprotein particles in PROMISE. In the validation cohort, association between HS and large TRL (OR: 8.16, 95 %CI:1.82-61.98), and mean sizes of TRL- (OR: 2.82, 95 %CI:1.14-9.29) and HDL (OR:0.35, 95 %CI:0.13-0.72) were confirmed. Conclusions: Large TRL, mean sizes of TRL-, and HDL were associated with radiographic and histopathologic HS. The use of lipoprotein particle size/number could improve cardiovascular risk assessment in HS.

Bichloride-based ionic liquids for the merged storage, processing, and electrolysis of hydrogen chloride.

Hydrogen chloride is produced as a by-product in industrial processes on a million-ton scale. Since HCl is inherently dangerous, its storage and transport are avoided by, e.g., on-site electrolysis providing H2 and Cl2 which usually requires complex cell designs and PFAS-based membranes. Here we report a complementary approach to safely store 0.61 kilogram HCl per kilogram storage material [NEt3Me]Cl forming the bichloride [NEt3Me][Cl(HCl)n]. Although HCl release is possible from this ionic liquid by heat or vacuum, the bichloride can be used directly to produce base chemicals like vinyl chloride. Alternatively, [NEt3Me][Cl(HCl)n] is electrolyzed under anhydrous conditions using a membrane-free cell to generate H2 and the corresponding chlorination agent [NEt3Me][Cl(Cl2)n], enabling the combination of these ionic liquids for the production of base chemicals.

Selective Use of CT Fractional Flow at a Large Academic Medical Center: Insights from Clinical Implementation after 1 Year of Practice.

Purpose This special report outlines a retrospective observational study of CT fractional flow reserve (CT-FFR) analysis using dual-source coronary CT angiography (CTA) scans performed without heart rate control and its impact on clinical outcomes. Materials and Methods All patients who underwent clinically indicated coronary CTA between August 2020 and August 2021 were included in this retrospective observational study. Scans were performed in the late systolic to early diastolic period without heart rate control and analyzed at the interpreting physician's discretion. Demographics, coronary CTA features, and rates of invasive coronary angiography (ICA), percutaneous coronary intervention (PCI), myocardial infarction, and all-cause death at 3 months were assessed by chart review. Results During the study period, 3098 patients underwent coronary CTA, of whom 113 with coronary bypass grafting were excluded. Of the remaining 2985 patients, 292 (9.7%) were referred for CT-FFR analysis. Two studies (0.7%) were rejected from CT-FFR analysis, and six (2.1%) analyses did not evaluate the lesion of concern. A total of 160 patients (56.3%) had CT-FFR greater than 0.80. Among patients with significant stenosis at coronary CTA, patients who underwent CT-FFR analysis presented with lower rates of ICA (74.5% vs 25.5%, P = .04) and PCI (78.9% vs 21.1%, P = .05). Conclusion CT-FFR was implemented in patients not requiring heart rate control by using dual-source coronary CTA acquisition and showed the potential to decrease rates of ICA and PCI without compromising safety in patients with significant stenosis and an average heart rate of 65 beats per minute. Keywords: Angiography, CT, CT-Angiography, Fractional Flow Reserve, Cardiac, Heart, Arteriosclerosis Supplemental material is available for this article. © RSNA, 2024.

Deep learning analysis of epicardial adipose tissue to predict cardiovascular risk in heavy smokers.

BACKGROUND: Heavy smokers are at increased risk for cardiovascular disease and may benefit from individualized risk quantification using routine lung cancer screening chest computed tomography. We investigated the prognostic value of deep learning-based automated epicardial adipose tissue quantification and compared it to established cardiovascular risk factors and coronary artery calcium. METHODS: We investigated the prognostic value of automated epicardial adipose tissue quantification in heavy smokers enrolled in the National Lung Screening Trial and followed for 12.3 (11.9-12.8) years. The epicardial adipose tissue was segmented and quantified on non-ECG-synchronized, non-contrast low-dose chest computed tomography scans using a validated deep-learning algorithm. Multivariable survival regression analyses were then utilized to determine the associations of epicardial adipose tissue volume and density with all-cause and cardiovascular mortality (myocardial infarction and stroke). RESULTS: Here we show in 24,090 adult heavy smokers (59% men; 61 ± 5 years) that epicardial adipose tissue volume and density are independently associated with all-cause (adjusted hazard ratios: 1.10 and 1.38; P < 0.001) and cardiovascular mortality (adjusted hazard ratios: 1.14 and 1.78; P < 0.001) beyond demographics, clinical risk factors, body habitus, level of education, and coronary artery calcium score. CONCLUSIONS: Our findings suggest that automated assessment of epicardial adipose tissue from low-dose lung cancer screening images offers prognostic value in heavy smokers, with potential implications for cardiovascular risk stratification in this high-risk population.

