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ABSTRACT Sclerostin, encoded by the Sost gene, is an important negative regulator of bone formation that has been proposed to have a key role in regulating the response to mechanical loading. To investigate the effect of long-term Sclerostin deficiency on mechanotransduction in bone, we performed experiments on unloaded or loaded tibiae of 10 week old female Sost−/− and wild type mice. Unloading was induced via 0.5U botulinum toxin (BTX) injections into the right quadriceps and calf muscles, causing muscle paralysis and limb disuse. On a separate group of mice, increased loading was performed on the left tibiae through unilateral cyclic axial compression of equivalent strains (+1200 µe) at 1200 cycles/day, 5 days/week. Another cohort of mice receiving equivalent loads (−9.0 N) also were assessed. Contralateral tibiae served as normal load controls. Loaded/unloaded and normal load tibiae were assessed at day 14 for bone volume (BV) and formation changes. Loss of BV was seen in the unloaded tibiae of wild type mice, but BV was not different between normal load and unloaded Sost−/− tibiae. An increase in BV was seen in the loaded tibiae of wild type and Sost−/− mice over their normal load controls. The increased BV was associated with significantly increased mid-shaft periosteal mineralizing surface/bone surface (MS/BS), mineral apposition rate (MAR), and bone formation rate/bone surface (BFR/BS), and endosteal MAR and BFR/BS. Notably, loading induced a greater increase in periosteal MAR and BFR/BS in Sost−/− mice than in wild type controls. Thus, long-term Sclerostin deficiency inhibits the bone loss normally induced with decreased mechanical load, but it can augment the increase in bone formation with increased load. © 2014 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Microscopic hematuria, a common finding on routine urinalysis of adults, is clinically significant when three to five red blood cells per high-power field are visible. Etiologies of microscopic hematuria range from incidental causes to life-threatening urinary tract neoplasm. The lack of evidence-based imaging guidelines can complicate the family physician's decision about the best way to proceed. Patients with proteinuria, red cell casts, and elevated serum creatinine levels should be referred promptly to a nephrology subspecialist. Microscopic hematuria with signs of urinary tract infection should resolve with appropriate treatment of the underlying infection. Patients with asymptomatic microscopic hematuria or with hematuria persisting after treatment of urinary tract infection also need to be evaluated. Because upper and lower urinary tract pathologies often coexist, patients should be evaluated using cytology plus intravenous urography, computed tomography, or ultrasonography. When urine cytology results are abnormal, cystoscopy should be performed to complete the investigation. [ABSTRACT FROM AUTHOR]

Background: Transforming growth factor-beta (TGF-beta) and bone morphogenetic proteins (BMPs) utilize parallel and related signaling pathways, however the interaction between these pathways in bone remains unclear. TGF-beta inhibition has been previously reported to promote osteogenic differentiation in vitro, suggesting it may have a capacity to augment orthopaedic repair. We have explored this concept using an approach that represents a template for the testing of agents with prospective orthopaedic applications.Methods: The effects of BMP-2, TGF-beta1, and the TGF-beta receptor (ALK-4/5/7) inhibitor SB431542 on osteogenic differentiation were tested in the MC3T3-E1 murine pre-osteoblast cell line. Outcome measures included alkaline phosphatase staining, matrix mineralization, osteogenic gene expression (Runx2, Alp, Ocn) and phosphorylation of SMAD transcription factors. Next we examined the effects of SB431542 in two orthopaedic animal models. The first was a marrow ablation model where reaming of the femur leads to new intramedullary bone formation. In a second model, 20 microg rhBMP-2 in a polymer carrier was surgically introduced to the hind limb musculature to produce ectopic bone nodules.Results: BMP-2 and SB431542 increased the expression of osteogenic markers in vitro, while TGF-beta1 decreased their expression. Both BMP-2 and SB431542 were found to stimulate pSMAD1 and we also observed a non-canonical repression of pSMAD2. In contrast, neither in vivo system was able to provide evidence of improved bone formation or repair with SB431542 treatment. In the marrow ablation model, systemic dosing with up to 10 mg/kg/day SB431542 did not significantly increase reaming-induced bone formation compared to vehicle only controls. In the ectopic bone model, local co-administration of 38 microg or 192 microg SB431542 did not increase bone formation.Conclusions: ALK-4/5/7 inhibitors can promote osteogenic differentiation in vitro, but this may not readily translate to in vivo orthopaedic applications. [ABSTRACT FROM AUTHOR]

