Citations

ABSTRACT BACKGROUND Platelet factor 4-polyanion enzyme-linked immunosorbent assays (ELISAs) are considered highly sensitive for diagnosing heparin-induced thrombocytopenia (HIT), such that current practice guidelines recommend use of ELISA-negative results to exclude HIT. Once HIT is ruled out, alternative, non-heparin-based anticoagulant treatments are ceased, and heparin reintroduction frequently occurs. METHODS Antigen-based and PF4-dependent functional testing were used to study PF4/polyvinyl sulfonate ELISA-negative platelet-activating antibodies in HIT-suspected patients and mice immunized with PF4/heparin. RESULTS Three patients with clinical presentations consistent with HIT tested negative in an ELISA using PF4-polyvinylsulfonate (PF4/PVS), an antigenic target very commonly used for HIT antibody detection. All three patients demonstrated PF4-dependent platelet activation in functional testing that was sensitive to blockade of platelet FcγRIIa receptors and inhibited by high concentrations of heparin, consistent with pathogenic HIT antibodies. Functional testing-based screening of 500 ELISA-negative patients identified three patients whose sera activated platelets in a PF4- and FcγRIIa-dependent manner, and had clinical histories consistent with HIT. Five of the six ELISA-negative HIT patients were re-exposed to heparin, which precipitated a decrease in platelet counts in all re-exposed patients, and one patient developed a new thrombus. To advance the study of ELISA-negative HIT antibodies, mice were immunized with PF4/heparin, and functional and antigenic assays were simultaneously used to successfully identify an ELISA-negative, PF4-dependent platelet-activating murine monoclonal antibody that recapitulated the serological characteristics of ELISA-negative HIT patients. CONCLUSIONS Recognition of ELISA-negative HIT is critical to avoid harm due to the cessation of alternative anticoagulation therapy and re-exposure of these patients to heparin.

Background: We investigated the impact of genetic risk factors for coronary heart disease (CHD) -polygenic risk score (PRS), familial hypercholesterolemia (FH), and family history (FamHx)- on CHD risk estimates, across the age spectrum, in two diverse cohorts of US adults -eMERGE IV (eIV) and All of Us (AoU). Methods: CHD was defined as myocardial infarction, unstable angina, and coronary revascularization. Self-identified race/ethnicity (SIRE) was used as a population descriptor. We calculated a PRS for CHD (PRS CHD , PGS004698), ascertained FH as the presence of pathogenic/likely pathogenic variants in FH genes, and defined FamHx as early-onset CHD in first-degree relatives. We employed Pooled Cohort Equations (PCE) to estimate the 10y risk of CHD for adults ≥40y and modeled the association of conventional risk factors with CHD in adults <40y. AoU served as the training set, and eIV as the testing set. We analyzed the impact of PRS CHD and FamHx on CHD risk estimates by a) using multivariable logistic regression and Cox proportional hazard models, assessing discrimination and the extent of risk reclassification; and b) net benefit analysis and decision curves to assess the performance of prediction models across actionable thresholds. Results: We analyzed data for 19348 participants from eIV (age 50±15, 68% female, 41% non-White) and 239645 participants from AoU (age 55±17, 61% female, 48% non-White). Genetic risk factors were significantly associated with CHD. PRS CHD performance varied by SIRE groups, while FamHx was consistent. The effects of PRS CHD and FamHx on CHD were independent and additive (Figure 1). In adults ≥40y, incorporating PRS CHD and FamHx into PCE improved discrimination (C-statistic increased from 0.719 to 0.753; P -diff=9.1×10 -3 , Figure 2) and reclassified risk in 19% and 20% of participants at the 7.5% and 10% 10y CHD risk thresholds, respectively. Between the 7.5% and 10% 10y CHD risk thresholds, incorporating PRS CHD and FamHx into the PCE improved the net benefit of the risk prediction models across White, Black, and Hispanic/Latino groups (Figure 3). Conclusion: PRS CHD and FamHx were independently and additively associated with CHD in two large diverse cohorts in the US. Incorporating PRS CHD and FamHx into PCE improved risk discrimination, reclassified risk in a significant portion of participants, and improved net benefit of the PCE across all three major SIRE groups, motivating the addition of these factors to clinical risk calculators.

