Cardiac Mass in a 78-Year-Old Patient With a History of Cancer: Diagnostic and Treatment Challenges.

Primary cardiac angiosarcoma is a rare, aggressive malignancy that commonly metastasizes to various organs. The presenting symptoms are typically nonspecific, so a comprehensive examination is required to confirm the diagnosis promptly. This case report describes the presentation of an older patient with a history of neoplasms. Echocardiography and biopsy were performed, but despite surgical intervention to resect a large right atrial mass, the patient died. A final diagnosis of primary angiosarcoma was made based on the resected specimen.

A PROGRESS-driven approach to cognitive outcomes after traumatic brain injury: A study protocol for advancing equity, diversity, and inclusion through knowledge synthesis and mobilization.

Evidence syntheses for advancing equitable traumatic brain injury (TBI) research, policy, and practice presents formidable challenges. Research and clinical frameworks are currently not specific to equity, diversity, and inclusion considerations, despite evidence that persons with TBI live in societies in which power imbalances and systems of social dominance may privilege some people and marginalize others. The present protocol outlines a strategy for a research program, supported by the Canadian Institutes of Health Research, that explores the integration of PROGRESS-Plus parameters in research with the goal of advancing open-science databases and tools to improve our understanding of equity in cognitive and brain health outcomes in TBI. PROGRESS-Plus is a framework outlining social, economic, and cultural parameters that may influence health opportunities and outcomes (e.g., place of residence, race, occupation, gender, etc.). A multistep research program is proposed to support three objectives: (1) organizing existing data on TBI-induced changes in cognition and brain health into a template to facilitate future research, including research using machine learning techniques; (2) updating published evidence with a more rigorous approach to the consideration of PROGRESS-Plus parameters; and (3) mobilizing knowledge on the current state of evidence that is relevant, equitable, and accessible. This program facilitates partnerships with knowledge users across clinical, research, academic, and community sectors to address the three research objectives through a unifying workflow of exchange, synthesis, and knowledge mobilization. We anticipate that this global collaboration between topic experts and community leaders in equity in brain health will add significant value to the field of TBI by promoting equity-transformative advancements in knowledge synthesis, policy, and practice.

A novel sequential treatment approach between denosumab and romosozumab in patients with severe osteoporosis.

In severe osteoporosis, the optimal approach for sequential treatment between denosumab and romosozumab is unclear. We utilised a novel overlapping strategy in three patients with very-high fracture risk despite long-term denosumab which led to greater bone density improvements than previously reported with standard approaches. Larger confirmatory prospective studies are needed. PURPOSE/INTRODUCTION: In patients with severe osteoporosis, the optimal approach for sequential treatment between denosumab and romosozumab has not been established. The ideal strategy would maximise gains in bone mineral density (BMD) with romosozumab and effectively mitigate the risk of rebound increased bone turnover when sequencing from denosumab. Limited studies exploring the sequence from denosumab to romosozumab report only modest-to-no improvement in BMD and inadequate suppression of rebound bone turnover. METHODS: We describe three patients with severe osteoporosis and multiple fragility fractures despite long-term denosumab. A novel overlapping sequential treatment approach was utilised to maximise therapeutic benefit given these patients had a very high fracture risk. Romosozumab was commenced 3 months after the last denosumab dose. Instead of waiting until completion of romosozumab, denosumab was recommenced 6 months after commencing romosozumab in response to rising bone turnover markers. RESULTS: Patients experienced a ~ 5-22% increase in lumbar spine BMD, and one patient had an 8% increase in total hip BMD after 12 months romosozumab. Serum bone turnover markers demonstrated an anabolic effect of romosozumab occurred despite overlapping treatment with denosumab. Recommencement of denosumab suppressed an increase in bone resorption in all cases. No new vertebral fractures occurred during this treatment. CONCLUSIONS: A novel overlapping sequential treatment approach between denosumab and romosozumab produced greater improvements in lumbar spine and hip BMD than previously reported with standard approaches. Larger prospective controlled studies are needed to confirm these findings and establish the optimal use of romosozumab in patients pre-treated with denosumab to maximise BMD gains and minimise fracture risk.

