Citations

Introduction Neurological post-acute sequelae of COVID-19 (neuroPASC) are associated with persistent cognitive dysfunction and quality-of-life decline. We aimed to identify clinical, behavioral and sociodemographic factors associated with neuroPASC symptom burden two years after COVID-19 among individuals without prior neurological disease. Methods In this prospective, observational study, individuals with neuroPASC ( n = 102) and controls without symptomatic COVID-19 ( n = 74), all without prior neurological, psychiatric, or post-viral conditions, were enrolled between February 2022 and June 2024 across five academic sites. An unsupervised algorithm identified clusters with differing self-reported neurological symptom burden within the neuroPASC group. Functional differences between clusters were evaluated using quality-of-life, neurological and cognitive evaluations. Demographics, behavioral history, comorbidities, and blood biomarkers were compared across clusters and controls. Multivariable logistic regression assessed predictors of neuroPASC severity, including demographics, body-mass-index, Charlson Comorbidity Index, Framingham Risk Score, pre-existing endocrine/metabolic and/or gastrointestinal/hepatobiliary conditions, COVID-19 vaccination prior to infection, hospitalization during acute infection, and cumulative alcohol use. Results Two clusters emerged based on neurological symptom burden, labeled “high-burden” and “low-burden” neuroPASC, reflecting differences in the number and frequency of symptoms. Both clusters had deficits in quality-of-life and cognitive function compared to controls, with greater impairment in high-burden than low-burden neuroPASC. The clusters did not differ by sex, education, tobacco and cannabis use, blood pressure, body-mass-index, HbA1C, days since infection, hospitalization during COVID-19, pre-COVID vaccination rate, antibody-positivity, inflammation, and neurodegeneration biomarkers. The high-burden cluster was older and exhibited higher comorbidity burden and greater cumulative alcohol use compared with the low-burden cluster and controls. Pre-existing endocrine/metabolic and gastrointestinal/hepatobiliary conditions were more common in high-burden (63%) than in low-burden neuroPASC (35%). After adjusting for clinical and demographic factors, these pre-existing conditions remained the only independent predictor of severity, conferring a 3.5-fold increase in the odds of high-burden versus low-burden neuroPASC. Discussion Older age, higher comorbidity burden, greater cumulative alcohol use, and endocrine/metabolic and gastrointestinal conditions, rather than acute COVID-19 severity, were observed in the high-burden neuroPASC cluster. After multivariable adjustment, only pre-existing endocrine/metabolic and/or gastrointestinal/hepatobiliary conditions remained independently associated with high-burden neuroPASC, conferring a 3.5-fold increase in odds and highlighting the need for targeted post-infection monitoring in at-risk patients.

Invasive lobular breast carcinoma (ILC), the most common special histological subtype of breast cancer, is characterized by nearly universal expression of estrogen receptor alpha (ER) and unique sites of metastases, neither of which is fully recapitulated by genetically engineered mouse models. Using reporter-labeled ILC mouse xenografts, herein we used mammary fat pad, tail vein and intracardiac orthotopic growth to analyze spontaneous and experimental metastasis and gene expression. We observed ER-positive primary tumors with single-file histology and collagen deposition, and spontaneous metastasis from the mammary fat pad to bones, ovaries, and brain including the leptomeninges, thereby closely mirroring the growth and metastatic spread of human ILC. Brain metastases showed strong ER staining, confirmed by sequencing analyses which identified estrogen signaling as top activated pathway, and the lesions exhibited robust response to endocrine therapy. In summary, we report endocrine responsive mammary fat pad, tail vein and intracardiac xenografts that faithfully demonstrate unique ILC features and can serve as invaluable pre-clinical translational platforms for validating candidate ILC genetic drivers and testing novel therapeutics.

ABSTRACT Background There is limited data regarding the surgical outcomes of urosymphyseal fistula (USF) repair with primary repair or autologous tissue transfer. We performed a study to compare outcomes of USF repair with primary repair, VRAM flap, and omental flap. Methods We retrospectively identified patients with a diagnosis of USF who underwent fistula decompression and urinary tract reconstruction. The minimal follow‐up was 3 months. Patients with distal urethral obstruction, radiation cystitis, or a non‐viable sphincter underwent anterior exenteration and flap transfer. Results Fifty‐six patients were included. Eleven patients underwent surgical management for USF using primary repair (19.6%), 34 had omental flap‐based reconstruction (60.8%), and a VRAM flap was used in 11 patients (19.6%). The 90‐day rate of sepsis was lower with omentum flap transposition (3%) compared with VRAM flap (27%) or primary repair (18%, p = 0.041). The rate of fistula recurrence was lower in the omentum flap group compared with USF primary repair (30%) or VRAM flap repair group (27.3%, p = 0.04). On multivariable analysis, USF repair with the omentum flap decreased the odds of fistula recurrence 90 days after surgery compared with primary repair (OR 0.012, p = 0.011) but not when compared with VRAM. Conclusion The omentum flap may offer a better safety profile in terms of decreasing the rate of early sepsis and rate of fistula recurrence for USF repair in comparison to primary repair. There is limited evidence regarding the superiority of the omentum flap to decrease the rate of late fistula recurrence when compared with the VRAM flap.

