Citations

Background/Objective: The COVID-19 pandemic led to a widespread transition to online learning. Yet, it is unclear how this shift in learning format impacted school attendance in adolescents with chronic pain, a group that struggles with school absenteeism. This study compared school attendance and format (e.g., in-person, online) in patients with chronic pain attending an Intensive Interdisciplinary Pain Treatment Program (IIPT) before the pandemic to an age- and gender-matched sample of youth attending the program after the pandemic. Methods: Participants were 226 school aged adolescents (13–18 years; M age = 15.89, SD = 1.46) enrolled in an IIPT before and after the COVID-19 pandemic. Patients admitted before March 2020 (pre-pandemic group; n = 113) were compared to an age- and gender-matched group of patients who were admitted to the IIPT from November 2021 to November 2023 (post-pandemic group = 113). Upon admission to the program, participants completed validated measures of internalizing symptoms and functional disability. They also completed structured questions related to pain and school history. Results: Significantly more patients in the post-pandemic group were attending school through online and home-schooling options (p < 0.01). Youth who attended the IIPT after the pandemic missed fewer school days (p < 0.05) than those who attended before the pandemic. The groups did not differ in functional disability or internalizing symptoms. However, participants in the post-pandemic group who attended online school missed more school days (p < 0.01) and experienced greater functional disability (p < 0.05) than those who attended in person. Conclusions: The findings highlight how the COVID-19 pandemic may lead to sustained changes in the way adolescents with chronic pain attend school, with implications for increased functional disability and school dropout among this vulnerable population.

Abstract Background Fluoroscopic‐gated proton therapy (FGPT) enables precise dose delivery to tumors affected by respiratory motion by tracking internal fiducial markers and delivering the proton beam when the marker is within a gating window. However, scatter radiation from fluoroscopic x‐rays may be detected by the dose monitor (DM) and mistakenly counted as proton monitor units (MU). To mitigate this issue, proton beam delivery is typically interrupted during the fluoroscopy pulse, a method known as interrupted continuous delivery (ICD). If the contamination from scattered fluoroscopic x‐rays is sufficiently low compared to the proton beam current, uninterrupted continuous delivery (UCD), in which fluoroscopic x‐rays are delivered concurrently with proton beams, may be feasible. UCD can enhance beam stability and improve treatment efficiency in particular for synchrotron‐based proton therapy systems using continuous beams. Purpose This study aimed to measure the contamination of scattered fluoroscopic x‐rays in DM and to evaluate the dose distribution when fluoroscopic x‐rays and proton beams are delivered simultaneously in FGPT. Methods x‐ray contamination was measured using a proton therapy system equipped with the FGPT system. Fluoroscopic x‐rays were delivered for 30 s under both in‐air and solid phantom conditions, with thicknesses of 10 and 30 cm, and DM counts were recorded. The dose rate was evaluated under various fluoroscopic conditions, both with and without the range shifter and mini ridge filter. To assess the dosimetric impact, six virtual treatment plans were created using anthropomorphic phantoms for cases involving the prostate, lung (both superficial and deep), liver (both superficial and deep), and pancreas. Scatter fluoroscopic x‐ray contamination was measured at the beam angles specified in the treatment plans under clinical setup conditions. Dose distributions were recalculated assuming simultaneous delivery with proton beam currents of 0.1, 1, 2, 4, 8, and 40 MU/s, and these were compared to the treatment plans. Results The scattered fluoroscopic x‐ray contamination in the DM increased with higher tube voltage, tube current, frame rate, and field size. The maximum dose rate was 0.247 MU/s with 125 kV tube voltage, 80 mA tube current, 30 s −1 frame rate, 19 × 19 cm 2 field size, and solid phantom of 10 cm. The dose rate of scattered fluoroscopic x‐rays peaked at a solid phantom thickness of approximately 5 cm. In an anthropomorphic phantom, scattered fluoroscopic x‐ray contamination varies based on anatomical site and beam angle. Dose evaluations indicated that if the proton beam current was ≥2 MU/s at the target and ≥1 MU/s at organs at risk, the differences in dose metrics were within 1% compared to the treatment plans. These beam currents are achievable with clinical systems. Conclusions Scattered fluoroscopic x‐rays were confirmed to contaminate the DM and be counted as proton MUs. However, under clinically realistic beam current conditions, their impact on dose distribution in UCD FGPT was negligible. These findings support the feasibility of implementing UCD FGPT.

