Citations

Abstract Objective: To define the incidence of donor-derived infection (DDI) in recipients of solid organ transplant (SOT) from donors with positive blood cultures and to assess the impact of shorter versus longer duration of targeted preemptive antibiotic therapy (PAT). Design: Retrospective, single-center, cohort study. Setting: Mayo Clinic Arizona. Patients: Recipients transplanted between 1/1/2019 and 7/1/2024 who received an organ from a donor with positive blood cultures. Methods: The primary outcome was incidence of DDI. Secondary outcomes included duration of PAT and incidence of donor blood culture contamination. Results: Among 199 SOT recipients from 167 unique donors with positive blood cultures, two recipients developed confirmed DDI within 30 days of SOT. Both cases were gram negative bacillary bacteremia not treated in donors and occurred immediately posttransplant prior to adequate recipient PAT. Six-month graft survival and recipient survival were 96.5% and 97.5% respectively. 139 recipients (69.8%) received PAT for a median duration of 7 days. There was no difference in rate of infections between recipients provided with ≤7 days versus 8–14 days of PAT for donor blood cultures; however, recipients who received 8–14 days had more Clostridioides difficile infections (CDIs) within 60 days of SOT (7.7% vs 1.5% ≤ 7 days, P = .040) and were more often discharged on intravenous antibiotics (32.3% vs 11.3%, P < .001). Conclusion: We observed a low rate of DDI following receipt of organs from donors with positive blood cultures. DDI occurred in cases without adequate donor/recipient treatment. Longer durations of targeted PAT resulted in more CDI and intravenous antibiotics on discharge.

Preeclampsia is a pregnancy-specific hypertensive disorder affecting up to 5% of pregnancies worldwide and is one of the leading causes of maternal and fetal morbidity and mortality globally. It is increasingly recognized that preeclampsia, from both clinical and pathophysiological standpoints, is a heterogeneous disease and that several mechanisms may lead to a clinical syndrome of hypertension, systemic disease, and proteinuria. Beyond its acute obstetric consequences, preeclampsia confers a significantly increased risk of future hypertension, cardiovascular disease, chronic kidney disease, and multimorbidity. Distinct underlying pathological mechanisms at the time of pregnancy may not only define clinical presentation and subtype of preeclampsia but may also make varying contributions to future cardiovascular and kidney disease. Emerging evidence implicates cellular senescence, a state of irreversible cell-cycle arrest accompanied by a proinflammatory senescence-associated secretory phenotype, as one of the mechanisms of preeclampsia that may serve as a mechanistic link between preeclampsia, accelerated cardiovascular aging, and future cardiovascular and kidney disease. This review synthesizes current evidence supporting the role of senescence in the pathophysiology of preeclampsia, demonstrated as accelerated epigenetic aging, increased senescence burden, and mesenchymal stem cell dysfunction, and discusses how persistence of senescence and propagation of senescent cells may contribute to vascular dysfunction decades after affected pregnancies. We further explore the translational implications of senolytic and senomorphic therapies as potential disease-modifying strategies in women with a history of preeclampsia.

ABSTRACT Background Quality of life and symptom burden of patients with myelofibrosis are well recognized and compounded in those with anemia; however, the effects of transfusion burden or anemia severity on quality of life have not been comprehensively characterized. This post hoc descriptive analysis explored the association between transfusion status or hemoglobin improvement and patient‐reported outcomes (PROs). Methods The analysis used pooled populations across treatment arms from 3 clinical trials (SIMPLIFY‐1, SIMPLIFY‐2, MOMENTUM); sample sizes for each PRO measure were dependent on the trials in which they were administered. Results At both baseline and week 24, transfusion independence was associated with umerically greater mean SF ‐36v2 and EORTC QLQ ‐ C30 scores than transfusion dependence; in the subgroup that was transfusion dependent at baseline, those who achieved transfusion independence at week 24 had greater PRO improvements than those who remained reliant on transfusions. Regardless of transfusion status, patients who achieved a hemoglobin improvement ≥ 1, ≥ 1.5, or ≥ 2 g/ dL from baseline also had clinically meaningful improvements in quality of life (assessed via mean EQ ‐ 5D ‐ 5L or SF ‐36v2 scores) and symptoms (assessed via PGIC or MPN ‐ SAF / MFSAF Total Symptom Score) at week 24 compared with those who did not. Conclusions Collectively, these results provide preliminary insights into the associations of transfusion status and anemia severity with quality of life in myelofibrosis; as current PRO measures do not directly evaluate the relationship between symptoms such as fatigue and anemia, development of new measures to more comprehensively capture the patient experience for those with anemia in myelofibrosis may be warranted. Trial Registration NCT01969838, NCT02101268, NCT04173494

We report a case of a 63-year-old male with metastatic hepatic PEComa harboring TSC2 and NF2 mutations who achieved a durable partial response to everolimus with only mild adverse effects. This case highlights the value of genomic profiling and the efficacy of mTOR inhibitors in hepatic PEComa management.

