Evaluation of bone mineral density (BMD) and trabecular bone score (TBS) in pheochromocytoma and paraganglioma; a multi-centric case-control study from India.

Pheochromocytoma and paraganglioma (PPGL) have been associated with low bone mineral density (BMD) due to excess sympathetic system stimulation. Our study revealed low BMD and TBS (trabecular bone score) in cases compared to matched controls. Plasma-free nor-metanephrine and hypertension duration found to be most consistent predictive factors. PURPOSE: Pheochromocytoma and paraganglioma (PPGL) have been associated with low bone mineral density (BMD) and increased fracture risks. Sympathetic nervous system stimulation has been shown to increase bone resorption and decrease bone formation via ß2 receptors. Chronic inflammation and increased cytokine production add to more bone loss. TBS (trabecular bone score) is an established surrogate marker for bone histomorphometry. BMD and TBS data in pheochromocytoma and PPGL are scarce. The aim was to assess the BMD and TBS in pheochromocytoma and PPGL and look for clinical and biochemical predictors. METHODS: This case-control study had sample size of 58 (29 cases and controls each). BMI-, age-, and sex-matched controls were taken for comparison. Both cases and controls had undergone DXA scan and BMD {Z-scores and bone mineral concentration (BMC) in g/cm2} and TBS were analyzed. Detailed clinical histories and relevant biochemistry values were noted. RESULTS: The mean age of our case population was 29.5 ± 9.4 years with a mean age of HTN onset at 26.86 ± 6.6 years. Lumbar spine BMC (0.86 ± 0.14 vs 0.96 ± 0.15; p = 0.036), femoral neck Z-score (- 1.23 ± 1.07 vs - 0.75 ± 0.97; p = 0.003), and whole body BMC (0.91 ± 0.14 vs 1.07 ± 0.11; p = 0.000) were significantly low in cases compared to controls. Similarly, TBS was significantly lower in cases compared to controls (1.306 ± 0.113 vs 1.376 ± 0.083; p = 0.001). CONCLUSION: This study establishes both low bone mass and poor bone quality in an Indian pheochromocytoma and PPGL patient's cohort. Plasma-free nor-metanephrine and duration of hypertension were found to be most consistent predictive factors in multivariate regression analysis.

Construction of a prognostic model for hepatocellular carcinoma patients receiving transarterial chemoembolization treatment based on the Tumor Burden Score.

BACKGROUND: Patients with hepatocellular carcinoma (HCC) who undergo transarterial chemoembolization (TACE) may have varied outcomes based on their liver function and tumor burden diversity. This study aims to assess the prognostic significance of the tumor burden score (TBS) in these patients and develop a prognostic model for their overall survival. METHODS: The study involved a retrospective analysis of 644 newly diagnosed HCC patients undergoing TACE treatment. The individuals were assigned randomly to a training cohort (n = 452) and a validation cohort (n = 192). We utilized a multivariate Cox proportional risk model to identify independent preoperative predictive factors. We then evaluated model performance using the area under the curve (AUC), consistency index (c-index), calibration curve, and decision curve analysis (DCA) methods. RESULTS: The multivariate analysis revealed four prognostic factors associated with overall survival: Tumor Burden Score, Tumor Extent, Types of portal vein invasion (PVI), and Child-Pugh score. The total score was calculated based on these factors. The model demonstrated strong discriminative ability with high AUC values and c-index, providing high net clinical benefits for patients. Based on the model's scoring results, patients were categorized into high, medium, and low-risk groups. These results were validated in the validation cohort. CONCLUSIONS: The tumor burden score shows promise as a viable alternative prognostic indicator for assessing tumor burden in cases of HCC. The new prognostic model can place patients in one of three groups, which will estimate their individual outcomes. For high-risk patients, it is suggested to consider alternative treatment options or provide the best supportive care, as they may not benefit significantly from TACE treatment.

Glucagon-like Peptide-1 Receptor Agonists and Diabetic Osteopathy: Another Positive Effect of Incretines? A 12 Months Longitudinal Study.

