BackgroundDespite guidelines for statin use to reduce atherosclerotic cardiovascular disease (ASCVD) from the American College of Cardiology and American Heart Association (ACC/AHA) and quality measures from the Centers for Medicare and Medicaid Services (CMS), inconsistencies in guideline adherence persist. While there are studies examining associations of individual factors with statin prescriptions, there is a paucity of literature considering multiple factors.MethodsWe conducted a cross-sectional, retrospective review of 20,923 medical charts of patients diagnosed with ASCVD, low-density lipoprotein cholesterol (LDL-c) ≥ 190 mg/dL, or ASCVD risk ≥ 20%, aged 40 to 75 years old. Statin prescribing rates were as follows: high-intensity statins (33.7%), low- or medium-intensity statins (33.5%), and no statin (32.8%).ResultsSex significantly affected high-intensity statin prescribing, as 35.2% of men and 30.3% of women received a high-intensity statin (p < 0.0001). Race significantly affected any statin prescribing as 67.4% of White patients, 59.0% of Black patients, and 64.1% of American Indian/Alaska Native patients received any statin prescription (p = 0.0074). The mean age for patients prescribed a high-intensity statin was also significantly lower (64.8 years) than those not (66.6 years) (p < 0.001). Increased number of appointments was statistically significant for increased use of high-intensity statins (p = 0.0001) and any statin (p = 0.0001). Female primary care providers (PCPs) had a prescribing rate of 71.0% while male PCPs had a rate of 68.5% for any statin (p = 0.0005).ConclusionsWe found that adherence to ACC/AHA and CMSguidelines remains incomplete and highlights several factors contributing to lower likelihood of statin prescription including patient and PCP demographics.

Abstract The Women Informed to Screen Depending on Measures of risk (WISDOM) Study (NCT02620852) is pragmatic randomized controlled trial evaluating risk assessment to inform the age to start, frequency and modality of breast cancer screening and risk reduction. The WISDOM Study uses a preference-tolerant design, enabling women who decline randomization to self-select their screening arm. The risk-based arm included comprehensive breast cancer risk assessment using the Breast Cancer Surveillance Consortium (BCSC) model and genetics. From August 2016 – February 2023, WISDOM enrolled a large, diverse, nationwide cohort of 46,289 participants − 77% non-Hispanic (NH) White, 9% Hispanic, 6% (NH) Black, and 5% (NH) Asian; demographic diversity increased over time. Mean age at baseline was 54 years. 28,335 (61.2%) were randomized, while 89% of those who self-selected their screening arm chose risk-based screening. The preference-tolerant design captured real-world screening preferences while maintaining scientific rigor and demonstrated strong preference for risk-based screening.

Abstract Background Illicit fentanyl use is endemic in the United States, yet availability of commercial FDA-approved assays is limited and typically relegated to automated chemistry platforms. Until recently, there were no FDA-approved point of care tests (POCT), despite the extremely common practice of POCT-based drug screening. The Abbott iCassette Fentanyl Urine Drug Screen assay is FDA-approved, CLIA-waived, for the detection of fentanyl in human urine (limit of detection: 1.0 ng/mL); the assay is reported to not detect fentanyl metabolites such as norfentanyl. Unfortunately, a commercial quality control (QC) product is not provided nor recommendations for one given, rather the manufacturer recommends the end user produce their own QC material using certified reference material. As manufacturing one’s own QC material in a setting that requires POCT assays is not generally feasible nor advisable, here we identified an appropriate commercial QC product and subsequently evaluated the assay manufacturer’s sensitivity claims. Methods Thermo Scientific DRI Fentanyl II High and Low Control Set, UTAK Fentanyl Analogs and UTAK Certified Drug Free Urine commercial QC products were evaluated for their ability to reliably produce a positive test result. Cerilliant fentanyl analytical reference standard material (F-013) was spiked into certified drug free urine at various concentrations to investigate the detection limits of the assay. Spiked concentrations were verified by mass spectrometry (LC-MS/MS). Further, the assay sensitivity was challenged with authentic fentanyl-positive urine specimens with known concentrations, as determined by LC-MS/MS. Results The DRI Fentanyl II High Control Set QC material with a claimed fentanyl concentration of 1.5 ng/mL failed to produce a clear positive (test line still visible, interpreted as negative) when dosing 100 µL and 200 µL on the cassette. UTAK Fentanyl Analogues QC material, with a fentanyl concentration of 3.5 ng/mL, reliably produced clear positive results (complete absence of test line). Cerilliant fentanyl standard spiked into drug free urine at 4.5 ng/mL produced a clear positive result while a faint test line was still visible (negative interpretation) at 0.6 ng/mL. Authentic patient urines with known fentanyl concentrations, as determined by LC-MS/MS, were unequivocally positive at fentanyl concentrations of 0.86 ng/mL and greater. An authentic specimen containing 0.05 ng/mL fentanyl produced a very faint test line (negative interpretation). Conclusion The iCassette Fentanyl assay may not produce reliable positive results when using QC material with fentanyl concentrations close to the claimed detection limit of 1.0 ng/mL. However, we found the assay’s sensitivity to be greater in authentic patient specimens versus QC material. This suggests either the assay sensitivity is variable across matrices (i.e. less sensitive in an artificial QC matrix) or the assay detects at least some fentanyl metabolites in addition to fentanyl. Ultimately we concluded that the assay was adequate for clinical use and we implemented with the UTAK material as the positive control.