Celebrating 50-years: the history and future of the International Society of Bone Morphometry.

The International Society of Bone Morphometry (ISBM) is dedicated to advancing research, education, and clinical practice for osteoporosis and other bone disorders by developing and improving tools for the quantitative imaging and analysis of bone. Its initial core mission was to promote the proper use of morphometric techniques in bone research and to educate and train clinicians and basic scientists in bone morphometry. This article chronicles the evolution of the ISBM and the history and development of bone morphometric techniques for the past 50-years, starting with workshops on bone morphometry in 1973, to the formal incorporation of the ISBM in 1996, to today. We also provide a framework and vision for the coming decades. This effort was led by ISBM presidents Dr Erica L. Scheller (2022-2024) and Dr Thomas J. Wronski (2009-2012) in collaboration with all other living ISBM presidents. Though the underlying techniques and questions have changed over time, the need for standardization of established tools and discovery of novel approaches for bone morphometry remains a constant. The ISBM fulfills this need by providing a forum for the exchange of ideas, with a philosophy that encourages the open discussion of pitfalls and challenges among clinicians, scientists, and industry partners. This facilitates the rapid development and adaptation of tools to meet emerging demands within the field of bone health at a high level.

An in silico approach to elucidate the pathways leading to primary osteoporosis: age-related vs. postmenopausal.

Numerical models of bone remodelling have traditionally been used to perform in silico tests of bone loss in postmenopausal women and also to simulate the response to different drug treatments. These models simulate the menopausal oestrogen decline by altering certain signalling pathways. However, they do not consider the simultaneous effect that ageing can have on cell function and bone remodelling, and thus on bone loss. Considering ageing and oestrogen decline together is important for designing osteoporosis treatments that can selectively counteract one or the other disease mechanism. A previously developed bone cell population model was adapted to consider the effect of ageing through: (1) the decrease of TGF- ß contained in the bone matrix and (2) an increased production of sclerostin by non-skeletal cells. Oestrogen deficiency is simulated in three different ways: (a) an increase in RANKL expression, (b) a decrease in OPG production, and (c) an increase in the responsiveness of osteoclasts to RANKL. The effect of ageing was validated using the cross-sectional study of (Riggs et al. in J Bone Miner Res 19: 1945-1954, 2004) on BMD of trabecular bone of the vertebral body of men. The joint effect of ageing and oestrogen deficiency was validated using these same clinical results but in women. In ageing, the effect of the increasing production of sclerostin is more important than the decrease of TGF- ß , while the three mechanisms used to simulate the effect of oestrogen deficiency produce almost identical responses. The results show that an early menopause leads to a lower average density in the fifth decade, but after the sixth decade the average density is independent of the age at menopause. Treatment of osteoporosis with denosumab was also simulated to conclude that the drug is not very effective if started before 10 years after menopause or before age 60.

Temporal patterns of osteoclast formation and activity following withdrawal of RANKL inhibition.

Rebound bone loss following denosumab discontinuation is an important clinical challenge. Current treatment strategies to prevent this fail to suppress the rise and overshoot in osteoclast-mediated bone resorption. In this study, we use a murine model of denosumab treatment and discontinuation to show the temporal changes in osteoclast formation and activity during RANKL inhibition and withdrawal. We show that the cellular processes that drive the formation of osteoclasts and subsequent bone resorption following withdrawal of RANKL inhibition precede the rebound bone loss. Furthermore, a rise in serum TRAP and RANKL levels is detected before markers of bone turnover used in current clinical practice. These mechanistic advances may provide insight into a more defined window of opportunity to intervene with sequential therapy following denosumab discontinuation.