Diabetic osteopathy is a frequent complication in patients with type 2 diabetes mellitus (T2DM). The association between T2DM and increased fracture risk has led to study the impact of new antidiabetic drugs on bone metabolism. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are incretin mimetic drugs which have many pleiotropic properties. The relationship between GLP-1RAs and bone is very complex: while in vitro and animal studies have demonstrated a protective effect on bone, human studies are scarce. We led a 12 months longitudinal study evaluating bone changes in 65 patients withT2DM for whom a therapy with GLP-1RAs had been planned. Fifty-four T2DM patients completed the 12-month study period; of them, 30 had been treated with weekly dulaglutide and 24 with weekly semaglutide. One-year therapy with GLP-1RAs resulted in a significant reduction in weight and BMI. Bone mineral density (BMD), bone metabolism, trabecular bone score (TBS), adiponectin, and myostatin were evaluated before and after 12 months of GLP-1RAs therapy. After 12 months of therapy bone turnover markers and adiponectin showed a significant increase, while myostatin values showed a modest but significant reduction. BMD-LS by DXA presented a significant reduction while the reduction in BMD-LS by REMS was not significant and TBS values showed a marginal increase. Both DXA and REMS techniques showed a modest but significant reduction in femoral BMD. In conclusion, the use of GLP-1RAs for 12 months preserves bone quality and reactivates bone turnover. Further studies are needed to confirm whether GLP-1RAs could represent a useful therapeutic option for patients with T2DM and osteoporosis.

A computational model elucidating mechanisms and variability in theta burst stimulation responses.

Theta burst stimulation (TBS) is a form of repetitive transcranial magnetic stimulation (rTMS) with unknown underlying mechanisms and highly variable responses across subjects. To investigate these issues, we developed a simple computational model. Our model consisted of two neurons linked by an excitatory synapse that incorporates two mechanisms: short-term plasticity (STP) and spike-timing-dependent plasticity (STDP). We applied a variable-amplitude current through I-clamp with a TBS time pattern to the pre- and post-synaptic neurons, simulating synaptic plasticity. We analyzed the results and provided an explanation for the effects of TBS, as well as the variability of responses to it. Our findings suggest that the interplay of STP and STDP mechanisms determines the direction of plasticity, which selectively affects synapses in extended neurons and underlies functional effects. Our model describes how the timing, number, and intensity of pulses delivered to neurons during rTMS contribute to induced plasticity. This not only successfully explains the different effects of intermittent TBS (iTBS) and continuous TBS (cTBS), but also predicts the results of other protocols such as 10 Hz rTMS. We propose that the variability in responses to TBS can be attributed to the variable span of neuronal thresholds across individuals and sessions. Our model suggests a biologically plausible mechanism for the diverse responses to TBS protocols and aligns with experimental data on iTBS and cTBS outcomes. This model could potentially aid in improving TBS and rTMS protocols and customizing treatments for patients, brain areas, and brain disorders.

TBS correlates with bone density and microstructure at trabecular and cortical bone evaluated by HR-pQCT.

INTRODUCTION: Trabecular bone score (TBS) estimates bone microstructure, which is directly measured by high-resolution peripheral quantitative computed tomography (HRpQCT). We evaluated the correlation between these methods and TBS influence on fracture risk assessed by FRAX. MATERIALS AND METHODS: We evaluated 129 individuals (82 women, 43 postmenopausal) 20 to 82.3 years without prevalent clinical or non-clinical morphometric vertebral fractures, using DXA (spine and hip), HR-pQCT at distal radius (R) and tibia (T) and TBS which classifies bone microarchitecture as normal (TBS ≥ 1.350), partially degraded (1.200 < TBS < 1.350), or degraded (TBS ≤ 1.200). RESULTS: Spine and hip BMD and HR-pQCT parameters at cortical bone: area (T), density (R,T) thickness (T) and trabecular bone: density (R,T), number (T) and thickness (R) were significantly better in the 78 individuals with normal TBS (group 1) versus the 51 classified as partially degraded (n = 42) or degraded microarchitecture (n = 9) altogether (group 2). TBS values correlated with age (r = - 0.55), positively with spine and hip BMD and all cortical and trabecular bone density and microstructure parameters evaluated, p < 0.05 all tests. Binary logistic regression defined age (p = 0.008) and cortical thickness (p = 0.018) as main influences on TBS, while ANCOVA demonstrated that HR-pQCT data corrected for age were not different between TBS groups 1 and 2. TBS adjustment increased FRAX risk for major osteoporotic fractures and hip fractures. CONCLUSION: We describe significant association between TBS and both trabecular and cortical bone parameters measured by HR-pQCT, consistent with TBS influence on fracture risk estimation by FRAX, including hip fractures, where cortical bone predominates.

