Citations

Abstract Background Laboratory results are critical in outpatient oncology, often used as a prerequisite to initiating chemotherapy; therefore, result turnaround time (TAT) is a key satisfaction metric. Slow or incomplete clot formation in serum separator tubes (SST™) contributes to delays in resulting core chemistry testing, including the Comprehensive Metabolic Panel (CMP). Although malignancy is often associated with hypercoagulability, many oncology patients also exhibit thrombocytopenia and hypofibrinogenemia; impairing clot formation and prolonging the customary 30-minute (SST™) clot time. Slow or incomplete clot formation can lead to additional manual and time-consuming workflows including managing instrument clot errors, manual aliquoting and centrifugation, validated pretreatment promoting fibrin formation with reptilase, and ultimately testing and reporting delays. Rapid serum tubes (RST™) advertise reduced clot time from 30 to approximately 5 minutes. The study aimed to evaluated transition from SST™ to RST™ in outpatient oncology clinics by evaluating the instrument-detected clot rate, reptilase rate, hemolysis rate, and TAT for CMP testing. Methods A pilot study was conducted at two Mayo Clinic Rochester, MN outpatient oncology collection sites. CMP specimens were collected in RST™ in place of SST™ (both Becton, Dickinson and Company, Franklin Lakes, NJ). Instrument flags due to clot-related errors were identified using middleware (Data Innovations, Colchester, VT). Clot rate was calculated as number of oncology CMP orders held with clot error divided by the total number of oncology CMP orders collected during the defined period. Pre-pilot clot data were collected 7/28/2025–8/1/2025 (n=419); pilot data 12/15/2025–12/19/2025 (n=410). Reptilase rate was calculated as number of oncology CMP orders with LIS reptilase comment divided by number of oncology CMP orders. Hemolysis rate was extracted from middleware (Roche Diagnostics, Indianapolis, IN) for 08/2025 (pre-pilot, n=1,598) and 12/2025 (pilot,709). Hemolysis rate was defined as number of samples with H-index =50 divided by total specimens with CMP orders. TAT metrics (mean, SD, and percentage meeting =120-minute goal) were collected 8/1/2025–8/31/2025 (pre-pilot, n=22,806) and 11/17/2025–12/31/2025 (pilot, n=432). Results During the pilot period, 432 collections with standalone orders for CMP were collected in RST™. The pre-pilot clot rate was 9.3% decreasing to 0.2% during pilot using RST. Reptilase use decreased from 1.2% to 0%. Hemolysis rate decreased from 2.1% to 0.2%. Mean TAT decreased from 78.8 to 69.0 minutes, with SD decreasing from 36.1 to 25.3 minutes. Compliance with the =120-minute TAT goal increased from 88% to 96%. Conclusion Impaired clot formation in SST™ exists as a pre-analytical obstacle to timely chemotherapy. RST™ substantially/consistently reduced clot-related instrument errors, eliminated reptilase use, decreased the hemolysis rate, and improved TAT performance. This targeted modification of collection tube selection represents a scalable, systems-level intervention that enhances pre-analytical quality without requiring additional instrumentation or staffing.

Abstract Background Severe deficiency of ADAMTS13 (A Disintegrin and Metalloproteinase with Thrombospondin motif type 1 member 13) enzyme activity can lead to thrombotic thrombocytopenic purpura, a life-threatening disorder. Prompt diagnosis and initiation of plasma exchange is necessitated upon clinical presentation. ADAMTS13 activity measurement relies on detecting the cleavage of von Willebrand Factor (VWF) at the A2 domain by the enzyme in test plasma. Most clinical tests use a 73-amino acid peptide segment of VWF (VWF73) as substrate and are fluorescence-based. However, their results sometimes do not concur with the clinical presentation. Here, we developed a highly sensitive, rapid, and reliable mass spectrometry-based assay to measure ADAMTS13 activity in plasma using matrix-assisted laser desorption/ionization (MALDI) mass spectrometry. Methods Test plasma, calibrators, or controls were incubated with VWF73 substrate for 30 min in Bis-Tris buffer, together with a stable-isotope labeled decapeptide as internal standard. Calibrators, along with controls, were prepared from a commercial pooled normal human plasma and standardized against the WHO International Standard ADAMTS13 Plasma 12/252 and were used to construct an eight-point calibration curve. SPE clean-up of reaction mixture was achieved under a positive nitrogen pressure of about 5 mmHg using Strata-X 33 µm polymeric reversed phase, 10 mg sorbent per well. The eluate was spotted onto the target plate, topped by a layer of the matrix a-cyano-4-hydroxycinnamic acid. Spectral data was acquired in positive ionization mode on a rapifleX MALDI Tissuetyper (Bruker). For quantification, intensity of target decapeptide was normalized by intensity of internal standard. The method was evaluated using 191 plasma samples, including 121 patient samples, along with a World Health Organization (WHO) international standard. Results Target decapeptide was generated upon incubation of VWF73 with plasma, which was measured by MALDI mass spectrometry, along with the internal standard. Total assay time was nearly one hour, with an assay range of 2–109 IU/dL. Intra-assay coefficient of variation (CV) was <2% and inter-assay CV was <6%. The throughput matched the current fluorescence resonance energy transfer (FRET) assay workflow. Based on the 10 IU/dL threshold for TTP, the results showed high agreement (Kappa coefficient, 0.89) with clinical testing using FRETS-VWF73 assay. Conclusion Our MALDI-MS assay combines rapid and minimal sample preparation with high sensitivity and reproducibility that has potential to improve patient care.

