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Cross-sectional imaging supplements endoscopy in detecting disease manifestations in inflammatory bowel diseases (IBD). This study aimed to evaluate the accuracy of PET/MRI in a paediatric population suspected of IBD. This prospective study consecutively included patients aged 8-17 years under diagnostic evaluation for IBD. Forty-three patients underwent a PET/MRI scan and subsequent ileocolonoscopy, of whom 26 patients diagnosed with IBD participated in a follow-up scan, hereof 19 with Crohn's disease (CD), five with Ulcerative colitis and two with unclassified IBD. The results of PET alone, MRI alone, and PET/MRI combined were compared to a reference standard of endoscopy and histopathology. Of the 208 intestinal segments analysed, 109 showed inflammation, and 99 had no inflammation. In the per-segment analysis PET had a sensitivity of 0.83 (95% CI 0.73-0.93), specificity of 0.59 (95% CI 0.47-0.71), and area under the receiver operating characteristic curve (AUROC) of 0.73 (95% CI 0.67-0.80). MRI had a sensitivity of 0.52 (95% CI 0.41-0.64), specificity 0.89 (95% CI 0.82-0.96), and AUROC of 0.72 (95% CI 0.66-0.77). PET/MRI had a sensitivity of 0.83 (95% CI 0.74-0.94), specificity of 0.57 (95% CI 0.44-0.69), and AUROC of 0.77 (95% CI 0.71-0.84). At follow-up, PET and MRI scores decreased, and the change in MRI was able to identify patients with a clinical response. The accuracy of the PET/MRI scan in detecting inflammation in the terminal ileum and colon was moderate and not superior to either modality alone. With technological advances and combined reading, PET/MRI may still be valuable in selected cases., (© 2024 The Author(s). Clinical Physiology and Functional Imaging published by John Wiley & Sons Ltd on behalf of Scandinavian Society of Clinical Physiology and Nuclear Medicine.)

Chronic kidney disease-mineral and bone disorder (CKD-MBD) contributes substantially to the burden of cardiovascular disease and fractures in patients with CKD. An increasing arsenal of diagnostic tools, including bone turnover markers and bone imaging, is available to support clinicians in the management of CKD-associated osteoporosis. Although not mandatory, a bone biopsy remains useful in the diagnostic workup of complex cases. In this special report, the European Renal Osteodystrophy (EUROD) initiative introduces the concept of a kidney-bone multidisciplinary team (MDT) for the diagnosis and clinical management of challenging cases of CKD-associated osteoporosis. In 2021, the EUROD initiative launched virtual clinical-pathological case conferences to discuss challenging cases of patients with CKD-associated osteoporosis, in whom a bone biopsy was useful in the diagnostic workup. Out of these, we selected four representative cases and asked a kidney-bone MDT consisting of a nephrologist, an endocrinologist and a rheumatologist to provide comments on the diagnostic and therapeutic choices. These cases covered a broad spectrum of CKD-associated osteoporosis, including bone fracture in CKD G5D, post-transplant bone disease, disturbed bone mineralization, severely suppressed bone turnover and severe hyperparathyroidism. Comments from the MDT were, in most cases, complementary to each other and additive to the presented approach in the cases. The MDT approach may thus set the stage for improved diagnostics and tailored therapies in the field of CKD-associated osteoporosis. We demonstrate the clinical utility of a kidney-bone MDT for the management of patients with CKD-MBD and recommend their establishment at local, national, and international levels., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Solar UVB light causes damage to the outermost layer of skin. This insult induces rapid local responses, such as dermal inflammation, keratinocyte cell death, and epidermal thickening, all of which have traditionally been associated with DNA damage response signaling. Another stress response that is activated by UVB light is the ribotoxic stress response (RSR), which depends on the ribosome-associated mitogen-activated protein 3 kinases (MAP3K) ZAKα and culminates in p38 and JNK activation. Using ZAK knockout mice, we here show that it is the RSR that is responsible for the early manifestation of UVB-induced skin inflammation and keratinocyte death and subsequent proliferation in vivo. We also show that the RSR controls both p38-mediated pyroptotic and JNK-mediated apoptotic programmed cell death of human keratinocytes in vitro. In sum, our work highlights that skin cells rely on a cytoplasmic and ribosomal stress signal rather than a nuclear and DNA-templated signal for rapid inflammatory responses to UV exposure., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Multiple myeloma (MM) is a clonal plasma cell proliferative malignancy characterized by a debilitating bone disease. Osteolytic destruction, a hallmark of MM, is driven by increased osteoclast number and exacerbated bone resorption, primarily fueled by the excessive production of RANKL, the master regulator of osteoclast formation, within the tumor niche. We previously reported that osteocytes, the most abundant cells in the bone niche, promote tumor progression and support MM bone disease by overproducing RANKL. However, the molecular mechanisms underlying RANKL dysregulation in osteocytes in the context of MM bone disease are not entirely understood. Here, we present evidence that MM-derived CCL3 induces upregulation of RANKL expression in both human and murine osteocytes. Through a combination of in vitro, ex vivo, and in vivo models and clinical data, we demonstrate that genetic or pharmacologic inhibition of CCL3 prevents RANKL upregulation in osteocytes and attenuates the bone loss induced by MM cells. Mechanistic studies revealed that MM-derived CCL3 triggers the secretion of HMGB1 by osteocytes, a process required for osteocytic RANKL upregulation by MM cells. These findings identify a previously unknown CCL3-HMGB1 signaling axis in the MM tumor niche that drives bone resorption by promoting RANKL overproduction in osteocytes.

Background: Magnetic resonance imaging (MRI) cerebral blood volume (CBV) measurements improve the diagnosis of recurrent gliomas. The study investigated the prognostic value of dynamic contrast-enhanced (DCE) CBV imaging in treated IDH wildtype glioblastoma when added to MRI or amino acid positron emission tomography (PET)., Methods: Hybrid [ 18 F]FET PET/MRI with 2CXM (2-compartment exchange model) DCE from 86 adult patients with suspected recurrent or residual glioblastoma were retrospectively analyzed. High CBV tumor volume (VOL CBV ), and contrast-enhancing (VOL CE ) and [ 18 F]FET active tumor (VOL FET ) volumes were delineated. Absolute and fractional high CBV subvolumes within VOL CE and VOL FET were determined. Associations with overall survival (OS) were assessed by Cox analysis., Results: Adjusted for methyltransferase gene status and steroid use all total tumor volumes were individually associated with shorter OS. Adding VOL CBV to VOL CE or VOL FET only the effect of VOL CBV was prognostic of OS (hazard ratio [HR] 1.327, P  = .042 and 1.352, P  = .011, respectively). High CBV subvolumes within both VOL CE and VOL FET were associated with shorter survival (HR 1.448, P  = .042 and 1.416, P  = .011, respectively), and the low CBV subvolumes with longer survival (HR 0.504, P  = .002 and .365, P  = .001, respectively). The fraction of VOL CE and VOL FET with high CBV was a strong predictor of OS with shorter median OS in upper versus lower tertiles (8.3 vs 14.5 months and 7.1 vs 15.6 months, respectively, both P  < .001)., Conclusions: The high CBV tumor volume was a strong prognosticator of survival and allowed for the separation of high- and low-risk subvolumes underlining the heterogeneous physiological environment represented in the contrast-enhancing or metabolically active tumor volumes of treated glioblastoma., Competing Interests: The authors declare no competing interests., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