Abstract Background Regulatory requirements by College of American Pathologists (CAP) require a semi-annual analytical measurement range (AMR) verification for analytes with less than 3-point calibrations. Proximity limits define the closeness of standards/linearity material to the lower limit of quantitation (LLoQ) and upper limit of quantitation (ULoQ) for a given analyte. These limits may be expressed in concentration units or percentages. Clinical Laboratory Standards Institute (CLSI) EP06-ED2 suggests method-specific proximity limits based on the analytical imprecision at the LLoQ and ULoQ. CAP recommends 10-15% at ULoQ and “reasonably close” to the LLoQ. Clearly, this requirement is subject to the Medical Director*s discretion. The aim of this study is to establish and standardize proximity limits based on workgroup consensus at a large rural health network. Methods A workgroup was formed to standardize the semi-annual AMR verification practices with key representatives from over 40 laboratories. Majority of the health system utilizes Abbott Alinity or Architect instruments for chemistry and immunoassay tests. Linearity material from third-party vendors like Maine Standards or AUDIT is used to assess the acceptability of established proximity limits. Analytical imprecision of the low level quality control material is taken into consideration for establishing low proximity limits. Results Proximity limits were established for 115 analytes spanning key testing areas such as chemistry, endocrinology, immunology, tumor markers and toxicology. Multiples of LLoQ or analytical imprecision at the lower end and 20% of the ULoQ at the upper end was reviewed for acceptability using linearity material. An exemplary proximity limit criteria for comprehensive metabolic panel is shown in Table 1. Importantly, these consensus based proximity limits considered crucial factors like analytical imprecision, clinical impact of error and the availability of test material near the limits. In addition to total allowable error, proximity limits could be utilized as acceptance criteria in the EP evaluator linearity and calibration verification module for semi-annual AMR verification studies. Conclusion Defining proximity limits in semi-annual AMR studies are crucial for evaluating the accuracy of quantitative measurement procedure and for regulatory compliance. Due to practical challenges, current regulations do not provide a formulary of proximity limits. Here we provide recommendations for method-specific proximity limits.

Background: Age-related knee osteoarthritis (KOA) is a debilitating and progressive whole-joint disease. Despite the increased use of cell-based therapies in clinical practice to alleviate KOA symptoms, there lacks robust evidence to guide their clinical utility. We recently reported the results of our randomized controlled trial comparing corticosteroid injections (CSI) to cell-based therapies of bone marrow aspirate concentrate (BMAC), stromal vascular fraction (SVF), and allogenic umbilical cord tissue in 480 patients with Kellgren-Lawrence grade 2 to 4 KOA, finding improvements in all groups at 1 year with no statistically significant differences between groups. Here, we further examine these data from our clinical trial using a responder/nonresponder approach. Hypothesis: Patients receiving a single injection of a cell-based therapy are more likely to be classified as responders than those receiving a CSI based on pain outcomes at 12 months. Study Design: Randomized controlled trial; Level of evidence, 2. Methods: We performed an analysis of 381 patients who completed 12 months’ follow-up. Responders were defined as patients with a ≥25% improvement in pain scores on the visual analog scale (VAS) or Knee Injury and Osteoarthritis Outcome Score (KOOS). Results: Our hypothesis was conditionally confirmed, with BMAC having a higher response rate than a CSI. The overall responder rate across all treatment methods at 12 months was 58.5% for the VAS and 44.9% for the KOOS. The adjusted odds ratio (aOR) of responder status according to the VAS for BMAC relative to CSI was 2.02 (95% CI, 1.09-3.76). Subgroup analyses identified the heterogeneity of treatment by sex. Male patients had higher odds of a positive response to cellular injections according to the VAS (aOR, 5.18 [95% CI, 1.93-13.85] for BMAC; aOR, 3.34 [95% CI, 1.23-9.06] for SVF; aOR, 2.85 [95% CI, 1.09-7.39] for umbilical cord tissue) relative to CSI. A higher proportion of female than male patients responded to CSI. Of the evaluated therapies, BMAC had the highest percentage of responders. Male patients, particularly those aged <60 years, responded more favorably to BMAC and SVF over other therapies. Conclusion: In addition to comparing the mean outcomes of treatment groups to one another, comparing the proportion of patients in treatment groups who reach a specific improvement threshold, that is, “responders,” can provide additional insight into which cellular therapies are most beneficial. The current results indicate that we can improve outcomes and guide the robust design of future clinical trials by identifying patient populations that are most likely to respond favorably to cellular and noncellular injections. This is a first step in personalized (precision-based) medicine for KOA. Registration: NCT03818737 (ClinicalTrials.gov)

