Citations

Abstract Front-line pharmaceutical interventions for treating acute graft-versus-host disease (GVHD) are not uniformly effective and have toxic side effects. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells with potent in vitro and in vivo immunosuppressive functions. Clinical translation of in vitro–generated MDSCs has been limited because of requirements for multiple, high infusion doses, the relatively low yield from peripheral blood–sourced MDSCs (PB-MDSCs), and inconsistent product quality. To circumvent these obstacles, we developed a methodology to generate MDSCs using human induced pluripotent stem cell (iPSC)–derived CD34+ cells. Compared with PB-MDSCs, iPSC-derived MDSCs (iMDSCs) shared similar morphology, phenotype, and suppressive function. We found that the CD14+ iMDSC subset possessed the highest suppressor function. In previous studies, we reported that MDSCs transferred into mice with GVHD lost suppressor function because of inflammasome activation and immature myeloid cell maturation. In striking contrast to human PB-MDSCs, we show herein that iMDSCs retained 95% of suppressor function in vitro despite exposure to lipopolysaccharide (LPS) plus adenosine triphosphate (ATP), which are stimuli that activate the inflammasome via danger-associated molecular patterns released during early posttransplant conditioning and GVHD-induced injury. In an in vivo xenogenic GVHD model with PB mononuclear cells, iMDSCs significantly increased recipient survival without loss of antileukemia effects. iMDSC RNA sequencing and gene knockdown studies revealed that the maintenance of the purine metabolizing enzyme, phosphoglycerate dehydrogenase, during LPS plus ATP treatment, was linked to iMDSC inflammasome resistance. Taken together, these findings provide a platform for translating in vitro–generated, off-the-shelf iMDSCs into the clinic for suppressing a spectrum of adverse immune responses, including GVHD.

Background and Objectives: Heart failure (HF) represents a major public health challenge worldwide, with rising prevalence, high morbidity and mortality rates, and substantial healthcare costs. Non-invasive telemonitoring has emerged as a promising adjunct in HF management, yet its clinical effectiveness remains unclear. Materials and Methods: In this systematic review, we summarize randomized controlled trials (RCTs) between 2004 and 2024 examining the efficacy of non-invasive telemonitoring on mortality, readmission, and quality of life (QoL) in HF. In addition, we characterize the heterogeneity of features of different telemonitoring interventions. Results: In total, 32 RCTs were included, comprising 13,294 participants. While some individual studies reported benefits, non-invasive telemonitoring demonstrated mixed effects on mortality, readmission rates, and QoL. The most common modality for interfacing with patients was by mobile application (53%), followed by web portals (22%), and stand-alone devices (19%). Periodic feedback (63%) was more common than continuous feedback (31%) or on-demand feedback (6%). Clinician reviews of patient telemonitoring data was event-triggered (44%) more commonly than based on a prespecified timeline (38%). In most designs (90%), patients played a passive role in telemonitoring. Conclusions: Non-invasive telemonitoring interventions for HF exhibited considerable variation in duration and system design and had a low rate of patient engagement. Future work should focus on identifying telemonitoring-responsive subgroups and refining telemonitoring strategies to complement traditional HF care.