Stopping denosumab, a medication commonly used to improve bone mass by blocking formation of bone resorbing osteoclasts, leads to a rebound loss in the bone which was gained during treatment. Current strategies to prevent this bone loss fail in most cases as they are unable to prevent the rise and overshoot in bone resorption by osteoclasts. Thie stems from an incomplete understanding of how osteoclasts behave during denosumab treatment and after treatment is discontinued. We use a mouse model of this phenomenon to show how osteoclast formation and activity changes throughout this process. We show that increases in the processes that drive the formation of osteoclasts can be detected in the circulation before bone loss occurs. These findings could therefore provide insight into a targeted 'window of opportunity' to intervene and prevent the rebound bone loss following stopping denosumab in patients.

A Rare Autopsy Case of Aggressive Combined Hepatocellular-Cholangiocarcinoma in 59-Year-Old Female.

Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a liver tumor with features of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). It consists of intermingled malignant biliary and hepatic tissue and thus a distinct entity, rather than two separate coexisting malignancies. A 59-year-old female with a history of hepatitis C and cirrhosis presented with abdominal pain and altered mental status. She developed hematemesis, and despite extensive interventions, she expired one day after her initial presentation. At autopsy, the liver was diffusely and markedly fibrotic with numerous nodules of varying size with invasion into adjacent vasculature. Microscopic examination of the nodules revealed cHCC-CC with stem cell features, lymphovascular invasion, and tumor emboli scattered throughout the right lung. The patient had end-stage liver disease due to the accumulation of damage and consequent fibrosis. This led to portal hypertension with subsequent massive gastrointestinal bleeding, hemorrhagic shock, and death. cHCC-CC is a rare, aggressive primary liver tumor with a poor prognosis. It can present with a cirrhotomemetic pattern with small nodules that can evade clinical and radiographic detection. Autopsy findings can provide valuable insights into the pathogenesis and clinical course of cHCC-CC, highlight the aggressive nature of the disease, and may inform future diagnostic and therapeutic strategies. Accurate diagnosis of this tumor is important for patient management and prognostication.

The performance of artificial intelligence chatbot large language models to address skeletal biology and bone health queries.

Artificial intelligence (AI) chatbots utilizing large language models (LLMs) have recently garnered significant interest due to their ability to generate humanlike responses to user inquiries in an interactive dialog format. While these models are being increasingly utilized to obtain medical information by patients, scientific and medical providers, and trainees to address biomedical questions, their performance may vary from field to field. The opportunities and risks these chatbots pose to the widespread understanding of skeletal health and science are unknown. Here we assess the performance of 3 high-profile LLM chatbots, Chat Generative Pre-Trained Transformer (ChatGPT) 4.0, BingAI, and Bard, to address 30 questions in 3 categories: basic and translational skeletal biology, clinical practitioner management of skeletal disorders, and patient queries to assess the accuracy and quality of the responses. Thirty questions in each of these categories were posed, and responses were independently graded for their degree of accuracy by four reviewers. While each of the chatbots was often able to provide relevant information about skeletal disorders, the quality and relevance of these responses varied widely, and ChatGPT 4.0 had the highest overall median score in each of the categories. Each of these chatbots displayed distinct limitations that included inconsistent, incomplete, or irrelevant responses, inappropriate utilization of lay sources in a professional context, a failure to take patient demographics or clinical context into account when providing recommendations, and an inability to consistently identify areas of uncertainty in the relevant literature. Careful consideration of both the opportunities and risks of current AI chatbots is needed to formulate guidelines for best practices for their use as source of information about skeletal health and biology.