Denosumab is a monoclonal anti-RANKL antibody that inhibits bone resorption, increases bone mass, and reduces fracture risk. Denosumab discontinuation causes an extensive wave of rebound resorption, but the cellular mechanisms remain poorly characterized. We utilized in situ hybridization (ISH) as a direct approach to identify the cells that activate osteoclastogenesis through the RANKL/OPG pathway. ISH was performed across species, skeletal sites, and following recombinant OPG (OPG:Fc) and parathyroid hormone 1-34 (PTH) treatment of mice. OPG:Fc treatment in mice induced an increased expression of RANKL mRNA mainly in trabecular, but not endocortical bone surface cells. Additionally, a decreased expression of OPG mRNA was detected in bone surface cells and osteocytes of both compartments. A similar but more pronounced effect on RANKL and OPG expression was seen one hour after PTH treatment. These findings suggest that bone surface cells and osteocytes conjointly regulate the activation of osteoclastogenesis, and that OPG:Fc treatment induces a local accumulation of osteoclastogenic activation sites, ready to recruit and activate osteoclasts upon treatment discontinuation. Analysis of publicly available single-cell RNA sequencing (scRNAseq) data from murine bone marrow stromal cells revealed that Tnfsf11 + cells expressed high levels of Mmp13, Limch1, and Wif1, confirming their osteoprogenitor status. ISH confirmed co-expression of Mmp13 and Tnfsf11 in bone surface cells of both vehicle- and OPG:Fc-treated mice. Under physiological conditions of human/mouse bone, RANKL is expressed mainly by osteoprogenitors proximate to the osteoclasts, while OPG is expressed mainly by osteocytes and bone-forming osteoblasts., (© 2024. The Author(s).)

Data on effects of strangulation in victims with a disability are lacking despite this population experiencing intimate partner violence at higher rates than women without a disability. A retrospective review was conducted on medical records of patients seeking care at a community-based, forensic nurse examiner program following an intimate partner violence-related strangulation event. The presence of disability was not associated with differences in reporting other types of victimization, additional abusive events, perpetrator characteristics, strangulation actions, or injury findings. Patients with a disability were more likely to report experiencing anoxic, hypoxic, and other physical symptoms following strangulation compared to patients without a disability., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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., (© 2024. The Author(s).)

Melengestrol acetate (MGA) implants are a progestin-based reversible contraceptive used to manage fertility in animals. MGA implants are recommended for replacement every 2 years; however, reproduction may be suppressed longer if implants are not removed. In this study, we investigated whether the probability of reproducing (pR) differed among nonimplanted females, females with MGA implants removed, and females whose implants were not removed. In addition, since implant loss in hamadryas baboons is a concern, we explored whether female age, institution, implant placement year, implant location, or implant placement type (intramuscular vs. subcutaneous) differed for females whose implants were lost compared to those that were not. The pR differed significantly across all three treatment conditions with the nonimplanted group having the highest pR. The pR plateaued at 63% after 40 months for the implant-removed group compared to 96% after 84 months in the nonimplanted group. There was no reproduction after contraception if implants were not removed (7.83-45.53 months). In the nonimplanted group, pR was significantly higher for older and parous females. In terms of implant loss, we found that implant placement type was significantly associated with implant loss, such that there were fewer losses when implants were placed intramuscularly (IM) as compared to subcutaneously. Our results suggest that placing MGA implants IM is likely to reduce loss. When loss is prevented, MGA implants are an effective form of contraception and are reliably reversibly in most individuals when removed. However, if not removed, they can prevent reproduction longer than 2 years., (© 2024 Wiley Periodicals LLC.)

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., (© 2024 The Authors. Published by The Texas Heart Institute®.)

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- β 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- β , 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., (© 2024. The Author(s).)

