Citations

Abstract Importance Mesenchymal stromal cells (MSCs) possess therapeutic properties that mediate repair. Obesity impairs MSC functionality and therapeutic efficacy, possibly by eliciting dynamic modifications of epigenetic markers, like 5-hydroxymethylcytosine (5hmC). Objective We hypothesized that human obesity alters the 5hmC landscape and anti-inflammatory capacity of adipose tissue-derived MSCs to activate the prominent inflammatory signaling mediator Interleukin (IL)-1β. Design, Setting, Participants, Intervention Adipose tissue samples were collected from obese and lean individuals (body mass index ≥30 or <30 kg/m2, respectively, n = 11 each) during weight-loss or kidney donation surgery. Main Outcomes and Measures MSCs were harvested and analyzed for 5hmC profiles (MeDIP-seq) and mRNA expression (RNA-seq) (n = 5 each). Subsequently, MSCs or a vehicle were injected into mice, (n = 6 each) and two-weeks later, kidneys were evaluated using in-vivo magnetic resonance imaging and ex vivo studies. The role of IL-1β was then studied in-vitro in MSC-induced immunomodulation using siRNA in macrophages. Results Compared to MSC from lean patients, obese-MSC genes showed 2087 differential 5hmC modifications and 175 differential mRNA expression. Among them, 14 genes with overlapping alterations were involved in regulation of cytokine production, prominently IL-1β. Injecting obese MSCs elevated renal expression of IL-1β and M1 macrophage count but lowered kidney perfusion. Silencing IL-1β in obese-MSCs in vitro reduced M1 phenotype switching in co-incubated macrophages. Conclusions and Relevance Obesity induces epigenetic and gene expression changes in MSCs, particularly in IL-1β, associated with impaired anti-inflammatory functionality of MSCs. Targeting IL-1β could be a useful therapeutic approach to modulate the decline in MSC functionality resulting from obesity.

Abstract Traumatic brain injury (TBI) can lead to chronic complications, including headache and facial hypersensitivity. Second-impact syndrome (SIS), occurring when a second TBI precedes recovery from an initial injury, often causes severe long-term symptoms. Neuroinflammation is implicated, but the comprehensive pathophysiology of SIS remains unclear. This study characterized neurological/behavioral outcomes, facial nociception, plasma inflammatory markers, and central nervous system (CNS) histopathology in rat models of SIS and single mild TBI. Female Wistar rats (n = 6/group) were assigned to naïve control, sham surgery, single impact (TBI), or double impact (SIS; intervals: 1h, 24h, 3d, 7d, 14d). Mild TBI was induced using a modified Marmarou weight-drop model. Assessments (facial mechanical sensitivity via von Frey, Neurological Severity Scale (NSS), Neurobehavioral Scale (NBS)) were performed pre-injury and on days 1,3,5,7 post-injury. Plasma IL-6 and TNF-α were measured by ELISA. Histopathology (H&E) assessed CNS inflammation. All impact groups developed transient facial mechanical allodynia and acute neurobehavioral deficits (impaired NSS/NBS at day 1). SIS groups, particularly with longer intervals (≥ 24h), exhibited more prolonged facial allodynia and significant neurological deficits compared to single TBI at specific timepoints. Plasma cytokines showed minimal changes. Histopathology revealed significantly elevated CNS inflammation in both TBI and SIS groups versus controls, with SIS groups (intervals 24h-14d) showing robust responses. Repeated TBI, especially with longer recovery intervals between injuries, results in more severe and prolonged facial allodynia, neurological deficits, and CNS neuroinflammation than a single mild TBI. These findings illuminate SIS pathophysiology and underscore the critical need for protection post-concussion.