Abstract Objective To assess the localization and lateralization values of ictal emotional features and ictal defensive behaviors in pediatric and young adult patients with frontal lobe epilepsy (FLE). Methods Children and young adults with FLE were identified from a single institution's epilepsy surgery database. Two epileptologists determined by consensus the presence of ictal emotional features (positive‐ smile, laughter, humming, singing; negative‐ fear, crying, anger, disgust, contempt, sadness) and ictal defensive behaviors (freezing with a fearful facial expression, shielding the face with hands, burying the face in a pillow, or exhibiting hyperkinetic motor behaviors like attempting to escape from bed or resisting restraint) in each patient's first video EEG (vEEG). Historic seizure semiology and vEEG reports were compared with the consensus vEEG analysis. Longitudinal changes in ictal emotional features were defined by the emergence or resolution of ictal emotional features between historic seizure semiology and re‐review of presurgical vEEG analysis. Subgroup analyses were conducted according to the seizure lateralization (left vs. right) and sublobar localization (precentral, medial, lateral, extensive) based on surgical extent. Results Twenty‐three FLE patients were included (female 39%; mean age at vEEG analysis: 11.28 years, range 1.75–20.17). The inter‐rater reliability was very good for both ictal emotional features ( κ = 0.81, 95% CI: 0.59–1) and ictal defensive behaviors ( κ = 0.91, 95% CI: 0.79–1). Ictal emotional features were observed in 10 patients (43.4%), with negative emotions present in 70% (7/10) of these cases. vEEG reports lacked documentation of ictal emotional features in two patients. Although ictal emotional features showed no statistical correlation by sublobar regions, ictal defensive behaviors were consistently seen in medial compared to lateral FLE (100% vs. 16.6%; p = 0.004). Longitudinal changes in ictal emotional features were observed in 8 (34.7%) patients. Significance Ictal emotional features were common in pediatric and young adult FLE patients and were mainly negative. Ictal defensive behaviors were more likely associated with medial FLE. Longitudinal changes in ictal emotional features occurred in about a third of pediatric and young adult patients with FLE. Plain Language Summary This study examined emotional features and defensive behaviors during seizures in children and young adults with FLE. Negative emotions were commonly seen during seizures. Ictal defensive behaviors were more frequently observed in patients with medial FLE, and recognizing these signs could help clinicians localize the seizures. Changes in emotional features were seen over time in about one‐third of children and young adult patients.

Objectives This study identified the prevalence of second victim experience (SVE) in a multidisciplinary sample of healthcare learners and explored personal experiences of trauma and desired forms of support following traumatic patient care events or situations. Method We used the validated SVE Support Tool-Revised and the Physician Well-Being Index (PWBI) to query healthcare learners at a large academic health system across the institution's medical, graduate medical education, and health sciences schools. The survey was open to all healthcare learners from April 8th, 2022 to May 30th, 2022. Here, we report on an analysis of respondents’ fixed responses describing the prevalence and characteristics of SVE. Results Of 2298 potential respondents, 206 answered at least one question (9.0% response rate). Of the 206 respondents, 205 answered questions inquiring if they had been a part of a stressful or traumatic patient care event or situation and 54.1% (111/205) answered in the affirmative. Of this group, 49.5% (51/103) reported feeling like a second victim (SV). The average PWBI of the exposed group was significantly higher (worse well-being) than the nonexposed group (3.4 vs 2.6, P = .0009). The most common forms of desired support for those exposed to a traumatic event and felt like an SV was conversation with peers 95.3% (41/43), family 81.4% (35/43), and a supervisor or manager 67.4% (29/43). Conclusion Findings suggest that many healthcare learners experience SVE and would benefit from connection to desired support strategies. Strategies to mitigate the impact of SVE on professional self-efficacy should be considered by education administrators. We present strategies from the literature and our institution that may be replicated for early identification and support of learners with SVE.

SummaryThe goal of this study was to ascertain the effect of patient body size on clinic‐ or patient‐delayed health care during the COVID‐19 pandemic and factors predicting delay. Primary survey data were collected in August 2021 from 3593 individuals living within the communities near Mayo Clinic facilities in Minnesota, Wisconsin, Arizona, and Florida. More people who identified with the higher‐weight BMI categories reported having their care appointments cancelled (62.3%) compared to those who identified with normative weight (38.0%) or underweight (47.7%; p < .001) and reported more frequently delaying their own care (67.9%) relative to those who identified with normative weight (47.0%) or underweight (62.3%; p < .001). Higher‐weight people were more likely than others to report delay was due to not knowing where to get care (UW: 5.6%, NW: 3.5%, HW: 7.0%, pchi‐square < .001), worrying about weight‐based judgement (UW: 2.1%, NW: 2.1%, HW: 4.5%, pchi‐square < .001), and fearing discrimination (UW: 2.9%, NW: 2.4%, HW: 5.5%, pchi‐square < .001). There was no difference across groups in delay due to fear of COVID‐19 exposure. Weight gain was associated with care delay in higher‐weight and normative weight groups. Having experienced more patient‐centred care pre‐COVID was associated with less care delay in the normative weight group, but more care delay in other groups. Higher‐weight people were more likely to have their care delayed by health care providers and to delay care themselves. Patient weight gain and concerns about discrimination and judgement about weight gain may have driven the delay of needed care during COVID‐19.