People tend to select romantic partners who belong to the same social group as themselves (i.e., endogamy). However, there is limited research on the proximal psychological motivations for choosing endogamous relationship partners. The purpose of this research was to develop a measure of motivations for endogamous relationship preferences and to assess whether such motivations were associated with actual dating experiences and attitudes toward endogamy across four common social categories: race and/or ethnicity, religion, social class, and education. Data from an online sample of participants (Study 1, n = 341) were used to generate items assessing motivations for endogamous relationship preferences. This initial set of items was administered to a new sample of participants (Study 2, n = 193) to establish the component structure of the measure and to examine whether the motivational components were associated with participants' past exogamous dating experiences as well as the perceived importance of dating within one's own racial and/or ethnic, religious, socioeconomic, and educational group. Endogamy motivations characterized by intergroup prejudice were the strongest and most consistent correlates of endogamous relationships and the perceived importance of endogamy. Study 3 (n = 332) replicated the component structure of the measure and the general pattern of associations documented in Study 2, and provided evidence for the measure's construct validity. The overall findings suggest that intergroup prejudice partially explains preferences for endogamous relationships., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Due to their potential impact on population growth, many studies have investigated factors affecting infant survival in mammal populations under human care. Here we used more than 30 years of Association of Zoos and Aquariums (AZA) studbook data and contraception data from the AZA Reproductive Management Center, along with logistic regression models, to investigate which factors affect infant survival in four Eulemur species managed as Species Survival Plans® in AZA. Across species, infant survival to 1 month ranged from 65% to 78%. Previous experience producing surviving offspring was positively correlated to infant survival in collared (Eulemur collaris), crowned (Eulemur coronatus), and mongoose (Eulemur mongoz) lemurs. Both dam age and previous use of contraception were negatively correlated to infant survival for collared lemurs, though our results suggest the latter may be confounded with other factors. Blue-eyed black lemurs (Eulemur flavifrons) were affected by birth location, suggesting differences in husbandry that may affect infant survival. These results can be used to assist in reproductive planning or to anticipate the likelihood of breeding success. Population managers may also be able to focus their reproductive planning on younger dams or those with previous experience to predict successful births. Future studies should seek to determine what aspects of previous dam success are most important to infant survival, investigate sire-related factors, and examine factors related to cause of death in infants that may lead to differential survival. Our hope is to present a framework that may be useful for investigating infant survival in other mammal species' breeding programs., (© 2024 Wiley Periodicals LLC.)

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Large variations in redox-related water parameters, like pH and dissolved oxygen (DO), have been documented in New Hampshire (United States) drinking-water wells over the course of a few hours under pumping conditions. These findings suggest that comparable sub-daily variability in dissolved concentrations of redox-reactive and toxic arsenic (As) also may occur, representing a potentially critical public-health data gap and a fundamental challenge for long-term As-trends monitoring. To test this hypothesis, discrete groundwater As samples were collected approximately hourly during one day in May and again in August 2019 from three New Hampshire drinking-water wells (2 public-supply, 1 private) under active pumping conditions. Collected samples were assessed by laboratory analysis (total As [As Tot ], As(III), As(V)) and by field analysis (As Tot ) using a novel integrated biosensor system. Laboratory analysis revealed sub-daily variability (range) in As Tot concentrations equivalent to 16 % - 36 % of that observed in the antecedent 3-year bimonthly trend monitoring. Thus, the results indicated that, along with previously demonstrated seasonality effects, the timing and duration of pumping are important considerations when assessing trends in drinking-water As exposures and concomitant risks. Results also illustrated the utility of the field sensor for monitoring and management of As Tot exposures in near-real-time., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Emily C. Hick reports a relationship with FREDsense Technologies Corp. that includes: employment and equity or stocks. David C. Lloyd reports a relationship with FREDsense Technologies Corp. that includes: employment and equity or stocks. Mhairi M. McDonald reports a relationship with FREDsense Technologies Corp. that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (© 2023 Wiley-VCH GmbH.)

Anti-Müllerian hormone (AMH) is secreted by granulosa cells of healthy, growing follicles and is positively correlated with the ovarian reserve. Maternal and environmental factors, such as nutrition, disease, parity and endocrine disruptors, are thought to have a profound impact on ovarian reserve development during early foetal life. For genetic progress, it can be advantageous to breed dairy replacements from heifers to expedite the generation interval; however, there is some evidence that nulliparous animals produce female offspring with smaller ovarian reserves compared with multiparous animals. The objective of this prospective, observational study was to determine whether maternal growth in the pre-conception and early gestational period of nulliparous dairy heifers is associated with pre-weaning AMH concentrations in their female offspring. Our hypothesis was that excessive growth in this period would negatively impact AMH concentrations. Seasonal, pasture-based dairy heifer calves (n = 156) born from nulliparous dams, from six Irish farms, were blood sampled at an average of 60 days of age in spring 2022 and tested for AMH. Mixed-effects linear regression models were constructed with Box-Cox transformed AMH concentration as the dependent variable. The independent variables tested included maternal average daily gain (ADG) from pre-breeding examination (PBE) to pregnancy diagnosis (PD) between 30 and 60 days in calf (DIC), ADG from PBE to PD over 60 DIC and ADG between the two PDs. Calf breed and age at sampling were forced into the models, and the farm was treated as a random effect in all models. We found that as ADG increased from the pre-breeding period to their first PD visit, the AMH concentration in their offspring reduced. However, ADG explained only a small amount of the variation in AMH concentrations (marginal R 2  = 0.041). In conclusion, the results of our study suggest that excessive growth prior to conception and in early gestation of nulliparous heifers could impact the ovarian reserve of their female offspring, and may imply that farmers should avoid excessive growth in the immediate pre-breeding and early gestational periods., (© 2023 The Authors. Reproduction in Domestic Animals published by Wiley-VCH GmbH.)

