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Christopher P Haycook,1 Joseph A Balsamo,2,3 Evan B Glass,1 Charles H Williams,4 Charles C Hong,5 Amy S Major,3,6 Todd D Giorgio1 1Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA; 2Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA; 3Department of Medicine, Division of Rheumatology and Immunology, Vanderbilt Medical Center, Nashville, TN 37232, USA; 4Department of Medicine, Division of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; 5Department of Medicine, Division of Cardiovascular Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA; 6U.S., Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37212, USACorrespondence: Todd D GiorgioDepartment of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USAEmail todd.d.giorgio@vanderbilt.eduBackground: Helper T cell activity is dysregulated in a number of diseases including those associated with rheumatic autoimmunity. Treatment options are limited and usually consist of systemic immune suppression, resulting in undesirable consequences from compromised immunity. Hedgehog (Hh) signaling has been implicated in the activation of T cells and the formation of the immune synapse, but remains understudied in the context of autoimmunity. Modulation of Hh signaling has the potential to enable controlled immunosuppression but a potential therapy has not yet been developed to leverage this opportunity.Methods: In this work, we developed biodegradable nanoparticles to enable targeted delivery of eggmanone (Egm), a specific Hh inhibitor, to CD4+ T cell subsets. We utilized two FDA-approved polymers, poly(lactic-co-glycolic acid) and polyethylene glycol, to generate hydrolytically degradable nanoparticles. Furthermore, we employed maleimide-thiol mediated conjugation chemistry to decorate nanoparticles with anti-CD4 F(ab’) antibody fragments to enable targeted delivery of Egm.Results: Our novel delivery system achieved a highly specific association with the majority of CD4+ T cells present among a complex cell population. Additionally, we have demonstrated antigen-specific inhibition of CD4+ T cell responses mediated by nanoparticle-formulated Egm.Conclusion: This work is the first characterization of Egm’s immunomodulatory potential. Importantly, this study also suggests the potential benefit of a biodegradable delivery vehicle that is rationally designed for preferential interaction with a specific immune cell subtype for targeted modulation of Hh signaling.Keywords: advanced delivery systems, eggmanone, autoimmunity, controlled release

Background: Patients with complex health needs are increasingly the focus of health system redesign. Objective: To characterize complex patients, as defined by their primary care physicians (PCPs), and to compare this definition with other commonly used algorithms. Design: Cohort study. Setting: 1 hospital-based practice, 4 community health centers, and 7 private practices in a primary care network in the United States. Participants: 40 physicians who reviewed a random sample of 120 of their own patients. Measurements: After excluding patients for whom they were not directly responsible, PCPs indicated which of their patients they considered complex. These patients were characterized, independent predictors of complexity were identified, and PCP-defined complexity was compared with 3 comorbidity-based methods (Charlson score, Higashi score, and a proprietary Centers for Medicare & Medicaid Services algorithm). Results: Physicians identified 1126 of their 4302 eligible patients (26.2%) as complex and assigned a mean of 2.2 domains of complexity per patient (median, 2.0 [interquartile range, 1 to 3]). Mental health and substance use were identified as major issues in younger complex patients, whereas medical decision making and care coordination predominated in older patients (P < 0.001 for trends by decade). Major independent predictors of PCP-defined complexity (P < 0.001) included age (probability of complexity increased from 14.8% to 19.8% with age increasing from 55 to 65 years), poorly controlled diabetes (from 12.7% to 47.6% if hemoglobin A(1c) level >=9%), use of antipsychotics (from 12.7% to 31.8%), alcohol-related diagnoses (from 12.9% to 27.4%), and inadequate insurance (from 12.5% to 19.2%). Classification agreement for complex patients ranged from 26.2% to 56.0% when PCP assignment was compared with each of the other methods. Limitation: Results may not be generalizable to other primary care settings. Conclusion: Primary care physicians identified approximately one quarter of their patients as complex. Medical, social, and behavioral factors all contributed to PCP-defined complexity. Physician-defined complexity had only modest agreement with 3 comorbidity-based algorithms. Primary Funding Source: Partners Community Healthcare, Inc. [ABSTRACT FROM AUTHOR]

Purpose: We aim to provide a comprehensive systematic review to determine the impact of early weightbearing compared to late weightbearing on the clinical outcomes of OLT patients treated with AOT with secondary aims to review the rate of return to sports and/or activities, patient satisfaction and complications., Methods: A systematic review of the PubMed, Embase, and The Cochrane Library databases was performed according to the PRISMA guidelines. Publications were divided into Group A where patients were allowed early weightbearing within the first 6 weeks while Group B consisted of patients who were only allowed weightbearing after 6 weeks. Unweighted estimates were calculated instead of quantitative random-effects meta-analysis due to the high heterogeneity and low level of evidence of the included studies., Results: A total of 44 studies with 1838 ankles were included. There were 25 studies in Group A and 19 studies in Group B. Both the AOFAS and VAS scores were not affected by early weightbearing after AOT for OLT. There were similar rate of return to sports and/or activities (71.4-100% vs 71.4-100%) and patient satisfaction (71.4-100% vs 65.7-100%). Notably, late weightbearers have lower rates of postoperative knee symptoms (0-30% vs 0-39.1%) despite more late weightbearers presenting with complication rates > 20% compared to early weightbearers (20% vs 14.3%) respectively. Late weightbearers also have higher rates of repeat surgery (0-26% vs 0-18.2%) compared to early weightbearers with the most common cause for repeat surgery being arthroscopic debridement for postoperative impingement pain., Conclusion: Protocols allowing for early weightbearing after AOT for OLT yielded similarly good outcomes in terms of AOFAS, VAS for pain, return to sports and/or daily activities and patient satisfaction when compared to late weightbearing. Although the differences in ranges for postoperative complications were not exceedingly different, late weightbearers have slightly lower rates of postoperative knee symptoms and marginally higher rates of repeat surgery with the most common cause for repeat surgery being arthroscopic debridement for postoperative impingement pain similar to the studies with low level of evidence appraised. The strength of these conclusions is limited due to the high level of heterogeneity, low level of evidence and high ROB in the literature reviewed., Level of Evidence: Level IV, systematic review of level I to level IV studies with predominantly level IV studies., (Copyright © 2024. Published by Elsevier Inc.)