A 57-year-old woman with a ROS1-rearranged NSCLC patient demonstrated a Lazarus response to crizotinib but later developed recurrent pulmonary embolism (PE) with right ventricular (RV) failure. This incident highlights the potential crizotinib-related thrombotic risk and the need for appropriate monitoring of vascular complications, particularly in limited-option settings such as Thailand.

ABSTRACT Background Delirium predicts adverse outcomes in older emergency department (ED) patients, but many acutely ill patients without delirium have underlying cognitive impairment that goes unrecognized. Whether cognitive impairment screening improves risk prediction beyond delirium remains uncertain. We compared practical bedside screening strategies for delirium, cognitive impairment, or both for predicting 90‐day functional decline and mortality in older adults admitted from the ED. Methods A prospective cohort comprising patients aged ≥ 65 years admitted from the ED of a large hospital in São Paulo, Brazil. Trained professionals screened for delirium using the brief Confusion Assessment Method (bCAM) and for cognitive impairment using the 10‐point Cognitive Screener (10‐CS). Patients were classified as having normal cognition (bCAM negative, 10‐CS > 5), delirium (bCAM positive), or cognitive impairment without delirium (bCAM negative, 10‐CS ≤ 5). Blinded investigators assessed decline in basic activities of daily living (ADL) and mortality within 90 days of admission. Fine‐Gray models (death as a competing risk) and Cox models estimated associations with outcomes, adjusting for sociodemographic and clinical factors. Results Among 830 patients (mean age = 80 ± 9 years; women = 47%), 427 (51.5%) had normal cognition, 171 (20.6%) had delirium, and 232 (27.9%) had cognitive impairment without delirium. Among delirium‐negative patients with cognitive impairment, 52% had no documented dementia diagnosis or reported memory problems. Compared with normal cognition, cognitive impairment without delirium was associated with 90‐day functional ADL decline (sub‐HR = 1.60; 95% CI = 1.03–2.49) and mortality (HR = 2.31; 95% CI = 1.18–4.51), with risks similar to those observed in delirium. A staged strategy (bCAM first, then 10‐CS if bCAM negative) showed higher discrimination than delirium‐only or 10‐CS‐only screening. Conclusions Cognitive impairment without delirium is common, often unrecognized, and predicts 90‐day adverse outcomes in older patients admitted from the ED. A brief staged screening strategy integrating delirium assessment with cognitive impairment testing among delirium‐negative patients may enhance early detection of cognitive vulnerability and support care planning.

The brain is a highly recurrent, nonlinear network hypothesized to remain near the edge of chaos for optimal performance. Excitation and inhibition must be balanced precisely within every neuron to ensure a consistent level of dynamical stability and rich dynamics during transition to chaos. However, analysis of biologically realistic synaptic weight matrices suggests that sparsity and low-dimensional structure interact such that there is no known synaptic balancing rule that constrains the stability (i.e., eigenvalues) of the network while also preserving computationally useful, low-dimensional structure. Further, even if a network were well-balanced, external stimuli interact with the nonlinear activation functions to unbalance the network in real time. Therefore, the brain must utilize dynamic, rather than static, mechanisms to actively regulate its level of stability. We propose that two specific adaptation mechanisms, spike frequency adaptation (SFA) and short-term synaptic depression (STD), continuously modulate the effective connectivity, keeping the brain near the edge of chaos and reducing dynamical fluctuations caused by stimuli. This theoretical framework links intrinsic and synaptic negative feedback mechanisms to network-level dynamics. This offers an explanation of why data-driven modeling of human brain signals, an exciting and useful method in epilepsy and anesthesiology research, seems to require linear time-varying (LTV) models which are refit every half second: difficult to observe adaptation processes interact with nonlinearities to make connectivity effectively dynamic at the macroelectrode scale. We suggest that compromised adaptation may underlie neurological conditions characterized by altered excitability, and that targeted brain stimulation could be used to probe the regulatory action of adaptation.

