Citations

ABSTRACT Chemotherapy-induced peripheral neuropathy (CIPN) is a common, debilitating complication of cancer therapy. Although axonal degeneration defines CIPN, the initiating cellular events remain unknown. Here, we show that CIPN is initiated by senescent peripheral fibroblasts rather than by the neuron itself. Across the mechanistically distinct chemotherapeutic agents paclitaxel and cisplatin, chemotherapy-induced senescence is unexpectedly restricted to peripheral fibroblasts rather than neurons and acts upstream of neuronal SARM1 activation. Genetic or pharmacological ablation of senescent fibroblasts prevents neuropathy and reverses established disease, demonstrating that these cells are required for both disease initiation and maintenance. Mechanistically, senescent fibroblasts drive neuropathic injury through an MK2-dependent senescence-associated secretory phenotype (SASP), and genetic or pharmacological inhibition of MK2 suppresses the SASP, preserves peripheral innervation and restores sensory function. Together, these findings redefine the cellular origin of CIPN and identify MK2-dependent fibroblast senescence as a therapeutic target.

Fibrous dysplasia (FD) is a benign bone neoplasm often considered a disease of childhood, with existing literature suggesting lesions typically become quiescent by young adulthood. Consequently, the presentations and surgical outcomes of adult patients remain poorly characterized. This retrospective review analyzed 50 adult patients treated surgically for craniofacial FD at a single institution between 1988 and 2024 to evaluate patterns of presentation, operative indications, and long-term outcomes. The cohort (54.0% male) had a mean follow-up of 15.8 years. Polyostotic involvement was present in 60.0% of patients, and the frontal bone was most affected (51.2%). The median age at presentation was 31 years, and the median age at initial surgery was 34.5 years. The most common surgical indications were visible growth (30.5%) and pain or headache (27.1%). Of the 59 surgeries performed to directly treat FD, bone contouring only was the most common initial operative approach (n=42), followed by en bloc resection and reconstruction (n=7). However, 12% of patients undergoing initial contouring required additional operations for continued growth. All secondary deformities requiring corrective surgery were ocular. In addition, several patients demonstrated delayed recurrence or progression decades after primary surgical intervention. These findings suggest that craniofacial FD may remain symptomatic or continue to progress into adulthood, challenging the traditional paradigm that these lesions necessarily become quiescent after skeletal maturity and highlighting the importance of long-term surveillance in the adult population.

Abstract Rationale Mechanically ventilated intensive care unit patients receive sedatives based on clinician observations of arousal and motor activity with potential for negative consequences and poor mitigation of symptoms. Objectives To test the preliminary efficacy of patient self-managed sedative therapy compared to usual care of nurse-administered sedation on self-reported anxiety, duration of mechanical ventilation, and delirium incidence (CAM-ICU). Methods A two-group, open-label, randomized, multicenter clinical trial in 5 Midwestern hospitals enrolled 161 patients receiving invasive mechanical ventilation who were willing and able to use a push-button device to self-administer sedation for up to 7 days. Patients were randomized 1:1 using center-stratified blocks to usual care (n = 81) or intervention (n = 80) with self-administered dexmedetomidine. Intervention patients were allowed 3 self-administered dexmedetomidine boluses per hour (0.25 mcg/kg) with 20-minute lock-outs. The initial basal infusion (0.2 mcg/kg/hr) was adjusted by nurses between 0.1-0.7 mcg/kg/hr based on patient-delivered boluses in the prior 2 hours. Analysis consisted of linear mixed-effects model for comparisons of anxiety ratings over time and duration of mechanical ventilation. Incidence of delirium was analyzed using generalized estimating equations. Measurement and Main Results Sample characteristics had a female (54.7%) and Caucasian preponderance (92.5%) with a median age of 62 years on protocol for a median of 88 hours. Nine intervention patients were extubated prior to protocol initiation. Patient self-reported three times daily anxiety ratings with a visual analog scale (VAS) ranged from 0-100 over time but were not significantly different between groups in either an intention-to-treat (ITT) or per protocol (PP) analysis (p = 0.94, p = 0.30 respectively). While intervention patients had shorter duration of MV [(mean 50.8(52.8) vs. usual care 68.7(58.2) hours), p = 0.02 ITT], PP analysis resulted in no difference between groups (mean 56.4 (53.0) vs. 68.7(58.2), p = 0.23). 10.2% of intervention patients developed new incidence of delirium vs. 8.5% of usual care which was not significantly different between groups by either ITT (p = 0.65) or PP analyses (p = 0.58). Conclusions Intervention patients had similar outcomes compared to usual care patients. Self-administration of sedative therapy is a safe, novel patient-centered intervention warranting further rigorous investigation for anxiety self-management.