ABSTRACT Background Pulsed‐field ablation (PFA) offers myocardial selectivity with minimal thermal injury, but depth for ventricular lesions may be insufficient or heterogeneous at clinically tolerable field strengths. Calcium electroporation—local calcium chloride (CaCl₂) infusion after PFA—may amplify electroporation‐mediated cell death while maintaining low energy settings. Objective To determine whether immediate post‐PFA CaCl₂ infusion enhances acute and chronic ventricular lesion formation in vivo. Methods Nine swine underwent focal ventricular PFA (750–1000 V, biphasic, 20 μs × 50 pulses, 200 ms interpulse) via an irrigated focal catheter and benchtop electroporator. Immediately post‐PFA, lesions were randomized to saline, 0.2 g Ca, or 0.4 g Ca infused locally through the catheter tip. Acute hearts were explanted for TTC analysis; surviving animals were studied at 7 days for chronic lesion geometry. Results Among 41 acute lesions (17 control, 12 Ca 0.2 g, 12 Ca 0.4 g), Ca 0.4 g increased dark‐zone depth (3.5 ± 1.4 vs. 2.3 ± 0.8 mm; p = 0.038) and pale‐zone depth (2.6 ± 1.3 vs. 1.3 ± 0.8 mm; p = 0.011) versus control. At 7 days ( n = 33 lesions), Ca 0.4 g produced larger scars than control (width 11.6 ± 2.1 vs. 10.0 ± 1.9 mm; p = 0.027; depth 4.2 ± 1 vs. 3.0 ± 0.8 mm; p < 0.001; volume 193.6.4 ± 82.3 vs. 109.4 ± 48.2 mm³; p = 0.001). Conclusions Local CaCl₂ infusion after ventricular PFA significantly augments acute electroporation effect and chronic lesion size at low output, supporting facilitated PFA as a strategy for deeper, more durable ventricular ablation.

ABSTRACT Introduction Although covalent Bruton's tyrosine kinase inhibitors (cBTKis) have transformed treatment of chronic lymphocytic leukemia and small lymphocytic leukemia (CLL/SLL), cBTKi‐related cardiotoxicity is a known side effect. This real‐world study evaluated incident cardiovascular adverse events (CVAE), healthcare resource utilization (HCRU), and costs among patients with CLL/SLL receiving cBTKis. Methods Adult patients with CLL/SLL who initiated ibrutinib or acalabrutinib treatment (index date) between 2020 and 2023 were identified using US claims data and followed up to 36 months post‐index. Incident CVAEs (not present pre‐index) were assessed during cBTKi treatment and patients were stratified by CVAE status. HCRU and costs were evaluated per 1000 patient‐months (PPPM). Results Overall, 2069 patients were identified (mean age of 73.7 ± 9.1 years, 40.4% female) with a mean treatment‐specific observation period of 11.4 ± 9.5 months. At least one incident CVAE was observed in 442 (21.4%) patients. The incidence rate was 21.6 PPPM for hypertension, 8.9 PPPM for atrial fibrillation, 8.6 PPPM for ventricular arrhythmias, and 8.3 PPPM for atrial flutter. Patients with incident CVAEs had significantly more total medical service days PPPM (4334 vs. 3138, p < 0.001), primarily driven by increased inpatient (690 vs. 230), outpatient (2798 vs. 2425), other visit (662 vs. 375), and ER days (184 vs. 109) than those without CVAEs. Total healthcare costs (PPPM) were substantially higher for patients with incident CVAEs ($20,250,560 vs. $17,413,460, p < 0.001) mainly due to higher inpatient ($3,417,948 vs. $915,839, p < 0.001), outpatient ($2,415,060 vs. $1,769,628, p < 0.01), and ER costs ($186,820 vs. $87,585, p < 0.001). Conclusions The observed class‐effect of high CVAEs with cBTKis underscores the unmet need for safer, more selective agents for CLL/SLL treatment. The HCRU and economic burden remain high for CLL/SLL, especially among patients experiencing CVAEs during cBTKi treatment. These findings emphasize the importance of optimizing clinical management to reduce CVAE risk and downstream impacts on HCRU and costs.

