Citations

AbstractBackgroundChronic wounds have been associated with an elevated burden of cellular senescence, a state of essentially irreversible cell cycle arrest, resistance to apoptosis, and a secretory phenotype. However, whether senescent cells contribute to wound chronicity in humans remains unclear. The objective of this article is to assess the role of clinicopathological characteristics and cellular senescence in the time‐to‐healing of chronic wounds.MethodsA cohort of 79 patients with chronic wounds was evaluated in a single‐center academic practice from February 1, 2005, to February 28, 2015, and followed for up to 36 months. Clinical characteristics and wound biopsies were obtained at baseline, and time‐to‐healing was assessed. Wound biopsies were analyzed histologically for pathological characteristics and molecularly for markers of cellular senescence. In addition, biopsy slides were stained for p16INK4a expression.ResultsNo clinical or pathological characteristics were found to have significant associations with time‐to‐healing. A Cox proportional hazard ratio model revealed increased CDKN1A (p21CIP1/WAF1) expression to predict longer time‐to‐healing, and a model adjusted for gender and epidermal hyperplasia revealed increased CDKN1A expression and decreased PAPPA expression to predict longer time‐to‐healing. Increased p16INK4a staining was observed in diabetic wounds compared to non‐diabetic wounds, and the same association was observed in the context of high dermal fibrosis.ConclusionsThe findings of this pilot study suggest that senescent cells contribute to wound chronicity in humans, especially in diabetic wounds.

OBJECTIVES Transesophageal echocardiography (TEE) is being increasingly utilized during orthotopic liver transplantation to guide perioperative management. Obstacles of improving TEE utilization include the challenge of becoming familiar with the TEE machine, optimizing TEE images, and translating skills acquired in didactic or simulator center-based training into clinical use. METHODS In an effort to expand TEE utilization and improve workflow among the liver transplantation (LT) anesthesiologists at our institution, a LT-specific TEE guide was created to serve as a reference and educational tool during LT. A 26-question survey was distributed to all LT anesthesiologists before and 6 months after implementation of the LT-specific TEE guide. RESULTS All seven LT anesthesiologists completed the survey questions during the study period. No statistically significant difference was detected in participant-reported confidence in optimizing targeted TEE views, performing technical aspects of the exam, navigating the knobs on the TEE machine, or in ability to identify abnormal cardiac pathology during the study period. One participant became basic-TEE certified during the study period. CONCLUSIONS Implementing a liver transplant-specific TEE guide is a strategy to expand TEE utilization, encourage longitudinal TEE education and reinforce concepts learned from hands-on education sessions; however, we did not detect a difference in participant-reported confidence of performing a TEE exam, ability to identify abnormal cardiac pathology or altering workflow. Further studies with larger sample sizes will be needed to evaluate the effectiveness of a LT-specific TEE guide.

AbstractVenetoclax (VEN) combined with hypomethylating agents (HMAs) is the standard of care for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) unfit for intensive chemotherapy. To date, real‐world data published on HMAs plus VEN have been either single‐center studies or using community‐based electronic databases with limited details on mutational landscape, tolerability, and treatment patterns in elderly patients. Therefore, we conducted a multicenter retrospective study to assess the real‐world experience of 204 elderly patients (≥75 years) with newly diagnosed AML treated with HMAs plus VEN from eight academic centers in the United States. Overall, 64 patients achieved complete remission (CR; 38%) and 43 CR with incomplete count recovery (CRi; 26%) for a CR/CRi rate of 64%, with a median duration of response of 14.2 months (95% CI: 9.43, 22.1). Among responders, 63 patients relapsed (59%) with median overall survival (OS) after relapse of 3.4 months (95% CI, 2.4, 6.7). Median OS for the entire population was 9.5 months (95% CI, 7.85–13.5), with OS significantly worse among patients with TP53‐mutated AML (2.5 months) and improved in patients harboring NPM1, IDH1, and IDH2 mutations (13.5, 18.3, and 21.1 months, respectively). The 30‐day and 60‐day mortality rates were 9% and 19%, respectively. In conclusion, HMAs plus VEN yielded high response rates in elderly patients with newly diagnosed AML. The median OS was inferior to that reported in the VIALE‐A trial. Outcomes are dismal after failure of HMAs plus VEN, representing an area of urgent unmet clinical need.