A lifetime of successive bone remodeling events leads to trabeculae which are composed of a patchwork of bone structural units (BSUs) called hemi-osteons or trabecular packets. Traditionally, only intact surface BSUs have been studied, which are those that have been created most recently. Accordingly, the complex changes in the size and distribution of BSU throughout the trabeculae have been overlooked. In this study, the BSUs within the trabeculae of the second lumbar vertebrae were manually traced, using ImageJ software, in osteopontin immunostained sections of eight young women (aged 19-38 yr) and eight older women (aged 69-96 yr). A series of BSU profile properties including area, width, length, and perimeter were quantified, along with properties of each trabecular profile such as the number of BSU and cement line length. The relationships between these properties and age, as well as selected trabecular microstructural properties assessed with microcomputed tomography, and bone strength assessed on the neighboring third lumbar vertebrae, were investigated. The median BSU profile length and perimeter decreased with age, while the median BSU profile area and width was unchanged. Moreover, age was associated with an increase in the number of BSU profiles and cement line length per trabecular profile area. However, changes in BSU profile geometry, the number of BSU profiles, and the cement line length per trabecular profile were strongly correlated with trabecular bone volume fraction, structure model index, and bone strength. Further research is needed to understand how these changes in BSU properties affect the mechanical and failure properties of trabecular bone., Competing Interests: The authors have no conflicts to disclose., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Abstract: Hyperpolarized 1-13C-pyruvate magnetic resonance spectroscopy (MRS) and MRS imaging (MRSI) offer noninvasive and real-time direct assessment of the altered metabolism of cancer cells known as the Warburg effect-a key hallmark of cancer. When combined with simultaneously acquired 18F-FDG PET in a PET/MR scanner, coined hyperPET by us, this dual-modality may unveil cancer-type specific glucose metabolic phenotypes with potential implications for patient prognostication, treatment-response assessment, and prediction. We here present the first human data of simultaneously acquired hyperpolarized MRS/MRSI and PET performed in a PET/MR scanner-and the first human hyperpolarized MRS/MRSI data from a patient with lymphoma., Competing Interests: Conflicts of interest and sources of funding: The authors declare that they have no conflicts of interest. This project received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreements no. 670261 (ERC Advanced Grant) and 668532 (Click-It), the Lundbeck Foundation, the Novo Nordisk Foundation, the Innovation Fund Denmark, the Danish Cancer Society, Arvid Nilsson Foundation, the Neye Foundation, the Research Foundation of Rigshospitalet, the Danish National Research Foundation (grant 126), the Research Council of the Capital Region of Denmark, the Danish Health Authority, the John and Birthe Meyer Foundation, the Danish Agency for Digitisation (no. 20196164), the Research Council for Independent Research, and the Nordic Neuroendocrine tumor Group. A.K. is a Lundbeck Foundation Professor., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Treatment of patients with low-grade and high-grade gliomas is highly variable due to the large difference in survival expectancy. New non-invasive tools are needed for risk stratification prior to treatment. The urokinase plasminogen activator receptor (uPAR) is expressed in several cancers, associated with poor prognosis and may be non-invasively imaged using uPAR-PET. We aimed to investigate the uptake of the uPAR-PET tracer [ 68 Ga]Ga-NOTA-AE105 in primary gliomas and establish its prognostic value regarding overall survival (OS), and progression-free survival (PFS). Additionally, we analyzed the proportion of uPAR-PET positive tumors to estimate the potential number of candidates for future uPAR-PRRT., Methods: In a prospective phase II clinical trial, 24 patients suspected of primary glioma underwent a dynamic 60-min PET/MRI following the administration of approximately 200 MBq (range: 83-222 MBq) [ 68 Ga]Ga-NOTA-AE105. Lesions were considered uPAR positive if the tumor-to-background ratio, calculated as the ratio of TumorSUVmax-to-Normal-BrainSUVmean tumor-SUVmax-to-background-SUVmean, was ≥ 2.0. The patients were followed over time to assess OS and PFS and stratified into high and low uPAR expression groups based on TumorSUVmax., Results: Of the 24 patients, 16 (67%) were diagnosed with WHO grade 4 gliomas, 6 (25%) with grade 3, and 2 (8%) with grade 2. Two-thirds of all patients (67%) presented with uPAR positive lesions and 94% grade 4 gliomas. At median follow up of 18.8 (2.1-45.6) months, 19 patients had disease progression and 14 had died. uPAR expression dichotomized into high and low, revealed significant worse prognosis for the high uPAR group for OS and PFS with HR of 14.3 (95% CI, 1.8-112.3; P = 0.011), and HR of 26.5 (95% CI, 3.3-214.0; P = 0.0021), respectively. uPAR expression as a continuous variable was associated with worse prognosis for OS and PFS with HR of 2.7 (95% CI, 1.5-4.8; P = 0.0012), and HR of 2.5 (95% CI, 1.5-4.2; P = 0.00073), respectively., Conclusions: The majority of glioma patients and almost all with grade 4 gliomas displayed uPAR positive lesions underlining the feasibility of 68 Ga-NOTA-AE105 PET/MRI in gliomas. High uPAR expression is significantly correlated with worse survival outcomes for patients. Additionally, the high proportion of uPAR positive gliomas underscores the potential of uPAR-targeted radionuclide therapy in these patients., Trail Registration: EudraCT No: 2016-002417-21; the Scientific Ethics Committee: H-16,035,303; the Danish Data Protection Agency: 2012-58-0004; clinical trials registry: NCT02945826, 26Oct2016, URL: https://classic., Clinicaltrials: gov/ct2/show/NCT02945826 ., (© 2024. The Author(s).)

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).)

Increased plasma levels of glucagon (hyperglucagonemia) promote diabetes development but are also observed in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). This may reflect hepatic glucagon resistance toward amino acid catabolism. A clinical test for measuring glucagon resistance has not been validated. We evaluated our glucagon sensitivity (GLUSENTIC) test, which consists of 2 study days: a glucagon injection and measurements of plasma amino acids and an infusion of mixed amino acids and subsequent calculation of the GLUSENTIC index (primary outcome measure) from measurements of glucagon and amino acids. To distinguish glucagon-dependent from insulin-dependent actions on amino acid metabolism, we also studied patients with type 1 diabetes (T1D). The δ-decline in total amino acids was 49% lower in MASLD following exogenous glucagon (P = 0.01), and the calculated GLUSENTIC index was 34% lower in MASLD (P < 0.0001) but not T1D (P > 0.99). In contrast, glucagon-induced glucose increments were similar in control participants and participants with MASLD (P = 0.41). The GLUSENTIC test and index may be used to measure glucagon resistance in individuals with obesity and MASLD., (© 2024 by the American Diabetes Association.)

Communicating the scientific consensus that human-caused climate change is real increases climate change beliefs, worry and support for public action in the United States. In this preregistered experiment, we tested two scientific consensus messages, a classic message on the reality of human-caused climate change and an updated message additionally emphasizing scientific agreement that climate change is a crisis. Across online convenience samples from 27 countries (n = 10,527), the classic message substantially reduces misperceptions (d = 0.47, 95% CI (0.41, 0.52)) and slightly increases climate change beliefs (from d = 0.06, 95% CI (0.01, 0.11) to d = 0.10, 95% CI (0.04, 0.15)) and worry (d = 0.05, 95% CI (-0.01, 0.10)) but not support for public action directly. The updated message is equally effective but provides no added value. Both messages are more effective for audiences with lower message familiarity and higher misperceptions, including those with lower trust in climate scientists and right-leaning ideologies. Overall, scientific consensus messaging is an effective, non-polarizing tool for changing misperceptions, beliefs and worry across different audiences., (© 2024. The Author(s).)

Background: The outstanding capabilities of modern Positron Emission Tomography (PET) to highlight small tumor lesions and provide pathological function assessment are at peril from image quality degradation caused by respiratory and cardiac motion. However, the advent of the long axial field-of-view (LAFOV) scanners with increased sensitivity, alongside the precise time-of-flight (TOF) of modern PET systems, enables the acquisition of ultrafast time resolution images, which can be used for estimating and correcting the cyclic motion. Methods: 0.25 s so-called [ 18 F]FDG PET histo image series were generated in the scope of for detecting respiratory and cardiac frequency estimates applicable for performing device-less data-driven gated image reconstructions. The frequencies of the cardiac and respiratory motion were estimated for 18 patients using Short Time Fourier Transform (STFT) with 20 s and 30 s window segments, respectively. Results: The Fourier analysis provided time points usable as input to the gated reconstruction based on eight equally spaced time gates. The cardiac investigations showed estimates in accordance with the measured pulse oximeter references ( p = 0.97) and a mean absolute difference of 0.4 ± 0.3 beats per minute (bpm). The respiratory frequencies were within the expected range of 10-20 respirations per minute (rpm) in 16 out of 18 patients. Using this setup, the analysis of three patients with visible lung tumors showed an increase in tumor SUV max and a decrease in tumor volume compared to the non-gated reconstructed image. Conclusions: The method can provide signals that were applicable for gated reconstruction of both cardiac and respiratory motion, providing a potential increased diagnostic accuracy.

Purpose: Here, we evaluate a PET displacement model with a Single-step and Numerical solution in healthy individuals using the synaptic vesicle glycoprotein (SV2A) PET-tracer [ 11 C]UCB-J and the anti-seizure medication levetiracetam (LEV). We aimed to (1) validate the displacement model by comparing the brain LEV-SV2A occupancy from a single PET scan with the occupancy derived from two PET scans and the Lassen plot and (2) determine the plasma LEV concentration-SV2A occupancy curve in healthy individuals., Methods: Eleven healthy individuals (five females, mean age 35.5 [range: 25-47] years) underwent two 120-min [ 11 C]UCB-J PET scans where an LEV dose (5-30 mg/kg) was administered intravenously halfway through the first PET scan to partially displace radioligand binding to SV2A. Five individuals were scanned twice on the same day; the remaining six were scanned once on two separate days, receiving two identical LEV doses. Arterial blood samples were acquired to determine the arterial input function and plasma LEV concentrations. Using the displacement model, the SV2A-LEV target engagement was calculated and compared with the Lassen plot method. The resulting data were fitted with a single-site binding model., Results: SV2A occupancies and V ND estimates derived from the displacement model were not significantly different from the Lassen plot (p = 0.55 and 0.13, respectively). The coefficient of variation was 14.6% vs. 17.3% for the Numerical and the Single-step solution in Bland-Altman comparisons with the Lassen plot. The average half maximal inhibitory concentration (IC 50 ), as estimated from the area under the curve of the plasma LEV concentration, was 12.5 µg/mL (95% CI: 5-25) for the Single-Step solution, 11.8 µg/mL (95% CI: 4-25) for the Numerical solution, and 6.3 µg/mL (95% CI: 0.08-21) for the Lassen plot. Constraining Emax to 100% did not significantly improve model fits., Conclusion: Plasma LEV concentration vs. SV2A occupancy can be determined in humans using a single PET scan displacement model. The average concentration of the three computed IC 50 values ranges between 6.3 and 12.5 µg/mL. The next step is to use the displacement model to evaluate LEV occupancy and corresponding plasma concentrations in relation to treatment efficacy., Clinical Trial Registration: NCT05450822. Retrospectively registered 5 July 2022 https://clinicaltrials.gov/ct2/results? term=NCT05450822&Search=Search., (© 2024. The Author(s).)