Background: Short-term results after arthroscopic/endoscopic lateral ligament repair for chronic lateral ankle instability have been satisfactory, although medium- to longer-term results are lacking., Purpose/hypothesis: The purpose of this study was to report the medium-term results of an all-inside endoscopic classic Bröstrom-Gould procedure where both the both lateral ligaments and the inferior extensor retinaculum can be approached directly, interchanging between arthroscopy for intracapsular structures and endoscopy for extracapsular structures. It was hypothesized that the all-inside endoscopic classic Bröstrom-Gould procedure would produce sustainable good outcomes at a medium term of 5 years., Study Design: Case series; Level of evidence, 4., Methods: A prospective database for 43 patients who underwent an all-inside endoscopic classic Bröstrom-Gould repair of the anterior talofibular ligament and calcaneofibular ligament with inferior extensor retinaculum augmentation was reviewed. Patient details, American Orthopaedic Foot & Ankle Society score, Karlsson score, ankle activity score (AAS), and patient satisfaction were collected and analyzed., Results: The study cohort of 43 patients with a mean age of 29.4 years (SD, 11.9 years) were reviewed at a mean follow-up of 63.1 months (SD, 8.5 months). The American Orthopaedic Foot & Ankle Society scores showed significant improvement from a mean of 69.6 (SD, 13.9) to 93.7 (SD, 10.7), while the Karlsson score improved from 59.7 (SD, 14.5) to 91.5 (SD, 14.5) at the final follow-up. The AAS showed that 32 (74.4%) patients maintained or had improvement in the AAS, from a mean of 5.38 (SD, 2.8) to 5.41 (SD, 2.8), with a mean satisfaction rate of 9.1 (SD, 1.3). Although the remaining 11 patients had a reduced AAS, at a mean of 4.6 (SD, 2.6), they reported a mean satisfaction rate of 7.4 (SD, 2.9). There were no surgical complications or reoperations reported in this cohort, although there were 3 patients with recurrent instability at their last follow-up, resulting in a failure rate of 7%., Conclusion: The current study is the first to report the medium-term outcomes of an all-inside endoscopic classic Bröstrom-Gould procedure. Overall, 93% of the patients had good functional outcomes, but approximately 25% of patients had decreased ankle activity levels at a mean of 5 years postoperatively, albeit with good satisfaction rates., Competing Interests: The authors declared that they have no conflicts of interest in the authorship and publication of this contribution. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

Background: Vitamin D is critical to bone health by regulating intestinal absorption of calcium, whereas proinflammatory cytokines, including IL-1, IL-6, IL-12, and TNF-α, are known to increase bone resorption. We hypothesized that vitamin D and these cytokines at the time of breast cancer diagnosis were predictive for fragility fractures in women receiving aromatase inhibitors (AIs)., Methods: In a prospective cohort of 1,709 breast cancer patients treated with AIs, we measured the levels of 25-hydroxyvitamin D (25OHD), IL-1β, IL-6, IL-12, and TNF-α from baseline blood samples. The associations of these biomarkers were analyzed with bone turnover markers (BALP and TRACP), bone regulatory markers (OPG and RANKL), bone mineral density (BMD) close to cancer diagnosis, and risk of fragility fractures during a median of 7.5 years of follow up., Results: Compared to patients with vitamin D deficiency, patients with sufficient levels had higher bone turnover, lower BMD, and higher fracture risk; the latter became non-significant after controlling for covariates including BMD and no longer existed when patients taking vitamin D supplement or bisphosphonates or with history of fracture or osteoporosis were excluded. There was a non-significant trend of higher levels of IL-1β and TNF-α associated with higher risk of fracture (highest vs. lowest tertile, IL-1β: adjusted HR=1.37, 95% CI=0.94-1.99; TNF-α: adjusted HR=1.38, 95% CI=0.96-1.98)., Conclusions: Our results do not support proinflammatory cytokines or vitamin D levels as predictors for risk of fragility fractures in women receiving AIs for breast cancer., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: There is a paucity of published research on symptomatic venous thromboembolism (sVTE) after distal femur fractures (DFFs). This study aimed to explore the prevalence and risk factors of sVTE in DFFs., Methods: We identified a total of 131 patients who underwent DFF surgeries without routine pharmacological thromboprophylaxis between October 2007 and November 2016. Cases of sVTE included symptomatic pulmonary embolism (sPE) and symptomatic deep vein thrombosis (sDVT). Patients with sVTE were compared to those without, and differences in demographics and fracture-related characteristics were explored. Multivariate logistic regression was used to eliminate confounding factors., Results: Of the 131 patients, 20 (15.3%) had sVTE, of whom 16 (12.2%) had sDVT and six (4.6%) had sPE (two patients had both sPE and sDVT). Notably, 17 (85.0%) sVTE patients were aged ≥60 years, while only 62 (55.9%) non-sVTE patients were aged ≥60 years (P = 0.014). Fourteen (82.4%) patients with sVTE had body mass index (BMI) ≥25 kg/m2, while 49 (53.3%) patients without sVTE had BMI ≥25 kg/m2 (P = 0.032). Multivariate logistic regression demonstrated that age ≥60 years (adjusted odds ratio [OR] 5.05; P = 0.040) and BMI ≥25 kg/m2 (adjusted OR 3.92; P = 0.045) were independently associated with a higher risk of sVTE after DFF., Conclusion: The prevalence of sVTE in DFFs is high at 15.3%. Advanced age (≥60 years) and being overweight (BMI ≥25 kg/m2) were two independent risk factors for sVTE in DFFs. The use of routine pharmacological thromboprophylaxis should be considered as a preventative measure., (Copyright © 2024 Copyright: © 2024 Singapore Medical Journal.)