Abstract Objective: The National Institutes of Health (NIH) Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (EXAMINER) is a validated laptop-based battery of executive functioning tests. A modified tablet version of the EXAMINER was developed on the UCSF Tablet-based Cognitive Assessment Tool (TabCAT-EXAMINER). Here we describe the battery and investigate the reliability and validity of a composite score. Methods: A diagnostically heterogeneous sample of 2135 individuals (mean age = 65.58, SD = 16.07), including controls and participants with a variety of neurodegenerative syndromes, completed the TabCAT-EXAMINER. A composite score was developed using confirmatory factor analysis and item response theory. Validity was evaluated via linear regressions that tested associations with neuropsychological tests, demographics, clinical diagnosis, and disease severity. Replicability of cross-sectional results was tested in a separate sample of participants ( n = 342) recruited from a frontotemporal dementia study. As this separate sample also collected longitudinal TabCAT-EXAMINER measures, we additionally assessed test-retest reliability and associations between baseline disease severity and changes in TabCAT-EXAMINER scores. Results: The TabCAT-EXAMINER score was normally distributed, demonstrated high test-retest reliability, and was associated in the expected directions with independent tests of executive functioning, demographics, disease severity, and diagnosis. Greater baseline disease severity was associated with more rapid longitudinal TabCAT-EXAMINER decline. Conclusions: The TabCAT-EXAMINER is a tablet-based executive functioning battery developed for observational research and clinical trials. Performance can be summarized as a single composite score, and results of this study support its reliability and validity in cognitive aging and neurodegenerative disease cohorts.

Background Tumors with mismatch repair deficiency (MMRd) classically display concomitant loss of MLH1/PMS2 or MSH2/MSH6 on immunohistochemistry (IHC) with microsatellite instability-high (MSI-High) status on molecular testing. Nevertheless, a different phenotype can occur in up to 15% of MMRd tumors (unusual phenotype). Data on the efficacy of immunotherapy in this population remain scarce. Methods We conducted a retrospective study within the IMMUNODIG MSI cohort including patients with advanced gastrointestinal MMRd tumors treated with immune checkpoint blockade in the real-world setting. We selected patients with both IHC and MSI assays data available. Unusual MMRd tumors were classified into four distinct groups: (1) isolated loss of PMS2 or MSH6 with MSI-H (isolated/MSI-H), (2) complex loss of MMR proteins with MSI-H (complex/MSI-H), (3) loss of one or more MMR proteins without MSI-H (MMRd-IHC/microsatellite stability (MSS) or MSI-low (MSI-L)), and (4) four MMR proteins retained with MSI-H (retained IHC/MSI-H). Results Out of 759 patients in the IMMUNODIG-MSI cohort, 571 patients met inclusion criteria. Of these, 90 (15.8%) had an unusual phenotype (47 isolated/MSI-H, 19 complex/MSI-H, 16 MMRd-IHC/MSS or MSI-L and 8 retained IHC/MSI-H). Compared with classical phenotypes, patients with a tumor harboring an unusual phenotype had a younger age at treatment (p=0.005), increased RAS mutation (p=0.005), reduced BRAF p.V600E mutation rates (p<0.001), a higher proportion of Lynch syndrome (p<0.001) and a higher prevalence of non-colorectal cancers (p=0.021). After a median follow-up of 28.1 months (mo), there was a significant difference in progression-free survival, with median values of not reached, 66.4 mo, 37.2 mo, 18.3 mo and 5.5 mo for complex/MSI-H, isolated/MSI-H, classical, retained IHC/MSI-H and MMRd-IHC/MSS or MSI-L subgroups, respectively (p<0.001). Notably, objective response rates were 59.1%, 58.7%, and 63.2% for complex/MSI-H, isolated/MSI-H and classical contrasting with 50% and 25% for retained IHC/MSI-H and MMRd-IHC/MSS or MSI-L, with no complete response observed in the latter two. Conclusion Our findings underscore the need for dual testing and advocate for the presence of both MMRd-IHC and MSI-H for optimal immunotherapy response. Of note, complex MMR aberrations and isolated PMS2/MSH6 losses with MSI-H may represent promising candidates for enhanced immunotherapy efficacy.