Theta burst stimulation: what role does it play in stroke rehabilitation? A systematic review of the existing evidence.

Various post-stroke dysfunctions often result in poor long-term outcomes for stroke survivors, but the effect of conventional treatments is limited. In recent years, lots of studies have confirmed the effect of repetitive transcranial magnetic stimulation (rTMS) in stroke rehabilitation. As a new pattern of rTMS, theta burst stimulation (TBS) was proved recently to yield more pronounced and long-lasting after-effects than the conventional pattern at a shorter stimulation duration. To explore the role of TBS in stroke rehabilitation, this review summarizes the existing evidence from all the randomized controlled trials (RCTs) so far on the efficacy of TBS applied to different post-stroke dysfunctions, including cognitive impairment, visuospatial neglect, aphasia, dysphagia, spasticity, and motor dysfunction. Overall, TBS promotes the progress of stroke rehabilitation and may serve as a preferable alternative to traditional rTMS. However, it's hard to recommend a specific paradigm of TBS due to the limited number of current studies and their heterogeneity. Further high-quality clinical RCTs are needed to determine the optimal technical settings and intervention time in stroke survivors.

Theta-burst stimulation as a therapeutic tool in neurological pathology: a systematic review.

TBS (theta-burst stimulation) is a novel therapeutic approach in a wide range of neurological diseases. The present systematic review aims to identify the various protocols used in the last years, to assess study quality and to offer a general overview of the current state of the literature. The systematic review was conducted according to the Preferred Reporting Item for Systematic Review and Meta-Analyses (PRISMA) guidelines. We applied the following inclusion criteria: (1) population over 18 years old with diagnosed neurological disorders, (2) patients treated with sessions of theta-burst stimulation, (3) randomized-controlled clinical trials, (4) articles in the English language, and (5) studies that report response and score reduction on a validated scale of the investigated disorder or remission rates. We included in the final analysis 56 randomized controlled trials focusing on different neurological pathologies (stroke, Parkinson`s disease, multiple sclerosis, tinnitus, dystonia, chronic pain, essential tremor and tic disorder), and we extracted data regarding study design, groups and comparators, sample sizes, type of coil, stimulation parameters (frequency, number of pulses, intensity, stimulation site etc.), number of sessions, follow-up, assessment through functional connectivity and neurological scales used. We observed a great interstudy heterogenicity that leads to a difficulty in drawing plain conclusions. TBS protocols have shown promising results in improving various symptoms in patients with neurological disorders, but larger and more coherent studies, using similar stimulation protocols and evaluation scales, are needed to establish guideline recommendations.

DXA beyond bone mineral density and the REMS technique: new insights for current radiologists practice.

Osteoporosis is the most prevalent skeletal disorder, a condition that is associated with significant social and healthcare burden. In the elderly, osteoporosis is commonly associated with sarcopenia, further increasing the risk of fracture. Several imaging techniques are available for a non-invasive evaluation of osteoporosis and sarcopenia. This review focuses on dual-energy X-ray absorptiometry (DXA), as this technique offers the possibility to evaluate bone mineral density and body composition parameters with good precision and accuracy. DXA is also able to evaluate the amount of aortic calcification for cardiovascular risk estimation. Additionally, new DXA-based parameters have been developed in recent years to further refine fracture risk estimation, such as the Trabecular Bone Score and the Bone Strain Index. Finally, we describe the recent advances of a newly developed ultrasound-based technology known as Radiofrequency Echographic Multi-Spectrometry, which represent the latest non-ionizing approach for osteoporosis evaluation at central sites.

Extensive evaluation of DNA methylation of functional elements in the murine Fkbp5 locus using high-accuracy DNA methylation measurement via targeted bisulfite sequencing.

