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Background: Age‐related changes in bone health increase the risk for complications in elderly patients undergoing orthopedic surgery. Osteoporosis is a key therapeutic target that needs to be addressed to ensure successful instrumentation surgery. The effectiveness of pharmacological interventions in orthopedic surgery, particularly the new drug romosozumab, is still unknown. We aim to evaluate the effect of 3‐month romosozumab treatment on biomechanical parameters related to spinal instrumentation surgery, using the Quantitative Computed Tomography (QCT)‐based Finite Element Method (FEM). Methods: This open‐labeled, prospective study included 81 patients aged 60 to 90 years, who met the osteoporosis criteria and were scheduled for either romosozumab or eldecalcitol treatment. Patients were assessed using blood samples, dual‐energy absorptiometry (DXA), and QCT. Biomechanical parameters were evaluated using FEM at baseline and 3 months post‐treatment. The primary endpoints were biomechanical parameters at 3 months, while secondary endpoints included changes in regional volumetric bone mineral density around the pedicle (P‐vBMD) and vertebral body (V‐vBMD). Results: Romosozumab treatment led to significant gains in P‐vBMD, and V‐vBMD compared to eldecalcitol at 3 months. Notably, the romosozumab group showed greater improvements in all biomechanical parameters estimated by FEM at 3 months compared to the eldecalcitol group. Conclusion: Romosozumab significantly increased the regional vBMD as well as biomechanical parameters, potentially offering clinical benefits in reducing post‐operative complications in patients with osteoporosis undergoing orthopedic instrumentation surgery. This study highlights the novel advantages of romosozumab treatment and advocates further research on its effectiveness in perioperative management. [ABSTRACT FROM AUTHOR]

Osteoporosis treatment plays a crucial role in preventing fractures, particularly in bedridden patients. We conducted a questionnaire survey presenting hypothetical clinical cases in 2015 and 2020 to investigate trends over a 5-year period. The target population included physicians working in clinics and hospitals within our neighbourhood. The cases were presented, and the questionnaire was administered in a confidential format. The orthopaedic surgeons were matched for age and practice, resulting in 74 cases being included in the analysis. Comparing the 2015 and 2020 results, we observed a notable increase in physicians who would perform "bone mineral density measurements of the lumbar spine and hip." Furthermore, there was a significant rise in the percentage of respondents willing to test for bone metabolic markers, such as serum type I collagen cross-linked N-telopeptide (NTX), procollagen I N-terminal propeptide (P1NP), and tartrate-resistant acid phosphatase 5b (TRACP-5b). Regarding therapeutic agents, bisphosphonates decreased in usage, whereas parathyroid hormone and romosozumab witnessed an increase. In conclusion, the percentage of physicians requesting bone mineral density measurements of the lumbar spine and hip increased over the five-year period. In addition, more physicians chose to utilise bone metabolic markers due to their ease of measurement through blood tests and reduced diurnal variation. Finally, there was a marked trend towards the administration of drugs capable of rapidly and effectively increasing bone mineral density at an early stage of treatment. [ABSTRACT FROM AUTHOR]

