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Background: Most patients with chronic lymphocytic leukaemia progress after treatment or retreatment with targeted therapy or chemoimmunotherapy and have limited subsequent treatment options. Response levels to the single-agent venetoclax in the relapsed setting is unknown. We aimed to assess venetoclax activity in patients with or without previous B-cell receptor-associated kinase inhibitor (BCRi) treatment., Methods: This multicentre, open-label, single-arm, phase 3b trial (VENICE-1) assessed activity and safety of venetoclax monotherapy in adults with relapsed or refractory chronic lymphocytic leukaemia, stratified by previous exposure to a BCRi. Eligible participants were aged 18 years or older with previously treated relapsed or refractory chronic lymphocytic leukaemia. Presence of del(17p) or TP53 aberrations and previous BCRi treatment were permitted. Patients received 5-week ramp-up to 400 mg of oral venetoclax once daily and were treated for up to 108 weeks, with 2 years follow-up after discontinuation, or optional extended access. The primary activity endpoint was complete remission rate (complete remission or complete remission with incomplete marrow recovery) in BCRi-naive patients. Analyses used the intent-to-treat (ie, all enrolled patients, which coincided with those who received at least one dose of venetoclax). This study was registered with ClinicalTrials.gov, NCT02756611, and is complete., Findings: Between June 22, 2016, and March 11, 2022, we enrolled 258 patients with relapsed or refractory chronic lymphocytic leukaemia (180 [70%] were male; 252 [98%] were White; 191 were BCRi-naive and 67 were BCRi-pretreated). Median follow-up in the overall cohort was 49·5 months (IQR 47·2-54·1), 49·2 months (47·2-53·2) in the BCRi-naive group, and 49·7 months (47·4-54·3) in the BCRi-pretreated group. Of 191 BCRi-naive patients, 66 (35%; 95% CI 27·8-41·8) had complete remission or complete remission with incomplete marrow recovery. 18 (27%; 95% CI 16·8-39·1) of 67 patients in the BCRi-pretreated group had complete remission or complete remission with incomplete marrow recovery. Grade 3 or worse treatment-emergent adverse events were reported in 203 (79%) and serious adverse events were reported in 136 (53%) of 258 patients in the overall cohort. The most common treatment-emergent adverse event was neutropenia (96 [37%]) and the most common and serious adverse event was pneumonia (21 [8%]). There were 13 (5%) deaths reported due to adverse events; one of these deaths (autoimmune haemolytic anaemia) was possibly related to venetoclax. No new safety signals were identified., Interpretation: These data demonstrate deep and durable responses with venetoclax monotherapy in patients with relapsed or refractory chronic lymphocytic leukaemia, including BCRi-pretreated patients, suggesting that venetoclax monotherapy is an effective strategy for treating BCRi-naive and BCRi-pretreated patients., Funding: AbbVie., Competing Interests: Declaration of interests APK is an advisory board member of and received research funding from Astra Zeneca, Janssen, Roche (Genentech), AbbVie, Bristol Myers Squibb, and LAVA. ÖA is an AbbVie speaker and advisory board member. YH declares honoraria from AbbVie, Janssen, AstraZeneca, Roche, and Medison; is an advisory board member for AbbVie, Jansen, AstraZeneca, Medison, and Eli Lilly; and declares a research grant from Janssen. BF is an advisory board member for Takeda Pharmaceuticals, Janssen, and Pfizer and declares speaker fees from AbbVie. MGD declares speaker fees from AbbVie. BL declares speakers bureau or honoraria from AbbVie, Alexion, AMGEN, Astellas, Astex, Bristol Myers Squibb (Celgene), Jazz, Janssen Novartis, Otsuka, Paladin, Pfizer, Roche, and Treadwell, and consulting fees from AbbVie, Novartis, and Pfizer. MM declares speaker bureau from AbbVie and honoraria from Janssen. PP declares a research support grant from AbbVie and honoraria or speaker's bureau from AbbVie, AstraZeneca, and Roche. AS declares consultancy or speaker fees from Alexion, AbbVie, AstraZeneca, ADC Therapeutics, Beigene, Bristol Myers Squibb, Celgene, Epizyme, Genentech, Janssen, Jazz Therapeutics, Kite Pharma, Eli Lilly, MorphoSys, Novartis, Pharmacyclics, SeaGen, GenMab, and TG Therapeutics; payments for presentations or lectures from AstraZeneca, ADC Therapeutics, AbbVie, Beigene, Genentech, GenMab, Jazz Therapeutics, Janssen, Kite Pharma, Eli Lilly, Pharmacyclics, SeaGen, and TG Therapeutics; and participation on the data safety monitoring board for Alexion. CM declares funding from AbbVie for microarray analysis. A-MvdK-K declares funding from AbbVie for funded microarray analysis. RP, BJC, XW, TB, KS, GEP, and TV are AbbVie employees and may hold stock or options. VK was an AbbVie employee at time of study and may hold stock or options. Francesco Forconi is an advisory board member for BeiGene; declares honoraria from AbbVie, Janssen-Cilag, Beigene, and AstraZeneca; speakers bureau from AbbVie, Janssen-Cilag, and AstraZeneca; and travel and accommodation from AbbVie, Janssen-Cilag, and Beigene. FD, DR, AT, MT, SL, BS, and LDR declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Purpose: The purpose of this study is to assess the prevalence of osteoporosis and fragility fractures in patients with liver cirrhosis (LC) and determine the associated risk factors, evaluating the usefulness of FRAX ® as a screening method to identify patients at a higher risk of fracture., Methods: This was a cross-sectional study. Demographic, clinical, and analytical data were collected in a randomized sample of LC patients attending the Hepatology Department of a university hospital. We assessed the absolute risk of fracture at 10 years (FRAX ® ) and based on the bone mineral density (BMD), the presence of morphometric vertebral fracture with a vertebral fracture assessment (VFA), or a thoracic and lumbar X-ray and bone microarchitecture with a trabecular bone score (TBS)., Results: Ninety-two patients were included (71% male); the mean age was 63 ± 11.3 years. The main etiology of LC was alcoholism (52.2%), and most patients were Child-Pugh A (80.4%), with a mean model for end-stage liver disease (MELD) score of 10.1 ± 3.6. Sixteen patients (17.4%) had osteoporosis, and fifty-four (58.7%) had osteopenia. Eight patients (8.7%) had suffered at least one fragility fracture. The absolute risk of a major fracture according to FRAX without the BMD was 5.7 ± 4.5%. Risk factors associated with osteoporosis were age and the female sex. BMI > 30 was a protective factor. A FRAX cut-off point for a major fracture > 6.6% had a sensitivity of 69% and a specificity of 85% for a diagnosis of osteoporosis., Conclusions: The prevalence of osteoporosis and fractures in patients with LC is high, particularly in older women. FRAX ® may be a useful method to identify candidates for bone densitometry. A FRAX value below 6.6% without the BMD can avoid unnecessary testing.