A precise prediction of the cure-induced shrinkage of an epoxy resin is performed using a finite element simulation procedure for the material behaviour. A series of experiments investigating the cure shrinkage of the resin system has shown a variation in the measured cure-induced strains. The observed variation results from the thermal history during the pre-cure. A proposed complex thermal expansion model and a conventional chemical shrinkage model are utilised to predict the cure shrinkage observed with finite element simulations. The thermal expansion model is fitted to measured data and considers material effects such as the glass transition temperature and the evolution of the expansion with the degree of cure. The simulations accurately capture the exothermal heat release from the resin and the cure-induced strains across various temperature profiles. The simulations follow the experimentally observed behaviour. The simulation predictions achieve good accuracy with 2-6% discrepancy compared with the experimentally measured shrinkage over a wide range of cure profiles. Demonstrating that the proposed complex thermal expansion model affects the potential to minimise the shrinkage of the studied epoxy resin. A recommendation of material parameters necessary to accurately determine cure shrinkage is listed. These parameters are required to predict cure shrinkage, allow for possible minimisation, and optimise cure profiles for the investigated resin system. Furthermore, in a study where the resin movement is restrained and therefore able to build up residual stresses, these parameters can describe the cure contribution of the residual stresses in a component.

Stress is a ubiquitous challenge in modern societies. Symptoms range from mood swings and cognitive impairment to autonomic symptoms. This study explores the link between work-related stress and the neurobiological element of brain processing, testing the hypothesis that patients with occupational stress have altered cerebral glucose consumption compared to healthy controls. The participants' present conditions were evaluated using an adapted WHO SCAN interview. Neural activity at rest was assessed by positron emission tomography (PET) with the glucose analogue [18F]fluorodeoxyglucose. Participants were genotyped for the Val158Met polymorphism of the COMT gene, believed to influence stress resilience. This study included 11 women with work-related stress and 11 demographically comparable healthy controls aged 28-62 years, with an average of 46.2 years. The PET scans indicated clusters of decreased glucose consumption primarily located in the white matter of frontal lobe sub-gyral areas in stress patients. COMT Val158Met polymorphism detection indicated no immediate relation of the homozygous alleles and stress resilience; however, healthy controls mainly had the heterozygous allele. In conclusion, the results support that work-related stress does affect the brain in the form of altered glucose metabolism, suggesting neurobiological effects could be related to white matter abnormalities rather than gray matter deterioration. Genotyping indicates a more complex picture than just that of the one type being more resilient to stress. Further studies recruiting a larger number of participants are needed to confirm our preliminary findings.

The accurate estimation of the tracer arterial blood concentration is crucial for reliable quantitative kinetic analysis in PET. In the current work, we demonstrate the automatic extraction of an image-derived input function (IDIF) from a CT AI-based aorta segmentation subsequently resliced to a dynamic PET series acquired on a Siemens Vision Quadra long-axial field of view scanner in 10 human subjects scanned with [ 15 O]H 2 O. We demonstrate that the extracted IDIF is quantitative and in excellent agreement with a delay- and dispersion-corrected sampled arterial input function (AIF). Perfusion maps in the brain are calculated and compared from the IDIF and AIF, respectively, showed a high degree of correlation. The results demonstrate the possibility of defining a quantitatively correct IDIF compared with AIFs from the new-generation high-sensitivity and high-time-resolution long-axial field-of-view PET/CT scanners.

Incorrect scatter scaling of positron emission tomography (PET) images can lead to halo artifacts, quantitative bias, or reconstruction failure. Tail-fitted scatter scaling (TFSS) possesses performance limitations in multiple cases. This study aims to investigate a novel method for scatter scaling: maximum-likelihood scatter scaling (MLSS) in scenarios where TFSS tends to induce artifacts or are observed to cause reconstruction abortion. [ 68 Ga]Ga-RGD PET scans of nine patients were included in cohort 1 in the scope of investigating the reduction of halo artifacts relative to the scatter estimation method. PET scans of 30 patients administrated with [ 68 Ga]Ga-uPAR were included in cohort 2, used for an evaluation of the robustness of MLSS in cases where TFSS-integrated reconstructions are observed to fail. A visual inspection of MLSS-corrected images scored higher than TFSS-corrected reconstructions of cohort 1. The quantitative investigation near the bladder showed a relative difference in tracer uptake of up to 94.7%. A reconstruction of scans included in cohort 2 resulted in failure in 23 cases when TFSS was used. The lesion uptake values of cohort 2 showed no significant difference. MLSS is suggested as an alternative scatter-scaling method relative to TFSS with the aim of reducing halo artifacts and a robust reconstruction process.

Objective: We present an algorithm to estimate the delay between a tissue time-activity curve and a blood input curve at a single-voxel level tested on whole-body data from a long-axial field-of-view scanner with tracers of different noise characteristics., Methods: Whole-body scans of 15 patients divided equally among three tracers, namely [ 15 O]H 2 O, [ 18 F]FDG and [ 64 Cu]Cu-DOTATATE, which were used in development and testing of the algorithm. Delay times were estimated by fitting the cumulatively summed input function and tissue time-activity curve with special considerations for noise. To evaluate the performance of the algorithm, it was compared against two other algorithms also commonly applied in delay estimation: name cross-correlation and a one-tissue compartment model with incorporated delay. All algorithms were tested on both synthetic time-activity curves produced with the one-tissue compartment model with increasing levels of noise and delays between the tissue activity curve and the blood input curve. Whole-body delay maps were also calculated for each of the three tracers with data acquired on a long-axial field-of-view scanner with high time resolution., Results: Our proposed model performs better for low signal-to-noise ratio time-activity curves compared to both cross-correlation and the one-tissue compartment models for non-[ 15 O]H 2 O tracers. Testing on synthetically produced time-activity curves showed only a small and even residual delay, while the one-tissue compartment model with included delay showed varying residual delays., Conclusion: The algorithm is robust to noise and proves applicable on a range of tracers as tested on [ 15 O]H 2 O, [ 18 F]FDG and [ 64 Cu]Cu-DOTATATE, and hence is a viable option offering the ability for delay correction across various organs and tracers in use with kinetic modeling., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Nielsen, Lindberg, Bordallo, Johnbeck, Law, Fischer, Andersen and Andersen.)

