Citations

Polycystic kidney disease (PKD) arises from mutations in cilia-associated genes, such as PKD1 and PKD2 , expressed in renal epithelial cells, leading to progressive kidney dysfunction and end-stage kidney disease (ESKD). PKD patients exhibit significant heterogeneity in disease progression, largely due to genetic and environmental modifiers. Like patients, mouse models of PKD also exhibit significant heterogeneity with regards to the gene mutated, age of disease onset, and rate of disease progression. To elucidate the cellular and molecular consequences of these variables, we constructed an integrated single-cell RNA sequencing atlas across mouse models of PKD, mapping changes in cell type composition, gene expression, and intercellular signaling networks across the whole atlas and within individual models. Across models, single cell RNA sequencing (scRNAseq) data revealed increased Spp1 (osteopontin) expression and signaling from PKD-enriched clusters. Global deletion of Spp1 in Pkd1 RC/RC mice resulted in a modest reduction in cyst severity and improved kidney function. From these studies, we created a freely available, searchable website (https://bmblx.bmi.osumc.edu/scPKD/) that can be used to identify cross- and intra-model changes in gene expression, guiding researchers to new therapeutic targets for treating PKD.

Abstract Inflammation is a key driver of coronary syndromes across the continuum from chronic coronary syndromes to acute coronary syndromes. It contributes to atherogenesis, plaque destabilization, and ischaemic events and influences myocardial injury, repair, and remodelling. Inflammatory activity is further amplified by metabolic and autoimmune comorbidities such as diabetes, obesity, and connective tissue diseases, with obesity representing a major driver of chronic low-grade inflammation through adipose tissue dysfunction and cytokine activation, while psychosocial stress and environmental exposures including air pollution serve as additional triggers. Genetic variations, including human leucocyte antigen genotypes, modulate individual susceptibility to vascular inflammation and myocardial injury. This expert consensus from the European Society of Cardiology’s Association for Acute CardioVascular Care summarizes the current understanding of inflammation across the full spectrum of coronary syndromes, including underlying mechanisms, relevant biomarkers, and imaging approaches that characterize vascular inflammation, and integrates insights from experimental and clinical studies. Importantly, this document provides explicit consensus-based guidance on when, how, and in whom inflammation should be assessed and treated in routine clinical practice. While the causal association between inflammation and atherosclerotic cardiovascular disease is well established, pharmacological modification of inflammation has produced conflicting evidence. Some agents, such as low-dose colchicine, have demonstrated modest reductions in cardiovascular events, although results across trials have been inconsistent. Other anti-inflammatory therapies have not shown clinical benefit, whereas selective cytokine inhibition with canakinumab has reduced cardiovascular risk at the cost of increased infection rates. The present manuscript also focuses on the evaluation of inflammatory activity in cardiovascular patients in routine clinical practice. It further discusses criteria for patient selection and clinical decision-making regarding the introduction of anti-inflammatory therapy in individuals with established atherosclerotic cardiovascular disease.

Abstract Objectives Erdheim-Chester disease (ECD) is one of 3 major types of histiocytic neoplasms, along with Rosai-Dorfman disease and Langerhans cell histiocytosis. It was first recognized as a neoplasm in the 2016 World Health Organization Classification of Haematolymphoid Tumours. About 80% to 90% of cases harbor MAPK pathway mutations. Methods We discuss the diagnosis of ECD using 3 illustrative cases, consider interpretative challenges, and present a diagnostic algorithm. Results Erdheim-Chester disease is a systemic disease that shows a characteristic pattern of organ involvement including bone, perinephric soft tissue, skin, heart, and central nervous system. Histologically, ECD shows a spectrum of xanthogranulomatous, lymphohistocytic, or fibrohistiocytic infiltrates. By immunohistochemistry, the neoplastic histiocytes have a macrophage phenotype with expression of CD163, negative to focal S100, and negative CD1a and langerin. These features alone are not specific and thus insufficient for diagnosis. Immunohistochemistry for cyclin D1 and BRAF V600E, correlation with clinical and imaging findings, and mutational analysis for MAPK pathway mutations all play important roles in establishing an ECD diagnosis. Conclusions The diagnosis of ECD is often challenging due to its clinical and histologic overlap with reactive inflammatory processes. Correlation of histology features with clinical findings, immunohistochemistry, and genetic studies is essential for an accurate and timely diagnosis.

