Citations

Abstract Background Preterm premature rupture of membranes (PPROM) and preterm labor (PTL) are adverse obstetrical outcomes that are strongly associated with cervical high-risk human papilloma virus (cHPV) infection at the time of pregnancy. Persistent cHPV may lead to oncogenic changes in the cervico-vaginal tract and can cause inflammation in gestational tissues, but it is unknown how persistent cHPV infection may affect obstetrical outcomes. The aim of this study is to evaluate whether persistent cHPV infection is associated with recurrent PPROM or PTL among patients with a prior spontaneous preterm birth due to PPROM/PTL, and to examine clinical and pathologic characteristics of cHPV infection in this population. Methods We conducted a retrospective cohort study of patients delivering at Mayo Clinic Rochester or Mayo Clinic Health System (5/1/2018–12/31/2023). Eligible patients had ≥ 1 spontaneous preterm birth due to PPROM/PTL and positive cHPV testing. Demographics and pregnancy outcomes from index and subsequent pregnancies were abstracted. Persistent cHPV was defined as > 1 pregnancy with positive cHPV testing. Results Of 191 index pregnancies, 90 (47.1%) and 30 (33.3%) had one and two subsequent pregnancies, respectively. Patients were predominantly White (91.3%), non‑Hispanic (94.2%), non-smokers (72.0%), and 34.8% were unvaccinated for HPV. Approximately one‑third (31%) experienced recurrent PPROM/PTL in the second pregnancy, with recurrence in 40.7% of those with persistent cHPV and 27.4% without (p = 0.69). Excisional procedures occurred before 12.0% of index pregnancies and 20–24% of subsequent pregnancies; recurrence of PTL/PPROM remained high regardless of procedure history. HPV strain data were available for 132 index pregnancies, and types 16 and 18 were more likely to persist into a subsequent pregnancy (p = 0.0043). CIN persistence occurred at similar rates in patients with and without persistent cHPV infection. Placental inflammation rates were high in both patients with persistent and non-persistent cHPV. Conclusion Recurrent PPROM/PTL, CIN persistence, and placental inflammation were common; a finding independent of persistent cHPV infection, excisional procedure history, or HPV vaccination status. These findings suggest that factors other than cHPV persistence may play a larger role in recurrent preterm birth. Larger studies with higher cHPV prevalence and subsequent pregnancies are needed to provide clarity.

As machine learning (ML)-based decision support tools proliferate in clinical practice, understanding how clinicians integrate personalized ML predictions alongside randomized controlled trial (RCT) evidence is critical. We designed a web-based clinical decision support system (CDSS) presenting survival and adverse event data from a simulated RCT and ML model across 12 synthetic multiple myeloma scenarios. In a within-subjects study with 32 physicians, we evaluated how clinicians synthesize competing evidence sources to make treatment decisions. When ML and RCT outputs were concordant, physicians reported greater confidence than with RCT data alone. When results were discordant, most physicians shifted toward the ML-supported treatment, often before reviewing any information about model training or validation, suggesting a tendency toward automation bias rather than algorithm avoidance. Despite reporting higher perceived reliability after viewing model quality disclosures, physicians were largely unable to describe the validation procedures they had reviewed. Taken together, these findings reveal that clinicians may over-rely on ML recommendations even when equipped with tools designed to support critical appraisal. We discuss implications for CDSS design, clinician training, and the institutional safeguards needed before ML-based systems are deployed in high-stakes oncology settings.

