Citations

Abstract Background Coronary computed tomography angiography (cCTA) is a widely used noninvasive diagnostic exam to assess patients for coronary artery disease (CAD). However, the spatial resolution of most CT scanners is limited due to the use of energy‐integrating detectors (EIDs). Purpose To develop a convolutional neural network ( I mproved LUMEN visualization through A rtificial super‐resolu T ion imag E s (ILUMENATE)) informed by photon‐counting‐detector (PCD)‐CT to improve EID‐CT image resolution and determine its impact on cCTA. Materials and methods With IRB approval, 30 patients undergoing clinically indicated cCTA were scanned with EID‐CT (SOMATOM Force, Siemens Healthineers, Forchheim, Germany) and subsequently with ultra‐high‐resolution (UHR) PCD‐CT (NAEOTOM Alpha, Siemens Healthineers) on the same day. ILUMENATE was trained on eight patient PCD‐CT datasets (67,890 patch pairs with 90% for training (61,101), 10% reserved for validation (6,789)) and applied to 22 unseen EID‐CT cases. Spatial resolution was evaluated using line profiles and percent diameter stenosis quantified with a severity score assigned. Two experienced radiologists, blinded to image type, selected preferred series and scored images for overall quality, sharpness, and noise comparing original EID‐CT and ILUMENATE output. Results Visual assessment and line profiles showed substantial resolution improvement with ILUMENATE. Percent diameter stenosis was significantly reduced (mean ± standard deviation: 4.42% ± 4.82%) using ILUMENATE ( p < 0.001) with nine lesions shifting down in severity score. Readers preferred ILUMENATE images in 22/22 cases and scored ILUMENATE superiorly for overall quality, sharpness, and noise ( p < 0.05). Conclusions ILUMENATE enhanced image resolution, resulting in improved overall image quality, reduced calcium blooming artifacts, and improved lumen visibility in cCTA exams performed using EID‐CT. This could potentially allow for improved accessibility to UHR image quality, allowing for more accurate assessment of CAD.

OBJECTIVE Despite the use of multiple glucose-lowering medications, glycemic targets are not met in a significant fraction of people with type 2 diabetes. In this prospective, observational study we assessed the prevalence of hypercortisolism, a potential contributing factor to inadequate glucose control. RESEARCH DESIGN AND METHODS Individuals with type 2 diabetes and HbA1c 7.5%–11.5% (58–102 mmol/mol) on two or more glucose-lowering medications with or without micro-/macrovascular complications or taking multiple blood pressure–lowering medications were screened with a 1-mg dexamethasone suppression test. Common causes of false-positive DSTs were excluded. The primary end point was the prevalence of hypercortisolism, defined as post-DST cortisol &gt;1.8 μg/dL (50 nmol/L). Characteristics associated with hypercortisolism were assessed with multiple logistic regression. The percentage and characteristics of participants with hypercortisolism and adrenal imaging abnormalities were also assessed. RESULTS Post-DST cortisol was unsuppressed in 252 of 1,057 participants (prevalence 23.8%; 95% CI 21.3, 26.5). Hypercortisolism prevalence was 33.3% among participants with cardiac disorders and 36.6% among those taking three or more blood pressure–lowering medications. Adrenal imaging abnormalities were reported in 34.7% of participants with hypercortisolism. Use of sodium–glucose cotransporter 2 inhibitors (odds ratio 1.558), maximum-dose glucagon-like peptide 1 receptor agonists (1.544), tirzepatide (1.981), or a higher number of blood pressure–lowering medications (1.390); older age (1.316); BMI &lt;30 kg/m2 (1.639); non-Latino/Hispanic ethnicity (3.718); and use of fibrates (2.676) or analgesics (1.457) were associated with higher prevalence (all P &lt; 0.03). CONCLUSIONS Hypercortisolism was associated with hyperglycemia in approximately one-quarter of individuals with inadequately controlled type 2 diabetes despite multiple medications.