The aim of this paper was to optimise the manufacturing parameters of a new maraging steel alloy with 8% Cr, reduced Ni content (7%), and no Co or Mo. This alloy was developed by ArcelorMittal and its trade name is LeanSi. The alloy was produced using the selective laser melting (SLM) process. In the as-built state, the microstructure of the alloy was fully martensitic. The optimisation of the manufacturing parameters was determined via a multivariate factorial design of experiments including 12 experiments and three factors. The factors (i.e., the fabrication parameters) analysed were laser power, scanning speed, and hatch distance. The objective was to eliminate porosity and maximise density. It was concluded that, to achieve this, the laser power should be set at 250 W, the scanning speed at 1000 mm/s, and the hatch distance at 80 microns. The porosity obtained under these manufacturing parameters was 0.06 ± 0.03% with a confidence level of 95%. If these manufacturing parameters were modified, the material exhibited a defective interlayer bond with the formation of "balling" and high porosity. The tensile specimens tested in the as-built state showed plastic deformation. However, all the aged specimens showed brittle fracture behaviour, evidenced by the presence of very small micro-cavities (where the fracture energy consumed was very small) and small cleavage planes. The specimens produced with the manufacturing parameters at their optimum levels and aged at 480 °C for 2 h achieved tensile strength values that averaged 1430 MPa. The porosity of these specimens was reduced by more than 85%. Reverse austenite was detected at ageing temperatures of 540 °C upwards.

