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The bone marrow immune microenvironment (BMME) is a critical factor in multiple myeloma (MM) pathogenesis. Despite higher incidence of MM among self-identified African Americans, the relationship between African genetic similarity and the BMME remains unclear. We present the largest analysis to date assessing the impact of Ancestry on the BMME in myeloma (N=320, including 64 with ≥50% African genetic similarity, AFR-High) leveraging our recently generated Immune Atlas. AFR-High was associated with enrichment of late T-effector cells, driven by rare cytotoxic CD4⁺ T cells, suggesting a distinct adaptive BMME. AFR-High exhibited expansion of late-differentiated adaptive NK cells with high cytotoxic GNLY and GZMH expression. AFR-High depicted reduced CD14⁺ monocytes, increased CD16⁺ non-classical monocytes, and expansion of macrophage-like monocyte populations with enrichment of metabolic adaptation, efferocytosis and phagocytic clearance programs, and immunoregulatory pathways. These findings reveal a shift from an innate inflammatory immune landscape toward adaptive cytotoxic and immunoregulatory remodeling associated with African genetic similarity in MM.

ABSTRACT Aims This study aimed to describe how emergency nurses (ENs) experience secondary traumatic stress (STS) within their practice environments, focusing on the strategies they use to cope and the supportive resources they draw upon to manage its impact on their lives. Design This paper presents the qualitative findings from a larger mixed‐methods survey study on STS among ENs. Methods A geographically diverse U.S. sample of ENs was recruited through social media to participate in an online survey. All participants ( n = 275) were asked to respond to open‐ended survey questions, and 118 of these participants provided answers to at least one open‐ended question. A self‐selected sample of 20 ENs completed semi‐structured interviews. Inductive content analysis was used to analyse open‐ended survey responses and interview transcripts. Results Three themes reflected ENs' experiences with STS: STS Is Real—It's Going to Affect Your Life; Something Must Be Wrong With Me: A Culture of Disconnection; and It's a Systems Issue, but We're in It Together. Participants described individual, unit, and organizational factors that influenced their experiences of STS and their access to and use of coping strategies and supportive resources. Conclusion ENs and nurse leaders acknowledged the impact of STS on their personal and professional lives and emphasized how the practice environment shaped their experiences. They perceived the accessibility of organizational resources, leadership behaviours, and team culture as influencing the individual strategies ENs use to manage the effects of repeated exposure to others' traumatic experiences. STS is a predictable occupational hazard for ENs; thus, healthcare organizations must invest in nurse‐identified supports to preserve workforce well‐being and clinical expertise. Implications for the Profession Assessing organizational readiness to address STS is recommended to ensure ENs receive effective, timely support. In response to these assessments, healthcare organizations should develop and implement policies that prioritize the mental health and well‐being of ENs, including proactive support systems and accessible mental health resources. Impact This study identifies participant‐perceived individual, team, leadership, and organizational conditions that may hinder or support ENs' management of STS. These findings identify potential targets for organizational assessment and support strategies intended to foster healthier practice environments and promote safe, high‐quality care. Reporting Method Consolidated Criteria for Reporting Qualitative Research (COREQ). Patient or Public Contribution This study did not include patient or public involvement in its design, conduct, or reporting.

Aging occurs heterogeneously across organs, leading to progressive tissue dysfunction. Cellular senescence is a stress response triggered by age-associated insults, yet the mechanisms regulating senescence and organ aging remain incompletely understood. Here, we defined a role for lysine-specific demethylase 1 (LSD1) in DNA damage–mediated senescence and organ aging. LSD1 was upregulated in aged organs and senescent cells. In response to natural aging or ionizing radiation–induced DNA damage, LSD1 interacted with and demethylated ATM at lysine 3,016, as confirmed using a newly generated ATM-K3016me antibody. This modification sustained ATM phosphorylation, amplified DNA damage signaling, and delayed checkpoint recovery, promoting senescence and organ aging. Inhibition of LSD1 accelerated ATM dephosphorylation via WIP1, enhanced DNA repair, reduced senescence and DNA damage, and prevented irradiation-induced hair graying. Elimination of senescent cells with senolytics reduced LSD1 protein in aged organs, indicating a feedback loop between LSD1 and senescence. Mechanistically, LSD1 underwent autophagosome-lysosome degradation through interaction with LC3 and Beclin1, and autophagy impairment during DNA damage contributed to LSD1 accumulation in senescent cells. This study revealed LSD1 as a key regulator of DNA damage–induced senescence and organ aging and suggested that targeting LSD1 may attenuate senescence, delay organ aging, and prevent hair graying.