Abstract Context Menstrual irregularities have been associated with cardiovascular disease (CVD) risk, but underlying etiologies may confer distinct risk profiles. Functional hypothalamic amenorrhea (FHA) has not been evaluated as a separate risk phenotype. Objective To assess the association between FHA phenotype and incident CVD and cardiometabolic risk factors. Design Prospective cohort study with biennial follow-up from 1993 to 2019. Setting Nurses’ Health Study II cohort. Participants The sample included 52,655 premenopausal women free of CVD in 1993. FHA phenotype was defined as irregular or absent cycles without PCOS traits combined with low body mass index and/or high physical activity. Intervention None Main Outcome Measures Incident CVD (coronary heart disease [CHD; myocardial infarction or coronary revascularization] and stroke) and incident elevated cholesterol, hypertension, and type 2 diabetes (T2DM). Results During up to 26 years of follow-up, 1,007 CVD events occurred. Among women who developed CVD, the median time to the first CVD event was 17.0 years (IQR, 11.3-21.0). FHA phenotype in mid-adulthood was associated with a 62% higher risk of CVD (95% confidence interval [CI]: 1.01–2.59), driven by an almost two-fold higher risk of CHD (hazard ratio [HR] = 1.91; 95% CI: 1.11–3.27), compared with women with regular cycles. FHA was also associated with T2DM (HR = 1.86; 95% CI: 1.41–2.47), but not hypertension or elevated cholesterol. Non-FHA menstrual irregularity was associated with elevated cholesterol, hypertension, and T2DM, but not CVD. FHA in early adulthood was not associated with outcomes. Conclusions FHA phenotype in mid-adulthood was associated with increased CHD risk independent of traditional risk factors. Menstrual history may serve as an early marker of cardiometabolic risk.

Abstract Background Lung transplant (LT) recipients are at high risk for severe respiratory syncytial virus (RSV) infection, but predictors of worse outcomes remain poorly defined. Methods Retrospective multicenter cohort study of adult LT recipients hospitalized with PCR-confirmed RSV infection between January 2016 and December 2019. Clinical characteristics, treatments, and outcomes within 90 days were analyzed. Logistic regression was used to identify predictors of outcomes, while Cox proportional hazards models assessed risk factors for mortality. Results 155 LT recipients were included. Median age was 61 years, RSV occurred a median of 14 months post-transplant. Risk factors for hypoxic respiratory failure were baseline oxygen use [OR 4.8, (1.29–23.93)] and lower respiratory tract symptoms [OR 3.74, (1.49–10.18)]. Older age increased the risk of mechanical ventilation [OR 1.06, (1.02–1.12)], while oral ribavirin was associated with reduced risk [OR 0.34, (0.14–0.82)]; this association was attenuated when oral and inhaled ribavirin were combined into a single exposure variable [OR 0.77, (0.22–2.66)]; oral ribavirin was not associated with reduced 90-day mortality [HR 5.27, (0.68–40.83)]. Secondary bacterial or fungal infections occurred in 33.5%, associated with prior mechanical ventilation. Lung function declined significantly post-RSV infection, with nearly half experiencing >10% decrease in FEV1. Ninety-day all-cause mortality was 7.7%, with mechanical ventilation independently associated with death [HR 7.79, (2.47–24.60)]. Conclusions RSV infection in LT recipients is associated with high morbidity, graft function decline, and mortality. The association between older age and severe outcomes suggests the importance of preventive strategies in this high-risk population.

Abstract Fungal periprosthetic joint infection (PJI) is a rare but serious complication of joint arthroplasty, with variable management and poorly defined outcomes. We conducted a systematic review and meta-analysis in accordance with PRISMA guidelines, searching Ovid MEDLINE, Embase, Scopus, and Ovid Cochrane Central. Cohort studies were included in the quantitative synthesis, while case reports and series were reviewed qualitatively. Outcomes were treatment success, failure, reinfection, and mortality. We included 160 studies: 42 cohort studies and 118 case reports or case series, with 1,025 fungal PJI cases. Pooled rates were 66.5% for treatment success, 36.5% for failure, 16.6% for reinfection, and 9.6% for mortality. Success and failure were extracted independently using study-specific definitions and are not necessarily complementary. Treatment-strategy estimates were descriptive; studies reporting DAIR had lower pooled success, but findings should be interpreted cautiously because of differences in patient selection, study design, and outcome definitions. These findings cannot establish comparative effectiveness.

