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Abstract Background There is growing evidence that low-density lipoprotein-triglyceride (LDL-TG) may be a better biomarker to define atherosclerotic cardiovascular disease (ASCVD) risk than LDL-cholesterol (LDL-C), which is currently used to stratify risk and as a treatment goal. Because LDL-TG typically requires additional advanced lipid testing, we developed an equation for estimating LDL-TG (eLDL-TG) from the results of the standard lipid panel. Methods Results from a general dyslipidemic population (N = 40 202), which were obtained with beta-quantification (BQ) reference method, were randomly divided into a training and validation datasets and used to develop the equation for estimating LDL-TG shown in Fig. 1A. Association of Sampson-NIH-LDL-C (NIH-LDL-C) and eLDL-TG with ASCVD risk markers was done in the National Heart and Nutrition Examination Survey (NHANES) (N = 37 053) and with ASCVD events in the Atherosclerosis Risk in Communities (ARIC) study (N = 14 749). Results The comparison between eLDL-TG and measured LDL-TG was only modest (R2 = 0.601, slope = 0.611), but eLDL-TG (Fig. 1B) showed better risk stratification than NIH-LDL-C (Fig. 1C) by survival curve analysis in ARIC. Moreover, receiver-operating characteristic (ROC) analysis showed that eLDL-TG was better than all other lipid-marker tests for ASCVD events (AUC: eLDL-TG = 0.633, HDL-C = 0.627, sdLDL-C = 0.621, remnant-cholesterol = 0.613, NonHDL-C = 0.613, TG = 0.603, apoB = 0.598, NIH-LDL-C = 0.590, TC = 0.568). In NHANES, eLDL-TG was more strongly associated with hypertriglyceridemia, obesity, diabetes, metabolic syndrome and increased high-sensitivity C-reactive protein than NIH-LDL-C. Inclusion of eLDL-TG in a Cox-Proportional Hazards Model along with other conventional risk factors (age, sex, race, diabetes, systolic blood pressure, smoking, HDL-C, and total cholesterol) did not further improve risk prediction. Conclusions Like LDL-C, LDL-TG can also be estimated from the results of the standard lipid panel. It is a better univariate risk marker than LDL-C and hence can be useful for initial ASCVD risk stratification.

ObjectiveTo develop evidence‐based consensus recommendations for the optimal timing of hip and knee arthroplasty to improve patient‐important outcomes including, but not limited to, pain, function, infection, hospitalization, and death at 1 year for patients with symptomatic and radiographic moderate‐to‐severe osteoarthritis or advanced symptomatic osteonecrosis with secondary arthritis of the hip or knee who have previously attempted nonoperative therapy, and for whom nonoperative therapy was ineffective, and who have chosen to undergo elective hip or knee arthroplasty (collectively referred to as TJA).MethodsWe developed 13 clinically relevant population, intervention, comparator, outcomes (PICO) questions. After a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to rate the quality of evidence (high, moderate, low, or very low), and evidence tables were created. A Voting Panel, including 13 physicians and patients, discussed the PICO questions until consensus was achieved on the direction (for/against) and strength (strong/conditional) of the recommendations.ResultsThe panel conditionally recommended against delaying TJA to pursue additional nonoperative treatment including physical therapy, nonsteroidal antiinflammatory drugs, ambulatory aids, and intraarticular injections. It conditionally recommended delaying TJA for nicotine reduction or cessation. The panel conditionally recommended delay for better glycemic control for patients who have diabetes mellitus, although no specific measure or level was identified. There was consensus that obesity by itself was not a reason for delay, but that weight loss should be strongly encouraged, and the increase in operative risk should be discussed. The panel conditionally recommended against delay in patients who have severe deformity or bone loss, or in patients who have a neuropathic joint. Evidence for all recommendations was graded as low or very low quality.ConclusionThis guideline provides evidence‐based recommendations regarding the optimal timing of TJA in patients who have symptomatic and radiographic moderate‐to‐severe osteoarthritis or advanced symptomatic osteonecrosis with secondary arthritis for whom nonoperative therapy was ineffective to improve patient‐important outcomes, including pain, function, infection, hospitalization, and death at 1 year. We acknowledge that the evidence is of low quality primarily due to indirectness and hope future research will allow for further refinement of the recommendations.