Abstract Isolated cardiac sarcoidosis (iCS), defined by granulomatous inflammation limited to the myocardium, represents the most diagnostically challenging and prognostically adverse form of sarcoidosis. As it is fundamentally a diagnosis of exclusion, iCS diagnosis relies on the absence of extracardiac sarcoid and the integration of multimodality imaging, endomyocardial biopsy, and molecular testing, each with inherent limitations. Cardiac magnetic resonance and positron emission tomography provide complementary assessment of inflammation, fibrosis, and ventricular function, enhancing diagnostic confidence. Electroanatomic mapping-guided biopsy may improve histologic yield, whereas genetic testing helps exclude phenocopies such as arrhythmogenic, hypertrophic, or dilated cardiomyopathies. Circulating biomarkers remain non-specific but may complement imaging-based algorithms. Future research should focus on harmonized imaging protocols, non-FDG radiotracers, and molecular tissue profiling to refine activity assessment and guide therapy. Multimodal, probability-based frameworks represent the most promising approach for earlier, more accurate diagnosis and risk stratification in iCS.

ABSTRACT Cancer mortality is inequitably distributed across the U.S. and globally, with historically marginalized groups, particularly racial and ethnic minorities, being disproportionately affected. Disproportionate representation in clinical cancer research is a consequence of inequitable access as well as a central factor contributing to outcome disparities; it limits efficacy and safety data for underrepresented groups while directing drug development to be most beneficial for those enrolled. To tackle this problem and improve the efficacy and safety of commercially available therapies, a consensus conference on strategies to promote Diversity, Equity, Inclusion, and Accessibility (DEIA) in cancer research was empaneled in September 2022. The resulting “Indianapolis Black Paper” presented here is an international collaborative white paper with authors from industry, academia, and the government, as well as patient advocacy and community health groups. First, it outlines the roles and responsibilities of key groups involved in clinical cancer research, as they relate to representation and equity. The Black Paper then delineates five steps to promote diversity in clinical research. This actionable strategy is called “DRIVE,” and it involves: incorporating a Diversity officer into clinical research studies, Ranking clinical studies for diversity, developing an Individual diversity, equity, inclusion, and access plan, a process for Verifying study diversity, and Elevating and Enhancing training of minority investigators and research team members. Finally, we outline the timeline and milestones of implementation. Purposefully ambitious and crosscutting industry, academia, and governmental policy, the Black Paper aims to address “injustices in health” with enhanced safety, purpose, and humanity.

Abstract Horlock, CF, Allen, LE, Jagim, AR, Jones, MT, and Fields, JB. In-season assessment of dietary intake and match demands of men’s collegiate Rugby Sevens players. J Strength Cond Res XX(X): 000–000, 2026—Limited research has examined the external workload demands and dietary intake of collegiate men's Rugby Sevens players. Therefore, the purpose of this study was to (a) quantify match demands in Division 1-AA collegiate Rugby Sevens across a competitive season, and (b) assess players' dietary intake relative to sport-specific nutrition guidelines. Division 1-AA men's collegiate Rugby Sevens players ( n = 13; age: mass: 87 ± 14 kg; body fat %: 20 ± 4%) wore a global positional system device during all matches ( n = 17). External load metrics were total distance (TD) (m), sprint distance (>20.1 km·h −1 ), high-intensity distance (>18.1–20.0 km·h −1 ), meters per minute (m·min −1 ), acceleration efforts (#), deceleration efforts (#), sprint efforts (#), high-speed efforts (#), player load (PL) (arbitrary unit [AU]), PL per minute (AU/min), and estimated energy expenditure (EE) (kcal). Dietary intake was assessed at the start of the season using a 4-day food log. Linear mixed models examined changes in workload parameters across tournament matches. Spearman's rank correlation and linear regression assessed relationships and predictability of EE and external workloads. One-samples t test compared dietary intake relative to established guidelines ( p ≤ 0.05). No significant differences in workload metrics were observed across individual matches. Total distance ( r = 0.968, p < 0.001), m·min −1 ( r = 0.973, p < 0.001), PL ( r = 0.912, p < 0.001), and PL/min ( r = 0.855, p < 0.001) had the strongest correlations with EE. Players significantly underconsumed calories ( p = 0.028) and carbohydrates ( p < 0.01). Monitoring external workloads and assessing dietary intake can provide coaches with strategies to optimize sports performance and nutrition support to prepare players for competition demands.