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., (© 2023. Springer Nature Limited.)

177 Lu-prostate-specific membrane antigen (PSMA) is an effective treatment for metastatic castration-resistant prostate cancer. Rarer treatment-related adverse events have not yet been described. Methods: We present case reviews of 2 men with a marked hypocalcemic osteosclerotic response to 177 Lu-PSMA-I&T therapy. A clinical dataset of 177 Lu-PSMA-I&T therapy was evaluated to estimate the incidence and clinical association with hypocalcemia. Results: Forty-one of the 127 men (32%) had a serum calcium drop, and 6 (5%) developed clinical hypocalcemia during 177 Lu-PSMA therapy. The baseline total tumor volume was significantly higher in those who developed hypocalcemia (median, 3,249 cm 3 [interquartile range, 1,856-3,852] vs. 465 [interquartile range 135-1,172]; P = 0.002). The mean prostate-specific antigen response in those with hypocalcemia was 78% (SD, 24%). Conclusion: Hypocalcemia may occur in response to 177 Lu-PSMA-I&T, particularly with both high-volume bone metastases and a significant prostate-specific antigen response, and may be severe, requiring corticosteroids. Further evaluation of 177 Lu-PSMA-induced hypocalcemia is required to better understand mechanisms, optimal treatments, and repercussions from any subsequent osteosclerotic response., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Across zoo's accredited by the Association of Zoos and Aquariums (AZA), species are typically managed as a single population to retain 90% of the founding members' gene diversity. Often, little is known about the specific geographic origins of the founders or how representative the ex situ population's genetic diversity is of the wild population. This study uses mitochondrial DNA (mtDNA) sequencing to investigate haplotype diversity and geographic female founder origin of the AZA-managed Angolan colobus (Colobus angolensis) monkey population. We obtained fecal samples from individuals closely related to founder animals at five zoos and found four haplotypes among 23 individuals. Analyzed together with wild C. angolensis haplotypes, we found two haplotypes identical to those found in Tanzanian populations: one haplotype, possessed by 13 individuals (descended from three founders), matched an East Usambara Mountains haplotype, while the other, possessed by seven individuals (from four founders), matched a haplotype found in both the South Pare Mountains and Rufiji River. Two haplotypes were not detected in wild populations but were closely related to haplotypes found in the Rufiji River (one individual descended from one founder) and Shimoni, Kenya (two individuals descended from one founder) populations, suggesting nearby origins. Thus, the AZA-managed population of Angolan colobus likely originated from several localities, but all have mtDNA lineages associated with the subspecies C. a. palliatus, a Vulnerable subspecies. Examining founders' mtDNA haplotypes may be a useful addition to the zoo population management toolkit to help improve breeding recommendations by identifying individuals with rare haplotypes and revealing likely kinship among founders., (© 2023 Wiley Periodicals LLC.)

Background: Distant relapse of breast cancer complicates management of the disease and accounts for 90% of breast cancer-related deaths. Monocyte chemoattractant protein-1 (MCP-1) has critical roles in breast cancer progression and is widely accepted as a pro-metastatic chemokine., Methods: This study explored MCP-1 expression in the primary tumour of 251 breast cancer patients. A simplified 'histoscore' was used to determine if each tumour had high or low expression of MCP-1. Patient breast cancers were retrospectively staged based on available patient data. p < 0.05 was used to determine significance and changes in hazard ratios between models were considered., Results: Low MCP-1 expression in the primary tumour was associated with breast cancer-related death with distant relapse in ER- breast cancers (p < 0.01); however, this was likely a result of most low MCP-1-expressing ER- breast cancers being Stage III or Stage IV, with high MCP-1 expression in the primary tumour significantly correlated with Stage I breast cancers (p < 0.05). Expression of MCP-1 in the primary ER- tumours varied across Stage I, II, III and IV and we highlighted a switch in MCP-1 expression from high in Stage I ER- cancers to low in Stage IV ER- cancers., Conclusion: This study has emphasised a critical need for further investigation into MCP-1's role in breast cancer progression and improved characterisation of MCP-1 in breast cancers, particularly in light of the development of anti-MCP-1, anti-metastatic therapies., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