FKBP5 is an important stress-regulatory gene implicated in stress-related psychiatric diseases. Single nucleotide polymorphisms of the FKBP5 gene were shown to interact with early life stress to alter the glucocorticoid-related stress response and moderate disease risk. Demethylation of cytosine-phosphate-guanine-dinucleotides (CpGs) in regulatory glucocorticoid-responsive elements was suggested to be the mediating epigenetic mechanism for long-term stress effects, but studies on Fkbp5 DNA methylation (DNAm) in rodents are so far limited. We evaluated the applicability of high-accuracy DNA methylation measurement via targeted bisulfite sequencing (HAM-TBS), a next-generation sequencing-based technology, to allow a more in-depth characterisation of the DNA methylation of the murine Fkbp5 locus in three different tissues (blood, frontal cortex and hippocampus). In this study, we not only increased the number of evaluated sites in previously described regulatory regions (in introns 1 and 5), but also extended the evaluation to novel, possibly relevant regulatory regions of the gene (in intron 8, the transcriptional start site, the proximal enhancer and CTCF-binding sites within the 5'UTR). We here describe the assessment of HAM-TBS assays for a panel of 157 CpGs with possible functional relevance in the murine Fkbp5 gene. DNAm profiles were tissue-specific, with lesser differences between the two brain regions than between the brain and blood. Moreover, we identified DNAm changes in the Fkbp5 locus after early life stress exposure in the frontal cortex and blood. Our findings indicate that HAM-TBS is a valuable tool for broader exploration of the DNAm of the murine Fkbp5 locus and its involvement in the stress response.

Update on the clinical use of trabecular bone score (TBS) in the management of osteoporosis: results of an expert group meeting organized by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO), and the International Osteoporosis Foundation (IOF) under the auspices of WHO Collaborating Center for Epidemiology of Musculoskeletal Health and Aging.

PURPOSE: Trabecular bone score (TBS) is a grey-level textural measurement acquired from dual-energy X-ray absorptiometry lumbar spine images and is a validated index of bone microarchitecture. In 2015, a Working Group of the European Society on Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) published a review of the TBS literature, concluding that TBS predicts hip and major osteoporotic fracture, at least partly independent of bone mineral density (BMD) and clinical risk factors. It was also concluded that TBS is potentially amenable to change as a result of pharmacological therapy. Further evidence on the utility of TBS has since accumulated in both primary and secondary osteoporosis, and the introduction of FRAX and BMD T-score adjustment for TBS has accelerated adoption. This position paper therefore presents a review of the updated scientific literature and provides expert consensus statements and corresponding operational guidelines for the use of TBS. METHODS: An Expert Working Group was convened by the ESCEO and a systematic review of the evidence undertaken, with defined search strategies for four key topics with respect to the potential use of TBS: (1) fracture prediction in men and women; (2) initiating and monitoring treatment in postmenopausal osteoporosis; (3) fracture prediction in secondary osteoporosis; and (4) treatment monitoring in secondary osteoporosis. Statements to guide the clinical use of TBS were derived from the review and graded by consensus using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach. RESULTS: A total of 96 articles were reviewed and included data on the use of TBS for fracture prediction in men and women, from over 20 countries. The updated evidence shows that TBS enhances fracture risk prediction in both primary and secondary osteoporosis, and can, when taken with BMD and clinical risk factors, inform treatment initiation and the choice of antiosteoporosis treatment. Evidence also indicates that TBS provides useful adjunctive information in monitoring treatment with long-term denosumab and anabolic agents. All expert consensus statements were voted as strongly recommended. CONCLUSION: The addition of TBS assessment to FRAX and/or BMD enhances fracture risk prediction in primary and secondary osteoporosis, adding useful information for treatment decision-making and monitoring. The expert consensus statements provided in this paper can be used to guide the integration of TBS in clinical practice for the assessment and management of osteoporosis. An example of an operational approach is provided in the appendix. This position paper presents an up-to-date review of the evidence base, synthesised through expert consensus statements, which informs the implementation of Trabecular Bone Score in clinical practice.

Long-term effect of denosumab on bone microarchitecture as assessed by tissue thickness-adjusted trabecular bone score in postmenopausal women with osteoporosis: results from FREEDOM and its open-label extension.