Objective: Inhibition and knockdown of GPR68 negatively affects glioblastoma cell survival in vitro by inducing ferroptosis. Herein, we aimed to demonstrate that inhibition of GPR68 reduces the survival of glioblastoma cells in vivo using two orthotopic larval xenograft models in Danio rerio, using GBM cell lines U87-MG and U138-MG. In vivo survival of the cancer cells was assessed in the setting of GPR68 inhibition or knockdown., Results: In vitro, shRNA-mediated knockdown of GPR68 inhibition demonstrated potent cytotoxic effects against U87 and U138 glioblastoma cell lines. This effect was associated with increased intracellular lipid peroxidation, suggesting ferroptosis as the underlying mechanism of cell death. Translating these findings in vivo, we established a novel xenograft model in zebrafish by successfully grafting fluorescently labeled human glioblastoma cells, which were previously shown to overexpress GPR68. shRNA knockdown of GPR68 significantly reduced the viability of grafted GBM cells within this model. Additionally, treatment with ogremorphin (OGM), a highly specific small molecule inhibitor of GPR68, also reduced the viability of grafted GBM cells with limited toxicity to the developing zebrafish embryos. This study suggests that therapeutic targeting of GPR68 with small molecules like OGM represents a promising approach for the treatment of GBM., (© 2024. The Author(s).)

Background: Pembrolizumab combined with neoadjuvant chemotherapy (NAC) is the current standard of care in early stage triple-negative breast cancer (TNBC) based on higher event-free survival and pathological complete response (pCR) in Keynote-522 (KN-522) clinical trial. However, this aggressive five-drug regimen is associated with increased risks for immune-related adverse events (irAEs). We investigated real-world clinical outcomes and toxicity of this regimen as well as factors predictive of pCR and irAEs., Methods: We identified and abstracted data from 153 early-stage TNBC patients treated with the KN-522 regimen between July 1, 2021, and December 31, 2023, at 4 academic institutions in the U.S. Descriptive analysis was conducted, univariate and multivariate analyses were performed to identify factors associated with pCR and irAEs., Results: The median age was 52 years (interquartile range, 42-60years), with 66% White and 24% Black patients with stage I/II (67%), node-negative disease (58%), grade 3 (86%) tumors, and ≥1 comorbidities (68%). Approximately 21% discontinued pembrolizumab, because of toxicity; ∼50% received a lower relative dose intensity (RDI) of chemotherapy (dose reduction or discontinuation). Of the 153 patients, 99 (64.7%) achieved pCR and 83 (54%) experienced an irAE, with 18 (12%) having ≥ grade 3 irAE. The majority (90%) of the irAEs were observed during neoadjuvant phase. Stage I/II versus stage III disease (OR 1.55, CI 1.04-2.33, P = .03), age (OR 0.96, CI 0.93-0.99, P = .01) and full versus reduced RDI of NAC (OR 1.53, CI 1.04-2.26, P = .03) were associated with higher pCR rates on multivariate analyses. Fewer cycles of pembrolizumab were associated with a higher likelihood of irAEs (OR 1.52, CI 1.07-2.16, P = .02), likely explained by the early discontinuation and receipt of less than 8 cycles of pembrolizumab in patients who experienced irAEs., Conclusions: Our study validates the clinical efficacy of KN-522 regimen; however, we observed a higher incidence of irAEs (54%) in this real-world population. Lower stage and younger age were associated with higher likelihood of achieving pCR. Toxicity-related chemotherapy dose reduction or discontinuation was observed to adversely impact the likelihood of achieving pCR., Competing Interests: Disclosure All authors have declared no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Paratenon preserving techniques to facilitate acute Achilles tendon rupture repair (AATR) functions by maintaining vascularity and biology for optimal healing response. Therefore, the purpose is to evaluate the outcomes following paratenon preserving repair of the midsubstance AATR. The hypothesis was that paratenon-preserving techniques demonstrate high return to play rates and low complication rates for the repair of the midsubstance AATR., Materials and Methods: A systematic review of the PubMed, Embase, and the Cochrane Library databases was performed by two authors using specific search terms and eligibility criteria. The assessment of the evidence was two-fold: level and quality of evidence. A meta-analysis of proportions for the various complication rates was performed using the restricted maximum likelihood method following the Freeman-Tukey double-arcsine transformation. Fixed effects models were employed if I 2  < 25% (low heterogeneity), and random effects models were employed if I 2  ≥ 25% (moderate to high heterogeneity)., Results: The pooled return to play rate was 90.3%. The pooled rerupture rate as reported was 0.9% (best-case scenario 0.8% and worst-case scenario 6.8%). No meaningful subgroup analysis for rerupture rates could be performed based on the meta-regression. The pooled complication rate other than reruptures was 4.8%. The pooled infection rates were 0.3%, DVT rates were 1.6%, and sural nerve injury rates were 0.3%., Conclusions: Paratenon preserving techniques that are minimally invasive in nature demonstrated safe and favorable outcomes with high return to play rates and low complication rates for the repair of the midsubstance AATR., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The biotechnological production of uridine diphosphate-d-xylose (UDP-d-xylose), the glycosyl donor in enzymatic for d-xylose, is an important precursor for advancing glycoengineering research on biopharmaceuticals such as heparin and glycosaminoglycans. Leveraging a recently discovered UDP-xylose salvage pathway, we have engineered a series of bifunctional chimeric biocatalysts derived from Solitalea canadensis galactokinase/uridyltransferase, facilitating the conversion of d-xylose to UDP-d-xylose. This study elucidates the novel assembly of eight fusion protein constructs, differing in domain orientations and linker peptide lengths, to investigate their functional expression in Escherichia coli , resulting in the synthesis of the first bifunctional enzyme that orchestrates a direct transformation from d-xylose to UDP-d-xylose. Fusion constructs with a NH 2 -GSGGGSGHM-COOH peptide linker demonstrated the highest expression and catalytic tenacity. For the highest catalytic conversion from d-xylose to UDP-d-xylose, we established an optimum pH of 7.0 and a temperature optimum of 30 °C, with an optimal fusion enzyme concentration of 3.3 mg/mL for large-scale UDP-d-xylose production. Insights into ATP and ADP inhibition further helped to optimize the reaction conditions. Testing various ratios of unfused galactokinase and uridyltransferase biocatalysts for UDP-xylose synthesis from d-xylose revealed that a 1:1 ratio was optimal. The K cat / K m value for the NH 2 -GSGGGSGHM-COOH peptide linker showed a 10% improvement compared with the unfused counterparts. The strategic design of these fusion enzymes efficiently routes for the convenient and efficient biocatalytic synthesis of xylosides in biotechnological and pharmaceutical applications., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Pediatric dilated cardiomyopathy (DCM) is a rare, yet life-threatening cardiovascular condition characterized by systolic dysfunction with biventricular dilatation and reduced myocardial contractility. Therapeutic options are limited with nearly 40% of children undergoing heart transplant or death within 2 years of diagnosis. Pediatric patients are currently diagnosed based on correlating the clinical picture with echocardiographic findings. Patient age, etiology of disease, and parameters of cardiac function significantly impact prognosis. Treatments for pediatric DCM aim to ameliorate symptoms, reduce progression of disease, and prevent life-threatening arrhythmias. Many therapeutic agents with known efficacy in adults lack the same evidence in children. Unlike adult DCM, the pathogenesis of pediatric DCM is not well understood as approximately two thirds of cases are classified as idiopathic disease. Children experience unique gene expression changes and molecular pathway activation in response to DCM. Studies have pointed to a significant genetic component in pediatric DCM, with variants in genes related to sarcomere and cytoskeleton structure implicated. In this regard, pediatric DCM can be considered pediatric manifestations of inherited cardiomyopathy syndromes. Yet exciting recent studies in infantile DCM suggest that this subset has a distinct etiology involving defective postnatal cardiac maturation, such as the failure of programmed centrosome breakdown in cardiomyocytes. Improved knowledge of pathogenesis is central to developing child-specific treatment approaches. This review aims to discuss the established biological pathogenesis of pediatric DCM, current clinical guidelines, and promising therapeutic avenues, highlighting differences from adult disease. The overarching goal is to unravel the complexities surrounding this condition to facilitate the advancement of novel therapeutic interventions and improve prognosis and overall quality of life for pediatric patients affected by DCM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Malinow, Fong, Miyamoto, Badran and Hong.)