Objective The incidence of hip osteoarthritis (OA) is increasing with the aging population, leading to interest in intra-articular orthobiologic injections to alleviate symptoms and potentially slow disease progression. This systematic review aims to evaluate the clinical outcomes associated with six orthobiologic therapies for hip OA: hyaluronic acid (HA), platelet-rich plasma (PRP), autologous cells therapy (ACT), microfragmented adipose tissue (MFAT), and bone marrow aspirate (BMA) and its concentration (BMAC). Methods We conducted a literature search according to the PRISMA guidelines. Studies were included in our review if they used at least one of the four orthobiologic therapies and reported on the clinical outcome using patient reported outcome measures (PROMs). Since there is a large variability among clinical outcomes, we focused on the three most utilized PROMs (VAS, WOMAC, and HHS) and the latest follow-up time point. Results Of the 716 studies reviewed, thirty-six studies (n=36) fit inclusion criteria. There were 21 studies examining HA, 11 on PRP, 3 for MFAT, 2 for ACT, and 3 on BMA/BMAC. Eight studies were randomized controlled trials and 28 were cohort studies. The mean age of the patient population ranged from 45 ± 17.0 to 74 ± 8.0. The baseline grade of osteoarthritis ranged from 1-4 but was most reported as moderate (2-3). Overall, there was an improvement in PROMs at the latest follow-up after receiving orthobiologic interventions. Discussion Orthobiologic injections have shown promise for improving PROMs in patients with hip OA. Future studies should evaluate long-term efficacy and include randomized trials to establish efficacy.

Background Level I trauma centers employ various orthopaedic call strategies based on resources and surgeon subspeciality availability. Objective We hypothesize when surgeons fellowship trained in trauma are solely on call that patient outcomes will be improved compared to a combined plan. Methods Retrospective cohort study from two 24-month time periods at an academic level one trauma center. The first cohort consisted of only trauma surgeons taking call. The second cohort consisted of a combination of trauma and other subspecialities taking call. The primary outcome analyzed was time from admission to operating room for hip, femoral shaft, distal femur, tibia shaft, pelvic ring and acetabulum fractures. Secondary outcomes analyzed included length of stay, 90 day incidence of reoperation, mortality, VTE and readmission. Results Eight hundred and fifty seven patients in the trauma cohort and 992 patients in the combined cohort met the inclusion criteria. The time from admission to index surgical procedure was significantly shorter in the trauma cohort (1.7 vs 2.4). Length of stay (8.95 vs 11 days) and 90 day mortality (1.8% vs 3.8%) was improved in the trauma cohort. There was no difference in 90 day rate of VTE, readmission or reoperation. Length of stay and time to OR in pelvic ring injuries and acetabulum fractures were doubled compared to the hybrid group. Conclusions Our findings suggest that when trauma fellowship trained surgeons are the only ones taking call patients have a shorter time from admission to index surgical procedure, length of stay and lower mortality rate.