ABSTRACT The Team Physician Consensus Statement delineates qualifications, duties, and responsibilities of the team physician and provides guidelines to individuals and organizations in selecting team physicians. These delineations and guidelines provide a foundation for best practices in the medical care of athletes and teams. The team physician’s education, training, and experience uniquely qualify them to provide the best medical care for the athlete. This document is not intended as a standard of care and should not be interpreted as such. It is only a guide and, as such, is of a general nature, consistent with the reasonable, objective practice of the healthcare profession. Adequate insurance should be in place to help protect the physician, the athlete, and the sponsoring organization. This document was originally developed as the first in the team physician consensus series, representing an ongoing project-based alliance of the major professional associations concerned about clinical sports medicine issues. The organizations are as follows: American Academy of Family Physicians, American Academy of Orthopedic Surgeons, American College of Sports Medicine, American Medical Society for Sports Medicine, American Orthopedic Society for Sports Medicine, and the American Osteopathic Academy of Sports Medicine.

Abstract Aims Catheter ablation is commonly performed in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) for management of ventricular arrhythmias (VAs). The impact of catheter ablation on cardiac function is unknown. The aim is to assess the impact of catheter ablation for VAs on cardiac function in patients with ARVC. Methods and results This retrospective study included consecutive patients with ARVC who underwent catheter ablation for VAs. Cardiac and valvular functions were assessed on pre- and post-procedure cardiac imaging. The severities of tricuspid regurgitation, pulmonic regurgitation, right ventricular (RV) enlargement, and RV systolic dysfunction was graded as absent (=0), mild (=1), mild-moderate (=2), moderate (=3), moderate-severe (=4), or severe (=5). Thirty-four patients were included. Median age at the time of ablation was 49 [inter-quartile range (IQR), 23] years, and 10 (29%) patients were female. After a median follow-up of 1 (IQR, 0) day, 11 (34%) patients had worsening RV function, and 4 (12%) patients had worsening left ventricular ejection fraction (LVEF) &gt;5%. Five (15%) patients required inotropic support. After a median follow-up of 6.5 (IQR, 6.4) months, 20 (59%) patients had repeat transthoracic echocardiograms. Among patients with worsening RV function post-ablation, one-sixth (17%) had improvement in the RV function at follow-up. In contrast, among patients who had an acute drop in LVEF post-ablation, two-thirds (67%) had improvement at follow-up. Conclusion Right ventricular dysfunction following catheter ablation in patients with ARVC is common, affecting one-third of patients. Patients undergoing catheter ablation of VAs should be counselled on the potential negative impact of ablation on cardiac function.

PURPOSE To reduce costs in genomic studies of time-to-event phenotypes like survival, researchers often sequence a subset of samples from a larger cohort. This process usually involves two phases: first, collecting inexpensive variables from all samples, and second, selecting a subset for expensive measurements, for example, sequencing-based biomarkers. Common two-phase designs include nested case-control and case-cohort designs. Additional designs include sampling subjects based on follow-up time, like extreme case-control designs. Recently an optimal two-phase design using a maximum likelihood-based method was proposed, which could accommodate arbitrary sample selection in the second phase. However, direct comparisons of this optimal design with others in terms of power and computational cost is lacking. METHODS This study performs a direct evaluation of typical two-phase designs, including Tao's optimal design, on type I error, power, effect size estimation, and computational time, using both simulated and real data sets. RESULTS Results show that the optimal design had the highest power and accurate effect size estimation under the Cox regression model. Surprisingly, logistic regression achieved similar power with much lower computational cost than a more sophisticated method. The study further applied these methods to the MP2PRT study, reporting hazard ratios of cancer subtypes on relapse risk. CONCLUSION Recommendations for selecting two-phase designs and analysis methods are regarding power, bias of estimated effect size, and computational time.