In postmenopausal women with osteoporosis, up to 10 years of denosumab treatment significantly and continuously improved bone microarchitecture assessed by tissue thickness-adjusted trabecular bone score, independently of bone mineral density. Long-term denosumab treatment decreased the number of high fracture-risk patients and shifted more patients to lower fracture-risk categories. PURPOSE: To investigate the long-term effect of denosumab on bone microarchitecture assessed by tissue thickness-adjusted trabecular bone score (TBSTT) in post-hoc subgroup analysis of FREEDOM and open-label extension (OLE). METHODS: Postmenopausal women with lumbar spine (LS) or total hip BMD T-score <-2.5 and ≥-4.0 who completed the FREEDOM DXA substudy and continued in OLE were included. Patients received either denosumab 60 mg subcutaneously every 6 months for 3 years and same-dose open-label denosumab for 7 years (long-term denosumab; n=150) or placebo for 3 years and open-label denosumab for 7 years (crossover denosumab; n=129). BMD and TBSTT were assessed on LS DXA scans at FREEDOM baseline, month 1, and years 1-6, 8, and 10. RESULTS: In long-term denosumab group, continued increases from baseline to years 4, 5, 6, 8, and 10 in BMD (11.6%, 13.7%, 15.5%, 18.5%, and 22.4%) and TBSTT (3.2%, 2.9%, 4.1%, 3.6%, and 4.7%) were observed (all P < 0.0001). Long-term denosumab treatment decreased the proportion of patients at high fracture-risk (according to TBSTT and BMD T-score) from baseline up to year 10 (93.7 to 40.4%), resulting in increases in the proportions at medium-risk (6.3 to 53.9%) and low-risk (0 to 5.7%) (P < 0.0001). Similar responses were observed in crossover denosumab group. Changes in BMD and TBSTT were poorly correlated during denosumab treatment. CONCLUSION: In postmenopausal women with osteoporosis, up to 10 years of denosumab significantly and continuously improved bone microarchitecture assessed by TBSTT, independently of BMD, and shifted more patients to lower fracture-risk categories.

Multidisciplinary tumor board analysis: validation study of a central tool in tumor centers.

The established standard to ensure state-of-the-art cancer treatment is through multidisciplinary tumor boards (TBs), although resource- and time-intensive. In this validation study, the multiple myeloma (MM)-TB was reexamined, aiming to validate our previous (2012-2014) results, now using the TB data from March 2020 to February 2021. We assessed MM-TB protocols, physicians' documentation, patient, disease, remission status, progression-free survival (PFS), and overall survival (OS) as left-truncated survival times. Moreover, TB-adherence, level of evidence according to grade criteria, time requirements, study inclusion rates, and referral satisfaction were determined. Within a 1-year period, 312 discussed patients were documented in 439 TB protocols. Patient and disease characteristics were typical for comprehensive cancer centers. The percentages of patients discussed at initial diagnosis (ID), with disease recurrence or in need of interdisciplinary advice, were 39%, 28%, and 33%, respectively. Reasons for the MM-TB presentation were therapeutic challenges in 80% or staging/ID-defining questions in 20%. The numbers of presentations were mostly one in 73%, two in 20%, and three or more in 7%. The TB adherence rate was 93%. Reasons for non-adherence were related to patients' decisions or challenging inclusion criteria for clinical trials. Additionally, we demonstrate that with the initiation of TBs, that the number of interdisciplinarily discussed patients increased, that TB-questions involve advice on the best treatment, and that levels of compliance and evidence can be as high as ≥ 90%. Advantages of TBs are that they may also improve patients', referrers', and physicians' satisfaction, inclusion into clinical trials, and advance interdisciplinary projects, thereby encouraging cancer specialists to engage in them.

A naturalistic study comparing the efficacy of unilateral and bilateral sequential theta burst stimulation in treating major depression - the U-B-D study protocol.