Background: Acute otitis media (AOM) is among the most common pediatric infections and a leading indication for antibiotic prescribing. Although current guidelines recommend 5 to 7 days of therapy for children 2 to 5 years of age with uncomplicated AOM, variation in antibiotic duration remains common. We evaluated whether a 5-day antibiotic course was associated with similar short-term outcomes compared with a 7-day course. Methods: We conducted a retrospective multicenter cohort study using electronic health record data from 44 pediatric emergency departments, urgent care centers, and primary care practices within an integrated health care system. Children 2 to 5 years of age with uncomplicated AOM treated with a single oral antibiotic during 2022 were included. The primary analysis compared children prescribed 5 versus 7 days of therapy. Treatment failure was defined as an AOM-related return encounter requiring a new systemic antibiotic prescription within 7 days after completion of therapy (EOT+7). Secondary analyses evaluated outcomes by antibiotic class and prespecified sensitivity analyses. Results: The final analytic cohort included 7528 children; 906 received 5-day therapy, and 1799 received 7-day therapy. Treatment failure occurred in 0.44% and 0.61%, respectively (absolute risk difference: −0.17%; 95% CI: −0.73 to 0.39; risk ratio: 0.72; 95% CI: 0.23-2.26). Findings were consistent across antibiotic-specific and sensitivity analyses. Conclusions: Among children 2 to 5 years of age with uncomplicated AOM, a 5-day antibiotic course was not associated with an increased risk of short-term treatment failure compared with a 7-day course, supporting guideline-concordant prescribing and outpatient antimicrobial stewardship.

The Impella 5.5 is an axillary mechanical circulatory support device used in patients with cardiogenic shock, but those with small left ventricular (LV) cavities may be at risk for suction events, hemolysis, malpositioning, hypoperfusion, and LV injury. Informally accepted guidelines, extrapolated from durable LVAD studies, suggest a minimum left ventricular internal dimension in diastole (LVIDd) of 58 mm, with some clinical practices using a more stringent ≤52 mm cutoff. We retrospectively analyzed 154 consecutive patients supported with Impella 5.5 between January 2020 and December 2024. Overall, 38 patients had an LVIDd ≤58 mm, and 116 had an LVIDd >58 mm; a key subgroup of 21 patients presented with a very small LVIDd of ≤52 mm]. Baseline demographics, comorbidities, body mass index, and renal function were similar [across groups], although those with larger LVIDd had lower ejection fractions (16% vs. 24%, p = 0.001). Median support duration was 24 days in all groups, and pre- and post-implant hemodynamic and laboratory improvements were comparable. Rates of transplantation (79% vs. 90%, p = 0.088) and LVAD implantation (2% vs. 6%, p = 0.159) did not differ significantly in the ≤58 mm cohort. Notably, within the ≤52 mm subgroup, 90-day survival remained high at 90.5% ( p = 0.336), with significant improvements in right atrial pressure (17 to 10 mmHg, p = 0.041), mean pulmonary artery pressure (36 to 26 mmHg, p = 0.008), and eGFR (45 to 57 mL/min/1.73m 2 , p = 0.003). Remarkably, native cardiac recovery was observed exclusively in the smaller LV cohorts, occurring in 11% of the ≤58 mm group ( p = 0.003 vs. 0%, p = 0.003) and reaching 19% in the ≤52 mm group (vs. 0% in larger cavities, p < 0.001), while durable LVAD escalation was entirely avoided in the ≤52 mm cohort (0% vs. 6%). Ninety-day event-free survival was excellent across all cohorts 92% vs. 96% in the primary analysis, with no major device-related complications, suction events, clinically significant hemolysis, bleeding, stroke, or escalation to Bi-VAD support. These findings strongly support the safety and feasibility of Impella 5.5 in extremely constrained, small LV cavities.

ABSTRACT Consumer‐grade wearables, including smartwatches, fitness trackers, and smart rings, are accessible tools for studying pharmacologic responses in real‐time, monitoring participant health in decentralized clinical trials, optimizing outcome measures, and delivering digital interventions that promote behavior change. However, incorporating consumer wearables into clinical studies is not as straightforward as simply purchasing devices and providing them to participants. It requires engaging with a complex engineering ecosystem with multiple investigator decisions on device selection, associated data management practices, and patient/participant engagement and technical support. This tutorial, based on experience running large clinical trials using consumer wearables, outlines the wearables market landscape across varying form factors and manufacturers as well as the data management software products supporting wearable use. It delineates the major decision processes involved in designing studies that incorporate wearables and presents a structured framework to guide the selection of devices and supporting data tools according to study objectives.