Allostatic load (AL) is an intermediary outcome through which neighborhood drivers of health may impact cancer survivorship outcomes. We examined associations of neighborhood stressors and AL in 2,553 women with breast cancer recruited into the Pathways Study in 2006-2013. AL score was derived from biomarkers in the cardiovascular, metabolic, and immune domains of physiological stress measured within 3 years after baseline. Neighborhood data were appended to participants' geocoded baseline addresses. Odds ratios (OR) and 95% confidence intervals (CI) were used to estimate associations between neighborhood stressors and risk of higher AL score. Adjusting for age and stage, high AL was positively associated with low versus high neighborhood socioeconomic status (nSES; OR=2.24, 95% CI=1.61-3.12) and green space (OR=1.55, 95% CI=1.18-2.03); high versus low traffic (OR=1.32, 95% CI=1.01-1.72), crime (OR=1.32, 95% CI=1.05-1.67), and household crowding (OR=1.57, 95% CI=1.22-2.01); and more versus no fast-food restaurants (OR=1.50, 95% CI=1.21-1.84). Associations remained for nSES and fast-food restaurants after co-adjustment with other neighborhood stressors, and for fast-food restaurants after additional adjustment with individual sociodemographic and lifestyle factors. Our preliminary findings can inform further studies of the physiological effects of neighborhood stressors, which collectively may help improve survivorship outcomes for the growing population of breast cancer survivors., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Maintaining cardiovascular health (CVH) is critical for breast cancer (BC) survivors, particularly given the potential cardiotoxic effects of cancer treatments. Poor CVH among Black BC survivors may be influenced by various area-level social determinants of health, yet the impact of neighborhood archetypes in CVH among this population remains understudied., Objectives: This study aimed to characterize the neighborhood archetypes where Black BC survivors resided at diagnosis and evaluate their associations with CVH., Methods: We assessed CVH 24 months post-diagnosis in 713 participants diagnosed between 2012 and 2017 in the Women's Circle of Health Follow-Up Study, a population-based study of Black BC survivors in New Jersey. Neighborhood archetypes, identified via latent class analysis based on 16 social and built environment features, were categorized into tertiles. Associations between neighborhood archetypes and CVH scores were estimated using polytomous logistic regression., Results: CVH scores were assessed categorically (low, moderate, and optimal) and as continuous variables. On average, Black BC survivors achieved only half of the recommended score for optimal CVH. Among the 4 identified archetypes, women in the Mostly Culturally Black and Hispanic/Mixed Land Use archetype showed the lowest CVH scores. Compared to this archetype, Black BC survivors in the Culturally Diverse/Mixed Land Use archetype were nearly 3 times as likely to have optimal CVH (relative risk ratio: 2.92; 95% CI: 1.58-5.40), with a stronger association observed in younger or premenopausal women. No significant CVH differences were noted for the other 2 archetypes with fewer built environment features., Conclusions: Neighborhood archetypes, integrating social and built environment factors, may represent crucial targets for promoting CVH among BC survivors., Competing Interests: This work was supported by grants from the National Institute on Minority Health and Health Disparities (R00MD013300), the New Jersey Commission on Cancer Research (COCR23PDF029), the National Cancer Institute (R01CA185623, R01CA100598, P01CA151135, P30CA072720-5929, and P30CA016056-8070), and the National Institute on Aging (1R01AG049970, 3R01AG049970-04S1, and R56AG049970) from National Institutes of Health, the American Cancer Society (RSGT-07-291-01-CPHPS), the Breast Cancer Research Foundation, the Pennsylvania Department of Health (SAP#4100072543), and the New Jersey Alliance for Clinical and Translational Science supported by the National Institutes of Health National Center for Advancing Translational Sciences (UL1TR003017); the New Jersey State Cancer Registry, Cancer Epidemiology Services, New Jersey Department of Health, is funded by the Surveillance, Epidemiology and End Results Program of the National Cancer Institute under contract 75N91021D00009, the National Program of Cancer Registries, Centers for Disease Control and Prevention under grant NU58DP007117, as well as the State of New Jersey and the Rutgers Cancer Institute of New Jersey. Dr Bandera has served on an Advisory Board for Pfizer to enhance minoritized and under-represented populations in clinical trials unrelated to this study; no conflicts of interest in connection with the submitted article were reported. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