Osteon morphology provides valuable information about the interplay between different processes involved in bone remodelling. The correct quantitative interpretation of these morphological features is challenging due to the complexity of interactions between osteoblast behaviour, and the evolving geometry of cortical pores during pore closing. We present a combined experimental and mathematical modelling study to provide insights into bone formation mechanisms during cortical bone remodelling based on histological cross-sections of quiescent human osteons and hypothesis-testing analyses. We introduce wall thickness asymmetry as a measure of the local asymmetry of bone formation within an osteon and examine the frequency distribution of wall thickness asymmetry in cortical osteons from human iliac crest bone samples from women 16-78 years old. Our measurements show that most osteons possess some degree of asymmetry, and that the average degree of osteon asymmetry in cortical bone evolves with age. We then propose a comprehensive mathematical model of cortical pore filling that includes osteoblast secretory activity, osteoblast elimination, osteoblast embedment as osteocytes, and osteoblast crowding and redistribution along the bone surface. The mathematical model is first calibrated to symmetric osteon data, and then used to test three mechanisms of asymmetric wall formation against osteon data: (i) delays in the onset of infilling around the cement line; (ii) heterogeneous osteoblastogenesis around the bone perimeter; and (iii) heterogeneous osteoblast secretory rate around the bone perimeter. Our results suggest that wall thickness asymmetry due to off-centred Haversian pores within osteons, and that nonuniform lamellar thicknesses within osteons are important morphological features that can indicate the prevalence of specific asymmetry-generating mechanisms. This has significant implications for the study of disruptions of bone formation as it could indicate what biological bone formation processes may become disrupted with age or disease., Competing Interests: Declaration of competing interest 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., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: New total-body PET scanners with a long axial field of view (LAFOV) allow for higher temporal resolution due to higher sensitivity, which facilitates perfusion estimation by model-free deconvolution. Fundamental tracer kinetic theory predicts that perfusion can be estimated for all tracers despite their different fates given sufficiently high temporal resolution of 1 s or better, bypassing the need for compartment modelling. The aim of this study was to investigate whether brain perfusion could be estimated using model-free Tikhonov generalized deconvolution for five different PET tracers, [ 15 O]H 2 O, [ 11 C]PIB, [ 18 F]FE-PE2I, [ 18 F]FDG and [ 18 F]FET. To our knowledge, this is the first example of a general model-free approach to estimate cerebral blood flow (CBF) from PET data., Methods: Twenty-five patients underwent dynamic LAFOV PET scanning (Siemens, Quadra). PET images were reconstructed with an isotropic voxel resolution of 1.65 mm 3 . Time framing was 40 × 1 s during bolus passage followed by increasing framing up to 60 min. AIF was obtained from the descending aorta. Both voxel- and region-based calculations of perfusion in the thalamus were performed using the Tikhonov method. The residue impulse response function was used to estimate the extraction fraction of tracer leakage across the blood-brain barrier., Results: CBF ranged from 37 to 69 mL blood min -1  100 mL of tissue -1 in the thalamus. Voxelwise calculation of CBF resulted in CBF maps in the physiologically normal range. The extraction fractions of [ 15 O]H 2 O, [ 18 F]FE-PE2I, [ 11 C]PIB, [ 18 F]FDG and [ 18 F]FET in the thalamus were 0.95, 0.78, 0.62, 0.19 and 0.03, respectively., Conclusion: The high temporal resolution and sensitivity associated with LAFOV PET scanners allow for noninvasive perfusion estimation of multiple tracers. The method provides an estimation of the residue impulse response function, from which the fate of the tracer can be studied, including the extraction fraction, influx constant, volume of distribution and transit time distribution, providing detailed physiological insight into normal and pathologic tissue., (© 2023. The Author(s).)

Multiple Myeloma (MM) is the second most common hematological malignancy and is characterized by clonal expansion of malignant plasma cells in the bone marrow. In spite of recent advances in the field of MM, the disease has remained incurable. MM is preceded by a premalignant state known as monoclonal gammopathy of undetermined significance (MGUS), with a risk of progression to MM of 1% per year. Establishing a scalable approach that refines the identification of MGUS patients at high risk of progression to MM can transform the clinical management of the disease, improve the patient's quality of life, and will have significant socioeconomic implications. Here, we provide evidence that changes in the bone marrow adipose tissue (BMAT) provide an early sign for progression from MGUS to MM. We employed AI-assisted histological analysis of unstained bone marrow biopsies from MGUS subjects with or without progression to MM within 10 years ( n = 24, n = 17 respectively). Although the BMAT fraction was not different between the two groups, bone marrow adipocyte (BMAd) density was decreased in MGUS patients who developed MM, compared to non-progressing MGUS patients. Importantly, the distribution profile for BMAd size and roundness was significantly different between the two groups, indicating a shift toward increased BMAd size and roundness in MGUS patients who developed MM. These early changes in the BMAT could serve as valuable early indicators for the transition from MGUS to MM, potentially enabling timely interventions and personalized treatment strategies. Finally, the AI-based approach for histological characterization of unstained bone marrow biopsies is cost-effective and fast, rendering its clinical implementation feasible.

Background: Recruitment and proliferation of osteoprogenitors during the reversal-resorption phase, and their differentiation into mature bone-forming osteoblasts is crucial for initiation of bone formation during bone remodeling. This study investigates the osteoprogenitors' gradual recruitment, proliferation, and differentiation into bone-forming osteoblasts within intracortical remodeling events of healthy adolescent humans., Methods: The study was conducted on cortical bone specimens from 11 adolescent human controls - patients undergoing surgery due to coxa valga. The osteoprogenitor recruitment route and differentiation into osteoblasts were backtracked using immunostainings and in situ hybridizations with osteoblastic markers (CD271/NGFR, osterix/SP7, COL3A1 and COL1A1). The osteoblastic cell populations were defined based on the pore surfaces, and their proliferation index (Ki67), density and number/circumference were estimated in multiplex-immunofluorescence (Ki67, TRAcP, CD34) stained sections., Results: During the reversal-resorption phase, osteoclasts are intermixed with (COL3A1 + NFGR + ) osteoblastic reversal cells, which are considered to be osteoprogenitors of (COL1A1 + SP7 + ) bone-forming osteoblasts. Initiation of bone formation requires a critical density of these osteoprogenitors (43 ± 9 cells/mm), which is reached though proliferation (4.4 ± 0.5 % proliferative) and even more so through recruitment of osteoprogenitors, but challenged by the ongoing expansion of the canal circumference. These osteoprogenitors most likely originate from osteoblastic bone lining cells and mainly lumen osteoprogenitors, which expand their population though proliferation (4.6 ± 0.3 %) and vascular recruitment. These lumen osteoprogenitors resemble canopy cells above trabecular remodeling sites, and like canopy cells they extend above bone-forming osteoblasts where they may rejuvenate the osteoblast population during bone formation., Conclusion: Initiation of bone formation during intracortical remodeling requires a critical density of osteoprogenitors on eroded surfaces, which is reached though proliferation and recruitment of local osteoprogenitors: bone lining cells and lumen osteoprogenitors., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix protein not previously described in the human central nervous system (CNS)., Objectives: We determined MFAP4 CNS expression and measured cerebrospinal fluid (CSF) and serum levels., Methods: Tissue was sampled at autopsy from patients with acute multiple sclerosis (MS) ( n = 3), progressive MS ( n = 3), neuromyelitis optica spectrum disorder (NMOSD) ( n = 2), and controls ( n = 9), including 6 healthy controls (HC). MFAP4 levels were measured in 152 patients: 49 MS, 62 NMOSD, 22 myelin oligodendrocyte glycoprotein-associated disease (MOGAD), and 19 isolated optic neuritis (ION)., Results: MFAP4 localized to meninges and vascular/perivascular spaces, intense in the optic nerve. At sites of active inflammation, MFAP4 reactivity was reduced in NMOSD and acute MS and less in progressive MS. CSF MFAP4 levels were reduced during relapse and at the onset of diseases (mean U/mL: MS 14.3, MOGAD 9.7, and ION 14.6 relative to HC 17.9. ( p = 0.013, p = 0.000, and p = 0.019, respectively). Patients with acute ON ( n = 68) had reduced CSF MFAP4 (mean U/mL: 14.5, p = 0.006). CSF MFAP4 levels correlated negatively with relapse severity (rho = -0.41, p = 0.017)., Conclusion: MFAP4 immunoreactivity was reduced at sites of active inflammation. CSF levels of MFAP4 were reduced following relapse and may reflect disease activity., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: S.S., M.N.O., M.W., S.M., S.T.L., K.S., and N.A. have nothing to disclose.T.M. has received speaker honoraria from Tanabe Mitsubishi Pharma, Novartis Pharma., Alexion Pharma., Teijin Pharma., Viela Bio, and Biogen Idec Japan; he has received research support from Cosmic Corporation, and Medical and Biological Laboratories Co.; and grant-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science, and Technology.J.F. has served on scientific advisory boards for and received funding for travel related to these activities as well as honoraria from Biogen Idec, Merck Serono, Sanofi-Aventis, Teva, Novartis, and Almirall.S.H. is a scientific advisor for Alcon, Santen, Sanofi, and Thea.S.MA. has received support for attending scientific meetings by Merck and Euroimmun and received speaker honoraria from Biogen.K.F. has received grants from the Ministry of Education of Japan, Ministry of Health, Welfare and Labor of Japan, and received personal fees from Roche/Chugai, Alexion, Viela Bio/ Horizon Therapeutics, Biogen, Eisai, Mitsubishi Tanabe, Novartis, Astellas, Tejin, Takeda, UCB, Merck Biopharma, Abbvie, Japan Tobacco, and Asahi Kasei Medical.K.R. has received research support from Novartis, Merck Serono, German Ministry of Education and Research, European Union (821283-2), Stiftung Charité (BIH Clinical Fellow Program), and Arthur Arnstein Foundation; and received travel grants from the Guthy-Jackson Charitable Foundation.T.L.A. has received nonfinancial support from Amgen, and free reagents from 10X genomics and ABD bioscience for projects outside the submitted work.R.M. reports personal fees from Alexion, Horizon Therapeutics, Merck, Biogen, Roche, and UCB, outside the submitted work.E.F. has served on advisory boards for Alexion, Genentech, and Horizon Therapeutics. He has received speaker honoraria from Pharmacy Times, and royalties from UpToDate. He was a site primary investigator in a randomized clinical trial on Inebilizumab in neuromyelitis optica spectrum disorder run by Medimmune/Viela-Bio/Horizon Therapeutics. He has received funding from the NIH (R01NS113828), is a member of the medical advisory board of the MOG project, and an editorial board member of the Journal of the Neurological Sciences and Neuroimmunology Reports.S.P. has received personal compensation for serving as a consultant for Genentech, Sage Therapeutics, and Astellas. He has received personal compensation for serving on scientific advisory boards or data safety monitoring boards for F. Hoffman-LaRoche AG, Genentech, and UCB. His institution has received compensation for serving as a consultant for Astellas, Alexion, and Viela Bio/MedImmune. All compensation is paid to Mayo Clinic. He has received research support from Alexion, Viela Bio/MedImmune, Roche/Genentech. He has a patent, Patent# 8,889,102 (Application#12-678350, Neuromyelitis Optica Autoantibodies as a Marker for Neoplasia)—issued; a patent, Patent# 9,891,219B2 (Application#12-573942, Methods for Treating Neuromyelitis Optica (NMO) by Administration of Eculizumab to an individual that is Aquaporin-4 (AQP4)-IgG Autoantibody positive)—issued.H.J.K. received a grant from the National Research Foundation of Korea and research support from Aprilbio and Eisai; received consultancy/speaker fees from Alexion, Aprilbio, Altos Biologics, Biogen, Celltrion, Daewoong, Eisai, GC Pharma, HanAll BioPharma, Handok, Horizon Therapeutics (formerly Viela Bio), MDimune, Mitsubishi Tanabe Pharma, Merck Serono, Novartis, Roche, Sanofi, Teva-Handok, and UCB; is a co-editor for the Multiple Sclerosis Journal and an associate editor for the Journal of Clinical Neurology.J.B. reports personal fees from Roche, Genentech, Horizon, Chugai Pharma, Clene Nanoscience, Reistone-Bio, Beigene, grants and personal fees from Alexion, grants from National Institutes of Health, and has a patent Aquaporumab issued.F.P. has served on the scientific advisory boards of Novartis and MedImmune; received travel funding and/or speaker honoraria from Bayer, Novartis, Biogen, Teva, Sanofi-Aventis/Genzyme, Merck Serono, Alexion, Chugai, MedImmune, and Shire; is an associate editor of Neurology: Neuroimmunology & Neuroinflammation; is an academic editor of PLoS ONE; consulted for Sanofi Genzyme, Biogen, MedImmune, Shire, and Alexion; received research support from Bayer, Novartis, Biogen, Teva, Sanofi-Aventis/Geynzme, Alexion, and Merck Serono; and received research support from the German Research Council, Werth Stiftung of the City of Cologne, German Ministry of Education and Research, Arthur Arnstein Stiftung Berlin, EU FP7 Framework Program, Arthur Arnstein Foundation Berlin, Guthy-Jackson Charitable Foundation, and NMSS.G.L.S. is an inventor of patents owned by the University of Southern DenmarkWO2014114298, WO2019086580, WO2014114298.B.G.W. receives royalties from RSR Ltd, Oxford University, Hospices Civil de Lyon, and MVZ Labor PD Dr. Volkmann und Kollegen GbR for a patent of NMO-IgG as a diagnostic test for neuromyelitis optica spectrum disorders, served on the adjudication committee for clinical trials conducted by MedImmune/VielaBio, Alexion, and UCB Biosciences and consulted for Chugai/Roche/Genentech, Horizon Therapeutics and Mitsubishi Tanabe regarding neuromyelitis optica spectrum disorders. He has received honoraria for speaking at internal meetings of Genentech, Novartis, and Horizon and at external meetings for Roche.H.L. has received fees for lectures from Merck, Novartis, Bristol Myers Squibb, and Sanofi-Aventis; and served as a consultant for Biogen Idec, and Roche.