Statement of Problem: Standard-diameter dental implants are not always applicable because of anatomic limitations of the residual ridge. Thus, mini-implants have been increasingly used and offer an alternative. However, data regarding prosthetic complications, maintenance factors, and clinical outcomes are limited., Purpose: The purpose of this systematic review and meta-analysis was to compare prosthetic complications and maintenance events and clinical outcomes in residual ridges rehabilitated with mandibular implant overdentures (IODs) by using standard implants or mini-implants., Material and Methods: Nine electronic databases were searched. Quantitative analyses to measure the risk ratio (RR) and standardized mean difference (SMD) were applied. Those methods were used to assess prosthetic complications and maintenance events (abutment adjustments, replacement of retentive element, occlusal adjustment, and overdenture fracture) and clinical outcomes related to postoperative pain, probing depth (PD), plaque index (PI), marginal bone loss (MBL), and implant survival rate., Results: Altogether, 7 publications were selected. Mini-implants presented reduced abutment adjustments (RR 0.23 [0.07, 0.73], P=.01), replacement of retentive element (RR 0.41 [0.31, 0.54], P<.001), occlusal adjustment (RR 0.53 [0.31, 0.91], P=.02), and overdenture fracture (RR 0.46 [0.23, 0.94], P=.03) compared with standard implants. Additionally, mini-implants presented lower values for PI at 6 months (SMD -0.27 [-0.47, -0.08], P=.006) and 12 months (SMD -0.25 [-0.46, -0.05], P=.01). No additional tangible differences were noted., Conclusions: Mini-implants might be an alternative choice based on the number of prosthetic complications and maintenance events. This was also confirmed by the comparable clinical data between standard implants and mini-implants., (Copyright © 2021 Editorial Council for The Journal of Prosthetic Dentistry. Published by Elsevier Inc. All rights reserved.)

The first-in-class inhibitor of exportin-1 (XPO1) selinexor is currently under clinical investigation in combination with the BTK inhibitor ibrutinib for patients with chronic lymphocytic leukaemia (CLL) or non-Hodgkin lymphoma. Selinexor induces apoptosis of tumour cells through nuclear retention of tumour suppressor proteins and has also recently been described to modulate natural killer (NK) cell and T cell cytotoxicity against lymphoma cells. Here, we demonstrate that XPO1 inhibition enhances NK cell effector function against primary CLL cells via downregulation of HLA-E and upregulation of TRAIL death receptors DR4 and DR5. Furthermore, selinexor potentiates NK cell activation against CLL cells in combination with several approved treatments; acalabrutinib, rituximab and obinutuzumab. We further demonstrate that lymph node associated signals (IL-4 + CD40L) inhibit NK cell activation against CLL cells via upregulation of HLA-E, and that inhibition of XPO1 can overcome this protective effect. These findings allow for the design of more efficacious combination strategies to harness NK cell effector functions against CLL., (© 2023. The Author(s).)

The effects of global change in marine ecosystems are expected to lower pH from the current 8.1-7.5-7.0, which will have significant impacts on marine species. The purpose of this study is to investigate whether the ecotoxicity of ten different natural clays change significantly in response to the acidification process and what factors are associated with the observed changes. In this study, the ecotoxicological response of a bacterium (Aliivibrio fischeri) was tested under current (pH= 8.1) and acidified (pH 7.5 and 7.0) conditions. The ecotoxicity detected in the solid phase test (SPT protocol) and in the contact water was affected by the pH, which increased the ecotoxicity from 2/10 clays (pH 8.10) to 7/10 clays (pH 7.00), also shifting the detected effects from low to high toxicity values. The analyses performed on the natural clays studied show that pH can affect the release of metals, metalloids and rare earths from the clays into the contact water phase, affecting the toxicity observed. This phenomenon depends on the type of clay and is closely related to its mineralogical composition. As consequence, in a globally changing scenario, ecotoxicity, even of natural materials such as clay, cannot be considered stable, but must be accurately revaluated depending on the mineralogical and chemical composition of the clay. Moreover, the mineralogical composition of clays showed different efficiency in absorbing bacteria on the surface of clay particles. It was found that live bacterial cells were absorbed on the clay surface in numbers that were dependent on both clay types and pH levels., 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 © 2023 Elsevier B.V. All rights reserved.)

Cortical and trabecular volumetric bone mineral density (vBMD), cortical thickness and surface BMD (sBMD, density-to-thickness ratio) were analyzed in the proximal femur of elite female football players and artistic swimmers using three-dimensional dual-energy X-ray absorptiometry (3D-DXA) software and compared to sedentary controls. Football players had significantly higher (p<0.05) vBMD (mg/cm 3 ) in the trabecular (263±44) and cortical femur (886±69) than artistic swimmers (224±43 and 844±89) and sedentary controls (215±51 and 841±85). Football players had also higher (p<0.05) cortical thickness (2.12±0.19 mm) and sBMD (188±22 mg/cm 2 ) compared to artistic swimmers (1.85±0.15 and 156±21) and sedentary controls (1.87±0.16 and 158±23). Artistic swimmers did not show significant differences in any parameter analyzed for 3D-DXA when compared to sedentary controls. The 3D-DXA modeling revealed statistical differences in cortical thickness and vBMD between female athletes engaged in weight-bearing (football) and non-weight bearing (swimming) sports and did not show differences between the non-weight bearing sport and the sedentary controls. 3D-DXA modeling could provide insight into bone remodeling in the sports field, allowing evaluation of femoral trabecular and cortical strength from standard DXA scans., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