Abstract Background The Alaska Tribal Health System is working to increase colorectal cancer (CRC) screening among Alaska Native peoples. It is unknown why people who initially agree might not follow through with screening completion. Methods As part of a larger intervention (NCT04336397) investigating multi-target stool DNA (mt-sDNA) test use in rural Alaska communities, we interviewed Alaska Native people who had agreed to colonoscopy or a mt-sDNA kit sent to their home, but who did not complete their selected test. Results Of 531 people who initially agreed but did not complete screening, 299 (56%) were able to be contacted for a follow-up survey. Of those, 256 (86%) answered the survey; 187/224 (83%) who had chosen mt-sDNA, and 69/75 (93%) who had chosen colonoscopy. Reported reasons for non-completion of stool DNA test kits included being busy or forgetting, being uncomfortable doing a stool test, and not knowing how to do the test or concerns over how to return the kit for processing. Reasons for non-completion of colonoscopy included scheduling issues, physical health issues, travel, and housing barriers, as well as cost, fear, and being too busy. Of note, many respondents in both groups indicated they would still be interested in CRC screening in the future or were currently pursuing screening. Conclusions This was the first exploration of reasons for non-adherence to CRC screening after initial test request by Alaska Native people. Many of the identified themes are amenable to health care system changes for future intervention to improve screening outreach and uptake.

Environmental conditions experienced early in life have profound consequences for vertebrate health, yet the molecular pathways linking developmental stress to aging and reduced lifespan remain poorly understood. Through a novel highly accurate epigenetic clock, developed from RRBS-based blood DNA methylation profiles, we show that experimental lifespan-reducing early-life stress rapidly accelerates epigenetic age in zebra finch chicks (Taeniopygia guttata). Corticosterone-treated 29-day-old chicks share differentially methylated loci with non-treated aged birds and cluster with 6-month-old birds. The transcriptional repressor ZBTB16 emerges as an epigenetically top age-correlated gene and is strongest affected by corticosterone. Elevated developmental corticosterone causes rapid epigenetic remodelling of metabolic pathways well-established in aging and longevity. Our results demonstrate epigenetic rewiring of the aging trajectory through conserved stress-survival mechanisms immediately following elevated early-life stress exposure.

Abstract Provided herein are novel aminocyclohexenyl-6,6-bicyclic compounds as 5-HT2A receptor agonists, pharmaceutical compositions, use of such compounds in treating depression, anxiety, substance abuse and headaches, and processes for preparing such compounds.

Abstract Selective prediction in clinical AI conventionally defers low-confidence predictions to human clinicians. But confidence captures only one dimension of prediction quality, and the patients it flags may not be the ones who most need human review. We propose reliability-gated selective prediction, where a composite of five dimensions—confidence, data sufficiency, cohort similarity, temporal stability, and uncertainty consistency—determines whether the model predicts or defers. Using 84,013 ICU admissions from MIMIC-IV and an XGBoost ensemble across three tasks (sepsis, mortality, vasopressor need), we find that reliability-based and confidence-based deferral policies select almost entirely disjoint patient subsets (Jaccard < 0.001 for all tasks). Confidence defers low-probability cases; reliability defers patients with sparse data and distributional unfamiliarity—precisely the failure modes invisible to confidence. The reliability gate achieves 1.4–2.4× lower Brier scores at every coverage level on temporal holdout. At 80% coverage, the number needed to review (NNR) is 2.7–3.9 for the reliability gate versus 32–2,085 for the confidence gate. A two-dimension composite (confidence and uncertainty consistency) matches the full five-dimension composite, providing a minimal deployment configuration. These findings replicate on MIMIC-III (46,187 patients, 2001–2012): Jaccard <0.001, Brier reduction 2.4–2.7×, and NNR 3–4. The reliability gate outperforms a conformal selective prediction baseline on Brier score across all tasks while providing per-dimension diagnostic information. These results define reliability as a deployment primitive for clinical AI: a multidimensional assessment of prediction trustworthiness that is not reducible to model confidence and generalizes across database versions and time periods.

Background: Many neurological and cognitive disorders have early oculomotor hallmarks. The Oculo-Cognitive Addition Test (OCAT) is a quick, objective screening tool that measures eye movement and time-based biomarkers of cognitive processing during simple mental addition tasks in under two minutes. Normative values for age, sex, education level, and apolipoprotein E Type 4 (APOE ε4) carrier status must be established so cognitively normal populations are not misdiagnosed. Methods: A total of 382 participants completed OCAT, with 350 participants making up the normative cohort from which raw gaze data were processed to derive fixations, saccades, blinks, pupillary dynamics, and time-based features. Separate multiple linear regression models were fitted for each feature with age, sex, education, and APOE ε4 carrier status as predictors to establish demographic-adjusted normative equations. Results: Processing time, fixation time, fixation size and fixation area and their variability increased progressively from the first to the third number within each addition sequence, consistent with increasing cognitive workload. Demographic-adjusted multiple linear regression models generated normative equations for individual OCAT features based on age, sex, education, and APOE ε4 carrier status. These models were used to derive individualized expected values, 95% reference intervals, and z-scores. Conclusions: These demographic-adjusted normative equations enable individualized interpretation of OCAT performance and are necessary steps towards clinical implementation.