ObjectiveTo develop evidence‐based consensus recommendations for the optimal timing of hip and knee arthroplasty to improve patient‐important outcomes including, but not limited to, pain, function, infection, hospitalization, and death at 1 year for patients with symptomatic and radiographic moderate‐to‐severe osteoarthritis or advanced symptomatic osteonecrosis with secondary arthritis of the hip or knee who have previously attempted nonoperative therapy, and for whom nonoperative therapy was ineffective, and who have chosen to undergo elective hip or knee arthroplasty (collectively referred to as TJA).MethodsWe developed 13 clinically relevant population, intervention, comparator, outcomes (PICO) questions. After a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to rate the quality of evidence (high, moderate, low, or very low), and evidence tables were created. A Voting Panel, including 13 physicians and patients, discussed the PICO questions until consensus was achieved on the direction (for/against) and strength (strong/conditional) of the recommendations.ResultsThe panel conditionally recommended against delaying TJA to pursue additional nonoperative treatment including physical therapy, nonsteroidal antiinflammatory drugs, ambulatory aids, and intraarticular injections. It conditionally recommended delaying TJA for nicotine reduction or cessation. The panel conditionally recommended delay for better glycemic control for patients who have diabetes mellitus, although no specific measure or level was identified. There was consensus that obesity by itself was not a reason for delay, but that weight loss should be strongly encouraged, and the increase in operative risk should be discussed. The panel conditionally recommended against delay in patients who have severe deformity or bone loss, or in patients who have a neuropathic joint. Evidence for all recommendations was graded as low or very low quality.ConclusionThis guideline provides evidence‐based recommendations regarding the optimal timing of TJA in patients who have symptomatic and radiographic moderate‐to‐severe osteoarthritis or advanced symptomatic osteonecrosis with secondary arthritis for whom nonoperative therapy was ineffective to improve patient‐important outcomes, including pain, function, infection, hospitalization, and death at 1 year. We acknowledge that the evidence is of low quality primarily due to indirectness and hope future research will allow for further refinement of the recommendations.

Background and Aims: Normal alkaline phosphatase (ALP) levels in ursodeoxycholic acid (UDCA)-treated patients with primary biliary cholangitis (PBC) are associated with better long-term outcome. However, second-line therapies are currently recommended only when ALP levels remain above 1.5 times the upper limit of normal (×ULN) after 12-month UDCA. We assessed whether, in patients considered good responders to UDCA, normal ALP levels were associated with significant survival gains. Approach and Results: We performed a retrospective cohort study of 1047 patients with PBC who attained an adequate response to UDCA according to Paris-2 criteria. Time to liver-related complications, liver transplantation, or death was assessed using adjusted restricted mean survival time (RMST) analysis. The overall incidence rate of events was 17.0 (95% CI: 13.7–21.1) per 1000 out of 4763.2 patient-years. On the whole population, normal serum ALP values (but not normal gamma-glutamyl transpeptidase (GGT), alanine aminotransferase (ALT), or aspartate aminotransferase (AST); or total bilirubin < 0.6 ×ULN) were associated with a significant absolute complication-free survival gain at 10 years (mean 7.6 months, 95% CI: 2.7 - 12.6 mo.; p = 0.003). In subgroup analysis, this association was significant in patients with a liver stiffness measurement ≥ 10 kPa and/or age ≤ 62 years, with a 10-year absolute complication-free survival gain of 52.8 months (95% CI: 45.7–59.9, p < 0.001) when these 2 conditions were met. Conclusions: PBC patients with an adequate response to UDCA and persistent ALP elevation between 1.1 and 1.5 ×ULN, particularly those with advanced fibrosis and/or who are sufficiently young, remain at risk of poor outcome. Further therapeutic efforts should be considered for these patients.