The role of lizards as potential pollinators on islands has been documented for either one or a few plants in different parts of the world, but it has never been assessed for an entire plant community. Here, we quantified interaction rate by lizards and evaluated intraspecific differences in the use of flowers on Cabrera Gran (Cabrera archipelago, Balearic Islands) by means of visual observations, automated cameras and the analysis of pollen grain samples. Overall, we recorded interactions of the Balearic wall lizard ( Podarcis lilfordi ) with flowers of 44 plant species, 72.7% of which were unknown to date. Although florivory occurs in some of these species (35%), the majority of visits were legitimate (65%); in addition, we found intraspecific differences in the interactions related to the sex and age of lizards. Our findings support the role of Balearic wall lizards as potential pollinators across the entire plant community, and their contribution to particular plant species, for instance the endangered Cistus heterophyllus carthaginensis . This study also documents the first record of another sympatric lizard ( Tarentola mauritanica ) visiting flowers and contributes to the few existing records of flower interactions involving geckos in the Paleartic ecozone.

Ante-mortem diagnosis of caprine tuberculosis, as in other ruminant species, is a complex process. Therefore, it is sometimes necessary to apply a combination of methods that increases the sensitivity of diagnosis while maintaining adequate specificity. In the present study, we analysed the use of ELISA based on a double-recognition methodology for the diagnosis of goat tuberculosis. Serum samples from animals with tuberculosis, confirmed by histopathological studies and presence of Ziehl-Neelsen-positive bacteria in the lesions, were used to assess sensitivity. Sera from flocks without tuberculosis were used to assess diagnostic specificity. The relationship between ELISA results and the type of tuberculous lesions, both macroscopic and microscopic, was analysed. The sensitivity and specificity of ELISA test were 69.9% and 97.9%, respectively. Sensitivity was higher in animals with macroscopic lesions, indicating more advanced forms of the disease. Similarly, a higher sensitivity was found in animals with microscopic lesions associated with active tuberculosis, such as cavitary lesions., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Chronic lymphocytic leukemia (CLL) cells have variably low surface IgM (sIgM) levels/signaling capacity, influenced by chronic antigen engagement at tissue sites. Within these low levels, CLL with relatively high sIgM (CLLhigh) progresses more rapidly than CLL with low sIgM (CLLlow). During ibrutinib therapy, surviving CLL cells redistribute into the peripheral blood and can recover sIgM expression. Return of CLL cells to tissue may eventually recur, where cells with high sIgM could promote tumor growth. We analyzed time to new treatment (TTNT) following ibrutinib in 70 patients with CLL (median follow-up of 66 months) and correlated it with pretreatment sIgM levels and signaling characteristics. Pretreatment sIgM levels correlated with signaling capacity, as measured by intracellular Ca2+ mobilization (iCa2+), in vitro (r = 0.70; P < .0001). High sIgM levels/signaling strongly correlated with short TTNT (P < .05), and 36% of patients with CLLhigh vs 8% of patients with CLLlow progressed to require a new treatment. In vitro, capacity of ibrutinib to inhibit sIgM-mediated signaling inversely correlated with pretherapy sIgM levels (r = -0.68; P = .01) or iCa2+ (r = -0.71; P = .009). In patients, sIgM-mediated iCa2+ and ERK phosphorylation levels were reduced by ibrutinib therapy but not abolished. The residual signaling capacity downstream of BTK was associated with high expression of sIgM, whereas it was minimal when sIgM expression was low (P < .05). These results suggested that high sIgM levels facilitated CLL cell resistance to ibrutinib in patients. The CLL cells, surviving in the periphery with high sIgM expression, include a dangerous fraction that is able to migrate to tissue and receive proliferative stimuli, which may require targeting by combined approaches., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Purpose: To compare frameworks manufactured by selective laser melting (SLM) and electron beam melting (EBM) with frameworks manufactured by milling, regarding dimensional precision after veneer layering and spark erosion for the all-on-six implant concept., Materials and Methods: Frameworks (n = 5/group) were manufactured by milling, SLM, and EBM. Dimensional precision of the frameworks was evaluated by marginal fit, screw loosening torque, and strain. Marginal fit was assessed by the single screw protocol. The screw-loosening torque was measured for the evaluation of screw stability. Tension distribution was analyzed with strain gauges. All frameworks received veneer layering followed by the marginal fit, screw-loosening torque, and strain gauge tests. Subsequently, the frameworks were subjected to the spark erosion process. The analyses were repeated after each stage (baseline, veneer layering, and spark erosion). Data was explored by two-way repeated-measures analysis of variance (ANOVA) with the Bonferroni test (α = .05)., Results: At baseline, the highest (worst) marginal fit values were displayed by SLM frameworks (mean ± standard deviation [SD]: 186.13 ± 21.27 μm), while the milling group (83.30 ± 12.03 μm) showed the lowest (best) values (P < .05). After veneer layering, EBM presented the worst marginal fit values (222.55 ± 52.56 μm; P < .05) among the groups. Over time (from the baseline to veneer layering), the marginal fit values increased (became worse) for milling (P = .002) and EBM (P < .001), while for SLM (P = .002) the values decreased (improved). Compared with veneer layering data, spark erosion improved the marginal fit values only for EBM (P = .005). Irrespective of time, the screw-loosening torque for the milling group showed higher values. The lowest strain was found for the SLM at baseline (P < .05), but it increased after veneer layering (P = .015) and after spark erosion (P = .028)., Conclusion: Additive technologies are promising for dental applications. In addition, all technologies demonstrated accuracy in the manufacturing of implant-supported frameworks, especially the EBM technology, which demonstrated biomechanical behavior similar to the milling technology after the intervals (baseline, veneer layering, and spark erosion) assessed in the study.