An imbalance between bone resorption and bone formation underlies the devastating osteolytic lesions and subsequent fractures seen in more than 90% of multiple myeloma (MM) patients. Currently, Wnt-targeted therapeutic agents that prevent soluble antagonists of the Wnt signaling pathway, sclerostin (SOST) and dickkopf-1 (DKK1), have been shown to prevent bone loss and improve bone strength in preclinical models of MM. In this study, we show increasing Wnt signaling via a novel anti-low-density lipoprotein receptor-related protein 6 (LRP6) antibody, which potentiates Wnt1-class ligand signaling through binding the Wnt receptor LRP6, prevented the development of myeloma-induced bone loss primarily through preventing bone resorption. When combined with an agent targeting the soluble Wnt antagonist DKK1, we showed more robust improvements in bone structure than anti-LRP6 treatment alone. Micro-computed tomography (μCT) analysis demonstrated substantial increases in trabecular bone volume in naïve mice given the anti-LRP6/DKK1 combination treatment strategy compared to control agents. Mice injected with 5TGM1eGFP murine myeloma cells had significant reductions in trabecular bone volume compared to naïve controls. The anti-LRP6/DKK1 combination strategy significantly improved bone volume in 5TGM1-bearing mice by 111%, which was also superior to anti-LRP6 single treatment; with similar bone structural changes observed within L 4 lumbar vertebrae. Consequently, this combination strategy significantly improved resistance to fracture in lumbar vertebrae in 5TGM1-bearing mice compared to their controls, providing greater protection against fracture compared to anti-LRP6 antibody alone. Interestingly, these improvements in bone volume were primarily due to reduced bone resorption, with significant reductions in osteoclast numbers and osteoclast surface per bone surface demonstrated in 5TGM1-bearing mice treated with the anti-LRP6/DKK1 combination strategy. Importantly, Wnt stimulation with either single or combined Wnt-targeted agents did not exacerbate tumor activity. This work provides a novel approach of targeting both membrane-bound and soluble Wnt pathway components to provide superior skeletal outcomes in patients with multiple myeloma and other bone destructive cancers. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

Introduction: Dysregulated inflammation and coagulation are underlying mechanisms driving organ injury after trauma and hemorrhagic shock. Heparan sulfates, cell surface glycosaminoglycans abundantly expressed on the endothelial surface, regulate a variety of cellular processes. Endothelial heparan sulfate containing a rare 3- O -sulfate modification on a glucosamine residue is anticoagulant and anti-inflammatory through high-affinity antithrombin binding and sequestering of circulating damage-associated molecular pattern molecules. Our goal was to evaluate therapeutic potential of a synthetic 3- O -sulfated heparan sulfate dodecasaccharide (12-mer, or dekaparin) to attenuate thromboinflammation and prevent organ injury., Methods: Male Sprague-Dawley rats were pre-treated subcutaneously with vehicle (saline) or dekaparin (2 mg/kg) and subjected to a trauma/hemorrhagic shock model through laparotomy, gut distention, and fixed-pressure hemorrhage. Vehicle and dekaparin-treated rats were resuscitated with Lactated Ringer's solution (LR) and compared to vehicle-treated fresh-frozen-plasma-(FFP)-resuscitated rats. Serial blood samples were collected at baseline, after induction of shock, and 3 hours after fluid resuscitation to measure hemodynamic and metabolic shock indicators, inflammatory mediators, and thrombin-antithrombin complex formation. Lungs and kidneys were processed for organ injury scoring and immunohistochemical analysis to quantify presence of neutrophils., Results: Induction of trauma and hemorrhagic shock resulted in significant increases in thrombin-antithrombin complex, inflammatory markers, and lung and kidney injury scores. Compared to vehicle, dekaparin treatment did not affect induction, severity, or recovery of shock as indicated by hemodynamics, metabolic indicators of shock (lactate and base excess), or metrics of bleeding, including overall blood loss, resuscitation volume, or hematocrit. While LR-vehicle-resuscitated rodents exhibited increased lung and kidney injury, administration of dekaparin significantly reduced organ injury scores and was similar to organ protection conferred by FFP resuscitation. This was associated with a significant reduction in neutrophil infiltration in lungs and kidneys and reduced lung fibrin deposition among dekaparin-treated rats compared to vehicle. No differences in organ injury, neutrophil infiltrates, or fibrin staining between dekaparin and FFP groups were observed. Finally, dekaparin treatment attenuated induction of thrombin-antithrombin complex and inflammatory mediators in plasma following trauma and hemorrhagic shock., Conclusion: Anti-thromboinflammatory properties of a synthetic 3- O -sulfated heparan sulfate 12-mer, dekaparin, could provide therapeutic benefit for mitigating organ injury following major trauma and hemorrhagic shock., Competing Interests: JL and YX are founders of Glycan Therapeutics, a company that has licensed dekaparin from The University of North Carolina for commercial development. JL, YX, and KA own equity or stock options in Glycan Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2023 Vidaurre, Osborn, Lowak, McDonald, Wang, Pa, Richter, Xu, Arnold, Liu and Cardenas.)