Heavy smokers are at increased risk of poor health outcomes, particularly outcomes related to cardiovascular disease. We explore how fat surrounding the heart, known as epicardial adipose tissue, may be an indicator of the health of heavy smokers. We use an artificial intelligence system to measure the heart fat on chest scans of heavy smokers taken during a lung cancer screening trial and following their health for 12 years. We find that higher amounts and denser epicardial adipose tissue are linked to an increased risk of death from any cause, specifically from heart-related issues, even when considering other health factors. This suggests that measuring epicardial adipose tissue during lung cancer screenings could be a valuable tool for identifying heavy smokers at greater risk of heart problems and death, possibly helping to guide their medical management and improve their cardiovascular health.

Deep Learning to Estimate Cardiovascular Risk From Chest Radiographs : A Risk Prediction Study.

BACKGROUND: Guidelines for primary prevention of atherosclerotic cardiovascular disease (ASCVD) recommend a risk calculator (ASCVD risk score) to estimate 10-year risk for major adverse cardiovascular events (MACE). Because the necessary inputs are often missing, complementary approaches for opportunistic risk assessment are desirable. OBJECTIVE: To develop and test a deep-learning model (CXR CVD-Risk) that estimates 10-year risk for MACE from a routine chest radiograph (CXR) and compare its performance with that of the traditional ASCVD risk score for implications for statin eligibility. DESIGN: Risk prediction study. SETTING: Outpatients potentially eligible for primary cardiovascular prevention. PARTICIPANTS: The CXR CVD-Risk model was developed using data from a cancer screening trial. It was externally validated in 8869 outpatients with unknown ASCVD risk because of missing inputs to calculate the ASCVD risk score and in 2132 outpatients with known risk whose ASCVD risk score could be calculated. MEASUREMENTS: 10-year MACE predicted by CXR CVD-Risk versus the ASCVD risk score. RESULTS: Among 8869 outpatients with unknown ASCVD risk, those with a risk of 7.5% or higher as predicted by CXR CVD-Risk had higher 10-year risk for MACE after adjustment for risk factors (adjusted hazard ratio [HR], 1.73 [95% CI, 1.47 to 2.03]). In the additional 2132 outpatients with known ASCVD risk, CXR CVD-Risk predicted MACE beyond the traditional ASCVD risk score (adjusted HR, 1.88 [CI, 1.24 to 2.85]). LIMITATION: Retrospective study design using electronic medical records. CONCLUSION: On the basis of a single CXR, CXR CVD-Risk predicts 10-year MACE beyond the clinical standard and may help identify individuals at high risk whose ASCVD risk score cannot be calculated because of missing data. PRIMARY FUNDING SOURCE: None.

Polygenic Scores and Preclinical Cardiovascular Disease in Individuals With HIV: Insights From the REPRIEVE Trial.

BACKGROUND: Coronary artery disease (CAD) is a leading cause of death among the 38.4 million people with HIV globally. The extent to which cardiovascular polygenic risk scores (PRSs) derived in non-HIV populations generalize to people with HIV is not well understood. METHODS AND RESULTS: PRSs for CAD (GPSMult) and lipid traits were calculated in a global cohort of people with HIV treated with antiretroviral therapy with low-to-moderate atherosclerotic cardiovascular disease risk enrolled in REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV). The PRSs were associated with baseline lipid traits in 4495 genotyped participants, and with subclinical CAD in a subset of 662 who underwent coronary computed tomography angiography. Among participants who underwent coronary computed tomography angiography (mean age, 50.9 [SD, 5.8] years; 16.1% women; 41.8% African, 57.3% European, 1.1% Asian), GPSMult was associated with plaque presence with odds ratio (OR) per SD in GPSMult of 1.42 (95% CI, 1.20-1.68; P=3.8×10-5), stenosis >50% (OR, 2.39 [95% CI, 1.48-3.85]; P=3.4×10-4), and noncalcified/vulnerable plaque (OR, 1.45 [95% CI, 1.23-1.72]; P=9.6×10-6). Effects were consistent in subgroups of age, sex, 10-year atherosclerotic cardiovascular disease risk, ancestry, and CD4 count. Adding GPSMult to established risk factors increased the C-statistic for predicting plaque presence from 0.718 to 0.734 (P=0.02). Furthermore, a PRS for low-density lipoprotein cholesterol was associated with plaque presence with OR of 1.21 (95% CI, 1.01-1.44; P=0.04), and partially calcified plaque with OR of 1.21 (95% CI, 1.01-1.45; P=0.04) per SD. CONCLUSIONS: Among people with HIV treated with antiretroviral therapy without documented atherosclerotic cardiovascular disease and at low-to-moderate calculated risk in REPRIEVE, an externally developed CAD PRS was predictive of subclinical atherosclerosis. PRS for low-density lipoprotein cholesterol was also associated with subclinical atherosclerosis, supporting a role for low-density lipoprotein cholesterol in HIV-associated CAD. REGISTRATION: URL: https://www.reprievetrial.org; Unique identifier: NCT02344290.