Extremely preterm infants are at high risk for bronchopulmonary dysplasia (BPD) and death. Multiple small randomized clinical trials showed that a combination of budesonide with surfactant compared with surfactant alone reduced BPD or death. To determine if early intratracheal administration of a combination of budesonide (0.25 mg/kg) mixed with surfactant, compared with surfactant alone, reduces physiologic BPD or death by 36 weeks' postmenstrual age in extremely preterm infants. This double-masked randomized clinical trial was conducted from April 2021 to June 2024 in the 17 centers of the United States Neonatal Research Network. Infants 22 to 28 weeks' gestation or 401 to 1000 g birth weight were enrolled after clinical decision to give surfactant, with the first dose of surfactant being study drug (prior surfactant was an exclusion criterion). Infants were randomly allocated 1:1 to receive 1 to 2 doses of budesonide + surfactant (poractant alfa) or surfactant alone via endotracheal tube within 50 hours of birth. The primary outcome was physiologic BPD or death by 36 weeks' postmenstrual age. There were 5 prespecified secondary outcomes and multiple prespecified exploratory and safety outcomes. The trial was stopped with 641 infants enrolled (55.3% of 1160 planned; mean birth weight, 810 g [SD, 256 g]; gestational age, 25.9 weeks [SD, 1.9 weeks]), because interim analysis at 50% enrollment reached the prespecified futility threshold. The incidence of BPD or death was 68.5% in the budesonide + surfactant group and 67.9% in the surfactant-alone group (adjusted relative risk [RR], 1.00 [95% CI, 0.90-1.11]). No differences were noted in mortality (15.3% vs 13.2%; adjusted RR, 1.13 [95% CI, 0.78-1.64]) or BPD among survivors to 36 weeks' postmenstrual age (62.9% vs 63.0%; adjusted RR, 0.99 [95% CI, 0.87-1.12]). More infants who received budesonide + surfactant compared with surfactant alone had hyperglycemia (66.7% vs 49.8%; adjusted RR, 1.33 [95% CI, 1.17-1.51]). In this large multicenter trial, the combination of budesonide with surfactant did not reduce the risk of BPD or death at 36 weeks' postmenstrual age in extremely preterm infants. ClinicalTrials.gov Identifier: NCT04545866.

Cardiac rhabdomyomas are the most common pediatric cardiac tumors and are frequently associated with tuberous sclerosis complex (TSC). Large fetal cardiac rhabdomyomas causing inflow or outflow obstruction can lead to hemodynamic compromise and arrhythmias, sometimes necessitating emergent perinatal interventions. We present the fetus of a 32-year-old with multiple intracardiac rhabdomyomas identified at 23weeks gestation. The largest, located in the left atrium (LA), enlarged by 32weeks, causing mitral inflow obstruction and moderate mitral regurgitation (MR). Maternal sirolimus therapy was initiated, leading to tumor regression and permitting delivery at 39weeks without the need for fetal or neonatal surgery. Postnatally, the infant developed hemodynamically significant refractory arrhythmias, requiring antiarrhythmics and inotropic support. Continued sirolimus therapy further reduced tumor burden and improved MR. This case adds to the growing evidence supporting transplacental sirolimus therapy (mTOR inhibition) for managing large, hemodynamically significant fetal cardiac rhabdomyomas. It also underscores the importance of anticipating and aggressively managing associated arrhythmias.