Heart rate variability (HRV) is a widely utilized approach for investigating cardiovascular health and human performance. Methodological approaches, analyses, and interpretations of HRV can vary extensively, and scientific debates on HRV reliability and utility remain. These debates have been amplified in recent years by the rapid growth and ubiquity of wearable devices, and their incorporation into scientific research studies. The present guidelines paper takes an evidence-based approach to propose more consistent and rigorous measurement and interpretation of HRV within human cardiovascular research and application. First, HRV has some utility as a cardiovascular risk stratification tool, but is not appropriate to employ as a specific marker of cardiac sympathetic outflow or sympathovagal balance. While time-domain and spectral analysis can more accurately reflect respiratory modulation of cardiac vagal (parasympathetic) activity, caution is necessary to avoid overinterpretation, particularly with respect to the concept of “vagal tone”. Numerous experimental, demographic, and environmental factors influence HRV assessment, interpretation, and reliability. Specifically, it is critical to account for non-modifiable (age, sex, race/ethnicity, etc.) and modifiable (i.e., exercise, physical fitness, etc.) factors within participant samples. Furthermore, technical approaches such as the HRV input signal (e.g., electrocardiography vs. photoplethysmography), length of recording, location of recordings (i.e., laboratory vs. field), respiratory rate and depth, and analytical approaches (i.e., time vs. frequency domain) can all impact rigor, reliability, and study interpretations. Finally, with respect to the rapid advancements of HRV assessment using wearable technology, investigators should interpret and contextualize findings within the limitations outlined in this guideline review.

ABSTRACT Beta‐lactam antibiotics (beta‐lactams) are first‐line treatments for most major infectious syndromes in acutely ill patients, with in vitro activity against common pathogens, demonstrated efficacy in trials, and a perceived low risk of adverse effects. The current dosing approach, informed by population‐level data, tends to be simplistically reduced to a “one size fits all” dosing method which only accounts for body weight (i.e., in pediatrics) and end organ function to estimate drug clearance (e.g., estimated glomerular filtration rate); this approach results in substantial variability in observed serum concentrations in acutely ill patients, which can compromise real‐world effectiveness and safety. Beta‐lactam dose individualization, therefore, defined as a dosing regimen for one patient informed by measured concentrations from that patient, has been recommended in international clinical guidelines. Comprehensive guidance on best practices for beta‐lactam dose individualization is lacking. To address this knowledge gap and develop guidance, a multidisciplinary panel of international experts was assembled from the disciplines of infectious diseases, critical care, pharmacometrics, and laboratory medicine, representing both adults and pediatrics. The panel systematically evaluated the literature, using the GRADE approach where feasible, to address broad thematic questions pertaining to whether beta‐lactam dose individualization should be pursued, for what indications beta‐lactam dose individualization is warranted, and the most critical considerations and best practices for implementation of beta‐lactam individualization. The resultant consensus recommendations will equip healthcare professionals caring for acutely ill patients treated with beta‐lactam therapy with the evidence and tools necessary to guide optimal use of beta‐lactam dose individualization.

Background Lumbar facet arthropathy (LFA) is a degenerative, arthritic joint disorder and a common specific cause of axial low back pain and functional impairment. Currently, no disease-modifying therapies are available for symptomatic LFA. Mesenchymal stem/stromal cell (MSC)-based therapy represents an emerging regenerative treatment modality with the promise to target the underlying pathophysiology of LFA. Despite encouraging clinical evidence supporting the safety and efficacy of MSC therapy in other osteoarthritis, its therapeutic utility in LFA remains largely unexplored. We recently completed a prospective, single-arm, open-label phase I clinical trial that demonstrated a favourable safety profile and preliminary clinical benefit following intra-articular administration of bone marrow-derived MSCs (BMSCs) in patients with symptomatic LFA. Building on these findings, we present the protocol for CellKine II , a prospective, randomised, double-blind, placebo-controlled, cross-over phase II clinical trial to evaluate the safety and preliminary efficacy of intra-articular delivery of allogeneic, culture-expanded BMSCs in patients with painful LFA. Methods and analysis This study is a single-centre, randomised, double-blind, placebo-controlled, cross-over phase II trial with a target accrual of 40 patients. Eligible patients will be randomly assigned in a 1:1 ratio to receive a single intra-articular injection of either Arm A: BMSC or Arm B: Placebo (dimethyl sulfoxide). At the 6-month follow-up, all patients will be unblinded. Patients initially randomised to Arm A will continue follow-up for up to 12 months. Patients initially randomised to Arm B may cross over to receive the BMSC treatment, followed by an additional 12 months of post-BMSC treatment follow-up, or they may continue observation for another 6 months without BMSC treatment. Overall, each patient will be followed up to 12 months after BMSC treatment. The primary endpoints are back pain, functional outcomes and adverse events at 6 months post-randomisation. Ethics and dissemination This study will be conducted in compliance with U.S. federal regulations and Mayo Clinic institutional research policies and procedures. The protocol has been approved by the Mayo Clinic Institutional Review Board (IRB) and the Data Safety Monitoring Board (IRB No. 21-013278). The results of this trial will be disseminated through publication in peer-reviewed journals and on ClinicalTrials.gov. Trial registration number NCT06001853 .