Elevated SLC7A2 expression is associated with an abnormal neuroinflammatory response and nitrosative stress in Huntington's disease.

We previously identified solute carrier family 7 member 2 (SLC7A2) as one of the top upregulated genes when normal Huntingtin was deleted. SLC7A2 has a high affinity for L-arginine. Arginine is implicated in inflammatory responses, and SLC7A2 is an important regulator of innate and adaptive immunity in macrophages. Although neuroinflammation is clearly demonstrated in animal models and patients with Huntington's disease (HD), the question of whether neuroinflammation actively participates in HD pathogenesis is a topic of ongoing research and debate. Here, we studied the role of SLC7A2 in mediating the neuroinflammatory stress response in HD cells. RNA sequencing (RNA-seq), quantitative RT-PCR and data mining of publicly available RNA-seq datasets of human patients were performed to assess the levels of SLC7A2 mRNA in different HD cellular models and patients. Biochemical studies were then conducted on cell lines and primary mouse astrocytes to investigate arginine metabolism and nitrosative stress in response to neuroinflammation. The CRISPR-Cas9 system was used to knock out SLC7A2 in STHdhQ7 and Q111 cells to investigate its role in mediating the neuroinflammatory response. Live-cell imaging was used to measure mitochondrial dynamics. Finally, exploratory studies were performed using the Enroll-HD periodic human patient dataset to analyze the effect of arginine supplements on HD progression. We found that SLC7A2 is selectively upregulated in HD cellular models and patients. HD cells exhibit an overactive response to neuroinflammatory challenges, as demonstrated by abnormally high iNOS induction and NO production, leading to increased protein nitrosylation. Depleting extracellular Arg or knocking out SLC7A2 blocked iNOS induction and NO production in STHdhQ111 cells. We further examined the functional impact of protein nitrosylation on a well-documented protein target, DRP-1, and found that more mitochondria were fragmented in challenged STHdhQ111 cells. Last, analysis of Enroll-HD datasets suggested that HD patients taking arginine supplements progressed more rapidly than others. Our data suggest a novel pathway that links arginine uptake to nitrosative stress via upregulation of SLC7A2 in the pathogenesis and progression of HD. This further implies that arginine supplements may potentially pose a greater risk to HD patients.

Effects of Pitavastatin on Coronary Artery Disease and Inflammatory Biomarkers in HIV: Mechanistic Substudy of the REPRIEVE Randomized Clinical Trial.