Artificial intelligence chatbots are increasingly used as a source of information in health care and research settings due to their accessibility and ability to summarize complex topics using conversational language. However, it is still unclear whether they can provide accurate information for questions related to the medicine and biology of the skeleton. Here, we tested the performance of three prominent chatbots­ChatGPT, Bard, and BingAI­by tasking them with a series of prompts based on well-established skeletal biology concepts, realistic physician­patient scenarios, and potential patient questions. Despite their similarities in function, differences in the accuracy of responses were observed across the three different chatbot services. While in some contexts, chatbots performed well, and in other cases, strong limitations were observed, including inconsistent consideration of clinical context and patient demographics, occasionally providing incorrect or out-of-date information, and citation of inappropriate sources. With careful consideration of their current weaknesses, artificial intelligence chatbots offer the potential to transform education on skeletal health and science.

Insights From the Histopathologic Analysis of Acquired and Genetic Thoracic Aortic Aneurysms and Dissections.

OBJECTIVE: The purpose of this study was to apply contemporary consensus criteria developed by the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology to the evaluation of aortic pathology, with the expectation that the additional pathologic information may enhance the understanding and management of aortic diseases. METHODS: A scoring system was applied to ascending aortic specimens from 42 patients with heritable thoracic aortic disease and known genetic variations and from 86 patients from a single year, including patients with known genetic variations (n = 12) and patients with sporadic disease (n = 74). RESULTS: The various types of lesions of medial degeneration and the overall severity of medial degeneration overlapped considerably between those patients with heritable disease and those with sporadic disease; however, patients with heritable thoracic aortic disease had significantly more overall medial degeneration (P = .004) and higher levels of elastic fiber fragmentation (P = .03) and mucoid extracellular matrix accumulation (P = .04) than patients with sporadic thoracic aortic disease. Heritable thoracic aortic disease with known genetic variation was more prevalent in women than in men (27.2% vs 9.8%; P = .04), and women had more severe medial degeneration than men (P = .04). Medial degeneration scores were significantly lower for patients with bicuspid aortic valves than for patients with tricuspid aortic valves (P = .03). CONCLUSION: The study's findings indicate considerable overlap in the pattern, extent, and severity of medial degeneration between sporadic and hereditary types of thoracic aortic disease. This finding suggests that histopathologic medial degeneration represents the final common outcome of diverse pathogenetic factors and mechanisms.

Neurovascular Complications of Iatrogenic Fusarium solani Meningitis.

A multinational outbreak of nosocomial fusarium meningitis occurred among immunocompetent patients who had undergone surgery with epidural anesthesia in Mexico. The pathogen involved had a high predilection for the brain stem and vertebrobasilar arterial system and was associated with high mortality from vessel injury. Effective treatment options remain limited; in vitro susceptibility testing of the organism suggested that it is resistant to all currently approved antifungal medications in the United States. To highlight the severe complications associated with fusarium infection acquired in this manner, we report data, clinical courses, and outcomes from 13 patients in the outbreak who presented with symptoms after a median delay of 39 days.

New Horizons: Translational Aspects of Osteomorphs.

Osteomorphs are a newly described osteoclast lineage cell in mice, which are suggested to play a significant role in the maintenance of bone resorption. Preclinical investigations revealed that osteomorphs are generated through the fission of multinucleated bone-resorbing osteoclasts and can also re-fuse with existing osteoclasts. Modifications to RANKL signaling have been shown to alter cycles of fission and re-fusion of osteomorphs in mice. These novel findings were also shown to contribute to the rebound phenomenon after cessation of anti-RANKL therapy in mice. Moreover, the absence of osteomorph-specific genes in mice exhibits bone structural and quality phenotypes. Given these insights, it could be speculated that osteomorphs play a significant role in bone homeostasis, bone metabolic diseases, and response to therapeutics. In this review, we discuss these potential translational roles for osteomorphs. Importantly, we highlight the need for future preclinical and clinical studies to verify the presence of osteomorphs in humans and explore further the translational implications of this discovery.

Longitudinal analysis of physical function in older adults: The effects of physical inactivity and exercise training.