Mice are valuable models extensively used to test vaccine candidates against Chlamydia abortus and to clarify immunopathological mechanisms of the bacteria. As this pathogen has the ability to reactivate during pregnancy, it is important to deepen the knowledge and understanding of some of the effects of female hormones on immunity and vaccination. This study is aimed at describing the role of sex hormones in the pathology of OEA during chlamydial clearance using ovariectomised mice and also gaining an understanding of how 17β-oestradiol or progesterone may impact the effectiveness of vaccination. Animals were treated with sex hormones and infected with C. abortus , and the kinetics of infection and immune response were analysed by means of bacterial isolation, histopathology, and immunohistochemistry. In a second phase of the study, protection conferred by an experimental vaccine after hormone treatment was assessed. Oestradiol showed a stimulatory effect on the immune response during infection, with a more efficient recruitment of macrophages and T-cells at the infection site. Furthermore, after vaccination, oestradiol-treated animals showed a stronger protection against infection, indicating that this hormone has a positive effect, stimulating a specific memory response to the pathogen.

Background: To this day, merely 8% of all estimated fungi species are documented and, in certain regions, its biodiversity is practically unknown. Inside the Fungi Kingdom, macrofungi and lichens assume a critical part in the ecosystem functionality and have a historical connection to mankind's social, clinical and nutritious uses. Despite their importance, the diversity of these groups has been widely overlooked in the sub-Antarctic Region of Chile, a crucial area in the study of climate change due to its extraordinary biodiversity and its proximity to Antarctica. Few studies regarding both groups have been conducted in this sub-Antarctic Region and the data are still scarce and inaccessible, as these are only published in specialised journals, unreachable to local communities., New Information: This publication presents a records compilation available in previous published scientific and technical reports on macrofungi and lichen diversity. In total, 1263 occurrence records of 618 species (341 records of 251 macrofungi species and 922 records of 367 lichen species) were digitised and integrated into the regional platform Biodiversity Information System for Aysén (SIB-Aysén) and into GBIF. Here, we provide the fullest dataset on one of the most diverse group of living beings in one of the the least-known world regions., (Laura Sánchez-Jardón, Laura del Rio-Hortega, Noemi Núñez Cea, Mario Mingarro, Paloma Manubens, Sebastián Zambrano, Belén Acosta Gallo.)