Abstract Objectives To address the gap between artificial intelligence (AI) model development and clinical implementation by developing a machine-learning model to predict cochlear implant (CI) eligibility based on routine hearing tests, while illustrating 3 practical lessons: reformulation for clinical utility, selection of problem-specific metrics, and handling input data variability. Materials and Methods Data were extracted from adult patients who underwent behavioral audiometric and subsequent CI candidacy testing (Arizona Biomedical and Consonant-Nucleus-Consonant tests) at Mayo Clinic between 2011 and 2023. Regression models were initially developed to predict AzBio and CNC scores using features from routine audiograms. Models were then reformulated into binary classification tasks using clinical thresholds (AzBio ≤60%; CNC <50%) and reported sensitivity and positive predictive value (PPV). Input data variability was assessed by analyzing test-retest differences in isophonemes scores. Results Binary classification models achieved sensitivity of 90.4% with PPV 80.2% at CNC 50/AzBio 60, outperforming referral heuristics (60/60 and 75/40). Applying the models to 50 700 historical audiograms identified 525 patients at PPV 90% (sensitivity 58%), 396 at PPV 94% (sensitivity 44%), and 1582 at PPV 71% (sensitivity 94%). Variability analyses indicated that attainable precision is bounded by noise in key predictors. Conclusion This study demonstrates how AI models can be translated into clinically actionable tools by reformulating regression outputs, selecting metrics aligned with clinical priorities, and addressing data variability. These strategies provide a scalable framework for implementing AI in health care and improving decision-making in diverse clinical contexts.

Failed pediatric endotracheal intubation, prompting surgical airway management via emergency front of neck access (eFONA), is an intrinsically challenging topic. While rare, all emergency airway providers must be equipped to handle these complex clinical scenarios, both through initial training and maintenance of competency. Needle cricothyrotomy is a commonly taught method in cannot intubate cannot oxygenate (CICO) scenarios for children under age eight. However, needle cricothyrotomy is technically difficult, profoundly rare, and maintaining competency is a challenge. From a multidisciplinary perspective, we examine the utility of continuing to teach needle cricothyrotomy and explore alternatives. This project group suggests that pediatric eFONA training across disciplines should focus on surgical tracheotomy rather than needle cricothyrotomy, with consideration given to specialty-specific human performance factors.

Abstract The role of DNA topoisomerase II beta (TOP2B) in cardiomyocyte differentiation is poorly understood. To address this, Human induced pluripotent stem cells (hiPSC) were differentiated into cardiomyocytes (CM) that are wildtype or contain a genomic deletion of Topoisomerase 2B (BKO). Both WT and BKO hiPSC could be induced to differentiate into sheets of beating cardiomyocytes. BKO hiPSC take slightly longer to differentiate into sheets of beating CM than WT iPSC. RNA was prepared from both undifferentiated and differentiated WT and BKO hiPSC. RNA seq was used to examine gene expression changes when the WT and BKO hiPSC were differentiated into CM. Gene expression changes following differentiation of BKO cells were largely similar to those in WT cells. In addition, the differentiated WT CM were treated with dexrazoxane (ICRF-187), a TOP2 catalytic inhibitor that targets both TOP2A and TOP2B, or topobexin, a new TOP2B selective catalytic inhibitor. Topobexin inhibition partially phenocopied a TOP2B deletion and thus providing an alternative to TOP2B gene knockout in many cell lines. In future, hiPSC derived CM with and without TOP2B and inhibition by topobexin ex vivo CM could be used to study anthracycline-induced cardiotoxicity and to screen for cardioprotectants. Highlights Used CRISPR-Cas9 to delete TOP2B from hiPSC Produced beating cardiomyocytes from both WT and TOP2B null hiPSC Transcriptome analysis of WT and TOP2B null hiPSC and derived cardiomyocytes RNA seq showed he specific TOP2B inhibitor topobexin largely phenocopies TOP2B gene inactivation in iPSC derived cardiomyocytes. Topobexin inhibition could be used as an alternative to a TOP2B gene knockout in many different cell types, speeding up the analysis of the function of TOP2B.

