Citations

Abstract Oxidative phosphorylation (OXPHOS) is a central function and a key indicator of mitochondrial fitness, yet studies in human tissue remain limited. Inclusion body myositis (IBM) is a progressive myopathy that lies at the intersection of aging, inflammation and mitochondrial dysfunction. We aimed to perform a comprehensive profiling of mitochondrial respiration in muscle tissue from patients with IBM. A wide battery of complementary approaches from RNA level to high-resolution respirometry on permeabilized muscle fibers was employed. The relationship between mitochondrial respiration, mitochondrial content, mitochondrial DNA (mtDNA) abnormalities and mitophagy was examined, along with the correlation with various clinical parameters to determine their clinical relevance. The study included a total of 67 patients with IBM and 45 controls. On high resolution respirometry of permeabilized muscle fibers, IBM samples exhibited reduced maximal mitochondrial respiration per tissue weight in State 3 (high substrates, high ADP) and uncoupled state with decreased coupling efficiency and higher leak control ratios. When adjusting for citrate synthase reflecting mitochondrial content, male patients had decreased State 3 intrinsic respiration, whereas female patients had greater intrinsic respiration under leak states. Complex I activity was decreased mainly in female patients, in whom complex II control ratio positively correlated with disease duration and severity. IBM was further associated with decreased RNA levels of all complexes, and lower protein expression of complex I, III, IV and V, likely related to the lower mtDNA content seen in IBM samples. Regarding the production of reactive oxygen species, IBM samples exhibited lower maximal H2O2 emission, accompanied by a higher total antioxidant capacity that positively correlated with disease duration in female patients. Lastly, correlation analyses suggested that impaired mitochondrial respiration, altered mitophagy, and reduced mtDNA content are interconnected in IBM and maybe of clinical significance. IBM is characterized by multifaceted, clinically relevant impairments in mitochondrial respiration. Future studies should further explore underlying pathomechanisms and the variation of mitochondrial respiration by disease stage.

Despite major advances in cardiac care and decades of research, neurodevelopmental (ND) outcomes among children with congenital heart disease (CHD) have shown little improvement over time, substantial variability in outcomes remains unexplained, and prediction of individual developmental trajectories remains limited. This article argues that one contributor to these limitations is the field's reliance on descriptive but mechanistically underspecified models that catalog risk factors without clearly explaining how specific environmental experiences influence neurobehavioral development. To address this gap, this paper proposes an integrated dimensional model of neurodevelopment in CHD that conceptualizes ND outcomes as arising from the independent and interactive effects of CHD-related brain vulnerability and exposure to environmental medical adversity organized along the dimensions of deprivation and threat. Drawing from the Dimensional Model of Adversity and Psychopathology, the framework integrates prenatal dysmaturation, perioperative brain injury, and persistent alterations in brain structure and connectivity with adverse experiences occurring across prenatal, intensive care, caregiving, educational, and socioeconomic contexts. The model predicts that deprivation-related exposures will preferentially affect cognitive, language, and executive functioning systems, whereas threat-related exposures will more strongly influence emotional learning, stress regulation, and risk for psychopathology. By organizing CHD-related experiences according to developmentally meaningful dimensions of adversity, this framework provides a more mechanistic account of ND heterogeneity in CHD, generates testable hypotheses regarding developmental trajectories, and may support more precise developmental surveillance and targeted intervention strategies.

Objective: To evaluate the relationship between race and social determinants of health and receipt of hysterectomy versus uterine-preserving fibroid treatment. Methods: A retrospective cohort study using deidentified claims and longitudinal health data from OptumLabs ® Data Warehouse. Patients aged 15–55 years with newly diagnosed fibroids between 2010 and 2023 were included. Menopausal individuals and those with gynecological cancer were excluded. The primary outcome was hysterectomy by any route versus uterine-preserving fibroid surgery within 180 days of fibroid diagnosis. We used logistic regression to assess associations between socioeconomic factors and receipt of hysterectomy after adjusting for pertinent covariates. Results: A total of 73,479 individuals were included; 50,645 received hysterectomy, 22,834 received a uterine-preserving treatment. Race, income, education level, and rurality were independently associated with the probability of hysterectomy. Odds of hysterectomy were lower for all people of color compared with White individuals (Asian odds ratio [OR] 0.61 [95% confidence interval (CI): 0.56–0.66], Black OR: 0.70 [95% CI: 0.67–0.73], and Hispanic OR: 0.90 [95% CI: 0.86–0.95]). Individuals with household income <$40,000, less than high school education, and rural address were more likely to undergo hysterectomy compared with those with income >$124,999 (OR: 1.15, 95% CI: 1.09–1.21), bachelor’s degree or higher (OR: 2.55, 95% CI: 1.78–3.65), and metropolitan address (OR: 1.70, 95% CI: 1.44–2.01). All associations were significant at p < 0.05. Conclusion: People with fewer socioeconomic advantages, such as lower household income, lower educational attainment, and rural address were more likely to receive hysterectomy rather than uterine-preserving fibroid treatment. After controlling for age, surgery year, and socioeconomic factors, people of color were less likely to receive hysterectomy rather than uterine-preserving fibroid treatment.