Statement of Problem: Milling is a well-established method for manufacturing prosthetic frameworks. However, information about the influence of ceramic veneer and spark erosion on the accuracy of the all-on-six complete-arch fixed frameworks manufactured from different materials is lacking., Purpose: The purpose of this in vitro study was to compare the accuracy of milled complete-arch fixed frameworks with zirconia, cobalt-chromium, and titanium at different steps of their manufacturing process and the influence of mechanical cycling., Material and Methods: Fifteen milled complete-arch fixed frameworks, supported by 6 implants, were made in zirconia, cobalt-chromium, and titanium (n=5). The fit was measured by the single-screw test protocol. Stress was measured by photoelastic analysis. The loosening torque was evaluated by tightening the screws, retightening them after 10 minutes, and then evaluating the loosening torque 24 hours later. Thereafter, all frameworks received ceramic veneer, and the previous tests were repeated. Cobalt-chromium and titanium frameworks received spark erosion after ceramic veneer, and all analyses were repeated. Before and after mechanical cycling, loosening torque was evaluated. The results were subjected to 2-way repeated-measures ANOVA and the Bonferroni test (α=.05)., Results: Titanium presented higher fit values than zirconia (P=.037) and similar to cobalt-chromium frameworks (P>.05) at baseline. After ceramic veneer, higher fit levels were observed for zirconia (P=.001) and cobalt-chromium (P=.008). Titanium showed higher stress values (P<.05) regardless of time. Baseline for all materials presented lower stress values (P<.05). Higher loosening torque values were found for the titanium group at baseline (P<.001) and after ceramic veneer (P<.001). Spark erosion improved fit and loosening torque values only for cobalt-chromium (P<.05). Mechanical cycling did not influence the loosening torque (P>.05)., Conclusions: Titanium milled complete-arch fixed frameworks presented poorer fit values than zirconia, although the loosening torque at baseline was higher. Ceramic veneer increased the fit levels for zirconia and cobalt-chromium, decreased the loosening torque values for cobalt-chromium, and enhanced stress levels. Spark erosion can be a reliable technique to improve fit and loosening torque for cobalt-chromium frameworks. Mechanical cycling did not decrease loosening torque., (Copyright © 2020 Editorial Council for the Journal of Prosthetic Dentistry. Published by Elsevier Inc. All rights reserved.)

Active faulting and deep-seated gravitational slope deformation (DGSD) are common geological hazards in mountain belts worldwide. In the Italian central Apennines, kilometer-thick carbonate sedimentary sequences are cut by major active normal faults that shape the landscape, generating intermontane basins. Geomorphological observations suggest that the DGSDs are commonly located in fault footwalls. We selected five mountain slopes affected by DGSD and exposing the footwall of active seismogenic normal faults exhumed from 2 to 0.5 km depth. Field structural analysis of the slopes shows that DGSDs exploit preexisting surfaces formed both at depth and near the ground surface by tectonic faulting and, locally, by gravitational collapse. Furthermore, the exposure of sharp scarps along mountain slopes in the central Apennines can be enhanced either by surface seismic rupturing or gravitational movements (e.g., DGSD) or by a combination of the two. At the microscale, DGSDs accommodate deformation mechanisms similar to those associated with tectonic faulting. The widespread compaction of micro-grains (e.g., clast indentation), observed in the matrix of both normal faults and DGSD slip zones, is consistent with clast fragmentation, fluid-infiltration, and congruent pressure-solution active at low ambient temperatures (<60°C) and lithostatic pressures (<80 MPa). Although clast comminution is more intense in the slip zones of normal faults because of the larger displacement accommodated, we are not able to find microstructural markers that allow us to uniquely distinguish faults from DGSDs., (© Wiley Periodicals LLC. The Authors.)

Background: Chronic lower limb ischemia develops earlier and more frequently in patients with type 2 diabetes mellitus. Diabetes remains the main cause of lower-extremity non-traumatic amputations. Current medical treatment, based on antiplatelet therapy and statins, has demonstrated deficient improvement of the disease. In recent years, research has shown that it is possible to improve tissue perfusion through therapeutic angiogenesis. Both in animal models and humans, it has been shown that cell therapy can induce therapeutic angiogenesis, making mesenchymal stromal cell-based therapy one of the most promising therapeutic alternatives. The aim of this study is to evaluate the feasibility, safety, and efficacy of cell therapy based on mesenchymal stromal cells derived from adipose tissue intramuscular administration to patients with type 2 diabetes mellitus with critical limb ischemia and without possibility of revascularization., Methods: A multicenter, randomized double-blind, placebo-controlled trial has been designed. Ninety eligible patients will be randomly assigned at a ratio 1:1:1 to one of the following: control group (n = 30), low-cell dose treatment group (n = 30), and high-cell dose treatment group (n = 30). Treatment will be administered in a single-dose way and patients will be followed for 12 months. Primary outcome (safety) will be evaluated by measuring the rate of adverse events within the study period. Secondary outcomes (efficacy) will be measured by assessing clinical, analytical, and imaging-test parameters. Tertiary outcome (quality of life) will be evaluated with SF-12 and VascuQol-6 scales., Discussion: Chronic lower limb ischemia has limited therapeutic options and constitutes a public health problem in both developed and underdeveloped countries. Given that the current treatment is not established in daily clinical practice, it is essential to provide evidence-based data that allow taking a step forward in its clinical development. Also, the multidisciplinary coordination exercise needed to develop this clinical trial protocol will undoubtfully be useful to conduct academic clinical trials in the field of cell therapy in the near future., Trial Registration: ClinicalTrials.gov NCT04466007 . Registered on January 07, 2020. All items from the World Health Organization Trial Registration Data Set are included within the body of the protocol., (© 2021. The Author(s).)