Osteolytic bone disease is present in about 80% of patients with multiple myeloma at the time of diagnosis. Managing bone disease in patients with multiple myeloma is a challenge and requires a multi-faceted treatment approach with medication, surgery, and radiation. The established treatments with intravenous or subcutaneous antiresorptives can cause debilitating adverse events for patients, mainly osteonecrosis of the jaw, which, traditionally, has been difficult to manage. Now, oral surgery is recommended and proven successful in 60-85% of patients. Patients with spinal involvement may benefit from surgery in the form of vertebroplasty and kyphoplasty for pain relief, improved mobility, and reestablished sagittal balance, as well as the restoration of vertebral height. These procedures are considered safe, but the full therapeutic impact needs to be investigated further. Ixazomib, the first oral proteasome inhibitor, increases osteoblast differentiation, and recently published preliminary results in patients treated with Ixazomib maintenance have promisingly shown increased trabecular volume caused by prolonged bone formation activity. Other novel potential treatment strategies are discussed as well.

A 51-year-old woman was referred to a periodontology practice for treatment of advanced generalized periodontitis stage IV, grade C. When the dental hygienist treated the distal surface of tooth 17 with the ultrasonic scaler, the patient indicated she heard a painful, high tone. The dental hygienist immediately stopped the treatment. At a subsequent attempt to treat the same distal surface, the patient heard a painful, high tone again. After two weeks, the high tone had not disappeared. The patient was referred to an ENT specialist. He confirmed the diagnosis: tinnitus in the right ear. Pharmacological treatment with prednisone did not produce a positive result. Ultrasonic treatment of periodontitis is generally considered safe. However, in exceptional cases, sudden deafness and/or tinnitus can occur. In the event of such complaints, it is recommended not to wait, but to refer the patient to an ENT specialist immediately.

Background: Skeletal stem/progenitor cells (SSPCs) in the bone marrow can differentiate into osteoblasts or adipocytes in response to microenvironmental signalling input, including hormonal signalling. Glucocorticoids (GC) are corticosteroid hormones that promote adipogenic differentiation and are endogenously increased in patients with Cushing´s syndrome (CS). Here, we investigate bone marrow adiposity changes in response to endogenous or exogenous GC increases. For that, we characterize bone biopsies from patients with CS and post-menopausal women with glucocorticoid-induced osteoporosis (GC-O), compared to age-matched controls, including postmenopausal osteoporotic patients (PM-O)., Methods: Transiliac crest bone biopsies from CS patients and healthy controls, and from postmenopausal women with GC-O and matched controls were analysed; an additional cohort included biopsies from women with PM-O. Plastic-embedded biopsies were sectioned for histomorphometric characterization and quantification of adipocytes. The fraction of adipocyte area per tissue (Ad.Ar/T.Ar) and marrow area (Ad.Ar/Ma.Ar), mean adipocyte profile area (Ad.Pf.Ar) and adipocyte profile density (N.Ad.Pf/Ma.Ar) were determined and correlated to steroid levels. Furthermore, the spatial distribution of adipocytes in relation to trabecular bone was characterized and correlations between bone marrow adiposity and bone remodeling parameters investigated., Results: Biopsies from patients with CS and GC-O presented increased Ad.Ar/Ma.Ar, along with adipocyte hypertrophy and hyperplasia. In patients with CS, both Ad.Ar/Ma.Ar and Ad.Pf.Ar significantly correlated with serum cortisol levels. Spatial distribution analyses revealed that, in CS, the increase in Ad.Ar/Ma.Ar near to trabecular bone (<100 µm) was mediated by both adipocyte hypertrophy and hyperplasia, while N.Ad.Pf/Ma.Ar further into the marrow (>100 µm) remained unchanged. In contrast, patients with GC-O only presented increased Ad.Ar/Ma.Ar and mean Ad.Pf.Ar>100 µm from trabecular bone surface, highlighting the differential effect of increased endogenous steroid accumulation. Finally, the Ad.Ar/Ma.Ar and Ad.Ar/T.Ar correlated with the canopy coverage above remodeling events., Conclusion: Increased cortisol production in patients with CS induces increased bone marrow adiposity, primarily mediated by adipocyte hypertrophy. This adiposity is particularly evident near trabecular bone surfaces, where hyperplasia also occurs. The differential pattern of adiposity in patients with CS and GC-O highlights that bone marrow adipocytes and their progenitors may respond differently in these two GC-mediated bone diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sørensen, Andreasen, Jensen, Hauge, Bollerslev, Delaissé, Kassem, Jafari, Diaz-delCastillo and Andersen.)