Importance: Cardiovascular disease (CVD) is increased in people with HIV (PWH) and is characterized by premature noncalcified coronary plaque. In the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE), pitavastatin reduced major adverse cardiovascular events (MACE) by 35% over a median of 5.1 years. Objective: To investigate the effects of pitavastatin on noncalcified coronary artery plaque by coronary computed tomography angiography (CTA) and on inflammatory biomarkers as potential mechanisms for MACE prevention. Design, Setting, and Participants: This double-blind, placebo-controlled randomized clinical trial enrolled participants from April 2015 to February 2018 at 31 US clinical research sites. PWH without known CVD who were taking antiretroviral therapy and had low to moderate 10-year CVD risk were included. Data were analyzed from April to November 2023. Intervention: Oral pitavastatin calcium, 4 mg per day. Main Outcomes and Measures: Coronary CTA and inflammatory biomarkers at baseline and 24 months. The primary outcomes were change in noncalcified coronary plaque volume and progression of noncalcified plaque. Results: Of 804 enrolled persons, 774 had at least 1 evaluable CTA. Plaque changes were assessed in 611 who completed both CT scans. Of 611 analyzed participants, 513 (84.0%) were male, the mean (SD) age was 51 (6) years, and the median (IQR) 10-year CVD risk was 4.5% (2.6-7.0). A total of 302 were included in the pitavastatin arm and 309 in the placebo arm. The mean noncalcified plaque volume decreased with pitavastatin compared with placebo (mean [SD] change, -1.7 [25.2] mm3 vs 2.6 [27.1] mm3; baseline adjusted difference, -4.3 mm3; 95% CI, -8.6 to -0.1; P = .04; 7% [95% CI, 1-12] greater reduction relative to placebo). A larger effect size was seen among the subgroup with plaque at baseline (-8.8 mm3 [95% CI, -17.9 to 0.4]). Progression of noncalcified plaque was 33% less likely with pitavastatin compared with placebo (relative risk, 0.67; 95% CI, 0.52-0.88; P = .003). Compared with placebo, the mean low-density lipoprotein cholesterol decreased with pitavastatin (mean change: pitavastatin, -28.5 mg/dL; 95% CI, -31.9 to -25.1; placebo, -0.8; 95% CI, -3.8 to 2.2). The pitavastatin arm had a reduction in both oxidized low-density lipoprotein (-29% [95% CI, -32 to -26] vs -13% [95% CI, -17 to -9]; P < .001) and lipoprotein-associated phospholipase A2 (-7% [95% CI, -11 to -4] vs 14% [95% CI, 10-18]; P < .001) compared with placebo at 24 months. Conclusions and Relevance: In PWH at low to moderate CVD risk, 24 months of pitavastatin reduced noncalcified plaque volume and progression as well as markers of lipid oxidation and arterial inflammation. These changes may contribute to the observed MACE reduction in REPRIEVE. Trial Registration: ClinicalTrials.gov Identifier: NCT02344290.

Risk factors for clonal hematopoiesis of indeterminate potential in people with HIV: a report from the REPRIEVE trial.

ABSTRACT: Clonal hematopoiesis of indeterminate potential (CHIP), the clonal expansion of myeloid cells with leukemogenic mutations, results in increased coronary artery disease (CAD) risk. CHIP is more prevalent among people with HIV (PWH), but the risk factors are unknown. CHIP was identified among PWH in REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) using whole-exome sequencing. Logistic regression was used to associate sociodemographic factors and HIV-specific factors with CHIP adjusting for age, sex, and smoking status. In the studied global cohort of 4486 PWH, mean age was 49.9 (standard deviation [SD], 6.4) years; 1650 (36.8%) were female; and 3418 (76.2%) were non-White. CHIP was identified in 223 of 4486 (4.97%) and in 38 of 373 (10.2%) among those aged ≥60 years. Age (odds ratio [OR], 1.07; 95% confidence interval [CI], 1.05-1.09; P < .0001) and smoking (OR, 1.37; 95% CI, 1.14-1.66; P < .001) associated with increased odds of CHIP. Globally, participants outside of North America had lower odds of CHIP including sub-Saharan Africa (OR, 0.57; 95% CI, 0.4-0.81; P = .0019), South Asia (OR, 0.45; 95% CI, 0.23-0.80; P = .01), and Latin America/Caribbean (OR, 0.56; 95% CI, 0.34-0.87; P = .014). Hispanic/Latino ethnicity (OR, 0.38; 95% CI, 0.23-0.54; P = .002) associated with significantly lower odds of CHIP. Among HIV-specific factors, CD4 nadir <50 cells/mm3 associated with a 1.9-fold (95%CI, 1.21-3.05; P = .006) increased odds of CHIP, with the effect being significantly stronger among individuals with short duration of antiretroviral therapy (ART; OR, 4.15; 95% CI, 1.51-11.1; P = .005) (Pinteraction= .0492). Among PWH at low-to-moderate CAD risk on stable ART, smoking, CD4 nadir, North American origin, and non-Hispanic ethnicity associated with increased odds of CHIP. This trial was registered at www.ClinicalTrials.gov as NCT02344290.

Cytomegalovirus IgG is Associated With Physical Function But Not Muscle Density in People With HIV.