Purpose of Review: Inhibition of receptor activator of nuclear factor kappa-B ligand (RANKL) with denosumab is an effective treatment in a number of conditions including osteoporosis where suppression of bone resorption is desired. However, denosumab discontinuation is associated with rebound increase in bone resorption and subsequent loss in bone mass and a rapid return to baseline fracture risk. We review recent data on the rebound increase in bone resorption following denosumab discontinuation and the potential mechanisms behind this phenomenon., Recent Findings: Osteoclasts have been considered to be highly specialised cells that undergo apoptosis after fulfilling their function of bone resorption. However, recent studies suggest that osteoclasts are longer lived cells which migrate through vasculature and are capable of undergoing fission into a novel cell type (the osteomorph) and re-fusion in a process termed osteoclast recycling. The life cycle of the osteoclast is more complex than previously appreciated. Osteoclast recycling provides a novel mechanistic framework to examine changes in osteoclast biology in response to treatment of bone diseases and provides an exciting new avenue towards personalised medicine., (© 2022. Crown.)

Purpose: This study aimed to identify and correlate pathological findings with clinical outcomes in patients after orthotopic heart transplantation (OHT) who either died or underwent a re-transplantation., Methodology and Study Design: Single-center retrospective analysis of primary OHT patients who died or were re-transplanted between October 2012 and July 2021. Clinical data were matched with corresponding pathological findings from endomyocardial biopsies on antibody-mediated rejection, cellular rejection, and cardiac allograft vasculopathy. Re-assessment of available tissue samples was performed to investigate acute myocardial injury (AMI) as a distinct phenomenon. These were correlated with clinical outcomes, which included severe primary graft dysfunction. Patients were grouped according to the presence of AMI and compared., Results: We identified 47 patients with truncated outcomes after the first OHT. The median age was 59 years, 36 patients (76%) were male, 25 patients (53%) had a prior history of cardiac operation, and 21 patients (45%) were supported with a durable assist device before OHT. Of those, AMI was identified in 22 (47%) patients (AMI group), and 25 patients had no AMI (non-AMI group). Groups were comparable in baseline and perioperative data. Histopathological observations in AMI group included a non-significant higher incidence of antibody-mediated rejection Grade 1 or higher (pAMR ≥ 1) (32% vs. 12%, P = 0.154), and non-significant lower incidence of severe acute cellular rejection (ACR ≥ 2R) (32% vs. 40%, P = 0.762). Clinical observations in the AMI group found a significantly higher occurrence of severe primary graft dysfunction (68% vs. 20%, P = 0.001) and a highly significant shorter duration from transplantation to death or re-transplantation (42 days [IQR 26, 120] vs. 1,133 days [711-1,664], P < 0.0001). Those patients had a significantly higher occurrence of cardiac-related deaths (64% vs. 24%, P = 0.020). No difference was observed in other outcomes., Conclusion: In heart transplant recipients with a truncated postoperative course leading to either death or re-transplantation, AMI in endomyocardial biopsies was a common pathological phenomenon, which correlated with the clinical occurrence of severe primary graft dysfunction. Those patients had significantly shorter survival times and higher cardiac-related deaths. The presence of AMI suggests a truncated course after OHT., Competing Interests: The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 McDonald, Mihalj, Zhao, Nathan, Matejin, Ottaviani, Jezovnik, Radovancevic, Kar, Gregoric and Buja.)