PURPOSE The combination of the Bruton tyrosine kinase inhibitor ibrutinib with bendamustine-rituximab for first-line treatment of mantle cell lymphoma (MCL) prolonged progression-free survival (PFS), but without improvement in overall survival (OS), likely because of toxicity. Acalabrutinib was shown to be efficacious and less toxic than ibrutinib in a head-to-head trial in chronic lymphocytic leukemia and therefore might lead to better outcomes in MCL. METHODS Patients 65 years and older with previously untreated MCL received acalabrutinib (100 mg twice daily) or placebo (until disease progression or unacceptable toxicity), plus six cycles of bendamustine (90 mg/m 2 once daily; days 1 and 2) and rituximab (375 mg/m 2 as a single dose; day 1) followed by rituximab maintenance in responding patients for 2 years. Crossover to acalabrutinib at disease progression was permitted. The primary end point was PFS per the independent review committee; overall response rate and OS were secondary end points. RESULTS In total, 598 patients were randomly assigned, with 299 in each arm. At a median follow-up of 49.8 months using the reverse Kaplan-Meier method, the median PFS was 66.4 months in the acalabrutinib arm and 49.6 months in the placebo arm (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.94]; P = .0160). Benefit was seen across all subgroups, including those with high-risk features. Overall response/complete response rates were 91.0%/66.6% and 88.0%/53.5% in the acalabrutinib and placebo arms, respectively. OS was not significantly different (HR, 0.86 [95% CI, 0.65 to 1.13]; P = .27). Grade 3 or greater adverse events were reported in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively. CONCLUSION The combination of acalabrutinib with bendamustine-rituximab significantly improved PFS. Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity.

Abstract An individual participant data (IPD) meta-analysis can assess the predictive value of data on outcomes at the individual level, offering a potential tool for developing personalized pain management. Pretreatment quantitative sensory testing (QST) may stratify patient groups, which are then linked to treatment outcomes. Our objective was to determine if measures of QST at baseline are related to treatment outcomes (at any time point) for pain and disability in lower-limb osteoarthritis. We performed a systematic review with an IPD meta-analysis. Searches were conducted in 9 databases until May 5, 2023 for intervention studies that measured baseline QST and longitudinal measures of participant-reported pain and disability. We performed a 2-stage approach to analyse longitudinal data. Individual models were fitted to each study and combined using random effects multivariate meta-analytic models. Study quality was assessed using the Joanna Briggs Institute checklist, and certainty of the evidence was assessed using GRADE. We identified 3082 records and included 1 hip and 28 knee datasets consisting of 2522 participants from 40 studies. Local warm detection thresholds (P = 0.024) predicted knee osteoarthritis pain outcomes (very-low certainty). Local warm detection thresholds (P = 0.030), remote cold detection thresholds (P = 0.05), and remote pressure tolerance thresholds (P = 0.007) predicted knee osteoarthritis disability outcomes (very-low certainty). Other QST variables were associated with hip and knee osteoarthritis pain and disability levels (eg, pressure pain thresholds), but this relationship did not change over time. This review finds that mechanism-based, QST methodologies do not consistently predict pain or disability on an individual level in hip or knee osteoarthritis.

Abstract J.A. McNeil: None. J. Herndon: None. A.Y. Chang: None. C.J. Davidge-Pitts: None. O. Hamidi: None. Background: Testosterone therapy (TT) in individuals assigned female at birth (AFAB) is linked to an atherogenic lipid profile, including lower HDL cholesterol, elevated triglycerides, and LDL cholesterol. Polycystic ovary syndrome (PCOS), characterized by androgen excess, affects 16-20% of cisgender individuals AFAB. Recent data suggests a greater PCOS prevalence in transmasculine transgender/gender diverse (TGD) individuals at 23.8% to 38.8%. Whether TT in AFAB individuals with history of PCOS triggers more adverse metabolic changes than in TGD individuals without PCOS remains uncertain. While cohort studies haven't indicated increased cardiovascular (CV) risk with TT, it's unclear if specific subgroups, such as those with PCOS, develop more CV risk factors. Objective: To compare the effects of TT on CV risk factors in TGD individuals with a history of PCOS vs. TGD without PCOS. Methods: We retrospectively reviewed 454 records in a multispecialty TGD clinic to identify 62 with PCOS, and 132 controls without PCOS (1:2 case-control ratio) matched on age. Data included longitudinal vital signs, metabolic profiles, and details on psychiatric and medical conditions. PCOS diagnosis was validated using Rotterdam criteria. Exclusions comprised individuals under 14, those on puberty-suppressing gonadotropin-releasing hormone analogues, or already undergoing TT at the initial visit. Results: Among 454 subjects, 62 (13.7%) were diagnosed with PCOS. At baseline, PCOS was associated with significantly higher BMI (p &lt; 0.01), SBP (p = 0.01), prevalence of obesity (p &lt; 0.01), obstructive sleep apnea (OSA, p &lt; 0.01), and type 2 diabetes mellitus (p = 0.01). History of PCOS was associated with greater metformin use (p &lt; 0.001), CV disease history (p = 0.003), and transaminitis (p = 0.03). After weight adjustment, only baseline metformin use differed significantly between PCOS and controls. 140 (72.2%) received TT, 50 (80.6%) with PCOS and 90 (68.2%) controls. After weight adjustment, notable baseline changes in ALT (p = 0.006), HDL (p &lt; 0.001), LDL (p &lt; 0.001), hypertension, and hypertriglyceridemia prevalence (p=0.001) were observed in the full cohort on TT. Compared to controls, PCOS patients on TT exhibited higher hypercholesterolemia prevalence (p = 0.03) and elevated bioavailable testosterone (p = 0.04) after weight correction. Conclusions: TGD Individuals with PCOS had significantly worse CV risk profile compared to controls before starting TT attributed to greater weight. Significant changes in ALT, LDL, HDL, and prevalence of hypertriglyceridemia were seen across the entire TGD cohort treated with TT, but only hypercholesterolemia prevalence remained significantly higher in TGD PCOS cases on TT when corrected for weight. PCOS history was not associated with greater changes in CV risk factors in TGD individuals starting TT. Sunday, June 2, 2024