BACKGROUND: Cytomegalovirus (CMV) seropositivity is associated with poor outcomes, including physical function impairment, in people without HIV. We examined associations between CMV IgG titer and physical function in virologically suppressed people with HIV (PWH). METHODS: REPRIEVE is a double-blind randomized trial evaluating pitavastatin for primary prevention of atherosclerotic cardiovascular disease in PWH. This analysis focused on participants enrolled in a substudy with additional biomarker testing, imaging [coronary CT angiography], and physical function measures at entry. CMV IgG was measured using quantitative enzyme immunoassay, physical function by Short Physical Performance Battery, and muscle density and area by CT. Associations between CMV IgG (risk factor) and outcomes were evaluated using the partial Spearman correlation and linear and log-binomial regression. RESULTS: Among 717 participants, 82% male, the median CMV IgG was 2716 (Q1, Q3: 807, 6672) IU/mL, all above the limit of quantification. Among 631 participants with imaging, there was no association between CMV IgG and CT-based muscle density or area, controlling for age (r = -0.03 and r = -0.01, respectively; P ≥ 0.38). Among 161 participants with physical function data, higher CMV IgG was associated with poorer overall modified Short Physical Performance Battery score ( P = 0.02), adjusted for age, nadir CD4, and high-sensitivity C-reactive protein. CONCLUSIONS: Higher CMV IgG titer was associated with poorer physical function, not explained by previous immune compromise, inflammation, or muscle density or area. Further mechanistic studies are needed to understand this association and whether CMV-specific therapy can affect physical function in PWH.

Agreement among high-sensitivity cardiac troponin assays and non-invasive testing, clinical outcomes, and quality-of-care outcomes based on the 2020 European Society of Cardiology Guidelines.

AIMS: Quality-of-care and safety of patients with suspected acute coronary syndrome (ACS) would benefit if management was independent of which high-sensitivity cardiac troponin (hs-cTn) assay was used for risk stratification. We aimed to determine the concordance of hs-cTn assays to risk-stratify patients with suspected ACS according to the European Society of Cardiology (ESC) 2020 Guidelines. METHODS AND RESULTS: Blood samples were obtained at arrival and at 2 h from patients with suspected ACS using four hs-cTn assays. The patients were classified into rule-out/observe/rule-in strata based on the ESC 2020 Guidelines. Concordance was determined among the assays for rule-out/observe/rule-in strata. The prevalences of significant underlying disease (≥50% stenosis on coronary computed tomography or inducible myocardial ischaemia on stress testing) and adjudicated ACS, plus quality-of-care outcomes, were compared. Among 238 patients (52.7 ± 8.0 years; 40.3% female), the overall concordance across assays to classify patients into rule-out/observe/rule-in strata was 74.0% (176/238). Platforms significantly differed for rule-out (89.9 vs. 76.5 vs. 78.6 vs. 86.6%, P < 0.001) and observe strata (6.7 vs. 20.6 vs. 17.7 vs. 9.2%, P < 0.001), but not for rule-in strata (3.4 vs. 2.9 vs. 3.8 vs. 4.2%, P = 0.62). Among patients in ruled-out strata, 19.1-21.6% had significant underlying disease and 3.3-4.2% had ACS. The predicted disposition of patients and cost-of-care differed across the assays (all P < 0.001). When compared with observed strata, conventional troponin-based management and predicted quality-of-care outcomes significantly improved with hs-cTn-based strategies (direct discharge: 21.0 vs. 80.3-90.8%; cost-of-care: $3889 ± 4833 vs. $2578 ± 2896-2894 ± 4371, all P < 0.001). CONCLUSION: Among individuals with suspected ACS, patient management may differ depending on which hs-cTn assay is utilized. More data are needed regarding the implications of inter-assay differences. TRAIL REGISTRATION: NCT01084239.

Interference Screw versus Cement Fixation in Anterior Cruciate Ligament Soft Tissue Grafts: A Biomechanical Study.

Shortcomings of fixation have been reported as a source of graft failure in anterior cruciate ligament (ACL) reconstruction. While interference screws have long been used as fixation devices for ACL reconstruction, they are not without complications. Previous studies have highlighted the use of bone void filler as a fixation method; however, no biomechanical comparisons using soft tissue grafts with interference screws exist to our knowledge. The purpose of this study is to evaluate the fixation strength of a calcium phosphate cement bone void filler compared with screw fixation in an ACL reconstruction bone replica model with human soft tissue grafts. In total, 10 ACL grafts were constructed using semitendinosus and gracilis tendons harvested from 10 donors. Grafts were affixed with either an 8-10 mm × 23 mm polyether ether ketone interference screw (n = 5) or with approximately 8 mL of calcium phosphate cement (n = 5) into open cell polyurethane blocks. Graft constructs were tested to failure in cyclic loading under displacement control at a rate of 1 mm per second. When compared with screw construct, the cement construct showed a 978% higher load at yield, 228% higher load at failure, 181% higher displacement at yield, 233% higher work at failure, and a 545% higher stiffness. Normalized data for the screw constructs relative to the cement constructs from the same donor showed 14 ± 11% load at yield, 54 ± 38% load at failure, and 172 ± 14% graft elongation. The results of this study indicate that cement fixation of ACL grafts may result in a stronger construct compared with the current standard of fixation with interference screws. This method could potentially reduce the incidence of complications associated with interface screw placement such as bone tunnel widening, screw migration, and screw breakage.