BMT CTN 1506 ("MORPHO") was a phase 3 study of post-hematopoietic cell transplantation (HCT) maintenance with gilteritinib versus placebo for patients with FLT3-ITD-mutated acute myeloid leukemia (AML) in first remission. Subgroup analysis indicated a significant benefit of post-HCT gilteritinib for participants in North America, but no benefit for those in Europe or Asia. We conducted a post-hoc analysis of the data focusing on days from AML diagnosis to HCT, pre-HCT FLT3 inhibitor use, and FLT3-ITD measurable residual disease (MRD). Participants transplanted &lt; 120 days from AML diagnosis and/or those treated with FLT3 inhibition pre-HCT were more likely to have improved survival from post-HCT gilteritinib. Pre-HCT MRD levels were higher (P = 0.001) in participants transplanted within 120 days from diagnosis and in those treated with a FLT3 inhibitor pre-HCT and transplanted within 120 days (P = 0.008). Pre-HCT MRD was dependent on both FLT3 inhibitor use and time to HCT, as participants treated with successive courses of chemotherapy + FLT3 inhibition had successively lower MRD by the time of HCT. Time from AML diagnosis to HCT and pre-HCT FLT3 inhibitor use both appeared to impact MRD levels immediately prior to HCT, and geographic differences in these two practice patterns likely accounted for the observed regional differences in benefit from post-HCT gilteritinib. Increasing the number of courses of treatment pre-HCT may lower MRD sufficiently to eliminate the need for post-HCT inhibition, but with a presumed risk of some patients experiencing early progression. This trial was registered at www.clinicaltrials.gov as #NCT02997202.

Abstract To report clinical and functional outcomes, including patient-reported outcome measures (PROMs), complications, reoperation rates, and arthritic progression in patients who sustained a knee dislocation (KD) type V fracture dislocation at minimum 2-year follow-up. A retrospective review from a prospectively collected database was performed to identify all patients with a KD type V fracture dislocation between 2001 and 2022 at a single institution. Patient demographics, pre- and postoperative clinical examination findings, intraoperative details, and postoperative complication rates were obtained from medical records. PROMs, including Visual Analog Scale (VAS), Tegner Activity Scale, Lysholm score, and International Knee Documentation Committee Subjective (IKDC) score were analyzed. A total of 11 patients (mean age: 33.9 ± 7.6, mean BMI: 33.5 ± 6.4 kg/m2) were included with a mean follow-up of 6.4 ± 5.4 years. Seven patients (64%) had a tibial plateau fracture involving the weight-bearing surface. Four patients (36%) had a concomitant nerve injury, one patient (9%) had a concomitant vascular injury, three patients (27%) had a concomitant cartilage injury (ICRS grade 3 + ), and seven patients (64%) had a concomitant meniscus injury. In all, 10 patients (82%) underwent fracture fixation. The mean postoperative Kellgren-Lawrence (KL) grade was 3.0 ± 1.0. Postoperative PROMs included VAS at rest of 2.0 ± 2.3, VAS with activity of 3.3 ± 3.2, IKDC of 68.3 ± 22.1, Lysholm of 79.0 ± 23.6, and Tegner of 4.3 ± 1.7. Nine patients (83%) experienced a complication, with four (36%) patients requiring a subsequent reoperation. Patients with a KD V fracture dislocation who underwent surgical management demonstrated high complication and reoperation rates with advanced radiographic evidence of osteoarthritis but ultimately satisfactory functional outcomes at mid-term follow-up. These findings underscore the complexity of KD V injuries and the importance of early recognition, multidisciplinary surgical planning, and patient counseling regarding the prolonged recovery and likelihood of residual symptoms. Level of evidence is IV—retrospective case series.