ABSTRACT Background Immunomodulatory agents (IMiDs) are a cornerstone in the successful management of multiple myeloma (MM). However, acquired IMiD resistance leading to disease relapses remains a major barrier. Hydrogen peroxide generation and oxidative stress are key mediators that determine IMiD's effectiveness in MM. Iron plays a key role in the generation of oxidative stress; therefore, cellular iron levels are tightly governed. FTH1 is the major iron storage protein that tightly regulates cellular iron availability. Hence, the present study is targeted to investigate the role of FTH1 in MM and IMiD resistance. Methods IMiD‐sensitive and IMiD‐resistant MM cells were analyzed for expression of iron‐metabolism genes. CRISPR‐cas9‐mediated knockout of FTH1 was performed and the after‐effects were assessed through multiple experiments. Results Initial analysis showed a positive correlation between FTH1 expression and IMiD resistance in MM cells. FTH1 ‐KO reduced IMiD sensitivity in the KMS11 cell line but had no effect on the RPMI8226 cell line. RNA‐seq data showed downregulation of ER‐stress and calcium signaling genes after FTH1 ‐KO. Further, KMS11‐ FTH1 KO cells exhibited lower intracellular ROS, labile‐iron, and mitochondrial superoxide levels along with increased CD63, suggesting activation of L‐ferritin secretory pathways. Conclusion Data reveals a link between FTH1 , labile iron, ROS, and IMiD resistance in MM cells.

Multiplex immunofluorescence and immunohistochemistry (mIF/IHC) are increasingly employed antibody-based technologies that use tissue sparingly and facilitate the detection of co-localized or neighboring biomarkers. Specifically, these platforms enable spatial analyses of the tumor microenvironment as well as extended applications, for example, describing normal tissue anatomy, autoimmunity, infectious diseases, etc. mIF/IHC has greatly enhanced biomarker discovery efforts, and a growing number of studies suggest superiority to traditional IHC. Standardization of staining approaches, reporting of image analysis strategies and resultant data is critical for facilitating cross-study comparisons, validation, deployment, and generalization of findings. To address this challenge, The Society for Immunotherapy of Cancer (SITC) previously published two articles providing best practice guidelines for mIF/IHC staining, image analysis, and data sharing. Here, SITC convened stakeholders to develop the third article in the series, a consensus checklist for scientific reporting of mIF/IHC data to support and complement the best practice guidelines. The checklist includes critical components of mIF/IHC applications to be defined within publications such as detailed descriptions of analytical validation; image acquisition, selection, and registration methods; and cell clustering and spatial analysis strategies, amongst others. Such information will help with data reproducibility and comparison across studies towards future drug and assay development.

ABSTRACT Plerixafor (PLX) is FDA approved for use in autologous peripheral blood stem cell donors but not in allogeneic donors. This study was completed by members of the ASFA HPC Donor Subcommittee to examine the incidence and characteristics of poor mobilizers (PM) among matched related donors (MRD), as well as factors associated with PLX use in MRD. Risks of poor mobilization in MRD were older age, especially donors older than 60 years, lower baseline platelet counts, and heavier recipients. PLX use in PM was low but safe, tripling the success rate for collection. This study adds evidence to the body of literature to support use of PLX in allogeneic donors who are PM.

Abstract The immune mechanisms underlying Kawasaki disease (KD), a febrile systemic vasculitis in children, are poorly understood. Reports indicate elevated levels of circulating IL-33 in acute KD patients; however, if IL-33 contributes to the pathogenesis of KD vasculitis remains unclear. Here, we used the Lactobacillus casei cell wall extract (LCWE)-induced murine model of KD to determine the contribution of IL-33 to vasculitis development. We observed increased expression of Il33 transcripts and IL-33 protein in LCWE-induced cardiovascular lesions. Bone marrow chimera experiments suggest that IL-33 production by both hematopoietic and stromal cells is important for LCWE-induced KD vasculitis; however, single-cell RNA sequencing, spatial transcriptomics, and flow cytometric analysis revealed that stromal cells were the predominant sources of IL-33. Furthermore, immune cells infiltrating LCWE-induced cardiovascular lesions expressed Il1rl1 transcripts, coding for the IL-33 receptor ST2. In vitro stimulation of bone marrow-derived macrophages with IL-33 enhanced their production of IL-1b and TNF-α. In vivo blockade of IL-33, using either neutralizing IL-33 antibody or Il33-/- mice, effectively attenuated LCWE-induced cardiovascular inflammation. Our results indicate that IL-33 contributes to LCWE-induced vascular inflammation through redundant mechanisms across multiple immune cell subsets rather than a single population and highlight IL-33 as a potential therapeutic target.