Positive Predictive Value of Cirrhosis and Chronic Pancreatitis Diagnoses in Individuals with Alcohol Use Disorder: A Single-Center Study.

BACKGROUND: Although accuracy of diagnosis codes for cirrhosis and chronic pancreatitis (CP) has been evaluated in multiple studies, none have focused on patients with alcohol use disorders (AUD). We evaluated the positive predictive value (PPV) for a verified diagnosis of cirrhosis and CP in AUD patients treated at a tertiary care center. METHODS: We performed a detailed review of electronic health records for AUD patients assigned ICD-9 or 10 codes for alcoholic cirrhosis (ALC) (n = 199), CP (n = 200), or both (n = 200). We calculated PPV for a verified diagnosis of cirrhosis and CP and performed multivariable regression analysis to assess the impact of relevant factors on PPV for a verified diagnosis. RESULTS: PPV of cirrhosis was 81.2% (95% CI 77.0 to 84.9%) which increased to 87.5% (95% CI 83.8 to 90.6%) if the definition was relaxed to include alcohol-related hepatitis. PPV of CP was 54.5% (95% CI 49.5 to 59.5%) which increased to 78% (95% CI 73.6 to 82.0%) when recurrent acute pancreatitis was included in the definition. In multivariable analyses, the odds of a verified diagnosis were significantly higher in individuals aged 65+ years for both cirrhosis (OR 12.23, 95% CI 2.19 to 68.42) and CP (OR 8.84, 95% CI 2.7 to 28.93) and in ever smokers for CP (OR 1.95, 95% CI 1.05 to 3.65). CONCLUSION: PPV for diagnosis codes in AUD patients is high for a verified diagnosis of cirrhosis but only modest for CP. While administrative datasets can provide reliable information for cirrhosis, future studies should focus on ways to boost the diagnostic validity of administrative datasets for CP.

The impact of a novel musculoskeletal consult service in an inpatient rehabilitation facility: A descriptive analysis.

BACKGROUND: Musculoskeletal (MSK) pathologies significantly affect the rehabilitation course for patients admitted to an inpatient rehabilitation facility (IRF). The impact of a specialized inpatient MSK consult service has not been previously evaluated. OBJECTIVE: To assess the demographics, pathologies, and impact on pain scores of patients who were evaluated by a specialized MSK consult service. DESIGN: Retrospective descriptive analysis of patients at an IRF who were evaluated by the MSK consult service. SETTING: Academic IRF. PARTICIPANTS: 230 patients evaluated by the MSK consult service over 4.5 years. INTERVENTIONS: MSK consult service composed of sports medicine fellowship-trained physiatrists who use history, physical examination, point-of-care ultrasound, and specialized MSK knowledge to assess and address MSK barriers to functional improvement. MAIN OUTCOME MEASURES: Primary rehabilitation diagnosis, length of stay, discharge destination, reason for consult, MSK diagnosis, need for injection, change in Numerical Pain Rating Scale (NPRS) pain scores, change in Functional Independence Measures (FIM). RESULTS: A total of 230 consults met inclusion criteria for analysis. The most common symptoms were shoulder pain (47%), knee pain (30%), and hip/groin pain (10.4%). The MSK consult service made 82 different musculoskeletal and neuromuscular diagnoses. The most common primary rehabilitation diagnosis was stroke (28.3%). Injections were performed in 44.3% of consults, with an average reduction in NPRS pain score of 2.3 (SD 1.9) and a statistically significant reduction in average NPRS pain scores in patients who underwent injections compared to those who did not (p < .001). CONCLUSIONS: This study is the first to examine the use of an innovative inpatient MSK physiatry consult service in an IRF. This promising consult service can play a pivotal role in patient care by reducing functionally limiting MSK pain to allow for better toleration of therapies and to optimize functional gains.

Noninvasive diagnosis of secondary infections in COVID-19 by sequencing of plasma microbial cell-free DNA.