ABSTRACT Background The impact of psychosocial health and socioeconomic status (SES) on long‐term lung transplant survival remains unclear. Methods We conducted a single‐center, retrospective 2:1 matched case‐control study of adult lung transplant recipients (1999–2019). Cases survived ≥6 years post‐transplant; controls survived <6 years. Matching was based on transplant year (±5 years) and indication. Psychosocial health and SES were assessed using the Psychosocial Assessment of Candidates for Transplant (PACT) score, Mayo Clinic Housing‐Based Socioeconomic Status (HOUSES) index, and Area Deprivation Index (ADI). Secondary covariates included insurance, marital status, employment, caregiver relationship, and proximity to the transplant center. Conditional logistic regression adjusted for age and gender was used. Results Among 189 patients (63 cases, 126 controls), PACT score, HOUSES index, and ADI were not significantly associated with long‐term survival. Patients with non‐family caregivers had lower odds of survival compared to those with a spouse or partner (OR = 0.16, p = 0.022). Regional residents had lower odds of long‐term survival compared to local recipients (OR = 0.55, p = 0.001). Conclusions Pre‐transplant psychosocial and SES measures were not significantly associated with long‐term survival. Caregiver relationships and geographic proximity may have a greater impact on outcomes, highlighting the importance of support systems and access to care.

Case: We present 3 cases of brachial plexus injuries (BPI) secondary to compressive hematomas during extracorporeal membrane oxygenation (ECMO), with follow-up ranging from 18 months to 12 years. Patients exhibited profound upper extremity deficits and underwent variable interventions, including surgical decompression. All demonstrated meaningful neurologic recovery. Conclusion: BPI is a rare but serious complication of ECMO. These cases highlight the importance of early recognition and hematoma evacuation, emphasizing the need for clinical vigilance to optimize neurologic outcomes following hematoma-induced nerve injury.

ABSTRACT Suicidality contributes substantially to global morbidity and mortality, yet despite its heritability, its biological etiology remains largely elusive. We conducted multi-ancestry genome-wide association study meta-analyses of suicidal ideation (259,747 cases), suicide attempt (64,993 cases), suicide death (9,197 cases), and suicidal behavior (suicide attempt/ death, 75,300 cases), across 54 cohorts (e.g., the Psychiatric Genomics Consortium, Million Veteran Program, UK Biobank). We identified 77 significant loci across meta-analyses, including 59 previously unreported for suicidality. SNP-based heritability ranged from 2.0-6.7% and there were strong, yet incomplete, genetic correlations between suicidality phenotypes (0.70-0.88). Fine-mapping prioritized putative causal SNPs and 20 credible genes. Enrichment analyses implicated synaptic pathways and neuronal populations predominantly in subcortical brain regions (e.g., amygdala excitatory, medium spiny, hippocampal CA1-3). Together, these findings establish suicidality as a polygenic set of traits with both shared and distinct genetic influences, providing a foundation for future studies of suicide biology and etiology.