Abstract Background Breast cancer is etiologically heterogeneous, but which risk factors differ in their associations across tumor subtypes remains unclear. We conducted a large, pooled analysis to evaluate independent, dose-response associations between breast cancer risk factors and quantitative tumor features. Methods Analyses of 15,731 invasive breast cancers from 24 studies evaluated associations (p-trend) between reproductive and hormonal factors, body mass index (BMI), alcohol, smoking, and family history in relation to quantitative immunohistochemistry measures on tissue microarrays (ER, PR, HER2, KI67, TP53) and tumor grade. Analyses in a subset of 10 population-based studies estimated subtype-specific odds ratios (ORs) comparing cases to controls. A Bayesian False Discovery Probability (BFDP) <0.2 was used to identify associations with strong statistical evidence. Results Nulliparity and later age at menopause were associated with higher ER-positivity (p-trend=0.021 and 0.001, respectively), with corresponding OR[ER+] (95% CI) = 1.49 (1.16-1.90) for nulliparous vs. parous and 1.07 (1.03-1.11) per 5 years. Current combined menopausal hormone therapy (MHT) use was associated with lower grade (p-trend<0.001), with OR [grade1] = 3.37 (2.69-4.21) for current vs. never users. Higher BMI was associated with lower ER-positivity and higher grade in premenopausal women (p-trend<0.001 and <0.001), with OR[ER+] = 0.80 (0.74-0.87) and OR[grade1] = 0.75 (0.63-0.88) per 5 units, and with higher PR-positivity and higher grade in postmenopausal women (p-trend<0.001 and <0.001), with OR[PR+] = 1.08 (1.03-1.14) and OR[grade 3] = 1.10 (1.04-1.17) per 5 units. Conclusion This pooled analysis of 15,731 cases showed that nulliparity, age at menopause, MHT, and BMI have independent, dose-response associations with ER, PR, and grade, clarifying patterns of etiologic heterogeneity. Associations with HER2, KI67 and TP53, or other risk factors did not meet our threshold for strong evidence.

Background: We had a large-scale measles exposure event affecting 626 patients. Management of exposed patients was urgent, involving quarantine, post-exposure prophylaxis (PEP), and symptom monitoring on a case-by-case basis. Cases were initially tracked and managed using a combination of multiple spreadsheets amongst stakeholders as well as lists within the electronic health record (EHR). Using shared spreadsheets and lists created significant challenges with maintaining and editing multiple copies and updating workbooks simultaneously. Methods: Infection Prevention and Control (IPAC) worked with primary care personnel and EHR developers to create a shared registry that would prioritize communication and follow-up for exposed patients based on age and immunity. Patients are initially added to the shared registry within the EHR by reviewing non-registry reports and tagging patients, identified using exposure timeframes that overlapped with the index measles cases, in a manner that transferred them to the shared registry. From this registry, measles, mumps, and rubella vaccine status can be confirmed, immune status can be identified, and criteria for PEP assigned. High-risk patients are then contacted with recommendations from IPAC and primary care. Communication and follow-up are tracked directly within the shared registry to ensure appropriate patient management. The exposure management registry is further leveraged throughout the measles outbreak timeframe by allowing real-time monitoring of patients that require additional precautions or guidance related to their exposure. Result: The shared registry enhanced documentation accuracy and transparency between stakeholders. It led to availability of real-time status of exposed patients for the duration of the measles outbreak timeframe. Overall, the registry enabled time-sensitive patient communication to all exposed patients and rapid identification of those who needed PEP. Communication could happen rapidly and seamlessly between care teams within the organization, and the necessary information could be shared quickly with public health authorities as required. Conclusion: Large scale exposures are a challenge to manage and ensure appropriate action and communication occurs. Errors can be prevented by having a single shared exposure management registry. A registry enables care teams to quickly identify and prioritize patients for measles follow-up, communication, PEP, and ongoing management across outbreak timeframes. This process reduces both time and operational burdens of exposure follow-up tracking outside of the EHR.

Abstract Introduction Underwater endoscopic mucosal resection (uEMR) technique has gained popularity for removal of large non-pedunculated colorectal polyps (LNPCPs) due to high en-bloc resection rates and lower recurrence rates. However, there is no information regarding outcomes of uEMR for giant colorectal polyps. Therefore, we aimed to evaluate the outcomes of uEMR for giant colorectal polyps across multiple centers in North America. Methods We conducted a multicenter retrospective study of adults with giant colorectal polyps undergoing uEMR between January 2019 and November 2025. Giant colorectal polyps were defined as LNPCPs ≥40 mm. Primary outcomes were technical success and rate of recurrent adenoma. Secondary outcomes were severe adverse events (SAEs) and predictors of technical success, recurrence, and SAEs. Results A total of 137 polyps, with mean polyp size 47.6 mm were included. Majority of the lesions were located in right colon (61%, n = 83) with the most common histopathology being high-grade dysplasia (HGD) (31.4%, n = 43). Technical success was achieved in 90.5% (n = 124) with en-bloc resection rate of 11.7% (n = 16). Polyp fibrosis (OR: 0.08) and HGD (OR: 0.15) were independent predictors of inability to achieve technical success. Of 92 (67.1%) patients with follow-up, recurrent polyp was present in 8.7% (n = 8). SAEs were noted in 9.5%, consisting of delayed bleeding (9.5%, n = 13), while no delayed perforation or post polypectomy syndrome was noted. Discussion Our study demonstrates that uEMR is technically feasible for the removal of giant colorectal polyps with an acceptable safety profile and recurrence rate.