Secondary infection (SI) diagnosis in severe COVID-19 remains challenging. We correlated metagenomic sequencing of plasma microbial cell-free DNA (mcfDNA-Seq) with clinical SI assessment, immune response, and outcomes. We classified 42 COVID-19 inpatients as microbiologically confirmed-SI (Micro-SI, n = 8), clinically diagnosed-SI (Clinical-SI, n = 13, i.e., empiric antimicrobials), or no-clinical-suspicion-for-SI (No-Suspected-SI, n = 21). McfDNA-Seq was successful in 73% of samples. McfDNA detection was higher in Micro-SI (94%) compared to Clinical-SI (57%, p = 0.03), and unexpectedly high in No-Suspected-SI (83%), similar to Micro-SI. We detected culture-concordant mcfDNA species in 81% of Micro-SI samples. McfDNA correlated with LRT 16S rRNA bacterial burden (r = 0.74, p = 0.02), and biomarkers (white blood cell count, IL-6, IL-8, SPD, all p < 0.05). McfDNA levels were predictive of worse 90-day survival (hazard ratio 1.30 [1.02-1.64] for each log10 mcfDNA, p = 0.03). High mcfDNA levels in COVID-19 patients without clinical SI suspicion may suggest SI under-diagnosis. McfDNA-Seq offers a non-invasive diagnostic tool for pathogen identification, with prognostic value on clinical outcomes.

Subconjunctival injection of human umbilical cord mesenchymal stem cells alleviates experimental allergic conjunctivitis via regulating T cell response.

BACKGROUND: T helper 2 (Th2) cells are thought to play critical roles in allergic conjunctivitis (AC). They release inflammatory cytokines to promote an allergic response in AC. Due to individual heterogeneity and long-term chronic management, current therapies do not always effectively control AC. Mesenchymal stem cells (MSCs) have been shown to be effective in treating allergy-related disorders, but it is unclear how exactly the Th2-mediated allergic response is attenuated. This study aims to elucidate the therapeutic effect and mechanism of the human umbilical cord MSCs (hUCMSCs) in a mouse model of experimental AC (EAC). METHODS: A mouse EAC model was established by inoculating short ragweed (SRW) pollen. After the SRW pollen challenge, the mice received a single subconjunctival or tail vein injection of 2 × 106 hUCMSCs, or subconjunctival injection of hUCMSCs conditioned medium (hUCMSC-CM), and dexamethasone eye drops was used as positive control; subsequent scratching behavior and clinical symptoms were assessed. Immunostaining and flow cytometry were carried out to show allergic reactions and the activation of CD4 + T cell subsets in the conjunctiva and cervical lymph nodes (CLNs). Gene expression was determined by RNA-seq and further verified by qRT-PCR and Western blot. Co-culture assays were performed to explore the regulatory role of hUCMSCs in the differentiation of CD4 + naive T cells (Th0) into Th2 cells. RESULTS: Subconjunctival administration of hUCMSCs resulted in fewer instances of scratching and lower inflammation scores in EAC mice compared to the tail vein delivery, hUCMSC-CM and control groups. Subconjunctival administration of hUCMSCs reduced the number of activated mast cells and infiltrated eosinophils in the conjunctiva, as well as decreased the number of Th2 cells in CLNs. After pretreatment with EAC mouse serum in vitro to mimic the in vivo milieu, hUCMSCs were able to inhibit the differentiation of Th0 into Th2 cells. Further evidence demonstrated that repression of Th2 cell differentiation by hUCMSCs is mediated by CRISPLD2 through downregulation of STAT6 phosphorylation. Additionally, hUMCSCs were able to promote the differentiation of Th0 cells into regulatory T cells in CLNs of EAC mice. CONCLUSIONS: Subconjunctival injection of hUCMSCs suppressed the Th2-allergic response and alleviated clinical symptoms. This study provides not only a potential therapeutic target for the treatment of AC but also other T cell-mediated diseases.

Biological and Clinical Implications of the Vascular Endothelial Growth Factor Coreceptor Neuropilin-1 in Human Immunodeficiency Virus.

Plasma vascular endothelial growth factor (VEGF) coreceptor neuropilin-1 (NRP-1) had the largest association with coronary plaque in the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) proteomics analysis. With little known about NRP-1 in people with human immunodeficiency virus (PWH), we explored its relation to other proteins in REPRIEVE and validated our findings through a Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) case-cohort study by assessing its relation to host factors and incident cardiovascular disease and cancer. Within REPRIEVE, NRP-1 was associated with proteins involved in angiogenesis, signal transduction, immunoregulation, and cell migration/adhesion. Within CNICS, NRP-1 was associated with key host factors, including older age and male sex. NRP-1 was associated with an increased hazard of multiple cancers but a decreased prostate cancer risk. Finally, NRP-1 was most strongly associated with mortality and type 2 myocardial infarction. These data suggest that NRP-1 is part of a clinically relevant immunoregulatory pathway related to multiple comorbidities in PWH. Clinical Trials Registration. NCT02344290.