ABSTRACT Bloodstream infections (BSIs) caused by opportunistic yeasts, namely those of the genus Candida , demonstrate strikingly high mortality rates and require early therapeutic intervention to optimize patient outcomes. Advancements in microbiological diagnosis of BSIs have introduced rapid molecular methods, including multiplex PCR panels, to detect common organisms directly from blood culture media. The BIOFIRE FilmArray Blood Culture Identification 2 (BCID2) assay is one such method and detects seven of the most common yeast species responsible for fungemia, enabling timelier therapeutic optimization by clinicians. Here, we evaluated the clinical performance of BCID2 for yeast identification from positive blood cultures between 2021 and 2025 at a tertiary medical center, compared to the reference standard method, which couples subculturing and diagnostic mass spectrometry. A total of 252 individual yeast identification events were confirmed using the reference method during our study period, 33 (13%) of which represent organisms that lack BCID2 PCR-based targets and 219 (87%) represent organisms targeted by this assay. Of the 219 identifications compatible with the BCID2 panel targets, 209 (95%) were correctly identified. Discordance between BCID2 and the reference method commonly stemmed from the inability of BCID2 to target all yeasts encountered clinically in blood culture, as well as its reduced accuracy in cultures where >1 yeast is present. Overall, these data suggest that the BCID2 assay is a rapid and accurate method to identify the most common organisms causing yeast BSI from blood culture; however, subculture-based reference techniques are important complementary tools in the clinical microbiology laboratory. IMPORTANCE Invasive fungal diseases, including bloodstream infections (BSIs) caused by yeasts, are increasing in prevalence alongside the growing global population of immunocompromised individuals. Prompt and targeted treatment is necessary for effective management of yeast BSI, and microbiological diagnostics play an important role in tailoring patient treatment. Rapid molecular assays that simultaneously detect multiple pathogens associated with a specific syndrome are attractive strategies to expedite pathogen identification. This includes the BIOFIRE FilmArray Blood Culture Identification 2 (BCID2) assay, which detects 33 organisms including 7 yeasts commonly associated with fungemia, directly from blood culture media. Its performance has been well established for the detection of bacteria and bacterial resistance markers from blood cultures. Here, we provide a yeast-specific snapshot into the microbiological performance of BCID2, highlighting its accuracy as well as limitations in detecting medically important yeasts compared to standard culture-based identification from a four-year specimen cohort collected in a tertiary care hospital.

ABSTRACT The World Health Organization (WHO) 5th Edition and International Consensus Classification (ICC) have continued to delineate more genetically defined acute leukemias. Both recognize genetic aberrations associated with myelodysplastic syndromes/neoplasms (MDS) as defining MDS‐related AML (AML‐MR). Mutations in RUNX1 are included in this category in the ICC, but not WHO. The current classifications are unclear on how acute leukemias with ambiguous lineage (ALAL), including those of mixed lineage (MPAL) and those without a defined lineage (AUL), should be categorized in the presence of such mutations. Our multi‐institutional study aims to determine the significance of RUNX1 mutation in ALAL compared to de novo AML. Newly diagnosed MPAL, AUL, and AML with RUNX1 mutations were collected. ALAL with MDS‐related cytogenetics, BCR::ABL1 , KMT2A rearrangements, or ZNF384 or BCL11b abnormalities were excluded. We analyzed 17 cases of ALAL and 71 cases of AML that met inclusion criteria. ALAL‐ RUNX1 and AML‐ RUNX1 showed overlapping mutational landscapes with frequent comutations in MDS‐associated genes. No ALAL‐ RUNX1 or AML‐ RUNX1 cases showed concomitant TP53 mutation. ALAL‐ RUNX1 had more bone marrow blasts and more karyotypic abnormalities; however, neither impacted survival, nor did RUNX1 variant allele frequency (VAF). Survival analysis revealed similarly poor outcomes between them. AML‐directed therapies and allogeneic hematopoietic stem cell transplant trended toward improved survival in ALAL‐ RUNX1; however, it did not reach significance. Our results suggest ALAL‐ RUNX1 is associated with younger age, higher blasts, and more karyotypic abnormalities, but has similar clinical and genetic features and outcomes to AML‐ RUNX1 . Our findings suggest, like other MR mutations, RUNX1 ‐mutated ALALs should be included within AML‐MR.