ABSTRACTBackgroundErenumab‐induced medication overuse headache (MOH) remission in participants with chronic migraine (CM) in a prospective, Phase 4, randomized, placebo‐controlled trial with an open‐label treatment period (OLTP). We present 1‐year results from the combined double‐blind treatment period (DBTP) and OLTP for the stratified nonopioid cohort.MethodsParticipants with CM‐MOH were randomized 1:1:1 to subcutaneous 70 or 140 mg erenumab every 4 weeks (QM) or placebo for the initial 24 weeks (DBTP). Those successfully completing DBTP could continue the 28‐week OLTP, maintaining the same erenumab dose received during DBTP or, if receiving placebo, randomly assigned 1:1 to erenumab 70 or 140 mg QM. OLTP endpoints were exploratory.ResultsOverall, 552 participants received erenumab (70 mg, n = 274; 140 mg, n = 278); 95.3% completed OLTP. One‐year MOH relapse in participants who achieved MOH remission at DBTP Month 6 was 2.7% (3/111) and 2.4% (3/124) with erenumab 70 and 140 mg, respectively; absence of MOH at study end was observed in 69.0% (189/274) and 75.5% (210/278) of participants. Sustained MOH absence over 1 year was reported in 60.5% (107/177) and 68.8% (119/173) of participants, respectively. Sustained improvements in measures of headache days, medication days, and function were observed in both groups. No new safety concerns were identified (grade ≥ 3, 35 [6.3%]; serious, 17 [3.1%]; adverse events leading to treatment discontinuation, 5 [0.9%]).ConclusionsErenumab was effective in inducing and sustaining MOH remission and improving function over 1 year. Treatment compliance remained high, with safety events consistent with erenumab's known safety profile.Trial RegistrationNCT03971071

ABSTRACT Background Acute pulmonary embolism (PE) is one of the most common causes of cardiovascular mortality in the United States. Significant variations in the management of various cardiovascular conditions have previously been reported, but this has been poorly elucidated for pulmonary embolism. Methods During 2016–2020, adult (≥ 18 years) nonelective admissions with PE, admitted to Northeast, Midwest, South, and West geographic regions were identified using the National Inpatient Sample. Outcomes of interest included in‐hospital mortality, utilization of PE therapies, non‐cardiac organ support, total hospitalization costs, and hospitalization duration. Results In this 5‐year duration, 904,260 admissions were identified ‐ Northeast, Midwest, South, and West had 166,050 (18.3%), 225,680 (24.9%), 350,160 (38.7%), and 162,370 (17.9%) admissions, respectively. On average, admissions to the Northeast were less comorbid, from a higher socioeconomic status, privately insured, and more commonly admitted to urban teaching and medium‐sized hospitals (all p < 0.001). The Northeast region also had the lowest rates of definitive PE therapies except surgical thrombectomy. In comparison to the Northeast, the in‐hospital mortality was higher in the South and West and lower in the Midwest region (3.1% vs 2.8% vs 3.2% vs 3.3%, p < 0.001). However, on adjusted analysis with Northeast as a reference, in‐hospital mortality was noted to be lower in the Midwest (adjusted odds ratio [aOR] 0.98, 95% confidence interval [CI] 0.67−0.84; p < 0.001), South (aOR 0.89, 95% CI 0.80−0.98; p < 0.05), and the West (aOR 0.88, 95% CI 0.78−0.99; p < 0.05). Conclusion In this study, we noted significant heterogeneity in the management and outcome of pulmonary embolism across various regions of the United States.

Abstract Dravet syndrome is a severe developmental and epileptic encephalopathy caused by heterozygous, loss‐of‐function, pathogenic variants in the SCN1A gene. It is characterized by frequent, often prolonged convulsive seizures. Dravet syndrome is associated with diverse comorbid conditions, including developmental impairment, intellectual disability, and behavioral disturbances, in addition to high mortality rates. Prompt diagnosis and treatment initiation are essential to reduce seizure frequency, status epilepticus, and potentially improve neurodevelopmental outcomes. Currently available therapies such as fenfluramine, stiripentol, and cannabidiol have demonstrated significant reduction in convulsive seizure frequency, based on randomized controlled trials and real‐world studies; however, they have not markedly affected non‐seizure symptoms. Emerging therapies such as genetic modulation are promising given their potential for disease modification, seizure frequency reduction, and improvement of non‐seizure outcomes. This review of observational studies and randomized clinical trials provides an overview of the natural history of Dravet syndrome, current treatment guidelines with recently approved medications, addressing both safety and efficacy, and new therapeutic approaches, including disease‐modifying therapies. The therapeutic landscape in Dravet syndrome is evolving, with the use of new antiseizure agents and precision therapies that target the SCN1A variant. Goals of treatment include improvement of seizure burden, neurodevelopment, comorbidities, and quality of life in individuals with Dravet syndrome.