➤ The concept of anteromedial cortical support (AMCS) serves as valuable guidance for the intraoperative reduction of trochanteric hip fractures.➤ Positive medial cortical support (MCS) and positive or neutral anterior cortical support (ACS) are desirable. Some evidence has suggested that positive MCS is potentially superior to neutral MCS.➤ Experimental studies underscore the vital importance of the anteromedial wall and reveal why positive MCS potentially outperforms neutral MCS.➤ Incorporating the AMCS concept, the Chang reduction quality criteria (CRQC) are a reliable alternative approach to evaluate the reduction quality of trochanteric hip fractures., Competing Interests: Disclosure: This work was supported by the National Natural Science Foundation of China (Grant No. 81772323), and the Shanghai Science and Technology Commission (Grant No. 23ZR1459300). The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article ( http://links.lww.com/JBJS/H978 )., (Copyright © 2024 by The Journal of Bone and Joint Surgery, Incorporated.)

Objectives: To conduct a systematic review and meta-analysis of prevalence of cardiovascular-related morbidity and mortality in patients with diabetic foot ulcers (DFU), as well as compare risks of cardiovascular-related morbidity and mortality between diabetic patients with and without DFU., Methods: A systematic search was conducted on Medline, Embase, and Cochrane databases for randomized controlled trials and observational studies which explored the association between DFU and cardiovascular-related morbidity & mortality, or compared differences in hazard ratios of cardiovascular diseases between diabetics with and without DFU. Frequentist, pairwise meta-analysis was performed on studies with two comparator arms, whereas single-arm studies reporting pooled incidences of cardiovascular-related mortality and morbidity were calculated based on exact binomial distributions. A random-effect meta-analysis model was used with heterogenicity of studies assessed using I 2 , τ 2 , and χ 2 statistics., Results: 10 studies were identified and included in the systematic review & meta-analysis of 8602 patients. DFU was consistently found to have significant association with cardiovascular-related morbidity and mortality, with pooled prevalences of all cause cardiovascular-related morbidity (37.1%), IHD (44.7%), CHF (25.1%), CAD (11.7%), and CVA (10.9%), and all cause cardiovascular-related mortality (14.6%), fatal IHD (6.2%), fatal CHF (3.67%), fatal CAD (7.92%), and fatal CVA (1.99%). Diabetic patients with DFU were found to have significantly increased risk of IHD (RR 1.25), CVA (RR 2.03), and all-cause cardiovascular-related mortality (RR 2.59) compared to those without DFU., Conclusions: The presence of DFU is associated with major adverse cardiac events. The alarming rates of cardiovascular-related morbidity and mortality in DFU patients highlight its potential role as a marker of cardiovascular complications and should prompt early clinical investigation and management., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Creatinine-cystatin C ratio (CCR) has been demonstrated as an objective marker of sarcopenia in clinical conditions but has not been evaluated as an osteoporosis marker in individuals with normal renal function., Methods: We selected 271,831 participants with normal renal function from UK Biobank cohort. Multivariable linear/logistic regression and Cox proportional hazards model were used to investigate the phenotypic relationship between CCR and osteoporosis in total subjects and gender-stratified subjects. Based on the genome-wide association study (GWAS) data, linkage disequilibrium regression (LDSC) and Mendelian randomization (MR) analysis were performed to reveal the shared genetic correlations and infer the causal effects, respectively., Results: Amongst total subjects and gender-stratified subjects, serum CCR was positively associated with eBMD after adjusting for potential risk factors (all P <0.05). The multivariable logistic regression model showed that the decrease in CCR was associated with a higher risk of osteoporosis/fracture in all models (all P <0.05). In the multivariable Cox regression analysis with adjustment for potential confounders, reduced CCR is associated with the incidence of osteoporosis and fracture in both total subjects and gender-stratified subjects (all P <0.05). A significant non-linear dose-response was observed between CCR and osteoporosis/fracture risk ( P non-linearity  < 0.05). LDSC found no significant shared genetic effects by them, but PLACO identified 42 pleiotropic SNPs shared by CCR and fracture (P<5×10- 8 ). MR analyses indicated the causal effect from CCR to osteoporosis/fracture., Conclusions: Reduced CCR predicted increased risks of osteoporosis/fracture, and significant causal effects support their associations. These findings indicated that the muscle-origin serum CCR was a potential biomarker to assess the risks of osteoporosis and fracture., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 He, Yang, Wang, Zhang, Gu, Hong, Bo, Deng and Lei.)

A time-dependent third-order shear deformation theory (TSDT) approach on the displacements of thick functionally graded material (FGM) conical shells under dynamic thermal vibration is studied. Dynamic equations of motion with TSDT for thick FGM conical shells are applied directly with the partial derivative of variable R *θ in the curve coordinates ( x , θ, z ) instead of y in the Cartesian coordinates ( x , y , z ) for thick FGM plates, where R * is the middle-surface radius at any point on conical shells. The generalized differential quadrature (GDQ) numerical method is used to solve the dynamic differential equations in equilibrium matrix forms under thermal loads. It is the novelty of the current study to identify the parametric effects of shear correction coefficient, environment temperature, TSDT model, and FGM power law index on the displacements and stresses in the thick conical shells only subjected to sinusoidal heating loads. The physical parts with values on the length-to-thickness ratio equals 5, and 10 FGMs can be used in an area of an airplane engine that usually operates near more than 1000 K of temperatures when the thermal stress is considered and affected. The important findings of the presented study are listed as follows. The values of normal stress are in decreasing tendencies with time in cases when the coefficient c1 equals 0.925925/mm 2 in TSDT and length-to-thickness ratio equals 5. The shear stress values in x plane z direction on the minor middle-surface radius ( r ) equals the major middle-surface radius ( R ) over 8 and length-to-thickness ratio equals to 5 can withstand T = 1000 K of pressure.