Background: Hip arthroscopy in patients with borderline hip dysplasia has satisfactory outcomes at short-term follow-up; however, the data on midterm outcomes are inconsistent, and failure rates are high in some studies, limiting understanding of the role and utility of hip arthroscopy in this patient cohort. Purpose: To provide an up-to-date, evidence-based review of the clinical outcomes of primary hip arthroscopy in patients with frank or borderline hip dysplasia at ≥5-year follow-up and report the failure rate and progression to total hip arthroplasty in this cohort. Study Design: Systematic review; Level of evidence, 4. Methods: A comprehensive literature search was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Studies were included if they evaluated outcomes of primary hip arthroscopy in patients with lateral center-edge angle (LCEA) <25° at ≥5-year follow-up. Risk of bias assessment was performed using the methodological index for non-randomized studies scoring system. Level of evidence was determined using criteria from the Oxford Centre for Evidence-Based Medicine. Results: Nine studies were included in this review. Patients with LCEA <25° demonstrated satisfactory clinical outcomes, high patient satisfaction, and significant postoperative improvements in patient-reported outcomes (PROs) at follow-up ranging from a ≥5 to 10 years. Studies comparing patients with dysplasia to those without did not demonstrate significant differences in preoperative, postoperative, or delta PROs or in failure, reoperation, or revision rates. There was no overall significant correlation between outcomes and LCEA stratification. Conclusion: Hip arthroscopy in carefully selected patients with LCEA <25° can be successful at mid- to long-term follow-up and may provide clinical outcomes and failure rates comparable with patients with normal LCEA, understanding that this is a singular, 2-dimensional radiographic measure that does not differentiate instability from impingement or combinations thereof, warranting future studies delineating these differences. These findings suggest that hip dysplasia may not be an absolute contraindication for isolated hip arthroscopy and may serve as a viable intervention with consideration of staged future periacetabular osteotomy (PAO). Importantly, this review does not suggest that hip arthroscopy alters the natural history of dysplasia; therefore, patients with dysplasia should be counseled on the potential utility of PAO by appropriate hip preservation specialists.

Abstract The absence of a standardized definition for graft-versus-host disease (GVHD) flares and data on its clinical course are significant concerns. We retrospectively evaluated 968 patients across 23 Mount Sinai Acute GVHD International Consortium (MAGIC) transplant centers who achieved complete response (CR) or very good partial response (VGPR) within 4 weeks of treatment. The cumulative incidence of flares within 6 months was 22%, and flares were associated with a higher risk of nonrelapse mortality (NRM; adjusted hazard ratio [aHR], 4.84; 95% confidence interval [CI], 3.19-7.36; P &lt; .001). Flares were more severe (grades 3/4, 41% vs 16%; P &lt; .001) and had more frequent lower gastrointestinal (LGI) involvement (55% vs 32%; P &lt; .001) than the initial GVHD. At CR/VGPR, elevated MAGIC biomarkers predicted the future occurrence of a flare, along with its severity and LGI involvement. In multivariate analyses, higher Ann Arbor (AA) biomarker scores at CR/VGPR were significant risk factors for flares (AA2 vs AA1: aHR, 1.81 [95% CI, 1.32-2.48; P = .001]; AA3 vs AA1: aHR, 3.14 [95% CI, 1.98-4.98; P &lt; .001]), as were early response to initial treatment (aHR, 1.84; 95% CI, 1.21-2.80; P = .004) and HLA-mismatched unrelated donor (aHR, 1.74; 95% CI, 1.00-3.02; P = .049). MAGIC biomarkers also stratified the risk of NRM both at CR/VGPR and at the time of flare. We conclude that GVHD flares are common and carry a significant mortality risk. The occurrence of future flares can be predicted by serum biomarkers that may serve to guide adjustment and discontinuation of immunosuppression.

Abstract Objective The pathological expansion of white adipose tissue (WAT) in obesity involves adipocyte hypertrophy accompanied by expansion of the collagen‐rich pericellular extracellular matrix (ECM) and development of crown‐like structures (CLS). Traditionally, WAT morphology is assessed through immunohistochemical analysis of WAT sections. However, manual analysis of large histological sections is time‐consuming, and the available digital tools for analyzing adipocyte size and pericellular ECM are limited. To address this gap, the authors developed the Adipose Tissue Analysis Toolkit (ATAT), an ImageJ plugin facilitating analysis of adipocyte size, WAT ECM, and CLS. Methods and Results ATAT utilizes local and image‐level differentials in pixel intensity to independently threshold image background, distinguishing adipocyte‐free tissue without user input. It accurately captures adipocytes in histological sections stained with common dyes and automates the analysis of adipocyte cross‐sectional area, total‐field, and localized region‐of‐interest ECM. ATAT allows fully automated batch analysis of histological images using default or user‐defined adipocyte detection parameters. Conclusions ATAT provides several advantages over existing WAT image analysis tools, enabling high‐throughput analyses of adipocyte‐specific parameters and facilitating the assessment of ECM changes associated with WAT remodeling due to weight changes and other pathophysiological alterations that affect WAT function.

Background: Little is known about the association between physical activity (PA) and cognitive trajectories in older adults. Objective: To examine the association between PA and change in memory, language, attention, visuospatial skills, and global cognition, and a potential impact of sex or Apolipoprotein E (APOE) ε4 status. Methods: Longitudinal study derived from the population-based Mayo Clinic Study of Aging, including 2,060 cognitively unimpaired males and females aged ≥70 years. Engagement in midlife (ages 50–65) and late-life (last year) PA was assessed using a questionnaire. Neuropsychological testing was done every 15 months (mean follow-up 5.8 years). We ran linear mixed-effect models to examine whether mid- or late-life PA at three intensities (mild, moderate, vigorous) was associated with cognitive z-scores. Results: Light intensity midlife PA was associated with less decline in memory function compared to the no-PA reference group (time x light PA; estimate [standard error] 0.047 [0.016], p = 0.004). Vigorous late-life PA was associated with less decline in language (0.033 [0.015], p = 0.030), attention (0.032 [0.017], p = 0.050), and global cognition (0.039 [0.016], p = 0.012). Females who were physically inactive in midlife experienced more pronounced cognitive decline than females physically active in midlife and males regardless of PA (p-values for time interaction terms with midlife PA levels and sex were all p < 0.05 for global cognition). APOE ε4 carriership did not moderate the association between PA and cognition. Conclusion: Engaging in PA, particularly of vigorous intensity in late-life, was associated with less pronounced decline in global and domain-specific cognition. This association may differ by sex.