BACKGROUND: Major depressive disorder (MDD) is a prevalent mental health condition affecting millions worldwide, leading to disability and reduced quality of life. MDD poses a global health priority due to its early onset and association with other disabling conditions. Available treatments for MDD exhibit varying effectiveness, and a substantial portion of individuals remain resistant to treatment. Repetitive transcranial magnetic stimulation (rTMS), applied to the left and/or right dorsolateral prefrontal cortex (DLPFC), is an alternative treatment strategy for those experiencing treatment-resistant MDD. The objective of this study is to investigate whether this newer form of rTMS, namely theta burst stimulation (TBS), when performed unilaterally or bilaterally, is efficacious in treatment-resistant MDD. METHODS: In this naturalistic, randomized double-blinded non-inferiority trial, participants with a major depressive episode will be randomized to receive either unilateral (i.e., continuous TBS [cTBS] to the right and sham TBS to the left DLPFC) or bilateral sequential TBS (i.e., cTBS to the right and intermittent TBS [iTBS] to the left DLPFC) delivered 5 days a week for 4-6 weeks. Responders will move onto a 6-month flexible maintenance phase where TBS treatment will be delivered at a decreasing frequency depending on degree of symptom mitigation. Several clinical assessments and neuroimaging and neurophysiological biomarkers will be collected to investigate treatment response and potential associated biomarkers. A non-inferiority analysis will investigate whether bilateral sequential TBS is non-inferior to unilateral TBS and regression analyses will investigate biomarkers of treatment response. We expect to recruit a maximal of 256 participants. This trial is approved by the Research Ethics Board of The Royal's Institute of Mental Health Research (REB# 2,019,071) and will follow the Declaration of Helsinki. Findings will be published in peer-reviewed journals. DISCUSSION: Comprehensive assessment of symptoms and neurophysiological biomarkers will contribute to understanding the differential efficacy of the tested treatment protocols, identifying biomarkers for treatment response, and shedding light into underlying mechanisms of TBS. Our findings will inform future clinical trials and aid in personalizing treatment selection and scheduling for individuals with MDD. TRIAL REGISTRATION: The trial is registered on https://clinicaltrials.gov/ct2/home (#NCT04142996).

High prevalence of vertebral deformity in tumor-induced osteomalacia associated with impaired bone microstructure.

PURPOSE: Patients with tumor-induced osteomalacia (TIO) often suffer from irreversible height loss due to vertebral deformity. However, the prevalence of vertebral deformity in TIO patients varies among limited studies. In addition, the distribution and type of vertebral deformity, as well as its risk factors, remain unknown. This study aimed to identify the prevalence, distribution, type and risk factors for vertebral deformity in a large cohort of TIO patients. METHODS: A total of 164 TIO patients were enrolled in this retrospective study. Deformity in vertebrae T4-L4 by lateral thoracolumbar spine radiographs was evaluated according to the semiquantitative method of Genant. Bone microstructure was evaluated by trabecular bone score (TBS) and high-resolution peripheral QCT (HR-pQCT). RESULTS: Ninety-nine (99/164, 60.4%) patients had 517 deformed vertebrae with a bimodal pattern of distribution (T7-9 and T11-L1), and biconcave deformity was the most common type (267/517, 51.6%). Compared with patients without vertebral deformity, those with vertebral deformity had a higher male/female ratio, longer disease duration, more height loss, lower serum phosphate, higher bone turnover markers, lower TBS, lower areal bone mineral density (aBMD), lower peripheral volumetric BMD (vBMD) and worse microstructure. Lower trabecular vBMD and worse trabecular microstructure in the peripheral bone and lower spine TBS were associated with an increased risk of vertebral deformity independently of aBMD. After adjusting for the number of deformed vertebrae, we found little difference in clinical indexes among the patients with different types of vertebral deformity. However, we found significant correlations of clinical indexes with the number of deformed vertebrae and the spinal deformity index. CONCLUSION: We reported a high prevalence of vertebral deformity in the largest cohort of TIO patients and described the vertebral deformity in detail for the first time. Risk factors for vertebral deformity included male sex, long disease duration, height loss, abnormal biochemical indexes and bone impairment. Clinical manifestation, biochemical indexes and bone impairment were correlated with the number of deformed vertebrae and degree of deformity, but not the type of deformity.

Bone quality in endocrine diseases: determinants and clinical relevance.