Background: Tumor-associated macrophages (TAMs) are a prominent immune subpopulation in the tumor microenvironment that could potentially serve as therapeutic targets for breast cancer. Thus, it is important to characterize this cell population across different tumor subtypes including patterns of association with demographic and prognostic factors, and breast cancer outcomes., Methods: We investigated CD163 + macrophages in relation to clinicopathologic variables and breast cancer outcomes in the Women's Circle of Health Study and Women's Circle of Health Follow-up Study populations of predominantly Black women with breast cancer. We evaluated 611 invasive breast tumor samples (507 from Black women, 104 from White women) with immunohistochemical staining of tissue microarray slides followed by digital image analysis. Multivariable Cox proportional hazards models were used to estimate hazard ratios for overall survival (OS) and breast cancer-specific survival (BCSS) for 546 cases with available survival data (median follow-up time 9.68 years (IQR: 7.43-12.33)., Results: Women with triple-negative breast cancer showed significantly improved OS in relation to increased levels of tumor-infiltrating CD163 + macrophages in age-adjusted (Q3 vs. Q1: HR = 0.36; 95% CI 0.16-0.83) and fully adjusted models (Q3 vs. Q1: HR = 0.30; 95% CI 0.12-0.73). A similar, but non-statistically significant, association was observed for BCSS. Macrophage infiltration in luminal and HER2+ tumors was not associated with OS or BCSS. In a multivariate regression model that adjusted for age, subtype, grade, and tumor size, there was no significant difference in CD163 + macrophage density between Black and White women (RR = 0.88; 95% CI 0.71-1.10)., Conclusions: In contrast to previous studies, we observed that higher densities of CD163 + macrophages are independently associated with improved OS and BCSS in women with invasive triple-negative breast cancer. Trial registration Not applicable., (© 2024. The Author(s).)

It is only partially understood how constitutive allelic methylation at imprinting control regions (ICRs) interacts with other regulation levels to drive timely parental allele-specific expression along large imprinted domains. The Peg13-Kcnk9 domain is an imprinted domain with important brain functions. To gain insights into its regulation during neural commitment, we performed an integrative analysis of its allele-specific epigenetic, transcriptomic, and cis-spatial organization using a mouse stem cell-based corticogenesis model that recapitulates the control of imprinted gene expression during neurodevelopment. We found that, despite an allelic higher-order chromatin structure associated with the paternally CTCF-bound Peg13 ICR, enhancer-Kcnk9 promoter contacts occurred on both alleles, although they were productive only on the maternal allele. This observation challenges the canonical model in which CTCF binding isolates the enhancer and its target gene on either side and suggests a more nuanced role for allelic CTCF binding at some ICRs., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: The impact of the COVID-19 pandemic restrictions in the US since March 2020 on cancer survivorship among Black and Hispanic breast cancer (BC) survivors remains largely unknown. We aimed to evaluate associations of the pandemic with participant characteristics, patient-reported outcomes (PROs), and lifestyle factors among Black and Hispanic BC survivors in the Women's Circle of Health Follow-Up Study and the New Jersey BC Survivors Study., Methods: We included 447 Black (n pre  = 364 and n post  = 83) and 182 Hispanic (n pre  = 102 and n post  = 80) BC survivors who completed a home interview approximately 24 months post-diagnosis between 2017 and 2023. The onset of the pandemic was defined as March 2020. The association of the pandemic with binary outcomes was estimated using robust Poisson regression models., Results: Hispanic and Black BC survivors recruited after the onset of the pandemic reported higher socioeconomic status and fewer comorbidities. Black women in the post-pandemic group reported a higher prevalence of clinically significant sleep disturbance (prevalence ratio (PR) 1.43, 95% CI 1.23, 1.68), lower sleep efficiency, and lower functional well-being, compared to the pre-pandemic group. Hispanic women were less likely to report low health-related quality of life (vs. high; PR 0.62, 95% CI 0.45, 0.85) after the onset of the pandemic., Conclusions: Ongoing research is crucial to untangle the impact of the pandemic on racial and ethnic minorities participating in cancer survivorship research, as well as PROs and lifestyle factors., Implications for Cancer Survivors: This study highlights the importance of considering the impact of the pandemic in all aspects of research, including the interpretation of findings., (© 2024. The Author(s).)

Competing Interests: Conflicts of Interest: The authors declare no disclosures or conflicts of interest.

Objectives: To examine sleep quality and self-reported causes of sleep disturbance among patients with breast cancer at diagnosis and one year later., Sample & Setting: 486 of 606 patients with histologically confirmed breast cancer completed a Pittsburgh Quality Sleep Index (PSQI) survey at the time of diagnosis and again one year later., Methods & Variables: In this secondary data analysis, descriptive statistics were computed for seven PSQI components and its global score. Wilcoxon signed-rank tests and McNemar's tests were used. Self-reported reasons for sleep disturbances were summarized., Results: PSQI scores significantly increased from baseline (mean = 6.75) to one-year follow-up (mean= 7.12), indicating worsened sleep. Sleep disturbance and onset latency scores increased, whereas sleep efficiency decreased. The two most frequently reported reasons for sleep disturbance were waking up late in the night or early in the morning (more than 50%) and needing to use the bathroom (49%). Feeling too hot and experiencing pain three or more times per week were reported by participants at baseline and one year later., Implications for Nursing: Results can aid in monitoring patient response to treatment methods and formulating benchmarks to manage sleep problems.