Abstract Germline variants in DDX41 are the most frequent genetic predisposition to adult hematologic malignancies. The most common variants are truncating, implicating loss of function in the pathogenesis. However, non-truncating variants account for 30-40% of cases, and their impact on essential DDX41 functions remains unknown. We utilized a genetic complementation assay to assess the functionality of 10 recurrent germline non-truncating variants of DDX41. All variants restored viability to Ddx41 -deficient hematopoietic progenitor cells at exogenous expression levels. In contrast, the hotspot mutant p.R525H, which is somatically acquired at disease onset in >50% of patients, failed to restore viability. CRISPR-based modeling in cell lines and mice revealed heterogeneity: some variants were non-functional at endogenous expression levels whereas others maintained complete functionality, supporting normal cell proliferation and even lifelong hematopoiesis in a homozygous setting. Notably, co-expression of p.R525H with some variants caused impaired hematopoietic progenitor cell viability, indicating a dominant-negative effect of p.R525H. In contrast, other variants, all classified as variants of unknown significance, were unaffected by the presence of p.R525H. A screen of 100 disease-associated variants confirmed that many non-truncating germline variants are susceptible to p.R525H-mediated dominant-negative effects, whereas wild-type DDX41 is not. These findings indicate that DDX41 variant curation is complicated by variable effects on functionality and variant-specific interactions with somatically-acquired DDX41 mutations. The dominant-negative effect of p.R525H provides a mechanistic basis for the conclusion of recent patient cohort analyses that co-occurrence with a somatic hotspot mutation is a reliable indicator of DDX41-driven disease in carriers of non-truncating variants.

PURPOSE In immunoglobulin light chain (AL) amyloidosis, amyloid fibrils cause organ dysfunction. Anselamimab, a monoclonal antibody, selectively binds to amyloid fibrils, accelerating their clearance. METHODS Newly diagnosed patients with European modification of Mayo 2004 stage IIIa or IIIb AL amyloidosis were randomly assigned to receive anselamimab or placebo with cyclophosphamide, bortezomib, and dexamethasone (with or without daratumumab). The primary end point was a hierarchical composite of time to all-cause mortality (ACM) and frequency of cardiovascular hospitalizations (CVHs), analyzed using the Finkelstein-Schoenfeld test and win ratio estimation. RESULTS Among 406 randomly assigned patients, the primary end point win ratio for anselamimab versus placebo was 1.11 (95% CI, 0.83, 1.50; P = .332) and the hazard ratio (HR) for ACM was 0.80 (95% CI, 0.57, 1.13; P = .290). CVH rates in the anselamimab and placebo groups were 0.59 (95% CI, 0.42, 0.83) and 0.89 (95% CI, 0.55, 1.43), respectively ( P = .145). Among patients with kappa isotype (n = 72), the win ratio was 2.06 (95% CI, 0.98, 4.31; P = .100) and anselamimab reduced ACM by 62% versus placebo (HR, 0.38; 95% CI, 0.17 to 0.86; nominal P = .012), and CVH by 71% (IRR, 0.29; 95% CI, 0.10 to 0.87; nominal P = .028) with improvements in Kansas City Cardiomyopathy Questionnaire-Overall Score. There was no clinical benefit observed in the lambda population. Anselamimab was generally well-tolerated; safety data were comparable between treatment arms overall. CONCLUSION Treatment with anselamimab, an antifibril antibody used alongside antiplasma cell dyscrasia therapy, while not meeting the primary end point in the overall population, significantly improved ACM and CVH in patients with kappa AL, potentially offering a new therapeutic option for this isotype.