Introduction: Artistic swimming seems not to benefit bone development like other out-of-water physical activities. To increase bone acquisition, artistic swimming should combine water training with weight-bearing impact or strength activities. Artistic swimmers can be a population at risk of developing osteopenia and osteoporosis in later life. The aim of the present study was to evaluate the effects of a training program on bone mineral density (BMD), bone mineral content (BMC) and body composition in an Olympic artistic swimming team., Methods: Sixteen women aged 17-21 years, who train 30 h/week, at the Olympic Training Centre (Barcelona, Spain), were followed up over two seasons. The 1st season involved regular artistic swimming training without specific training to reduce the risk of osteopenia. The exercise intervention, jumping rope and whole-body vibration, was added in the 2nd season. The protocol included 20 min of training 2 days per week, over a 22-week period. Dual energy x-ray absorptiometry measured the bone variables and body composition. The daily diet, medical history and bone turnover markers were evaluated., Results: The intervention program increased BMD on lumbar spine (2.10%, p = 0.002), total hip (2.07%, p = 0.001), and femoral neck (2.39%, p = 0.02). Lower limb's fat mass decreased (10.17%, p = 0.038). No significant differences were found for any of the measured anthropometric characteristics between both time points in the 1st season. In conclusions, combined jump rope and vibration should be considered to reduce the risk of bone damage in artistic swimmers., (© 2021. The Japanese Society Bone and Mineral Research.)

Introduction: To assess the clinical and cost-effectiveness of therapeutic drug monitoring (TDM) based on serum adalimumab levels compared to standard of care in patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis., Methods: This was a non-inferiority, multicentric, non-randomized, pragmatic trial including adult patients diagnosed with moderate-to-severe, clinically stable rheumatic diseases treated with adalimumab. Consecutive patients were assigned 1:2 to the control (CG) or the intervention group (IG), based on the site of inclusion, and followed up for 18 months. Adalimumab serum levels were measured at each study visit and released to the IG only to modify dosing strategy. Data on disease activity, healthcare resource utilization and health-related quality of life (HRQoL) measured through the EQ-5D-5L were collected. Number of persistent and overall flares, time to first flare, days experiencing high disease activity, total direct costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER) were calculated., Results: Of the 169 recruited patients, 150 were included in the analysis (52 and 98 patients in the CG and IG, respectively). The primary endpoint was not met as persistent flares were not significantly lower in the IG, although mean (SD) number of flares was numerically lower in the IG (0.67 [0.70] versus 0.90 [0.82], P = 0.073), respectively. Based on EQ-5D-5L utilities, HRQoL was significantly higher in the IG at 3 (P = 0.001) and 6 months (P = 0.035), which overall translated into 0.075 QALYs gained per patient for the IG at month 18. Overall, direct costs were significantly lower for the IG patients (€15,311.59 [4,870.04] versus €17,378.46 [6,556.51], P = 0.030), resulting in the intervention being dominant, leading to increased QALY at a lower overall cost CONCLUSION: Adalimumab dose tapering based on TDM for rheumatic patients led to an increased quality of life and QALY gain and entailed lower costs, being a more cost-effective alternative than clinically guided management., (© 2021. The Author(s).)

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease that leads to joint deformity and disability, as well as muscle involvement. Sarcopenia is characterized by a progressive age-related loss of muscle mass and strength., Aim: The aim of this study was to evaluate the prevalence of sarcopenia and possible contributing factors associated with sarcopenia in RA patients., Patients and Methods: Adult RA patients (n = 105) of both sexes and 100 subjects as control group (CG) matched by age, sex, and body mass index were included in this cross-sectional study. Whole-body composition was measured by dual-energy x-ray absorptiometry. Sarcopenia was defined according to European Working Group on Sarcopenia in Older People 2 as low muscle strength (handgrip) and low muscle mass (appendicular skeletal muscle mass [ASM] index by dual-energy x-ray absorptiometry). The association between sarcopenia and associated factors was evaluated using logistic regression analyses., Results: Significantly lower percentage of lean mass and ASM were found in the whole RA group compared with controls. However, lower lean parameters (total lean mass, percentage of lean mass, and ASM) were observed only in female subjects. The ASM index was significantly lower in female subjects with RA (RA 31.0% vs CG 11.9%) without differences in male subjects. On the other hand, fat mass and most adipose indices were significantly higher in both female and male subjects with RA. Female RA patients had higher prevalence of sarcopenia and sarcopenic obesity. Through univariate logistic regression analysis, the time of corticosteroids use, cumulative corticosteroid dose, previous fragility fractures, total lean mass, and ASM were associated with sarcopenia., Conclusions: Higher prevalence of sarcopenia and sarcopenic obesity were found in female RA patients. Sarcopenia was found in younger female subjects with RA compared with healthy control subjects. Sarcopenia was associated with previous fragility fractures in female patients with RA., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