Lack of exercise contributes to systemic inflammation and is a major cause of chronic disease. The long-term impact of initiating and sustaining exercise in late life, as opposed to sustaining a sedentary lifestyle, on whole-body health measures such as physical performance is not well known. This is an exploratory study to compare changes in physical performance among older adults initiating exercise late in life versus inactive older adults. Data from two observational cohorts were included in this analysis, representing two activity groups. The Active group cohort comprises older adults (n = 318; age 72.5 ± 7.2 years) enrolled in a supervised exercise program, "Gerofit." The inactive group comprises older adults (n = 146; age 74.5 ± 5.5 years) from the Italian study "Act on Ageing" (AOA) who self-reported being inactive. Participants in both groups completed physical performance battery at baseline and 1-year including: 6-min walk test, 30-s chair stand, and timed up-and-go. Two-sample t-tests measured differences between Gerofit and AOA at baseline and 1-year across all measures. Significant between-group effects were seen for all performance measures (ps = 0.001). The AOA group declined across all measures from baseline to 1 year (range -18% to -24% change). The Gerofit group experienced significant gains in function for all measures (range +10% to +31% change). Older adults who initiated routine, sustained exercise were protected from age-related declines in physical performance, while those who remained sedentary suffered cumulative deficits across strength, aerobic endurance, and mobility. Interventions to reduce sedentary behaviors and increase physical activity are both important to promote multi-system, whole-body health.

Real-Time Live Imaging of Osteoclast Activation via Cathepsin K Activity in Bone Diseases.

Intravital fluorescence imaging of functional osteoclasts within their intact disease context provides valuable insights into the intricate biology at the microscopic level, facilitating the development of therapeutic approaches for osteoclast-associated bone diseases. However, there is a lack of studies investigating osteoclast activity within deep-seated bone lesions using appropriate fluorescent probes, despite the advantages offered by the multi-photon excitation system in enhancing deep tissue imaging resolution. In this study, we report on the intravital tracking of osteoclast activity in three distinct murine bone disease models. We utilized a cathepsin K (CatK)-responsive two-photon fluorogenic probe (CatKP1), which exhibited a notable fluorescence turn-on response in the presence of active CatK. By utilizing CatKP1, we successfully monitored a significant increase in osteoclast activity in hindlimb long bones and its attenuation through pharmacological intervention without sacrificing mice. Thus, our findings highlight the efficacy of CatKP1 as a valuable tool for unraveling pathological osteoclast behavior and exploring novel therapeutic strategies.

Impact of the COVID-19 pandemic on community-based brain injury associations across Canada: a cross-sectional survey study.

Background: The COVID-19 pandemic created new difficulties for people living with brain injury, their families, and caregivers while amplifying the challenges of community-based associations that support them. We aimed to understand the effects of the pandemic on clients who live with brain injury, as well as on the provision of community brain injury services/programs in Canada. Methods: Online cross-sectional survey conducted in January 2022. Representatives of brain injury associations across Canada completed the 31 open- and closed-ended questions about meeting clients' needs, addressing public health guidelines, and sustaining the association. Data were analyzed using descriptive statistics (close-ended questions) and qualitative content analysis (open-ended questions). Results: Of the 45 key representatives from associations in Pacific/Western (40%), Central (56%), and Atlantic Canada (4%), the majority were paid executive directors (67%). Participants reported that the most frequent psychosocial challenges experienced by their clients during the pandemic were social isolation (98%), loneliness (96%), and anxiety (93%). To alleviate these challenges, associations implemented wellness checks and psychosocial support. Most respondents (91%) affirmed that clients faced multiple technological barriers, such as a lack of technological knowledge and financial resources for devices and/or internet. In the open-ended questions, twenty-nine (64%) associations reported providing clients with devices, technology training, and assistance. Regarding public health measures, thirty (67%) respondents reported that clients had challenges understanding and/or following public health guidelines. Forty-two associations (93%) provided tailored information to help clients understand and comply with public health measures. Although associations (67%) received pandemic-related funding from the Canadian government they still struggled with the association's sustainability. Thirty-four (76%) lost funding or financial resources that prevented them from delivering programs or required the use of reserve funds to continue to do so. Only 56% reported receiving sufficient funding to address additional COVID-19-related expenses. Conclusion: Although the pandemic added further challenges to the sustainability of brain injury associations across Canada, they quickly adapted services/programs to respond to the increasing and varied needs of clients, while complying with protective measures. To ensure community associations' survival it is essential to aptly recognize the vital role played by these associations within the brain injury care continuum.