Abstract Background Highly modulated radiotherapy delivery demands functional multileaf collimator (MLC) quality assurance (QA) with the ability to measure very low doses during short (<1 s) temporal segments of beam delivery. A radiochromic film with adequate sensitivity in the few‐cGy range is therefore needed. LD‐V1 film was designed for 2–20 cGy measurements in diagnostic kV energy ranges, but its performance for megavoltage (MV) beam qualities has not been well characterized. Purpose To demonstrate the feasibility of LD‐V1 film for low‐dose MV measurements and characterize its signal dependence under conditions relevant for clinical QA. Methods A 6 MV calibration curve was generated using eight dose levels between 0 and 40 cGy and compared with EBT4 film irradiated under identical conditions. Film characteristics evaluated included dose response, scanner and film signal uniformity, scan repeatability, energy dependence, post‐exposure signal evolution, scanning‐orientation dependence, and one‐dimensional (1‐D) profile visualization. Results LD‐V1 demonstrated higher net optical density (OD) and significantly less measurement uncertainty compared to EBT4 at dose levels less than 40 cGy. Significant energy dependence between kV and MV beam qualities was seen. Average net OD differences of 6.3% were seen between landscape and portrait scanning orientations. Post‐irradiation signal growth followed a logarithmic trend, stabilizing at ∼24 h. Scan‐to‐scan variation was <0.1%. Film‐signal uniformity was within 3.9%. 1‐D profiles showed discernible dose fall‐off for doses as low as 10 cGy. Conclusions LD‐V1 demonstrates suitability for low‐dose MV measurements and exhibits improved low‐dose sensitivity relative to EBT4, indicating its potential value for MLC QA in highly dynamic treatment deliveries. Nonetheless, its pronounced energy and scanning‐orientation dependence underscores the need for rigorous and consistent calibration and handling procedures.

Pulsed Electric Field (PEF) ablation is a non-thermal cancer treatment that disrupts tumor cell membranes while preserving the immune microenvironment and promoting immunogenic cell death. We present a case of a patient with metastatic hormone receptor-positive, HER2-low breast cancer who achieved a durable clinical response after PEF in combination with an immune checkpoint inhibitor (pembrolizumab). The patient remained off systemic therapy for 14 months without disease progression. Single-cell spatial molecular imaging (SMI) and gene set enrichment analysis (GSEA) were performed to evaluate immune microenvironment changes pre- and post-PEF treatment. Spatial transcriptomics of the tumor cell compartment revealed a post-PEF enrichment of immune-related pathways, including interferon alpha/beta and gamma signaling and MHC class I antigen processing and presentation, alongside increased infiltration of immune cells: CD8+ T cells, plasmablasts, and monocytes within the tumor neighborhood. This hypothesis-generating case suggests PEF’s potential to reshape the tumor-immune microenvironment when combined with immune checkpoint blockade, warranting further studies on its role in combination immunotherapy strategies.

Effective translation relies on high performance teams integrating diverse disciplines to bring new drugs, medical devices, diagnostics or behavioral interventions into improved health. Despite substantial advancements informed by the Science of Team Science (SciTS), challenges remain in effective translational team (TT) operations, while limited institutional, scholarly, and practitioner legitimacy of team science expertise constrains efforts to address them. Here, we describe an essential member of the TT, the Team Science Professional (TSP). Serving as a team educator and facilitator of team interventions, the TSP plays a pivotal role in facilitating effective team performance. Current challenges faced by this nascent profession are defining career pathways and establishing competencies needed for expert performance. To address these challenges, the authors, representing a spectrum of academic universities organized as a special interest group (SIG) of the Association of Clinical and Translational Science (ACTS), propose a suite of individualized, standardized and pathway-selective micro-credentials (digital badges). Digital badges in “Team Science (TS) Fundamentals,” “TS Practitioner,” “TT Trainer” and “TT Intervention Expert” are described, along with preliminary feasibility and usability evaluations of the submission process. These stackable credentials provide a customizable, portable recognition of skills and help advance career pathways for TSPs. In so doing, the Digital Badge Initiative will enhance the capacity of translational science “Hubs” such as those supported by Clinical and Translational Science Awards to conduct effective and rigorous translation. Moving forward, the ACTS TSP SIG will be examining the impact of digital badging on standardization and its effect on career recognition and retention.