Neuroimaging holds an essential position in global healthcare, as brain-related disorders are a substantial and growing burden. Non-degenerative disorders such as stress, depression and anxiety share common function related traits of diffuse and fluctuating changes, such as change in brain-based functions of mood, behavior and cognitive abilities, where underlying physiological mechanism remain unresolved. In this study we developed a novel application for studying intra-subject task-activated brain function by the quantitative physiological measurement of the change in glucose metabolism in a single scan setup. Data were acquired on a PET/MR-scanner. We implemented a functional [ 18 F]-FDG PET-scan with double boli-tracer administration and finger-tapping activation, as proof-of-concept, in five healthy participants. The [ 18 F]-FDG data were analyzed using a two-tissue compartment double boli kinetic model with an image-derived input function. For stand-alone visual reference, blood oxygenation level dependent (BOLD) functional MRI (fMRI) was acquired in the same session and analyzed separately. We were able to measure the cerebral glucose metabolic rate during baseline as well as activation. Results showed increased glucose metabolic rate during activation by 36.3-87.9% mean 62.0%, locally in the peak seed region of M1 in the brain, on an intra-subject level, as well as very good spatial accuracy on group level, and localization compared to the BOLD fMRI result at subject and group level. Our novel method successfully determined the relative increase in the cerebral metabolic rate of glucose on a voxel level with good visual association to fMRI at the subject-level, holding promise for future individual clinical application. This approach will be easily adapted in future clinical perspectives and pharmacological interventions studies.

Although failure to establish a vascular network has been associated with many skeletal disorders, little is known about what drives development of vasculature in the intracortical bone compartments. Here, we show that intracortical bone resorption events are coordinated with development of the vasculature. We investigated the prevalence of vascular structures at different remodeling stages as well as their 3D organization using proximal femoral cortical bone from 5 girls and 6 boys (aged 6-15 years). A 2D analysis revealed that non-quiescent intracortical pores contained more vascular structures than quiescent pores (p < 0.0001). Type 2 pores, i.e., remodeling of existing pores, had a higher density of vascular structures than type 1 pores, i.e., de novo created pores (p < 0.05). Furthermore, pores at the eroded-formative remodeling stage, had more vascular structures than pores at any other remodeling stage (p < 0.05). A 3D reconstruction of an intracortical remodeling event showed that osteoclasts in the advancing tip of the cutting cone as well as preosteoclasts in the lumen expressed vascular endothelial growth factor-A (VEGFA), while VEGFA-receptors 1 and 2 mainly were expressed in endothelial cells in the adjacent vasculature. Consequently, we propose that the progression of the vascular network in intracortical remodeling events is driven by osteoclasts expressing VEGFA. Moreover, the vasculature is continuously reconfigured according to the demands of the remodeling events at the surrounding bone surfaces., Competing Interests: Declaration of competing interest The following research grants have been received: However, none of our founders had any role in conceptualization, analysis, or interpretation of the study and I can, as last author of the submitted manuscript declare that none of the authors have any personal financial interest to declare in connection this manuscript., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Multiple myeloma (MM) is a neoplasia of B plasma cells that often induces bone pain. However, the mechanisms underlying myeloma-induced bone pain (MIBP) are mostly unknown. Using a syngeneic MM mouse model, we show that periosteal nerve sprouting of calcitonin gene-related peptide (CGRP + ) and growth associated protein 43 (GAP43 + ) fibers occurs concurrent to the onset of nociception and its blockade provides transient pain relief. MM patient samples also showed increased periosteal innervation. Mechanistically, we investigated MM induced gene expression changes in the dorsal root ganglia (DRG) innervating the MM-bearing bone of male mice and found alterations in pathways associated with cell cycle, immune response and neuronal signaling. The MM transcriptional signature was consistent with metastatic MM infiltration to the DRG, a never-before described feature of the disease that we further demonstrated histologically. In the DRG, MM cells caused loss of vascularization and neuronal injury, which may contribute to late-stage MIBP. Interestingly, the transcriptional signature of a MM patient was consistent with MM cell infiltration to the DRG. Overall, our results suggest that MM induces a plethora of peripheral nervous system alterations that may contribute to the failure of current analgesics and suggest neuroprotective drugs as appropriate strategies to treat early onset MIBP. SIGNIFICANCE STATEMENT Multiple myeloma (MM) is a painful bone marrow cancer that significantly impairs the quality of life of the patients. Analgesic therapies for myeloma-induced bone pain (MIBP) are limited and often ineffective, and the mechanisms of MIBP remain unknown. In this manuscript, we describe cancer-induced periosteal nerve sprouting in a mouse model of MIBP, where we also encounter metastasis to the dorsal root ganglia (DRG), a never-before described feature of the disease. Concomitant to myeloma infiltration, the lumbar DRGs presented blood vessel damage and transcriptional alterations, which may mediate MIBP. Explorative studies on human tissue support our preclinical findings. Understanding the mechanisms of MIBP is crucial to develop targeted analgesic with better efficacy and fewer side effects for this patient population., (Copyright © 2023 the authors.)

Proper bone remodeling depends not only on a team of bone-resorbing osteoclasts and bone-forming osteoblasts. It also depends on the site-specific delivery of a large amount of osteoblast lineage cells to the bone remodeling site. How this delivery occurs is poorly known. Here, we gained insight into this mechanism by analyzing the distribution of markers of osteoblastogenesis on bone surfaces and in their bone marrow neighborhood in human cancellous bone. We found a CD271-positive/PDGFβ-R-positive cell layer surrounding the bone marrow that provides osteoblastogenic potential along all bone surfaces, whether quiescent or remodeling. This bone marrow envelope cell layer takes the appearance of a canopy above remodeling sites, where it then also shows an upregulation of the proliferation marker Ki67, smooth muscle actin (SMA), tenascin C, fibronectin, and MMP13. This indicates that the canopy is a region of the bone marrow envelope where early markers of osteoblastogenesis are activated concurrently with initiation of bone remodeling. Importantly, the high proliferation index in the canopy is not associated with increasing cell densities at the canopy level, but it is at the bone surface level, thereby supporting delivery of cells from the canopy to the bone surface. This delivery route explains why lack of canopies was previously found to coincide with lack of bone formation, and fits current knowledge on the canopies as a target for regulators of bone remodeling. We conclude that the coordination of bone marrow envelope activities and bone surface activities allows integrating osteoblastogenesis and bone remodeling into the same functional unit, and propose that the bone marrow envelope is critical for preserving bone health. © 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).)

Upon transplantation, skeletal stem cells (also known as bone marrow stromal or mesenchymal stem cells) can regulate bone regeneration by producing secreted factors. Here, we identify KIAA1199 as a bone marrow stromal cell-secreted factor in vitro and in vivo. KIAA1199 plasma levels of patients positively correlate with osteoporotic fracture risk and expression levels of KIAA1199 in patient bone marrow stromal cells negatively correlates with their osteogenic differentiation potential. KIAA1199-deficient bone marrow stromal cells exhibit enhanced osteoblast differentiation in vitro and ectopic bone formation in vivo. Consistently, KIAA1199 knockout mice display increased bone mass and biomechanical strength, as well as an increased bone formation rate. They also exhibit accelerated healing of surgically generated bone defects and are protected from ovariectomy-induced bone loss. Mechanistically, KIAA1199 regulates osteogenesis by inhibiting the production of osteopontin by osteoblasts, via integrin-mediated AKT and ERK-MAPK intracellular signaling. Thus, KIAA1199 is a regulator of osteoblast differentiation and bone regeneration and could be targeted for the treatment or management of low bone mass conditions., (© 2023. The Author(s).)

Purpose: Conventional magnetic resonance imaging (MRI) can for glioma assessment be supplemented by positron emission tomography (PET) imaging with radiolabeled amino acids such as O-(2-[ 18 F]fluoroethyl)-L-tyrosine ([ 18 F]FET), which provides additional information on metabolic properties. In neuro-oncology, patients often undergo brain and skull altering treatment, which is known to challenge MRI-based attenuation correction (MR-AC) methods and thereby impact the simplified semi-quantitative measures such as tumor-to-brain ratio (TBR) used in clinical routine. The aim of the present study was to examine the applicability of our deep learning method, DeepDixon, for MR-AC in [ 18 F]FET PET/MRI scans of a post-surgery glioma cohort with metal implants., Methods: The MR-AC maps were assessed for all 194 included post-surgery glioma patients (318 studies). The subgroup of 147 patients (222 studies, 200 MBq [ 18 F]FET PET/MRI) with tracer uptake above 1 ml were subsequently reconstructed with DeepDixon, vendor-default atlas-based method, and a low-dose computed tomography (CT) used as reference. The biological tumor volume (BTV) was delineated on each patient by isocontouring tracer uptake above a TBR threshold of 1.6. We evaluated the MR-AC methods using the recommended clinical metrics BTV and mean and maximum TBR on a patient-by-patient basis against the reference with CT-AC., Results: Ninety-seven percent of the studies (310/318) did not have any major artifacts using DeepDixon, which resulted in a Dice coefficient of 0.89/0.83 for tissue/bone, respectively, compared to 0.84/0.57 when using atlas. The average difference between DeepDixon and CT-AC was within 0.2% across all clinical metrics, and no statistically significant difference was found. When using DeepDixon, only 3 out of 222 studies (1%) exceeded our acceptance criteria compared to 72 of the 222 studies (32%) with the atlas method., Conclusion: We evaluated the performance of a state-of-the-art MR-AC method on the largest post-surgical glioma patient cohort to date. We found that DeepDixon could overcome most of the issues arising from irregular anatomy and metal artifacts present in the cohort resulting in clinical metrics within acceptable limits of the reference CT-AC in almost all cases. This is a significant improvement over the vendor-provided atlas method and of particular importance in response assessment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ladefoged, Andersen, Andersen, Anderberg, Engkebølle, Madsen, Højgaard, Henriksen and Law.)