Radiotherapy remains a common treatment modality for cancer despite skeletal complications. However, there are currently no effective treatments for radiation-induced bone loss, and the consequences of radiotherapy on skeletal progenitor cell (SPC) survival and function remain unclear. After radiation, leptin receptor–expressing cells, which include a population of SPCs, become localized to hypoxic regions of the bone and stabilize the transcription factor hypoxia-inducible factor-2α (HIF-2α), thus suggesting a role for HIF-2α in the skeletal response to radiation. Here, we conditionally knocked out HIF-2α in leptin receptor–expressing cells and their descendants in mice. Radiation therapy in littermate control mice reduced bone mass; however, HIF-2α conditional knockout mice maintained bone mass comparable to nonirradiated control animals. HIF-2α negatively regulated the number of SPCs, bone formation, and bone mineralization. To test whether blocking HIF-2α pharmacologically could reduce bone loss during radiation, we administered a selective HIF-2α inhibitor called PT2399 (a structural analog of which was recently FDA-approved) to wild-type mice before radiation exposure. Pharmacological inhibition of HIF-2α was sufficient to prevent radiation-induced bone loss in a single-limb irradiation mouse model. Given that ~90% of patients who receive a HIF-2α inhibitor develop anemia because of off-target effects, we developed a bone-targeting nanocarrier formulation to deliver the HIF-2α inhibitor to mouse bone, to increase on-target efficacy and reduce off-target toxicities. Nanocarrier-loaded PT2399 prevented radiation-induced bone loss in mice while reducing drug accumulation in the kidney. Targeted inhibition of HIF-2α may represent a therapeutic approach for protecting bone during radiation therapy. Editor's summary: Radiotherapy frequently leads to bone loss. Here, Guo and colleagues explored the role of hypoxia signaling through HIF-2α in skeletal progenitor cells as a negative regulator of bone mass after radiotherapy in mice. Selective knockout of HIF-2α in leptin receptor-expressing skeletal progenitor cells rescued mice from decreased bone mass after total body irradiation. Pharmacologic inhibition of HIF-2α improved bone integrity; however, systemic treatment caused off-target effects. Therefore, a bone-targeting nanocarrier was developed to deliver localized HIF-2α inhibition, which alleviated radiation-induced bone loss without systemic off-target effects. This represents a promising targeted strategy that awaits further clinical validation. —Molly Ogle [ABSTRACT FROM AUTHOR]

Introduction: Burnout among healthcare professionals in intensive care units (ICUs) is a serious issue that leads to early retirement and medication errors. Their gender, lower years of experience, and lower education have been reported as risk factors. Simultaneously, mutual support—commonly referred to as "back-up behavior," in which staff members support each other—is critical for team performance. However, little is known about the influence of mutual support among ICU healthcare professionals on burnout. The U.S. Agency for Healthcare Research and Quality refers to mutual support as the involvement of team members in: assisting one another, providing and receiving feedback, and exerting assertive and advocacy behaviors when patient safety is threatened. Objective: This study aimed to verify the hypothesis that lower mutual support among ICU healthcare professionals is associated with increased probability of burnout. Methods: A web-based survey was conducted from March 4 to 20, 2021. All ICU healthcare professionals in Japan were included. An invitation was sent via the mailing list of the Japanese Society of Intensive Care Medicine and asked to mail to local communities and social network services. We measured burnout severity using the Maslach Burnout-Human Services Survey and mutual support using the TeamSTEPPS Teamwork Perceptions Questionnaire, as well as occupational background. The cutoff value for burnout was predefined and conducted logistic regression. Results: We received 335 responses, all of which were analyzed. The majority of respondents were nurses (58.5%), followed by physicians (18.5%) and clinical engineers (10.1%). The burnout group scored significantly lower on mutual support than the non-burnout group. After adjusting for covariates in a logistic regression, low mutual support was an independent factor predicting a high probability of burnout. Conclusions: This study suggests that it is important to focus on mutual support among ICU healthcare professionals to reduce the frequency of burnout. [ABSTRACT FROM AUTHOR]

Objectives To determine the expression of hepatocyte growth factor (HGF) in RA biological fluids, the role of HGF in monocyte migration and the therapeutic effect of the c-Met inhibitor savolitinib in an arthritis model mice. Methods HGF/c-Met expression in serum, SF and synovial tissues (STs) obtained from RA patients and controls, as well as RA fibroblast-like synoviocytes (FLSs), was evaluated by ELISA and immunostaining. To determine the function of HGF in RA SF, we preincubated RA SF with a neutralizing anti-HGF antibody and measured the chemotactic ability of a human acute monocytic leukaemia cell line (THP-1). Additionally, examinations were conducted of SKG mice treated with savolitinib for 4 weeks. Results HGF levels in serum from RA patients were significantly higher than those in the controls and were decreased by drug treatment for 24 weeks. Additionally, the HGF level in SF from RA patients was higher than that in SF from OA patients. HGF and c-Met expression was also noted in RA STs. Stimulation of RA FLSs with TNF-α increased HGF/c-Met expression in a concentration-dependent manner, and c-Met signal inhibition suppressed production of fractalkine/CX3CL1 and macrophage inflammatory protein-1α/CCL3. When HGF was removed by immunoprecipitation, migration of THP-1 in RA SF was suppressed. In SKG mice, savolitinib significantly suppressed ankle bone destruction on µCT, with an associated reduction in the number of tartrate-resistant acid phosphatase-positive osteoclasts. Conclusion HGF produced by inflammation in synovium of RA patients activates monocyte migration to synovium and promotes bone destruction via a chemotactic effect and enhanced chemokine production. [ABSTRACT FROM AUTHOR]