PURPOSE: Bone is one of the main targets of hormones and endocrine diseases are frequent causes of secondary osteoporosis and fractures in real-world clinical practice. However, diagnosis of skeletal fragility and prediction of fractures in this setting could be a challenge, since the skeletal alterations induced by endocrine disorders are not generally captured by dual-energy X-ray absorptiometry (DXA) measurement of bone mineral density (BMD), that is the gold standard for diagnosis of osteoporosis in the general population. The aim of this paper is to review the existing evidence related to bone quality features in endocrine diseases, proposing assessment with new techniques in the future. METHODS: A comprehensive search within electronic databases was performed to collect reports of bone quality in primary hyperparathyroidism, hypoparathyroidism, hyperthyroidism, hypercortisolism, growth hormone deficiency, acromegaly, male hypogonadism and diabetes mellitus. RESULTS: Using invasive and non-invasive techniques, such as high-resolution peripheral quantitative computed tomography or DXA measurement of trabecular bone score (TBS), several studies consistently reported altered bone quality as predominant determinant of fragility fractures in subjects affected by chronic endocrine disorders. CONCLUSIONS: Assessment of skeletal fragility in endocrine diseases might take advantage from the use of techniques to detect perturbation in bone architecture with the aim of best identifying patients at high risk of fractures.

Associations of Lean Mass, Muscular Strength, and Physical Function with Trabecular Bone Score in Older Adults.

INTRODUCTION/BACKGROUND: Trabecular bone score (TBS) is an indirect measurement of bone quality and microarchitecture determined from dual-energy X-ray absorptiometry (DXA) imaging of the lumbar spine. TBS predicts fracture risk independent of bone mass/density, suggesting this assessment of bone quality adds value to the understanding of patients' bone health. While lean mass and muscular strength have been associated with higher bone density and lower fracture risk among older adults, the literature is limited regarding the relationship of lean mass and strength with TBS. The purpose of this study was to determine associations of DXA-determined total body and trunk lean mass, maximal muscular strength, and gait speed as a measure of physical function, with TBS in 141 older adults (65-84 yr, 72.5 +/- 5.1 yr, 74% women). METHODOLOGY: Assessments included lumbar spine (L1-L4) bone density and total body and trunk lean mass by DXA, lower body (leg press) and upper body (seated row) strength by one repetition maximum tests, hand grip strength, and usual gait speed. TBS was derived from the lumbar spine DXA scan. Multivariable linear regression determined the contribution of proposed predictors to TBS. RESULTS: After adjusting for age, sex, and lumbar spine bone density, upper body strength significantly predicted TBS (unadjusted/adjusted R2= 0.16/ 0.11, ß coefficient =0.378, p=0.005), while total body lean mass index showed a trend in the expected direction (ß coefficient =0.243, p=0.053). Gait speed and grip strength were not associated with TBS (p>0.05). CONCLUSION: Maximum strength of primarily back muscles measured as the seated row appears important to bone quality as measured by TBS, independent of bone density. Additional research on exercise training targeting back strength is needed to determine its clinical utility in preventing vertebral fractures among older adults.

Refining Evaluation of Bone Mass and Adipose Distribution in Dunnigan Syndrome.

Familial partial lipodystrophies (FPLD) are rare diseases characterized by selective loss of subcutaneous adipose tissue at different sites. This cross-sectional observational study aimed to estimate adipose tissue in the bone marrow (BMAT), intra (IMCL) and extra-myocyte lipids (EMCL), and define the bone phenotype in the context of FPLD2/Dunnigan syndrome (DS). The subjects comprised 23 controls (C) and 18 DS patients, matched by age, weight and height. Blood samples, dual-energy X-ray absorptiometry for bone mineral density (BMD) and trabecular bone score (TBS) and 1H-spectroscopy using magnetic resonance to estimate BMAT in the lumbar spine, IMCL, EMCL and osteoclastogenesis were assessed. The prevalence of diabetes mellitus was 78% in DS patients. Glucose, HbA1c, triglycerides, insulin and HOMA-IR levels were elevated in DS, whereas HDLc, 25(OH)D, PTH and osteocalcin levels were reduced. BMD was similar between groups at all sites, except 1/3 radius, which was lower in DS group. TBS was reduced in DS. DS presented increased osteoclastogenesis and elevated BMAT, with greater saturation levels and higher IMCL than the C group. HOMA-IR and EMCL were negatively associated with TBS; osteocalcin and EMCL were correlated negatively with BMD. This study contributes to refining the estimation of adipose tissue in DS by showing increased adiposity in the lumbar spine and muscle tissue. DXA detected lower TBS and BMD in the 1/3 radius, suggesting impairment in bone quality and that bone mass is mainly affected in the cortical bone.