Abstract Tumor cells develop various strategies to evade immune surveillance, one of which involves altering the metabolic state of the tumor microenvironment. In response to metabolic stress in the tumor microenvironment, several tumor-infiltrating immune subsets upregulate CD36 to take up lipids. This leads to impaired antitumor immunity, as intratumoral regulatory T cells exhibit increased survival and suppressive activity, whereas CD8+ T cells become more susceptible to ferroptosis and exhaustion. In this study, we develop a humanized anti-CD36 IgG4 antibody, PLT012, against the lipid-binding domain of CD36 with excellent safety and favorable pharmacokinetic features in mice and cynomolgus monkeys. PLT012 alone or in combination with PD-L1 blockade or standard-of-care immunotherapy results in robust antitumor immunity in both immunotherapy-sensitive and -resistant hepatocellular carcinomas (HCC). Notably, PLT012 also reprograms the immune landscape of human HCC ex vivo. Our findings provide proof-of-concept evidence that PLT012 reprograms antitumor immunity in HCC, positioning it as a first-in-class immunotherapy targeting CD36. Significance: Despite the success of cancer immunotherapies, like immune checkpoint inhibitors, many patients still fail to demonstrate significant responses because of metabolic constraints in tumors. PLT012 rejuvenates antitumor immunity by targeting metabolic pathways to reprogram the immune landscape of liver cancer and liver metastasis, with potential to influence future HCC immunotherapy.

Abstract Background Instruments to assess patient-reported outcomes (PRO) should generate high-quality evidence. Reliable PRO evidence is essential to policymakers, in conjunction with outcomes such as survival and radiological response, to understand the net clinical benefit of antitumor treatments. This study aimed to establish the content validity of 215 identified PRO measures used in patients with brain tumors. Methods A survey (n = 148 items) was developed reflecting aspects of the WHO International Classification of Functioning, Disability, and Health (ICF) framework. Patients with brain tumors, their proxies, and healthcare professionals (HCPs) were asked to rate each survey item on relevance. An item was considered a relevant issue if ≥25% of the patients or proxies or ≥50% of the HCPs considered that item to be an issue. Next, all items in the identified PRO measures were linked to ICF and relevant items in the survey, and the percentage of content coverage was calculated. Results In total, 114 patients, 71 proxies, and 65 HCPs from different countries completed the survey. Fifty-six of 148 (37.8%) items in the survey were considered relevant. The most important aspects mentioned by both patients and proxies were difficulty concentrating, difficulty remembering, multitasking, and handling stress. Depending on the definition, between 35% and 49% of PRO measures were considered to have sufficient content validity (≥80% coverage). Conclusion The content validity was insufficient in more than half of the identified PRO measures, particularly multidimensional measures. Future research should investigate whether different approaches to PRO assessment better meet the needs of all stakeholders.