Transcatheter Aortic-Valve Replacement in Low-Risk Patients at Five Years.

BACKGROUND: A previous analysis in this trial showed that among patients with severe, symptomatic aortic stenosis who were at low surgical risk, the rate of the composite end point of death, stroke, or rehospitalization at 1 year was significantly lower with transcatheter aortic-valve replacement (TAVR) than with surgical aortic-valve replacement. Longer-term outcomes are unknown. METHODS: We randomly assigned patients with severe, symptomatic aortic stenosis and low surgical risk to undergo either TAVR or surgery. The first primary end point was a composite of death, stroke, or rehospitalization related to the valve, the procedure, or heart failure. The second primary end point was a hierarchical composite that included death, disabling stroke, nondisabling stroke, and the number of rehospitalization days, analyzed with the use of a win ratio analysis. Clinical, echocardiographic, and health-status outcomes were assessed through 5 years. RESULTS: A total of 1000 patients underwent randomization: 503 patients were assigned to undergo TAVR, and 497 to undergo surgery. A component of the first primary end point occurred in 111 of 496 patients in the TAVR group and in 117 of 454 patients in the surgery group (Kaplan-Meier estimates, 22.8% in the TAVR group and 27.2% in the surgery group; difference, -4.3 percentage points; 95% confidence interval [CI], -9.9 to 1.3; P = 0.07). The win ratio for the second primary end point was 1.17 (95% CI, 0.90 to 1.51; P = 0.25). The Kaplan-Meier estimates for the components of the first primary end point were as follows: death, 10.0% in the TAVR group and 8.2% in the surgery group; stroke, 5.8% and 6.4%, respectively; and rehospitalization, 13.7% and 17.4%. The hemodynamic performance of the valve, assessed according to the mean (±SD) valve gradient, was 12.8±6.5 mm Hg in the TAVR group and 11.7±5.6 mm Hg in the surgery group. Bioprosthetic-valve failure occurred in 3.3% of the patients in the TAVR group and in 3.8% of those in the surgery group. CONCLUSIONS: Among low-risk patients with severe, symptomatic aortic stenosis who underwent TAVR or surgery, there was no significant between-group difference in the two primary composite outcomes. (Funded by Edwards Lifesciences; PARTNER 3 ClinicalTrials.gov number, NCT02675114.).

Visceral Adiposity Index as a Measure of Cardiovascular Disease in Persons With Human Immunodeficiency Virus.

Background: Persons with well-treated human immunodeficiency virus (HIV) demonstrate a 2-fold higher risk of cardiovascular disease (CVD), which may be related to excess visceral adipose tissue (VAT). The visceral adiposity index (VAI) is a score to approximate VAT by combining biochemical measures with anthropometrics without quantification by imaging. We evaluated VAI in association with cardiometabolic factors among persons with HIV (PWH). Methods: Forty-five PWH on antiretroviral therapy and virologically controlled with increased abdominal VAT (VAT area >110 cm2 on CT) and no known CVD were included. VAI was calculated using standard sex-specific formulas. Coronary plaque was assessed using coronary CT angiography. Results: Participants were predominantly male (73%), white (53%), and non-Hispanic (84%), with a mean age of 55 (standard deviation, 7) years. Among PWH, median VAI was calculated to be 4.9 (interquartile range [IQR], 2.8-7.3). Log VAI correlated with log VAT (r = 0.59, P < .0001) and anthropometric measures (body mass index: r = 0.36, P = .02; waist circumference: r = 0.43, P = .004; waist-to-hip ratio: r = 0.33, P = .03). Participants with coronary plaque had a higher VAI compared to those without coronary plaque (median, 5.3 [IQR, 3.4-10.5] vs 2.8 [IQR, 1.8-5.0]; P = .004). VAI (area under the curve = 0.760, P = .008) performed better than the atherosclerotic CVD risk score to predict the presence of plaque in receiver operating characteristic analyses. Conclusions: VAI may be a useful biomarker of metabolic dysfunction and increased CVD risk that may occur with VAT accumulation in PWH. Clinical Trials Registration: NCT02740179.