ABSTRACT The prognostic relevance of multiple myeloma (MM)‐defined high‐risk (HR) cytogenetic abnormalities in AL amyloidosis is incompletely defined. We retrospectively evaluated 517 newly diagnosed AL amyloidosis patients seen at Mayo Clinic between 2012 and 2021 who had baseline plasma cell FISH. HR cytogenetics were defined as t (4;14), t (14;16), t (14;20), del(17p), or 1q gain/amplification (+1q). HR abnormalities were identified in 151 patients (29%); +1q accounted for most HR cases (122/151, 81%). Compared with standard‐risk (SR), patients harboring +1q demonstrated a greater clonal disease burden, including higher dFLC and bone marrow plasma cells, greater intact immunoglobulin secretion, higher plasma cell proliferative index, and enrichment for modified SLiM‐CRAB features. Hematologic and organ response patterns of +1q patients were generally comparable to SR patients, whereas non‐1q HR patients had a higher proportion of early hematologic responses. Patients harboring +1q demonstrated significantly inferior overall survival (OS) compared with both non‐1q HR patients and SR patients (median OS 57 months vs. not reached vs. 120 months, p = 0.02). In multivariable piecewise Cox analysis, the adverse prognostic impact of +1q was most evident beyond 24 months from diagnosis (HR 2.89, 95% CI 1.64–5.09, p < 0.001), whereas non‐1q HR lesions were not independently prognostic. These findings suggest that +1q identifies a biologically distinct AL amyloidosis subset characterized by plasma cell–dominant features and inferior long‐term disease control. In contrast, other MM‐defined HR cytogenetic abnormalities appear to have limited prognostic relevance in AL amyloidosis.

Background. The VPS35 p.D620N variant causes autosomal dominant Parkinson's disease (PD) and has been shown to activate the LRRK2 kinase pathway, resulting in increased Rab substrate phosphorylation in peripheral immune cells and elevated urinary bis(monoacylglycero)phosphate (BMP) levels. Recently, a VPS35 variant of unknown significance (c.959C>T; p.A320V) was described in two late-onset sporadic PD patients. Methods. We ascertained a family from the Canary Islands in which six siblings were chronically exposed to high doses of pesticides. Three siblings developed levodopa-responsive, akinetic-rigid PD, while the other three remained unaffected. Whole-exome sequencing was performed in the three affected siblings. The frequency of the resulting candidate variant was assessed in 23,327 PD patients and 9,235 controls from four independent cohorts. Members of this pedigree and unrelated controls were assessed for LRRK2 kinase activity in monocytes and neutrophils and BMP levels in urine. Results. The three affected siblings were all heterozygous for p.A320V, whereas the three unaffected siblings did not carry the variant. In the combined PD case-control cohort, p.A320V was identified in six patients and one control. However, unlike p.D620N, heterozygous carrier status for p.A320V was not associated with increased LRRK2 kinase activity or elevated urine BMP levels. Conclusions. While VPS35 p.A320V co-segregated with PD in this family, it did not exhibit the characteristic LRRK2-associated biomarker signature observed in VPS35 p.D620N carriers. It is possible that p.A320V exerts a subtle effect on VPS35 function that was not captured by the assays performed and that chronic pesticide exposure contributed to disease penetrance in this pedigree.

The NCCN Guidelines for Survivorship offer guidance for health care providers who care for survivors of adult-onset cancer. These guidelines include screening, evaluation, and treatment recommendations for common physical and psychosocial problems resulting from cancer and its treatment and provide a framework for care coordination. They also present guidance for helping cancer survivors to enhance their wellness and maintain a healthy lifestyle. This article summarizes the panel’s current recommendations and recent updates regarding anxiety, depression, distress, and trauma in cancer survivors.

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.

Abstract Background The potential risks and benefits of moderate‐intensity exercise in the management of fetal growth restriction (FGR) are controversial. Objective We sought to evaluate fetal responses to a 30‐min bout of moderate‐intensity exercise in pregnancies complicated by FGR. Study design This prospective study included 28 participants at a single academic institution. Pregnant individuals between 28w0d and 36w6d gestation with a diagnosis of FGR with normal Dopplers were enrolled. FGR was defined as total estimated fetal weight less than 10th percentile for estimated gestational age or abdominal circumference less than 10th percentile. Participants were excluded for body mass index (BMI) > 40, tobacco or substance use, hypertension on medications, or other contraindications to exercise. Participants exercised on a treadmill at a moderate intensity monitored using rate of perceived exertion (Borg scale) for 30 min. Fetal umbilical artery (UA), middle cerebral artery (MCA), aortic Dopplers, and maternal uterine artery Dopplers were sampled immediately before and after exercise. Biophysical profile and non‐stress tests were also performed. Maternal vital signs and rate of perceived exertion were monitored throughout exercise. Cerebro‐placental ratios (CPRs) were calculated after sampling. We hypothesized that there is no significant difference in fetal well‐being or Doppler flow in fetuses with FGR immediately after a 30‐min bout of moderate‐intensity maternal exercise compared to pre‐exercise. Results Biophysical profiles and non‐stress tests were reassuring before and after exercise. The primary outcome of UA Doppler values did not differ from pre‐ to post‐exercise. There was no difference in MCA, aortic Dopplers, or CPR. There was an increase in fetal heart rate ( p < 0.05) post‐exercise, which returned to baseline within several minutes. There was a decrease in uterine artery Dopplers ( p < 0.05) post‐exercise, which was driven by a non‐significant decrease in systolic flow and an increase in diastolic flow. Conclusions In this cohort, there were no acute adverse changes in fetal status after a single bout of moderate‐intensity maternal exercise with fetuses with FGR. These findings add to the limited available data in pregnancies complicated by FGR with normal Dopplers. Additional studies are needed to investigate the fetal and maternal effects of vigorous‐intensity and chronic exercise in this population or in populations with more evidence of placental dysfunction. Clinical trial registration NCT06039319.