We compared the image quality and quantification parameters through bayesian penalized likelihood reconstruction algorithm (Q.Clear) and ordered subset expectation maximization (OSEM) algorithm for 2-[ 18 F]FDG-PET/CT scans performed for response monitoring in patients with metastatic breast cancer in prospective setting. We included 37 metastatic breast cancer patients diagnosed and monitored with 2-[ 18 F]FDG-PET/CT at Odense University Hospital (Denmark). A total of 100 scans were analyzed blinded toward Q.Clear and OSEM reconstruction algorithms regarding image quality parameters (noise, sharpness, contrast, diagnostic confidence, artefacts, and blotchy appearance) using a five-point scale. The hottest lesion was selected in scans with measurable disease, considering the same volume of interest in both reconstruction methods. SUL peak (g/mL) and SUV max (g/mL) were compared for the same hottest lesion. There was no significant difference regarding noise, diagnostic confidence, and artefacts within reconstruction methods; Q.Clear had significantly better sharpness ( p < 0.001) and contrast ( p = 0.001) than the OSEM reconstruction, while the OSEM reconstruction had significantly less blotchy appearance compared with Q.Clear reconstruction ( p < 0.001). Quantitative analysis on 75/100 scans indicated that Q.Clear reconstruction had significantly higher SUL peak (5.33 ± 2.8 vs. 4.85 ± 2.5, p < 0.001) and SUV max (8.27 ± 4.8 vs. 6.90 ± 3.8, p < 0.001) compared with OSEM reconstruction. In conclusion, Q.Clear reconstruction revealed better sharpness, better contrast, higher SUV max , and higher SUL peak , while OSEM reconstruction had less blotchy appearance.

Objective: Drugs targeting the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) are emerging as treatments for type-2 diabetes and obesity. GIP acutely decreases serum markers of bone resorption and transiently increases bone formation markers in short-term clinical investigations. However, it is unknown whether GIP acts directly on bone cells to mediate these effects. Using a GIPR-specific antagonist, we aimed to assess whether GIP acts directly on primary human osteoclasts and osteoblasts., Methods: Osteoclasts were differentiated from human CD14+ monocytes and osteoblasts from human bone. GIPR expression was determined using RNA-seq in primary human osteoclasts and in situ hybridization in human femoral bone. Osteoclastic resorptive activity was assessed using microscopy. GIPR signaling pathways in osteoclasts and osteoblasts were assessed using LANCE cAMP and AlphaLISA phosphorylation assays, intracellular calcium imaging and confocal microscopy. The bioenergetic profile of osteoclasts was evaluated using Seahorse XF-96., Results: GIPR is robustly expressed in mature human osteoclasts. GIP inhibits osteoclastogenesis, delays bone resorption, and increases osteoclast apoptosis by acting upon multiple signaling pathways (Src, cAMP, Akt, p38, Akt, NFκB) to impair nuclear translocation of nuclear factor of activated T cells-1 (NFATc1) and nuclear factor-κB (NFκB). Osteoblasts also expressed GIPR, and GIP improved osteoblast survival. Decreased bone resorption and improved osteoblast survival were also observed after GIP treatment of osteoclast-osteoblast co-cultures. Antagonizing GIPR with GIP(3-30)NH2 abolished the effects of GIP on osteoclasts and osteoblasts., Conclusions: GIP inhibits bone resorption and improves survival of human osteoblasts, indicating that drugs targeting GIPR may impair bone resorption, whilst preserving bone formation., Competing Interests: Conflicts of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of (ESE) European Society of Endocrinology.)

Economic inequality is associated with preferences for smaller, immediate gains over larger, delayed ones. Such temporal discounting may feed into rising global inequality, yet it is unclear whether it is a function of choice preferences or norms, or rather the absence of sufficient resources for immediate needs. It is also not clear whether these reflect true differences in choice patterns between income groups. We tested temporal discounting and five intertemporal choice anomalies using local currencies and value standards in 61 countries (N = 13,629). Across a diverse sample, we found consistent, robust rates of choice anomalies. Lower-income groups were not significantly different, but economic inequality and broader financial circumstances were clearly correlated with population choice patterns., (© 2022. The Author(s).)

Whole-exome sequencing of two patients with idiopathic complex neurodevelopmental disorder (NDD) identified biallelic variants of unknown significance within FIBCD1, encoding an endocytic acetyl group-binding transmembrane receptor with no known function in the central nervous system. We found that FIBCD1 preferentially binds and endocytoses glycosaminoglycan (GAG) chondroitin sulphate-4S (CS-4S) and regulates GAG content of the brain extracellular matrix (ECM). In silico molecular simulation studies and GAG binding analyses of patient variants determined that such variants are loss-of-function by disrupting FIBCD1-CS-4S association. Gene knockdown in flies resulted in morphological disruption of the neuromuscular junction and motor-related behavioural deficits. In humans and mice, FIBCD1 is expressed in discrete brain regions, including the hippocampus. Fibcd1 KO mice exhibited normal hippocampal neuronal morphology but impaired hippocampal-dependent learning. Further, hippocampal synaptic remodelling in acute slices from Fibcd1 KO mice was deficient but restored upon enzymatically modulating the ECM. Together, we identified FIBCD1 as an endocytic receptor for GAGs in the brain ECM and a novel gene associated with an NDD, revealing a critical role in nervous system structure, function and plasticity., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)

Background: Deep convolutional neural networks have demonstrated robust and reliable PET attenuation correction (AC) as an alternative to conventional AC methods in integrated PET/MRI systems. However, its whole-body implementation is still challenging due to anatomical variations and the limited MRI field of view. The aim of this study is to investigate a deep learning (DL) method to generate voxel-based synthetic CT (sCT) from Dixon MRI and use it as a whole-body solution for PET AC in a PET/MRI system., Materials and Methods: Fifteen patients underwent PET/CT followed by PET/MRI with whole-body coverage from skull to feet. We performed MRI truncation correction and employed co-registered MRI and CT images for training and leave-one-out cross-validation. The network was pretrained with region-specific images. The accuracy of the AC maps and reconstructed PET images were assessed by performing a voxel-wise analysis and calculating the quantification error in SUV obtained using DL-based sCT (PET sCT ) and a vendor-provided atlas-based method (PET Atlas ), with the CT-based reconstruction (PET CT ) serving as the reference. In addition, region-specific analysis was performed to compare the performances of the methods in brain, lung, liver, spine, pelvic bone, and aorta., Results: Our DL-based method resulted in better estimates of AC maps with a mean absolute error of 62 HU, compared to 109 HU for the atlas-based method. We found an excellent voxel-by-voxel correlation between PET CT and PET sCT (R 2  = 0.98). The absolute percentage difference in PET quantification for the entire image was 6.1% for PET sCT and 11.2% for PET Atlas . The regional analysis showed that the average errors and the variability for PET sCT were lower than PET Atlas in all regions. The largest errors were observed in the lung, while the smallest biases were observed in the brain and liver., Conclusions: Experimental results demonstrated that a DL approach for whole-body PET AC in PET/MRI is feasible and allows for more accurate results compared with conventional methods. Further evaluation using a larger training cohort is required for more accurate and robust performance., (© 2022. The Author(s).)