BACKGROUND: Small, randomized trials of patients with cervical artery dissection showed conflicting results regarding optimal stroke prevention strategies. We aimed to compare outcomes in patients with cervical artery dissection treated with antiplatelets versus anticoagulation. METHODS: This is a multicenter observational retrospective international study (16 countries, 63 sites) that included patients with cervical artery dissection without major trauma. The exposure was antithrombotic treatment type (anticoagulation versus antiplatelets), and outcomes were subsequent ischemic stroke and major hemorrhage (intracranial or extracranial hemorrhage). We used adjusted Cox regression with inverse probability of treatment weighting to determine associations between anticoagulation and study outcomes within 30 and 180 days. The main analysis used an as-treated crossover approach and only included outcomes occurring with the above treatments. RESULTS: The study included 3636 patients (402 [11.1%] received exclusively anticoagulation and 2453 [67.5%] received exclusively antiplatelets). By day 180, there were 162 new ischemic strokes (4.4%) and 28 major hemorrhages (0.8%); 87.0% of ischemic strokes occurred by day 30. In adjusted Cox regression with inverse probability of treatment weighting, compared with antiplatelet therapy, anticoagulation was associated with a nonsignificantly lower risk of subsequent ischemic stroke by day 30 (adjusted hazard ratio [HR], 0.71 [95% CI, 0.45–1.12]; P =0.145) and by day 180 (adjusted HR, 0.80 [95% CI, 0.28–2.24]; P =0.670). Anticoagulation therapy was not associated with a higher risk of major hemorrhage by day 30 (adjusted HR, 1.39 [95% CI, 0.35–5.45]; P =0.637) but was by day 180 (adjusted HR, 5.56 [95% CI, 1.53–20.13]; P =0.009). In interaction analyses, patients with occlusive dissection had significantly lower ischemic stroke risk with anticoagulation (adjusted HR, 0.40 [95% CI, 0.18–0.88]; P interaction =0.009). CONCLUSIONS: Our study does not rule out the benefit of anticoagulation in reducing ischemic stroke risk, particularly in patients with occlusive dissection. If anticoagulation is chosen, it seems reasonable to switch to antiplatelet therapy before 180 days to lower the risk of major bleeding. Large prospective studies are needed to validate our findings.

Abstract Background The ataxia-telangiectasia mutated (ATM) protein coordinates the cellular response to therapeutic radiation, and ATM inhibitors can potentially enhance the efficacy of radiation in otherwise radiation-resistant tumors. Methods The small molecule ATM kinase inhibitor WSD0628 was specifically designed for enhanced distribution across the blood-brain barrier to more effectively treat glioblastoma (GBM) and brain metastases in combination with radiation therapy (RT). GBM and brain metastasis patient-derived xenograft models were used to understand target inhibition, radiosensitization, inhibition of the DNA damage response, and in vivo efficacy. Results Initial in vitro characterization of WSD0628 demonstrates a high level of selectivity across kinase families, limited aldehyde oxidase liability, and low risk of hERG interactions. Consistent with a central role for ATM in radiation response, WSD0628 blocked radiation-induced signaling and enhanced radiosensitivity in U251 glioma cells and brain tumor PDXs GBM120 and M12. In comparison to control or RT alone in orthotopic PDXs, the combination of WSD0628 with RT markedly prolonged median survival—GBM12 (19, 55, and 408 days, respectively); GBM43 (26, 44, and 143 days, respectively); GBM120 (51, 89, and 231 days, respectively); M12 (17, 39, and 190 days, respectively). Pharmacokinetic and pharmacodynamic testing after treatment in orthotopic GBM43 tumors showed inhibitory levels of WSD0628 and a reduction of γH2AX foci in the combination-treated tumors. Conclusions Collectively, these results suggest a promising role for WSD0628 in combination with RT in brain tumors and provide the rationale for an ongoing Phase 0/1A clinical trial testing this combination in recurrent GBM.