Understanding the Early Impacts of the COVID-19 Pandemic on Brain Injury Associations Across Canada: A Qualitative Study.

The COVID-19 pandemic has increased challenges for people living with brain injury and community associations to support this vulnerable population. This study aimed to gain an in-depth understanding of the challenges faced by brain injury survivors during the first year of the pandemic and how community brain injury associations adapted their services to respond to these needs. Findings from seven focus-group with 31 representatives of Canadian brain injury associations revealed 4 main themes: (1) Addressing evolving client needs; (2) Keeping clients safe; (3) Challenges and opportunities navigating the digital world; and (4) Sustaining brain injury associations in the face of uncertainties and disruptions. To comply with public health measures, associations reported pivoting their service delivery online, despite recognizing the difficulties this could create for many brain injury survivors in accessing and using technology. Our findings also highlight concrete directions for not-profit organizations providing instrumental help with activities, acting as a liaison and interpreter of public health guidelines, and in connecting with clients using technology while handling potential cognitive and technological challenges. Addressing these issues has the potential to protect people living with brain injury and community associations from external threats, like pandemics, in the future.

Minimally invasive longitudinal intravital imaging of cellular dynamics in intact long bone.

Intravital two-photon microscopy enables deep-tissue imaging at high temporospatial resolution in live animals. However, the endosteal bone compartment and underlying bone marrow pose unique challenges to optical imaging as light is absorbed, scattered and dispersed by thick mineralized bone matrix and the adipose-rich bone marrow. Early bone intravital imaging methods exploited gaps in the cranial sutures to bypass the need to penetrate through cortical bone. More recently, investigators have developed invasive methods to thin the cortical bone or implant imaging windows to image cellular dynamics in weight-bearing long bones. Here, we provide a step-by-step procedure for the preparation of animals for minimally invasive, nondestructive, longitudinal intravital imaging of the murine tibia. This method involves the use of mixed bone marrow radiation chimeras to unambiguously double-label osteoclasts and osteomorphs. The tibia is exposed by a simple skin incision and an imaging chamber constructed using thermoconductive T-putty. Imaging sessions up to 12 h long can be repeated over multiple timepoints to provide a longitudinal time window into the endosteal and marrow niches. The approach can be used to investigate cellular dynamics in bone remodeling, cancer cell life cycle and hematopoiesis, as well as long-lived humoral and cellular immunity. The procedure requires an hour to complete and is suitable for users with minimal prior expertise in small animal surgery.

Allograft nephrectomy vs. no nephrectomy for failed renal transplants.

The role of allograft nephrectomy (AN) in failed renal transplants is a topic of debate, owing to controversial results reported in the literature and the fact that most of the studies are limited by a retrospective design and small numbers of participants. Allograft nephrectomy is most likely of benefit in the patient with recurrent allograft intolerance syndrome (AIS) following pulse steroids. Immunosuppression weaning in the presence of clinical signs related to a chronic inflammatory state is also reasonable grounds to pursue AN. Studies are mainly inconclusive but suggest that AN has no overall benefit for allograft survival after retransplant. This topic is still of interest in the transplant field and is particularly relevant for patients who are likely to require retransplantation within their lifetime. Further assessment is needed in the form of randomized controlled trials that control for various AN indications and immunosuppression regimens, and have clearly defined survival outcomes.