Bruton tyrosine kinase inhibitors (BTKis) and BCL2 inhibitor (BCL2i)–containing regimens significantly improve survival outcomes in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Results from randomized clinical trials have demonstrated that time-limited treatment with BCL2i-containing regimens resulted in higher rates of undetectable measurable residual disease (uMRD) than BTKi monotherapy or chemoimmunotherapy (CIT). Pirtobrutinib (a noncovalent BTKi) and lisocabtagene maraleucel (CD19-directed CAR T-cell therapy) are newer options for relapsed or refractory disease after prior therapy with BTKi and BCL2i-contining regimens. Histologic transformation of CLL/SLL to diffuse large B-cell lymphoma (Richter transformation) is associated with a poor prognosis. Molecular analysis to determine whether there is clonal relationship between CLL/SLL and transformed diffuse large B-cell lymphoma is useful to select an appropriate treatment option. These NCCN Guideline Insights highlight significant updates to the NCCN Guidelines for the treatment of CLL/SLL and Richter transformation.

Purpose Survivors of critical illness often acquire significant physical, cognitive, and psychological burdens following their intensive care unit (ICU) stay, termed “post-intensive care syndrome” (PICS). Screening for PICS is generally not performed outside of research settings largely due to lack of a simple assessment tool and time constraints. Methods This was a prospective cohort study at a single academic medical center in the USA. We included adults (18 years or older) who spent greater than 48 h in any ICU within the medical center. Following transfer out of the ICU and at 3 months, psychological, cognitive, and physical functioning were assessed using the Hospital Anxiety and Depression Scale, Impact of Event Scale-Revised, Montreal Cognitive Assessment-blind, and Barthel Index. We compared these validated questionnaires to a brief, 15-item PICS screening tool (5 questions/domain) that was developed by our multidisciplinary study team and administered to study participants after ICU discharge to general care. The primary objectives of this study were to assess the ability of validated screening tools administered at ICU discharge to predict PICS at 3 months and develop a novel screening tool for identifying patients at risk of PICS. Major Findings 191 participants completed the initial questionnaire, and 109 (56%) completed the 3-month follow-up. PICS tool scores were compared to 3-month follow-up data from validated questionnaires to evaluate predictive performance. Overall, the screening tool weakly-to-moderately correlated with continuous outcomes of the validated measures at 3-month follow-up. When evaluating sensitivity and specificity for individual domains, the screening tool had an area under curve of >0.7 for all three domains, indicating moderate-to-good sensitivity and specificity. Conclusions We developed a brief PICS screening tool that is feasible to use without prior training that modestly predicted the development of PICS following ICU stay.

Summary Family history of haematological malignancy (FHHM) reflects inherited susceptibility to non‐Hodgkin lymphoma (NHL), but its prognostic significance remains poorly understood. We used a cohort study of 1994 NHL patients to evaluate associations between FHHM and clinical outcomes across lymphoma subtypes. We estimated associations, adjusted for sex and lymphoma‐specific prognostic index, of self‐reported FHHM in a first‐degree relative with overall survival (OS), event‐free survival (EFS) and lymphoma‐specific survival (LSS) using multivariable Cox regression models and with failure to achieve EFS at 24 months (EFS24) using logistic regression. FHHM prevalence was 12.8%, and the median follow‐up among survivors was 12.0 years. FHHM was not associated with OS. In subtype‐specific analyses, FHHM was associated with inferior LSS (hazard ratio [HR] = 1.98, 95% confidence interval [CI] 1.11–3.53) in follicular lymphoma (FL); this association and the association with EFS24 failure strengthened among those treated with front‐line immunochemotherapy (EFS24 failure odds ratio = 2.57, 95% CI 1.08–5.99; LSS HR = 2.68, 95% CI 1.09–6.58). In mantle cell lymphoma, FHHM was associated with inferior EFS (HR = 1.70, 95% CI 1.02–2.85). Interaction testing did not demonstrate significant heterogeneity of FHHM effects by lymphoma subtype. FHHM may be associated with adverse outcomes in select NHL groups, particularly FL. These findings warrant further investigation of germline and environmental factors potentially contributing to more aggressive FLs.