Proper control of gene expression levels upon various perturbations is a fundamental aspect of cellular robustness. Protein-level dosage compensation is one mechanism buffering perturbations to stoichiometry of multiprotein complexes through accelerated proteolysis of unassembled subunits. Although N-terminal acetylation- and ubiquitin-mediated proteasomal degradation by the Ac/N-end rule pathway enables selective compensation of excess subunits, it is unclear how widespread this pathway contributes to stoichiometry control. Here we report that dosage compensation depends only partially on the Ac/N-end rule pathway. Our analysis of genetic interactions between 18 subunits and 12 quality control factors in budding yeast demonstrated that multiple E3 ubiquitin ligases and N-acetyltransferases are involved in dosage compensation. We find that N-acetyltransferases-mediated compensation is not simply predictable from N-terminal sequence despite their sequence specificity for N-acetylation. We also find that the compensation of Pop3 and Bet4 is due in large part to a minor N-acetyltransferase NatD. Furthermore, canonical NatD substrates histone H2A/H4 were compensated even in its absence, suggesting N-acetylation-independent stoichiometry control. Our study reveals the complexity and robustness of the stoichiometry control system. Author summary: Quality control of multiprotein complexes is important for maintaining homeostasis in cellular systems that are based on functional complexes. Proper stoichiometry of multiprotein complexes is achieved by the balance between protein synthesis and degradation. Recent studies showed that translation efficiency tends to scale with stoichiometry of their subunits. On the other hand, although protein N-terminal acetylation- and ubiquitin-mediated proteolysis pathway is involved in selective degradation of excess subunits, it is unclear how widespread this pathway contributes to stoichiometry control due to the lack of a systematic investigation using endogenous proteins. To better understand the landscape of the stoichiometry control system, we examined genetic interactions between 18 subunits and 12 quality control factors (E3 ubiquitin ligases and N-acetyltransferases), in total 114 combinations. Our data suggest that N-acetyltransferases are partially responsible for stoichiometry control and that N-acetylation-independent pathway is also involved in selective degradation of excess subunits. Therefore, this study reveals the complexity and robustness of the stoichiometry control system. Further dissection of this complexity will help to understand the mechanisms buffering gene expression perturbations and shaping proteome stoichiometry. [ABSTRACT FROM AUTHOR]

There is growing interest in "osteosarcopenia" as the coexistence of osteoporosis and sarcopenia exacerbates negative outcomes. However, limited information is available regarding the risk factors of osteosarcopenia development in patients with osteoporosis. Therefore, we retrospectively reviewed 276 consecutive patients with postmenopausal osteoporosis who regularly visited Showa University Hospital. Patients were eligible for the study if they were ≥65 years of age and underwent dual-energy X-ray absorptiometry, blood sampling, and physical performance assessment. Patients were divided into the osteosarcopenia and osteoporosis alone groups according to the diagnostic criteria of the Asian Working Group for Sarcopenia. Of the 276 patients with osteoporosis, 54 patients (19.6%) had osteosarcopenia. Patients in the osteosarcopenia group had a greater risk of frailty than did those in the osteoporosis alone group (odds ratio 2.33; 95% confidence interval, 1.13–4.80, P = 0.028). Low body mass index seemed to be the strongest factor related to the development of osteosarcopenia, and none of the patients in the osteosarcopenia group were obese (BMI ≥27.5 kg/m2). Multiple logistic analyses revealed that patients aged 65–74 years who had comorbidities such as kidney dysfunction and high levels of HbA1c were at risk of developing osteosarcopenia. Thus, we strongly recommend the assessment of the key components of the diagnosis of osteosarcopenia in an osteoporosis clinic for patients with low body mass index. Furthermore, appropriate assessments, including comorbidities, will help in identifying patients at greater risk of developing osteosarcopenia. [ABSTRACT FROM AUTHOR]