Dual sourcing inventory management with nonconsecutive lead times from a supply chain perspective: a numerical study.

We study a stochastic multi-period two-echelon dual sourcing inventory system where the buyer can source a product from two different suppliers: a regular and an expedited supplier. The regular supplier is a low-cost offshore supplier, whereas the expedited supplier is a responsive nearshore supplier. Such dual sourcing inventory systems have been well studied in the literature, mostly being solely evaluated from the buyer's perspective. Since the buyer's decisions have an impact on the supply chain profit, we adopt the perspective of the entire supply chain, i.e., by taking the suppliers explicitly into consideration. In addition, we study this system for general (nonconsecutive) lead times for which the optimal policy is unknown or very complex. We numerically compare the performance of two different policies in a two-echelon setting: the Dual-Index Policy (DIP) and the Tailored Base-Surge Policy (TBS). From earlier studies we know that when the lead time difference is one period, DIP is optimal from the buyer's perspective, but not necessarily from the supply chain perspective. On the other hand, when the lead time difference grows to infinity, TBS becomes optimal for the buyer. In this paper, we evaluate the policies numerically (under various conditions) and we show that from a supply chain perspective, TBS typically outperforms DIP at a limited lead time difference of a few time periods. Based on data collected from 51 manufacturing firms, the results of our paper imply for many supply chains with a dual sourcing setting that TBS quickly becomes a beneficial policy alternative, especially given its simple and appealing structure.

Reliability of theta burst stimulation as a neuromodulation tool.

Theta burst stimulation (TBS), a specific version of transcranial magnetic stimulation (TMS), is known to induce long-term plasticity of the brain with a short-term administration. Although many studies and treatments have increasingly used TBS as a neuromodulation tool, its reliability is still in question. This article reviews a study by Boucher et al. (Boucher PO, Ozdemir RA, Momi D, Burke MJ, Jannati A, Fried PJ, Pascual-Leone A, Shafi MM, Santarnecchi E. Sci Rep 11: 21170, 2021) that found minimal reliability of TBS by examining different TBS protocols (intermittent/continuous/sham) and considers possible alternative explanations for the variability of TBS effects.

Effect of degeneration on bone mineral density, trabecular bone score and CT Hounsfield unit measurements in a spine surgery patient population.

This study investigated the impact of spinal degeneration on bone mineral density (BMD), trabecular bone score (TBS), and CT Hounsfield units in an at-risk population. We found that BMD was increased by degeneration, whereas TBS and HU were unaffected. These findings support that TBS is not adversely affected by spinal degeneration. INTRODUCTION: This study evaluated the impact of spinal degeneration on BMD and TBS measured by dual-energy x-ray absorptiometry (DXA) and on CT HU in a spine surgery patient population. METHODS: A retrospective study of 63 patients referred for consideration of spine surgery or with history of spine surgery was performed. Patients were included if a DXA scan and a CT containing the lumbar spine were obtained within 18 months of each other. DXA data were collected and analyzed by vertebral level. Individual vertebrae were assessed for degenerative changes by qualitative evaluation of the anterior and posterior elements using CT. Degeneration scores were compared to BMD T-scores, TBS and CT HU at individual vertebral levels L1-4, and after applying International Society for Clinical Densitometry (ISCD) criteria for excluding vertebrae from diagnostic consideration. RESULTS: Mean patient age and BMI were 67.2 years and 27.8 kg/m2, respectively; 79.4% were female. Mean (SD) lowest T-scores of the hip, spine, and lowest overall T-score were - 1.3 (1.4), - 1.7 (0.9), and - 1.9 (1.0), respectively. Osteoporosis was present by T-score in 38% and osteopenia in 52%; 10% had a history of osteoporotic fracture. The mean degeneration score of individual vertebrae was 4.1 on a 0-6 scale. T-score correlated moderately with degeneration score (Spearman's rho 0.484, p < 0.001), whereas TBS and HU were unrelated. ISCD excluded vertebrae had a higher degeneration score than included vertebrae (p = < 0.001). CONCLUSIONS: In a spine surgery population, TBS and CT HU values are unrelated to degeneration score and thus appear unaffected by lumbar vertebral degenerative changes. Additionally, these data support the ISCD criteria for vertebral exclusion.