Despite their ability to reduce fracture-risk and increase Bone Mineral Density (BMD) in osteoporotic women, bisphosphonates are reported to reduce formation of new bone. Reduced bone formation has been suggested to lead to accumulation of microfractures and contribute to rare side effects in cortical bone such as atypical femur fractures. However, most studies are limited to trabecular bone. In this study, the cortical bone remodeling in human iliac bone specimens of 65 non-treated and 24 alendronate-treated osteoporotic women was investigated using a new histomorphometric classification of intracortical pores. The study showed that only 12.4 ± 11% of the cortical pore area reflected quiescent pores/osteons in alendronate-treated patients versus 8.5 ± 5% in placebo, highlighting that new cortical remodeling events remain to be activated. The percent and size of eroded pores (events in resorption-reversal phase) remained unchanged, but their contribution to total pore area was 1.4-fold higher in alendronate versus placebo treated patients (66 ± 22% vs 48 ± 22%, p < 0.001). On the other hand, the mixed eroded-formative pores (events with mixed resorption-reversal-formation phases) was 2-fold lower in alendronate versus placebo treated patients (19 ± 14% vs 39 ± 23% of total pore area, p < 0.001), and formative pores (event in formation phase) was 2.2-fold lower in alendronate versus placebo treated patients (2.1 ± 2.4% vs 4.6 ± 3.6%, p < 0.01), and their contribution to total pore area was 2.4-fold lower (1.3 ± 2.1% vs 3.1 ± 4.4%, p < 0.05). Importantly, these differences between alendronate and placebo treated patients were significant in patients after 3 years of treatment, not after 2 years of treatment. Collectively, the results support that cortical remodeling events activated during alendronate treatment has a prolonged reversal-resorption phase with a delayed transition to formation, becoming increasingly evident after 3-years of treatment. A potential contributor to atypical femur fractures associated with long-term bisphosphonate treatment., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Bone tissue is continuously remodeled. In trabecular bone, each remodeling transaction forms a microscopic bone structural unit (BSU), also known as a hemiosteon or a trabecular packet, which is bonded to existing tissue by osteopontin-rich cement lines. The size and shape of the BSUs are determined by the size and shape of the resorption cavity, and whether the cavity is potentially over- or under-filled by the subsequent bone formation. The present study focuses on the recently formed trabecular BSUs, and how their 2D size and shape changes with age and trabecular microstructure. The study was performed using osteopontin-immunostained frontal sections of L2 vertebrae from 8 young (aged 18.5-37.6 years) and 8 old (aged 69.1-96.4 years) control females, which underwent microcomputed tomography (μCT) imaging prior to sectioning. The contour of 4230 BSU profiles (181-385 per vertebra) within 1024 trabecular profiles were outlined, and their 2D width, length, area, and shape were assessed. Of these BSUs, 22 (0.5%) were generated by modeling-based bone formation (i.e. without prior resorption), while 99.5% were generated by remodeling-based bone formation (i.e. with prior resorption). The distributions of BSU profile width, length, and area were significantly smaller in the old versus young females (p < 0.005), and the median profile width, length, and area were negative correlated with age (p < 0.018). Importantly, these BSU profile size parameters were more strongly correlated with trabecular bone volume (BV/TV, p < 0.002) and structure model index (SMI, p < 0.008) assessed by μCT, than age. Moreover, the 2D BSU size parameters were positively correlated to the area of the individual trabecular profiles (p < 0.0001), which were significantly smaller in the old versus young females (p < 0.024). The BSU shape parameters (aspect ratio, circularity, and solidity) were not correlated with age, BV/TV, or SMI. Collectively, the study supports the notion that not only the BSU profile width, but also its length and area, are more influenced by the age-related bone loss and shift from plates to rods (SMI), than age itself. This implies that BSU profile size is mainly driven by changes in the trabecular microstructure, which affect the size of the resorption cavity that the BSU refills., (Copyright © 2022. Published by Elsevier Inc.)

The strictly regulated bone remodeling process ensures that osteoblastic bone formation is coupled to osteoclastic bone resorption. This coupling is regulated by a panel of coupling factors, including clastokines promoting the recruitment, expansion, and differentiation of osteoprogenitor cells within the eroded cavity. The osteoprogenitor cells on eroded surfaces are called reversal cells. They are intermixed with osteoclasts and become bone-forming osteoblast when reaching a critical density and maturity. Several coupling factors have been proposed in the literature, but their effects and expression pattern vary between studies depending on species and experimental setup. In this study, we investigated the mRNA levels of proposed secreted and membrane-bound coupling factors and their receptors in cortical bone remodeling events within the femur of healthy adolescent human controls using high-sensitivity RNA in situ hybridization. Of the proposed coupling factors, human osteoclasts showed mRNA-presence of LIF , PDGFB , SEMA4D , but no presence of EFNB2 , and OSM . On the other hand, the osteoblastic reversal cells proximate to osteoclasts presented with LIFR , PDGFRA and PLXNB1 , but not PDGFRB , which are all known receptors of the proposed coupling factors. Although EFNB2 was not present in mature osteoclasts, the mRNA of the ligand-receptor pair EFNB2:EPHB4 were abundant near the central blood vessels within intracortical pores with active remodeling. EPHB4 and SEMA4D were also abundant in mature bone-forming osteoblasts. This study highlights that especially LIF:LIFR , PDGFB:PDGFRA , SEMA4D:PLXNB1 may play a critical role in the osteoclast-osteoblast coupling in human remodeling events, as they are expressed within the critical cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Borggaard, Nielsen, Delaisse, Andreasen and Andersen.)

Background: Pain is a common complication for patients with metastatic bone disease. Animal models suggest that the pain, in part, is driven by pathological sprouting and reorganization of the nerve fibers innervating the bone. Here, we investigate how these findings translate to humans., Methods: Bone biopsies were collected from healthy volunteers ( n = 7) and patients with breast cancer and metastatic bone disease (permissions H-15000679, S-20180057 and S-20110112). Cancer-infiltrated biopsies were from patients without recent anticancer treatment ( n = 10), patients with recent anticancer treatment ( n = 10), and patients with joint replacement surgery ( n = 9). Adjacent bone sections were stained for (1) protein gene product 9.5 and CD34, and (2) cytokeratin 7 and 19. Histomorphometry was used to estimate the area of bone marrow and tumor burden. Nerve profiles were counted, and the nerve profile density calculated. The location of each nerve profile within 25 μm of a vascular structure and/or cancer cells was determined., Results: Cancer-infiltrated bone tissue demonstrated a significantly higher nerve profile density compared to healthy bone tissue. The percentage of nerve profiles found close to vascular structures was significantly lower in cancer-infiltrated bone tissue. No difference was found in the percentage of nerve profiles located close to cancer between the subgroups of cancer-infiltrated bone tissue. Interestingly, no correlation was found between nerve profile density and tumor burden., Conclusions: Together, the increased nerve profile density and the decreased association of nerve profiles to vasculature strongly suggests that neuronal sprouting and reorganization occurs in human cancer-infiltrated bone tissue., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hansen, Sayilekshmy, Sørensen, Jørgensen, Kanneworff, Bengtsson, Grum-Schwensen, Petersen, Ejersted, Andersen, Andreasen and Heegaard.)

The mechanisms of obesity and type 2 diabetes (T2D)-associated impaired fracture healing are poorly studied. In a murine model of T2D reflecting both hyperinsulinemia induced by high-fat diet and insulinopenia induced by treatment with streptozotocin, we examined bone healing in a tibia cortical bone defect. A delayed bone healing was observed during hyperinsulinemia as newly formed bone was reduced by -28.4 ± 7.7% and was associated with accumulation of marrow adipocytes at the defect site +124.06 ± 38.71%, and increased density of SCA1+ (+74.99 ± 29.19%) but not Runx2+ osteoprogenitor cells. We also observed increased in reactive oxygen species production (+101.82 ± 33.05%), senescence gene signature (≈106.66 ± 34.03%), and LAMIN B1- senescent cell density (+225.18 ± 43.15%), suggesting accelerated senescence phenotype. During insulinopenia, a more pronounced delayed bone healing was observed with decreased newly formed bone to -34.9 ± 6.2% which was inversely correlated with glucose levels (R2 = 0.48, P < .004) and callus adipose tissue area (R2 = .3711, P < .01). Finally, to investigate the relevance to human physiology, we observed that sera from obese and T2D subjects had disease state-specific inhibitory effects on osteoblast-related gene signatures in human bone marrow stromal cells which resulted in inhibition of osteoblast and enhanced adipocyte differentiation. Our data demonstrate that T2D exerts negative effects on bone healing through inhibition of osteoblast differentiation of skeletal stem cells and induction of accelerated bone senescence and that the hyperglycemia per se and not just insulin levels is detrimental for bone healing., (© The Author(s) 2022. Published by Oxford University Press.)

Patients with brain metastases, the most common intracranial tumor, have an average survival ranging from a few months to 40 months, and new treatment initiatives are needed. Cryoablation is a minimally invasive, well-tolerated, and effective procedure commonly applied for treatment of renal tumors and certain other malignancies. We aimed to examine the clinical usefulness of this procedure in a step-by-step program starting with cerebral cryoablation in healthy pigs. In four terminal and four non-terminal non-tumor bearing pigs, we studied immediate and delayed effects of cerebral cryoablation. Safety was assessed by computed tomography (CT), and clinical observation of behavior, neurological deficits, and wellbeing. Effects were assessed by histological and immuno-histochemical analyses addressing structural and metabolic changes supported by additional magnetic resonance imaging (MRI) and positron emission tomography (PET) in the non-terminal animals. Using CT-guidance, cryoablation probes were successfully inserted without complications, and ice formation could be monitored real-time with CT. No animal developed neurological deficits or signs of discomfort. Histological and immunohistochemical analyses, MRI, and PET revealed profound structural and biological damage within the lesion. MRI and PET revealed no long-term damage to healthy tissue outside the cryoablation zone. Cerebral cryoablation appears to be a feasible, safe, and controllable procedure that can be monitored successfully with CT. The net effect is a dead brain lesion without damage of either nearby or remote healthy structures. Immediate changes are local hemorrhage and edema; delayed effects are perfusion defects, immune system activation, and astrogliosis., (© 2022. The Author(s).)