Background: Glioblastoma multiforme (GBM) stands as a formidable challenge in oncology because of its aggressive nature and severely limited treatment options. Despite decades of research, the survival rates for GBM remain effectively stagnant. A defining hallmark of GBM is a highly acidic tumor microenvironment, which is thought to activate pro-tumorigenic pathways. This acidification is the result of altered tumor metabolism favoring aerobic glycolysis, a phenomenon known as the Warburg effect. Low extracellular pH confers radioresistant tumors to glial cells. Notably GPR68, an acid sensing GPCR, is upregulated in radioresistant GBM. Usage of Lorazepam, which has off target agonism of GPR68, is linked to worse clinical outcomes for a variety of cancers. However, the role of tumor microenvironment acidification in GPR68 activation has not been assessed in cancer. Here we interrogate the role of GPR68 specifically in GBM cells using a novel highly specific small molecule inhibitor of GPR68 named Ogremorphin (OGM) to induce the iron mediated cell death pathway: ferroptosis., Method: OGM was identified in a non-biased zebrafish embryonic development screen and validated with Morpholino and CRISPR based approaches. Next, A GPI-anchored pH reporter, pHluorin2, was stably expressed in U87 glioblastoma cells to probe extracellular acidification. Cell survival assays, via nuclei counting and cell titer glo, were used to demonstrate sensitivity to GPR68 inhibition in twelve immortalized and PDX GBM lines. To determine GPR68 inhibition's mechanism of cell death we use DAVID pathway analysis of RNAseq. Our major indication, ferroptosis, was then confirmed by western blotting and qRT-PCR of reporter genes including TFRC. This finding was further validated by transmission electron microscopy and liperfluo staining to assess lipid peroxidation. Lastly, we use siRNA and CRISPRi to demonstrate the critical role of ATF4 suppression via GPR68 for GBM survival., Results: We used a pHLourin2 probe to demonstrate how glioblastoma cells acidify their microenvironment to activate the commonly over expressed acid sensing GPCR, GPR68. Using our small molecule inhibitor OGM and genetic means, we show that blocking GPR68 signaling results in robust cell death in all thirteen glioblastoma cell lines tested, irrespective of genetic and phenotypic heterogeneity, or resistance to the mainstay GBM chemotherapeutic temozolomide. We use U87 and U138 glioblastoma cell lines to show how selective induction of ferroptosis occurs in an ATF4-dependent manner. Importantly, OGM was not-acutely toxic to zebrafish and its inhibitory effects were found to spare non-malignant neural cells., Conclusion: These results indicate GPR68 emerges as a critical sensor for an autocrine pro-tumorigenic signaling cascade triggered by extracellular acidification in glioblastoma cells. In this context, GPR68 suppresses ATF4, inhibition of GPR68 increases expression of ATF4 which leads to ferroptotic cell death. These findings provide a promising therapeutic approach to selectively induce ferroptosis in glioblastoma cells while sparing healthy neural tissue., (© 2023. The Author(s).)

Competing Interests: Disclosures None.

Background: Polygenic risk scores (PRSs) for coronary artery disease (CAD) potentially improve cardiovascular risk prediction. However, their relationship with histopathologic features of CAD has never been examined systematically., Methods: From 4327 subjects referred to CVPath by the State of Maryland Office Chief Medical Examiner for sudden death between 1994 and 2015, 2455 cases were randomly selected for genotyping. We generated PRS from 291 known CAD risk loci. Detailed histopathologic examination of the coronary arteries was performed in all subjects. The primary study outcome measurements were histopathologic plaque features determining severity of atherosclerosis, including %stenosis, calcification, thin-cap fibroatheromas, and thrombotic CAD., Results: After exclusion of cases with insufficient DNA sample quality or with missing data, 954 cases (mean age, 48.8±14.7 years; 75.7% men) remained in the final study cohort. Subjects in the highest PRS quintile exhibited more severe atherosclerosis compared with subjects in the lowest quintile, with greater %stenosis (80.3%±27.0% versus 50.4%±38.7%; adjusted P <0.001) and a higher frequency of calcification (69.6% versus 35.8%; adjusted P =0.004) and thin-cap fibroatheroma (26.7% versus 9.5%; adjusted P =0.007). Even after adjustment for traditional CAD risk factors, subjects within the highest PRS quintile had higher odds of severe atherosclerosis (ie, ≥75% stenosis; adjusted odds ratio, 3.77 [95% CI, 2.10-6.78]; P <0.001) and plaque rupture (adjusted odds ratio, 4.05 [95% CI, 2.26-7.24]; P <0.001). Moreover, subjects within the highest quintile had higher odds of CAD-associated cause of death, especially among those aged ≤50 years (adjusted odds ratio, 4.08 [95% CI, 2.01-8.30]; P <0.001). No statistically significant associations were observed with plaque erosion after adjusting for covariates., Conclusions: This is the first autopsy study investigating associations between PRS and atherosclerosis severity at the histopathologic level in subjects with sudden death. Our pathological analysis suggests PRS correlates with plaque burden and features of advanced atherosclerosis and may be useful as a method for CAD risk stratification, especially in younger subjects., Competing Interests: Disclosures R. Virmani and A.V. Finn have received institutional research support from R01 HL141425 Leducq Foundation Grant; 480 Biomedical; 4C Medical; 4Tech; Abbott; Accumedical; Amgen; Biosensors; Boston Scientific; Cardiac Implants; Celonova; Claret Medical; Concept Medical; Cook; CSI; DuNing, Inc; Edwards LifeSciences; Emboline; Endotronix; Envision Scientific; Lutonix/Bard; Gateway; Lifetech; Limflo; MedAlliance; Medtronic; Mercator; Merill; Microport Medical; Microvention; Mitraalign; Mitra Assist; NAMSA; Nanova; Neovasc; NIPRO; Novogate; Occlutech; OrbusNeich Medical; Phenox; Profusa; Protembis; Qool; Recor; Senseonics, Shockwave; Sinomed; Spectranetics; Surmodics; Symic; Vesper; W.L. Gore; and Xeltis. A.V. Finn has received honoraria from Abbott Vascular; Biosensors; Boston Scientific; Celonova; Cook Medical; CSI; Lutonix Bard; Sinomed; and Terumo Corporation and is a consultant to Amgen; Abbott Vascular; Boston Scientific; Celonova; Cook Medical; Lutonix Bard; and Sinomed. R. Virmani has received honoraria from Abbott Vascular; Biosensors; Boston Scientific; Celonova; Cook Medical; Cordis; CSI; Lutonix Bard; Medtronic; OrbusNeich Medical; CeloNova; SINO Medical Technology; ReCore; Terumo Corporation; W. L. Gore; and Spectranetics and is a consultant to Abbott Vascular; Boston Scientific; Celonova; Cook Medical; Cordis; CSI; Edwards Lifescience; Lutonix Bard; Medtronic; OrbusNeich Medical; ReCore; Sinomededical Technology; Spectranetics; Surmodics; Terumo Corporation; W.L. Gore; and Xeltis. N. Sotoodehnia is supported by the Laughlin family endowment and the following NIH and foundation awards: R01HL141989 and AHA19SFRN348300063. The other authors report no conflicts.