Background: Arthrofibrosis (AF) after anterior cruciate ligament reconstruction (ACLR) remains a challenge. There is a paucity of data on arthroscopic interventions for AF after ACLR. Purpose: To (1) describe the patient, injury, and surgical characteristics and patient-reported outcomes (PROs) of those requiring an arthroscopic intervention for loss of motion after ACLR and (2) compare outcomes between patients undergoing an early intervention (within 3 months) versus those undergoing a late intervention (after 3 months). Study Design: Case series; Level of evidence, 4. Methods: Patients with a history of ACLR and a subsequent operative procedure for postoperative AF at a single institution between 2000 and 2018 were retrospectively identified. Arthroscopic interventions included lysis of adhesions, capsular release with or without manipulation under anesthesia, and excision of cyclops lesions. Patients were excluded if they had a knee dislocation or multiple-ligament injury, a periarticular fracture, or less than 2-year follow-up from the arthroscopic intervention. PROs including the Tegner activity score, visual analog scale pain score, and International Knee Documentation Committee score as well as knee range of motion (ROM) were recorded. Results: A total of 40 patients were included with a mean age of 27.2 years (range, 11.0-63.8 years) at surgery and a mean follow-up of 10.0 years (range, 2.9-20.7 years). The mean preoperative flexion and extension were 102° (range, 40°-150°) and 8° (range, 0°-25°), respectively. The mean postoperative flexion and extension were 131° (range, 110° to 150°) and 0° (range, –10° to 5°), respectively. After the arthroscopic intervention, the mean ROM improved from 94° (range, 40°-140°) preoperatively to 131° (range, 107°-152°) at final follow-up ( P < .001), and the visual analog scale pain score improved from 3.0 preoperatively to 1.2 postoperatively ( P = .001). Overall, 13 patients (32.5%) underwent an intervention within 3 months and 27 (67.5%) after 3 months. The early intervention group had a higher postoperative International Knee Documentation Committee score compared with the late intervention group (86.8 vs 71.7, respectively; P = .035). Conclusion: An arthroscopic intervention for AF after ACLR successfully improved knee ROM and pain. Patients who underwent either early or late surgery obtained satisfactory motion and function, although improved PROs were observed when the intervention occurred within 3 months of the primary procedure.

A large number of variants identified through clinical genetic testing in disease susceptibility genes are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion) can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analysis of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC) and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity—findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared with classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and preformatted Excel calculators for implementation of the method for rare variants in BRCA1, BRCA2, and other high-risk genes with known penetrance.

Abstract Background Subjective cognitive decline (SCD) has gained recent interest as a potential harbinger of neurodegenerative diseases such as Alzheimer’s disease (AD) and cerebrovascular disease (CVD). In addition, SCD can be related to depressive symptomatology. However, the association between AD and CVD biomarkers, depressive symptomatology, and SCD is still unclear. We investigated the association of AD and CVD biomarkers and depressive symptomatology with SCD in individuals with subjective memory complaints (SCD-memory group) and individuals with subjective concentration complaints (SCD-concentration group). Methods We recruited a population-based cohort of 217 individuals (all aged 70 years, 53% female participants, 119 SCD-memory individuals, 23 SCD-concentration individuals, and 89 controls). AD and CVD were assessed through cerebrospinal fluid levels of the Aβ42/40 ratio and phosphorylated tau, and white matter signal abnormalities on magnetic resonance imaging, respectively. Associations between biomarkers, depressive symptomatology, and SCD were tested via logistic regression and correlation analyses. Results We found a significant association between depressive symptomatology with SCD-memory and SCD-concentration. Depressive symptomatology was not associated with AD and CVD biomarkers. Both the phosphorylated tau biomarker and depressive symptomatology predicted SCD-memory, and the Aβ42/40 ratio and depressive symptomatology predicted SCD-concentration. Conclusions The role of depressive symptomatology in SCD may differ depending on the stage within the spectrum of preclinical AD (as determined by amyloid-beta and tau positivity), and does not seem to reflect AD pathology. Our findings contribute to the emerging field of subclinical depressive symptomatology in SCD and clarify the association of different types of subjective complaints with distinct syndromic and biomarker profiles.

Introduction The Florida-California Cancer Research, Education, and Engagement (CaRE 2 ) Health Equity Center is a triad partnership committed to increasing institutional capacity for cancer disparity research, the diversity of the cancer workforce, and community empowerment. This article provides an overview of the structure, process innovations, and initial outcomes from the first 4 years of the CaRE 2 triad partnership. Methods CaRE 2 serves diverse populations in Florida and California using a “molecule to the community and back” model. We prioritize research on the complex intersection of biological, environmental, and social determinants health, working together with scientific and health disparities communities, sharing expertise across institutions, bidirectional training, and community outreach. Partnership progress and outcomes were assessed using mixed methods and four Program Steering Committee meetings. Results Research capacity was increased through development of a Living Repository of 81 cancer model systems from minority patients for novel cancer drug development. CaRE 2 funded 15 scientific projects resulting in 38 publications. Workforce diversity entailed supporting 94 cancer trainees (92 URM) and 34 ESIs (32 URM) who coauthored 313 CaRE 2 -related publications and received 48 grants. Community empowerment was promoted via outreaching to more than 3000 individuals, training 145 community cancer advocates (including 28 Community Scientist Advocates), and publishing 10 community reports. CaRE 2 members and trainees together have published 639 articles, received 61 grants, and 57 awards. Conclusion The CaRE 2 partnership has achieved its initial aims. Infrastructure for translational cancer research was expanded at one partner institution, and cancer disparities research was expanded at the two cancer centers.