Distal radial fractures represent the most common fractures of the upper extremity. Operative treatment is performed for approximately one-third of distal radial fractures in the adult population. Complications following operative treatment of distal radial fractures vary depending on the treatment modality and can be stratified into preoperative and postoperative complications. Complications can occur in the near, intermediate and long term. The most common complications seen are tendon irritation and rupture, chronic regional pain syndrome (CRPS), carpal tunnel syndrome, ulnar or radial neuropathy, compartment syndrome, malunion, inadequate fixation or loss of fixation, symptomatic hardware, post-traumatic arthritis, stiffness and infection. Careful planning, treatment and patient selection can help to mitigate these complications. Level of evidence: V

Abstract VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, caused by somatic mutations in UBA1, is an autoinflammatory disorder with diverse systemic manifestations. Thrombosis is a prominent clinical feature of VEXAS syndrome. The risk factors and frequency of thrombosis in VEXAS syndrome are not well described, due to the disease’s recent discovery and the paucity of large databases. We evaluated 119 patients with VEXAS syndrome for venous and arterial thrombosis and correlated their presence with clinical outcomes and survival. Thrombosis occurred in 49% of patients, mostly venous thromboembolism (VTE; 41%). Almost two-thirds of VTEs were unprovoked, 41% were recurrent, and 20% occurred despite anticoagulation. The cumulative incidence of VTE was 17% at 1 year from symptom onset and 40% by 5 years. Cardiac and pulmonary inflammatory manifestations were associated with time to VTE. M41L was positively associated specifically with pulmonary embolism by univariate (odds ratio [OR]: 4.58, confidence interval [CI] 1.28-16.21, P = .02) and multivariate (OR: 16.94, CI 1.99-144.3, P = .01) logistic regression. The cumulative incidence of arterial thrombosis was 6% at 1 year and 11% at 5 years. The overall survival of the entire patient cohort at median follow-up time of 4.8 years was 88%, and there was no difference in survival between patients with or without thrombosis (P = .8). Patients with VEXAS syndrome are at high risk of VTE; thromboprophylaxis should administered be in high-risk settings unless strongly contraindicated.

Background: Wrestling is a physically demanding sport with young athletes prone to traumatic shoulder instability and a paucity of data evaluating the results of shoulder instability surgery (SIS). Purpose: To assess reoperation rates, patient-reported outcomes, and return to wrestling (RTW) after SIS in a cohort of competitive wrestlers. Study Design: Case series; Level of evidence, 3. Methods: All competitive wrestlers with a history of shoulder instability and subsequent surgery at a single institution between 1996 and 2020 were identified. All directions of shoulder instability (anterior shoulder instability [ASI], posterior shoulder instability [PSI], and traumatic multidirectional shoulder instability [TMDI]) were analyzed. Exclusions included revision SIS and <2 years of follow-up. Athletes were contacted for determination of complications, RTW, and Western Ontario Shoulder Instability Index scores. Results: Ultimately, 104 wrestlers were included with a mean age at initial instability of 16.9 years (range, 12.0-22.7 years), mean age at surgery of 18.9 years (range, 14.0-29.0 years), and a mean follow-up of 5.2 years (range, 2.0-22.0 years). A total of 58 (55.8%) wrestlers were evaluated after a single shoulder instability event, while 46 (44.2%) sustained multiple events before evaluation. ASI was the most common direction (n = 79; 76.0%), followed by PSI (n = 14; 13.5%) and TMDI (n = 11; 10.6%). Surgical treatment was most commonly an arthroscopic soft tissue stabilization (n = 88; 84.6%), with open soft tissue repair (n = 13; 12.5%) and open bony augmentation (n = 3; 2.9%) performed less frequently. RTW occurred in 57.3% of wrestlers at a mean of 9.8 months. Recurrent instability was the most common complication, occurring in 18 (17.3%) wrestlers. Revision SIS was performed in 15 (14.4%) wrestlers. Across the entire cohort, survivorship rates free from recurrent instability and revision surgery were 90.4% and 92.5% at 2 years, 71.9% and 70.7% at 5 years, and 71.9% and 66.5% at 10 years, respectively. Preoperative recurrent instability was an independent risk factor for postoperative recurrent instability (hazard ratio, 3.8; 95% CI, 1.33-11.03; P = .012). Conclusion: Competitive wrestlers with multiple dislocations before initial clinical evaluation were 3.8 times more likely to experience postoperative recurrent instability. Patients should be counseled that despite SIS, only 57.3% returned to wrestling after surgery.