Lateral ankle sprain is a common injury with a substantial negative impact on physical function, quality of life and health economic burden. Chronic lateral ankle instability (CLAI) as a sequela of lateral ankle sprain can lead to the development of posttraumatic ankle osteoarthritis in the long term. In this article, we explore the epidemiology, burden and definition of CLAI for the appropriate clinical assessment and imaging evaluation of patients with lateral ankle sprain and CLAI. Following that, recent advances and evidence on management of CLAI is critically distilled and summarized., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: James Calder reports a relationship with Arthrex that includes: speaking and lecture fees., (© 2023 Delhi Orthopedic Association. All rights reserved.)

Purpose: Differential elongation of the gastrocnemius after Achilles tendon rupture (ATR) may compromise the ability of athletes to return to competition. Recognition of this differential elongation of the gastrocnemius relative to the soleus is vital to treat patients with weakness in push-off. This paper describes a novel technique performed for selective shortening of the gastrocnemius to treat push-off weakness., Methods: Three patients with differential proximal retraction of the gastrocnemius greater than 20 mm after treatment for ATR with inability to run and jump underwent surgical correction with this novel technique and were followed-up for 2 years. A novel selective shortening of the gastrocnemius with autologous hamstring graft was performed in these patients. The Achilles Tendon Total Rupture Score (ATRS) and American Orthopaedic Foot and Ankle Society (AOFAS) hindfoot score were recorded preoperatively and at the final follow-up., Results: All three patients were able to return to running and jumping at final follow-up. The ATRS improved significantly in the strength, fatigue, running and jumping domains but there appeared to be a less notable improvement in activities of daily living domain. The AOFAS score showed improvement with the greatest margin in the domain of activity limitation., Conclusion: This procedure is the first described selective shortening method of the gastrocnemius tendons after differential elongation following ATR. It is a safe and reliable technique providing improved ATRS and AOFAS scores in three patients who were all able to return to running and jumping sports at 2-year follow-up., Level of Evidence: IV., (© 2023. The Author(s) under exclusive licence to European Society of Sports Traumatology, Knee Surgery, Arthroscopy (ESSKA).)

Background: Suture button fixation is frequently used to stabilize the distal tibiofibular syndesmosis in athletes sustaining an isolated ligamentous syndesmosis injury., Purpose: To report on a series of periprosthetic fibula fractures adjacent to the lateral suture button after a subsequent unrelated ankle injury or progressive stress injury after initial ankle syndesmosis stabilization using the knotless TightRope (Arthrex)., Study Design: Case series; Level of evidence, 4., Methods: Eight elite athletes with periprosthetic fibula fractures and stress injuries around the lateral suture buttons were evaluated. In all athletes, the knotless TightRope had been used to stabilize an isolated ligamentous ankle syndesmotic injury, after which all patients recovered and returned to professional sports at their preinjury level. The athletes subsequently developed an acute fibula fracture or a fibula stress fracture related to the 3.7-mm drill hole in the fibula adjacent to the lateral suture buttons after a mean of 14.1 months (range, 5-29 months). The management of these complications was analyzed., Results: Five athletes sustained a periprosthetic fibula fracture in the form of undisplaced spiral Weber B injuries after a subsequent, unrelated injury. Poor healing response was noted with initial nonoperative treatment for the first 2 athletes, and surgical intervention was performed with successful union of the fracture and return to sports. The subsequent 3 athletes had early surgery with uneventful recovery. Another 3 athletes developed stress injuries adjacent to the fibula suture button without a history of acute trauma. In 2 of the 3 athletes, the position of lateral suture buttons was in the anterior third of the fibula. Initial nonoperative management yielded poor healing response, and subsequent surgical intervention was required to enable healing and return to sports., Conclusion: Nonoperative management of fractures adjacent to the fibula suture button of a knotless TightRope may lead to a delay in union. Therefore, early surgical intervention should be considered in elite athletes, whose return-to-sports time is critical. Care is needed to ensure that the fibula hole for the suture button is centrally located because the eccentric placement of the fibula hole in the anterior third of the fibula may contribute to the development of a stress reaction or stress fracture. Surgical intervention for a periprosthetic fibula stress fracture leads to satisfactory resolution of symptoms., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: T.C. has received consulting fees from Arthrex, Orthosolutions, and Stryker. J.C. has received education payments from Arthrex. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto. Ethical approval for this study was waived by the National Health Service Health Research Authority., (© The Author(s) 2023.)

The relative abundance of Wnt receptors plays a crucial role in controlling Wnt signaling in tissue homeostasis and human disease. While the ubiquitin ligases that ubiquitylate Wnt receptors are well-characterized, the deubiquitylase that reverses these reactions remains unclear. Herein, we identify USP46, UAF1, and WDR20 (USP46 complex) as positive regulators of Wnt signaling in cultured human cells. We find that the USP46 complex is similarly required for Wnt signaling in Xenopus and zebrafish embryos. We demonstrate that Wnt signaling promotes the association between the USP46 complex and cell surface Wnt coreceptor, LRP6. Knockdown of USP46 decreases steady-state levels of LRP6 and increases the level of ubiquitylated LRP6. In contrast, overexpression of the USP46 complex blocks ubiquitylation of LRP6 by the ubiquitin ligases RNF43 and ZNFR3. Size exclusion chromatography studies suggest that the size of the USP46 cytoplasmic complex increases upon Wnt stimulation. Finally, we show that USP46 is essential for Wnt-dependent intestinal organoid viability, likely via its role in LRP6 receptor homeostasis. We propose a model in which the USP46 complex increases the steady-state level of cell surface LRP6 and facilitates the assembly of LRP6 into signalosomes via a pruning mechanism that removes sterically hindering ubiquitin chains., (© 2023. Springer Nature Limited.)