AbstractInterruptive alerts can negatively impact clinical workflows and contribute to alert fatigue, provider frustration, and burnout. Given that interruptive alert overriding is a heterogeneous and recurring phenomenon, occurring across different organizational contexts with varying characteristics and circumstances, we hypothesize a pragmatic approach with multimodal interventions to address malfunctioning alert populations and maintain those contributing to better patient care.This study aimed to develop a systematic approach to screen, identify, and correct malfunctioning interruptive alerts within a tertiary healthcare system.We performed screening by assessing the alert population, exploring available resources, and defining alert population inclusion and exclusion criteria. We identified interruptive alerts and then conducted an exploratory analysis. We shared insights from discussions with our expert panel to validate our findings and find gaps in current alert monitoring. We then performed focus groups and interviews as part of a root cause analysis. To address the findings of these investigations, we prioritized which alerts to improve, evaluated solutions, and recommended steps to improve our governance structure.We developed an approach to assess around 1,500 unique alerts in a tertiary center from January to June 2023. We introduced two approaches to visually analyze alert populations: alert-focused analysis and people- and systems-focused analysis. We utilized an expert panel to further enhance the power and speed of alert evaluation and then investigated one emerging alert with focus groups, identifying root causes for its malfunction. This alert demonstrated how enterprise practice changes, coupled with design and cultural issues, can trigger significant alert malfunctions.A multi-modal intervention approach is needed to evaluate interruptive alerts and act quickly on findings. Utilizing both analytical and nonanalytical methods can work in synergy to facilitate this framework. Such approaches may reduce time and be valuable tools for optimally allocating resources to tackle institutional alert challenges.

Abstract Background Patients living with diabetes and chronic conditions may face significant burden managing their health. Many of these patients use digital medicine tools such as continuous glucose monitoring systems. Although measures exist to assess treatment burden from tasks such as managing medications and attending healthcare visits, there is no patient-reported measure that captures the burden of digital care. Therefore, the purpose of this study is to validate the Treatment Burden Questionnaire Plus Digital (TBQ + D), a patient-reported measure of treatment burden that includes using digital tools for adults with diabetes. Methods Adult patients with type 1 or type 2 diabetes mellitus completed the 25-item TBQ + D (scored 0 [none] to 10 [maximum] per item; total score range 0–250). We evaluated ease of administration, internal consistency, and tested hypotheses about the relationship between TBQ + D scores and treatment complexity, digital tool use intensity, social risk factors, and digital comfort to assess TBQ + D’s validity. Results Of 324 patients approached, 300 (93%) consented and completed the TBQ + D (mean age 57 [SD 17]; 50% female; 50% with type 2). The mean TBQ + D score was 53.7 (SD 41.6). Internal consistency was excellent (Cronbach’s α = 0.94). As hypothesized, higher TBQ + D scores were reported by patients with type 1 vs. type 2 diabetes mellitus (61.7 vs. 45.7; p = .0008), maximal/moderate vs. minimal to no digital tool use (56.5/60.7 vs. 41.3; p = .001), those on intensive insulin therapy vs. other treatments (61.4 vs. 38.0; p < .0001), and those with greater social vulnerability (p < .0106). TBQ + D scores were not significantly higher in patients with HbA1c ≥ 8% (p = .055) or less comfortable with digital technology (p = .08). Conclusions TBQ + D is a novel and valid measure of treatment burden in patients living with diabetes, inclusive of digital burden, that can play a role in fostering minimally disruptive care for patients with diabetes.

Abstract Background The incidence, epidemiology, and clinical characteristics of enterococcal bloodstream infection (BSI) have not previously been studied on a population-based level in the United States. Methods We utilized the Expanded Rochester Epidemiology Project medical records linkage system to conduct a contemporary 5-year, retrospective, population-based study of monomicrobial enterococcal (ME) BSI among adult residents of 8 counties in southeast Minnesota from January 1, 2018 to December 31, 2022. Results A total of 109 cases of ME-BSI were identified. The overall age- and sex-adjusted incidence rate was 6.7 per 100 000 person-years (95% confidence interval, 5.4–7.9). Multivariable analysis revealed that male sex (P &lt; .001) and older age (P &lt; .001) were each independently associated with increased incidence, whereas no temporal association was demonstrated (year effect, P = .475). The median age of incident cases was 76.8 years (interquartile range, 65.0–83.3). Urinary tract source was the most common presumed source (42.2%), and Enterococcus faecalis was the predominant (83.5%) pathogen. Overall, 14.4% of patients met modified Duke criteria for definite infective endocarditis. Cumulative mortality was 28.4% at 12 weeks and 43.1% at 1 year. Conclusions In this population-based study, ME-BSI was significantly associated with older age and male sex. There was a high rate of mortality at 12 weeks and 1 year, with ∼1 out of 7 cases complicated by definite infective endocarditis. These findings underscore the importance of ongoing investigation of this syndrome.