Abstract Repetitive head impacts sustained during American football have been associated with neuropathological changes such as white matter shear injuries. However, the impact of specific factors, such as age of first exposure and cumulative head impact burden, on white matter integrity remains unclear. This study investigated in vivo white matter microstructural changes using diffusion tensor imaging and tract-based spatial statistics in 165 male former American football players (mean age 57.3 years, range 45–74) and 52 unexposed asymptomatic male controls (mean age 59.4 years, range 45–74) in the DIAGNOSE CTE Research Project. Compared to controls, former football players exhibited significantly higher fractional anisotropy (FA) in 1.97% of the white matter skeleton (1552 voxels; Cohen’s d = 0.587) and higher tissue-corrected FA (FAt) in 1.48% of the white matter skeleton (1004 voxels; Cohen’s d = 0.616). No significant differences were observed for mean diffusivity, axial diffusivity, radial diffusivity, or free water between football players and controls. Among football players, there were no significant differences in the white matter microstructure between players diagnosed with traumatic encephalopathy syndrome and those without the diagnosis. Lower FA was significantly associated with older age (P &lt; 0.00001) and an earlier age of first exposure to tackle football (P &lt; 0.01), while lower FAt was associated with greater cumulative head impact burden, specifically higher linear acceleration (P &lt; 0.04) and rotational force (P &lt; 0.02). This study highlights the influential role of exposure factors on white matter microstructure in former American football players, as well as the utility of diffusion tensor imaging to aid in characterizing the long-term effects of repetitive head impacts in contact sport athletes.

Abstract Severe neuropathies with predominant involvement of motor fibres can resemble lower motor neuron disease (LMND) phenotypes. Given the fatal prognosis of LMND, identifying underlying autoimmune syndromes is crucial to provide treatment options to patients. We investigated a novel autoantibody binding pattern observed on murine teased sciatic nerve fibres. Target antigens were identified using immunoprecipitation combined with mass spectrometry. Target specificity of these autoantibodies was validated in cell-based assays, neutralization assays and knock-out models. A retrospective study cohort consisting of different neuropathies (chronic inflammatory demyelinating polyradiculopathy n = 86, Guillain–Barré syndrome n = 37, multifocal motor neuropathy n = 18, diabetic neuropathy n = 30, other inflammatory neuropathies n = 10), amyotrophic lateral sclerosis (n = 50), multiple sclerosis (n = 50) and healthy controls (n = 50) was negative for septin multimer autoantibodies. Histopathological analysis of skin and the sural nerve including electron microscopy was performed in one seropositive patient, and autoantibody binding was characterized in vitro. Extensive immunotherapy was initiated in one patient, with clinical and serological follow-up over 4 years. Among 3543 total samples tested, three patients (two male, one female)—diagnosed with the LMND variant of amyotrophic lateral sclerosis (aged 65, 72 and 79 years, respectively)—showed a novel and distinct autoantibody binding pattern of indirect immunofluorescence staining on peripheral nerves, targeting Schmidt–Lanterman incisures (SLIs), paranodes and the abaxonal myelin. Target identification and validation revealed septin multimers as autoantibody epitopes. Despite the primarily intracellular location of septins, autoantibody binding was evident in living myelinated dorsal root ganglia, primarily at SLIs (‘incisuropathy’). Septin multimer autoantibodies further initiated complement deposition on fixed and permeabilized cell-based assays. Sural nerve and skin biopsies showed inflammation, myelin and axonal pathology. Extensive immunotherapy in one patient was followed by disease stabilization over 3 years. The other two patients died of rapid disease progression: one of them received no immunotherapy while the other had ineffective treatments with single administrations of intravenous immunoglobulin and rituximab. Our data suggest that septin multimer autoimmunity occurs in severe motor-predominant neuropathies which can clinically resemble a neurodegenerative LMND. Screening for septin multimer autoantibodies should be considered in patients presenting with this phenotype. Follow-up studies need to determine the direct pathogenicity of septin multimer autoantibodies, their potential as a biomarker of an autoimmune syndrome and responses to immunotherapy in larger cohorts.