Abstract Osteosarcoma (OS) is one of the top ranking and deadliest primary malignant bone tumor of youngsters and adolescents. OS has poor prognostic features due to its immunosuppressive “ cold ” tumor microenvironment, obstructing the anti-tumor effector functions of immune cells (including cytotoxic CD8⁺ T lymphocytes)․ Recent developments have focused on the role of Gut Microbiota in modulating effector immune responses in various cancers. However, the immunomodulatory role of gut microbiota and its derived gut-associated metabolites (GAMs) in OS still remains unclear. Here we report that peripheral CD8⁺ T lymphocytes in osteosarcoma patients are less frequent in circulation, hypo-producers of effector cytokines (IFN-γ and TNF-α), and have compromised metabolic fitness․ We characterized and investigated the effect of a panel of microbiota-derived GAMs on CD8⁺ T lymphocytes, confirming their immunomodulatory role with respect to CD8⁺ T lymphocytes activation, cellular metabolism and effector functions․ Indole-3-lactic acid (ILA; product of tryptophan metabolism), was observed to be the strongest immunostimulant among all the GAMs studied. ILA enhanced the anti-tumor effector functions of CD8⁺ T lymphocytes through increased glucose uptake, a higher mitochondrial bio-mass and increased production of IFN-γ and TNF-α․ Moreover, ILA-primed cytotoxic T lymphocytes exhibited considerably higher cytotoxicity and increased apoptosis of osteosarcoma cells (U2OS)․ Altogether, our data demonstrates that ILA acts as a microbial-derived immune modulator to metabolically reprogram and restore dysfunctional CD8⁺ T lymphocytes against osteosarcoma․ This study for the first time demonstrates the therapeutic potential of exploiting the nexus between “ Gut-Immune-Bone Tumor” ternary as a safe and cost-effective combinatorial immunotherapy against osteosarcoma․ Graphical Abstract Indole-3-Lactic Acid (ILA) Reinvigorates CD8 + T-Cell Immunity in Osteosarcoma Circulating CD8 + T cells from osteosarcoma patients exhibit impaired metabolic fitness, reduced effector cytokine production, and diminished tumoricidal activity. Screening of gut-associated metabolites identified the microbial tryptophan metabolite indole-3-lactic acid (ILA) as the most potent immunomodulator. ILA restores glucose uptake and mitochondrial biomass, enhances IFN-γ and TNF-α production, promotes polyfunctional CD8 + T-cell responses, and significantly improves CTL-mediated killing of osteosarcoma cells, highlighting its potential as a microbiota-derived immunometabolic therapeutic for osteosarcoma.

Background: Corticosteroids are widely used in pericarditis despite guideline recommendations reserving them for select indications. Observational studies have reported inconsistent associations between corticosteroid use and pericarditis recurrence, and optimal dosing and tapering strategies remain unclear. We conducted a systematic review of oral corticosteroids for acute or recurrent pericarditis to characterize patterns of treatment and evaluate the association between corticosteroids and pericarditis recurrence across different disease contexts. Methods: MEDLINE, EMBASE, CENTRAL, and Scopus were searched from inception to November 26, 2025. Studies enrolling adults with acute or recurrent pericarditis treated with oral corticosteroids were included. Randomized trials, cohort studies, and case–control studies reporting clinical outcomes were eligible. Risk of bias was assessed using the Newcastle–Ottawa Scale (NOS). Data were synthesized descriptively due to anticipated clinical and methodological heterogeneity. Results: Ten studies (2 prospective, 8 retrospective) including 2632 patients (800 corticosteroid-treated) met inclusion criteria. Prednisone was most frequently studied, with heterogeneous dosing (0.25–1.0 mg/kg/day) and non-standardized tapering strategies. Follow-up ranged from 1 to 6.7 years, and overall risk of bias was moderate with limited adjustment for confounding. Findings on recurrence were inconsistent in acute idiopathic and post-procedure pericarditis, while most studies in recurrent pericarditis reported higher recurrence with corticosteroid exposure. Conclusions: Evidence evaluating oral corticosteroids in pericarditis is limited by heterogeneity, confounding, and inconsistent reporting of treatment strategies. Observational data show variable associations with recurrence across clinical contexts. High-quality randomized trials stratified by pericarditis etiology and acuity are needed to define the optimal use of corticosteroids in pericarditis.