Background: The objective of the present study was to categorize the presentation and treatment of acute limb ischemia (ALI) in young patients and compare the adverse outcomes after revascularization compared with that of older patients., Methods: All the patients who had presented to a multi-institution healthcare system with ALI from 2016 to 2020 were identified. The presenting features, operative details, and outcomes were included in the present analysis. Patients with existing peripheral arterial disease (acute on chronic) were analyzed separately from those without (de novo thrombosis or embolus). Within these groups, younger patients (age, ≤50 years) were compared with older patients (age, >50 years). The 3-month major adverse limb event-free survival was the primary outcome., Results: A total of 232 patients (age, 60 ± 16 years; 44% female sex, 87% white race) were included in the analysis. Of the 232 patients, 119 were in the acute on chronic cohort and 113 were in the de novo thrombosis/embolism cohort. Age did not affect the overall outcomes (P = .45) or the outcomes for the acute on chronic group (P = .17). However, in the de novo thrombosis/embolism cohort, patients aged ≤50 years had worse major adverse limb event-free survival compared with patients aged >50 years (hazard ratio, 2.47; 95% confidence interval, 1.08-5.68; P = .03) after adjustment for Rutherford class, interval from presentation to the operating room, and smoking status. In the de novo thrombosis/embolism group, the operative approach was similar across the age groups (endovascular, 12% vs 14%; open, 48% vs 41%; hybrid, 41% vs 45%; P = .78). In the younger patients, embolism was more likely from a proximal arterial source (71%). In contrast, in the older patients, the source of embolism was more often a cardiac source (86%). The rates of hypercoagulable disease were equal across the age groups (10% vs 10%; P = .95). The In-hospital mortality was 3% overall (acute on chronic, 5%; de novo, 3%)., Conclusions: Despite advances in interventional options, for patients with ALI due to de novo thrombosis or embolus, younger age was associated with worse short-term limb-related outcomes., (Copyright © 2022 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Multiple myeloma is a hematological malignancy affecting the plasma cells. It is the second most common hematologic cancer in adults. Over 90% of patients develop local osteolytic lesions and skeletal-related events at some point during the progression of the disease. Bone lesions can induce severe pain and immobility and can also increase the risk of fractures and osteomyelitis. Skeletal complications are associated with poor clinical outcomes, affecting quality of life and mortality. Current standards of care for myeloma, e.g., autologous stem-cell transplantation (ASCT) and chemotherapy, do not lessen the risk of adverse events in bone. Once bone lesions are present, bone-targeted interventions are limited, with bone antiresorptive drugs being a mainstay of treatment. This review highlights the growing literature surrounding osteolytic lesions and bone infections associated with multiple myeloma and assesses current and emerging treatments. Emerging evidence from clinical trials suggests that denosumab can reduce skeletal-related events, and the potential application of bortezomib/1D11 can reduce bone destruction and pathological fractures in MM patients. Once established, bone lesions are prone to develop osteomyelitis - especially in immunocompromised individuals. Antibiotics and surgical interventions have been used to manage bone infections in most reported cases. As the bone infection risk associated with MM bone lesions become more evident, there is scope to improve patient management by mitigating this risk with prophylactic antimicrobial therapy., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2022 Published by Elsevier GmbH.)

Defense of reproductive choice is an important motivation in women's self-protection psychology for which the "staying alive theory" cannot fully account. Evidence indicates that some elements of women's self-protection psychology function to protect reproductive choice rather than survival, or may be equally well explained by either motivation. Integrating perspectives will result in greater explanatory breadth and precision in theory testing.

Background: Current EMS stroke screening tools facilitate early detection and triage, but the tools' accuracy and reliability are limited and highly variable. An automated stroke screening tool could improve stroke outcomes by facilitating more accurate prehospital diagnosis and delivery. We hypothesize that a machine learning algorithm using video analysis can detect common signs of stroke. As a proof-of-concept study, we trained a computer algorithm to detect presence and laterality of facial weakness in publically available videos with comparable accuracy, sensitivity, and specificity to paramedics., Methods and Results: We curated videos of people with unilateral facial weakness ( n = 93) and with a normal smile ( n = 96) from publicly available web-based sources. Three board certified vascular neurologists categorized the videos according to the presence or absence of weakness and laterality. Three paramedics independently analyzed each video with a mean accuracy, sensitivity and specificity of 92.6% [95% CI 90.1-94.7%], 87.8% [95% CI 83.9-91.7%] and 99.3% [95% CI 98.2-100%]. Using a 5-fold cross validation scheme, we trained a computer vision algorithm to analyze the same videos producing an accuracy, sensitivity and specificity of 88.9% [95% CI 83.5-93%], 90.3% [95% CI 82.4-95.5%] and 87.5 [95% CI 79.2-93.4%]., Conclusions: These preliminary results suggest that a machine learning algorithm using computer vision analysis can detect unilateral facial weakness in pre-recorded videos with an accuracy and sensitivity comparable to trained paramedics. Further research is warranted to pursue the concept of augmented facial weakness detection and external validation of this algorithm in independent data sets and prospective patient encounters., Competing Interests: MM and OU disclose ownership interest in Neuroview Diagnostics, LLC. Neuroview Diagnostics played no role in study funding, data collection, or data analysis. AS and GR served as unpaid scientific advisors for Neuroview Diagnostics, LLC. AS receives research support for a prehospital stroke trial from Diffusion Pharmaceuticals, Inc. MM, YZ, OU, AS, and GR disclose U.S. Provisional Patent Application No. 62/620,096 and International Patent Application No. PCT/US19/14605. BBW serves as Deputy Editor of the journal, Neurology. AS is past section Editor of the Neurology podcast. The remaining 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 © 2022 Aldridge, McDonald, Wruble, Zhuang, Uribe, McMurry, Lin, Pitchford, Schneider, Dalrymple, Carrera, Chapman, Worrall, Rohde and Southerland.)

Whether the Colobus angolensis that reside in the fragmented forests in eastern Kenya and Tanzania represent one subspecies or two has been debated for 50 years. Morphological and more recent genetic and ecological studies suggest that these populations represent two subspecies, C. a. palliatus and C. a. sharpei. However, their distribution of mitochondrial variation remains unresolved since the genetic study only characterized four populations at the range ends. Therefore, we characterized five populations in the area of the hypothesized subspecies divide. We identified eight new haplotypes which, combined with those previously identified, provided 26 haplotypes from nine populations for analysis. Haplotypes found south of the Rufiji River cluster together but separately from northern haplotypes. The largest sequence differences within cytochrome b occur between population pairs representing opposite sides of the river; their mean difference (1.5%) is more than that of other primate subspecies. Analysis of molecular variance attributes most of the variation to that north versus south of the river. These results support the previous subspecies distinction between C. a. palliatus (northern) and C. a. sharpei (southern), divided by the Rufiji River. The estimated time of the most recent common ancestor of all haplotypes indicates that the subspecies have been isolated from each other for approximately 550,000 years. The common ancestor of northern and southern haplogroups was 370,000 and 290,000 years ago, respectively. Nevertheless, the correlation between genetic and geographic distances suggests that isolation-by-distance contributed to population structuring. Significant variation among populations, with only three haplotypes shared between populations, also indicates that an extended period of isolation drove population distinctiveness. Considering these results, we evaluate hypotheses about the founding and differentiation of these subspecies during Pleistocene climatic fluctuations and propose a novel, more direct migration route from Central Africa to their current range navigating Lake Tanganyika, the central Tanzanian corridor, and the Rufiji River., (© 2022 Wiley Periodicals LLC.)

The skeleton is a common site for the establishment of distant metastases. Once cancers occupy bone, the prognosis is poor as disease recurrence and visceral spread is imminent. Understanding the pathways and cellular interactions, which regulate tumour cell seeding, dormancy and growth in bone, is pertinent to improving outcomes for patients with advanced cancers. Advances in imaging techniques have facilitated the development of the concept that the behavior of bone marrow resident cells dictates the fate of tumour cells upon arrival in bone. This review summarises recent findings achieved through intravital imaging. It highlights the importance of developing both longitudinal static and acute dynamic data to develop our understanding of tumour cell engraftment, dormancy, activation and the subsequent establishment of metastases. We also describe how imaging techniques have developed our knowledge of the elements that make up the complex bone microenvironment which tumour cells interact with to survive and grow. We also discuss how through combining these imaging insights with single cell RNA sequencing data, we are entering a new era of research which has the power to define the cell-cell interactions which control tumour cell growth in bone., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Sex differences in religiosity are cross-culturally common and robust, yet it is unclear why sex differences in some cultures are larger than in others. Although women are more religious than men in most countries, religions frequently provide asymmetrical benefits to men at the expense of women. Two global analyses (51 countries and 74 countries) found that country-level gender equality was consistently and negatively associated with religiousness (i.e. religious attendance, reported importance of God and frequency of prayer) for men, more than for women, leading to a larger sex difference in religiousness in more gender-equal countries. Results were especially robust for religious attendance, and hold accounting for country-level wealth, as well as individuals' religious affiliation, the moralization of sexuality, age and education level. We interpret results through a rational choice lens, which assumes that people are more drawn to religion when it is consistent with their reproductive goals.

Objective: Facial weakness is a common sign of neurological diseases such as Bell's palsy and stroke. However, recognizing facial weakness still remains as a challenge, because it requires experience and neurological training., Methods: We propose a framework for facial weakness detection, which models the temporal dynamics of both shape and appearance-based features of each target frame through a bi-directional long short-term memory network (Bi-LSTM). The system is evaluated on a "in-the-wild"video dataset that is verified by three board-certified neurologists. In addition, three emergency medical services (EMS) personnel and three upper level residents rated the dataset. We compare the evaluation of the proposed algorithm with other comparison methods as well as the human raters., Results: Experimental evaluation demonstrates that: (1) the proposed algorithm achieves the accuracy, sensitivity, and specificity of 94.3%, 91.4%, and 95.7%, which outperforms other comparison methods and achieves the equal performance to paramedics; (2) the framework can provide visualizable and interpretable results that increases model transparency and interpretability; (3) a prototype is implemented as a proof-of-concept showcase to show the feasibility of an inexpensive solution for facial weakness detection., Conclusion: The experiment results suggest that the proposed framework can identify facial weakness effectively., Significance: We provide a proof-of-concept study, showing that such technology could be used by non-neurologists to more readily identify facial weakness in the field, leading to increasing coverage and earlier treatment.