BACKGROUND Pleural effusions are frequently seen among patients with hematopoietic stem cell transplantation (HSCT). In the majority of cases, they are related to infections and volume overload. Medications have also been reported to cause pleural effusion in the general population, albeit very rarely. Dasatinib-induced pleural effusion has been reported in patients with chronic myeloid leukemia but not in those with HSCT. We here report a case of dasatinib-induced pleural effusion following HSCT for acute lymphocytic leukemia (ALL). The proposed mechanism of dasatinib-induced pleural effusion involves build-up of fluid due to an immune-mediated vascular insult. CASE REPORT A 72-year-old man who received HSCT for ALL was treated with dasatinib to prevent a recurrence. After 6 months, the patient was admitted to the hospital for pneumonia, which was observed as bilateral pleural effusion upon chest X-ray. After completing the antibiotics course, he developed recurrent pleural effusion during hospitalization. Repeated thoracentesis of the fluid revealed an exudative lymphocytic effusion with negative culture and cytology. Dasatinib was withdrawn and the pleural effusion resolved gradually. CONCLUSIONS In patients with dasatinib-induced pleural effusions following HCTS, withdrawal of the drug leads to symptom resolution, thereby avoiding unnecessary procedures. This case illustrates that dasatinib-induced pleural disease typically manifests with lymphocytic exudative fluid. Physicians should be aware that pleural effusion is a possible medication-related adverse effect, which may be missed in cases of infection in patients following HSCT.

How may we quantify the value of physical resources, such as entangled quantum states, heat baths or lasers? Existing resource theories give us partial answers; however, these rely on idealizations, like perfectly independent copies of states or exact knowledge of a quantum state. Here we introduce the general tool of "currencies" to quantify realistic descriptions of resources, applicable in experimental settings when we do not have perfect control over a physical system, when only the neighbourhood of a state or some of its properties are known, or when slight correlations cannot be ruled out. Currencies are a subset of resources chosen to quantify all the other resources-like Bell pairs in LOCC or a lifted weight in thermodynamics. We show that from very weak assumptions in the theory we can already find useful currencies that give us necessary and sufficient conditions for resource conversion, and we build up more results as we impose further structure. This work generalizes axiomatic approaches to thermodynamic entropy, work and currencies made of local copies. In particular, by applying our approach to the resource theory of unital maps, we derive operational single-shot entropies for arbitrary, non-probabilistic descriptions of resources.

Rheumatoid arthritis (RA) patients had a higher risk of developing low bone mineral density (BMD) or osteoporosis. RA patients on classic disease-modifying antirheumatic drug (c-DMARD) therapy showed significantly lower BMD than controls, while no significant differences in most parameters were found between RA patients receiving biological disease-modifying antirheumatic drugs (b-DMARDs) and controls. The 3D analysis allowed us to find changes in the trabecular and cortical compartments., Introduction: To evaluate cortical and trabecular bone involvement of the hip in RA patients by dual-energy X-ray absorptiometry (DXA) and 3D analysis. The secondary end-point was to evaluate bone involvement in patients treated with classic (c-DMARD) or biological (b-DMARD) disease-modifying antirheumatic drug therapies and the effect of the duration of the disease and corticosteroid therapy on 3D parameters., Methods: A cross-sectional study of 105 RA patients and 100 subjects as a control group (CG) matched by age, sex, and BMI was carried out. BMD was measured by DXA of the bilateral femoral neck (FN) and total hip (TH). The 3D analyses including trabecular and cortical BMD were performed on hip scans with the 3D-Shaper software., Results: FN and TH BMD and trabecular and cortical vBMD were significantly lower in RA patients. The c-DMARD (n = 75) group showed significantly lower trabecular and cortical vBMD than the CG. Despite the lower values, the b-DMARD group (n = 30) showed no significant differences in most parameters compared with the CG. The trabecular and cortical 3D parameters were significantly lower in the group with an RA disease duration of 1 to 5 years than in the CG, and the trabecular vBMD was significantly lower in the group with a duration of corticosteroid therapy of 1 to 5 years than in the CG, while no significant differences were found by standard DXA in the same period., Conclusions: RA patients had a higher risk of developing low BMD or osteoporosis than controls. RA patients receiving c-DMARD therapy showed significantly lower BMD than controls, while no significant differences in most parameters were found between RA patients receiving b-DMARDs and controls. 3D-DXA allowed us to find changes in trabecular and cortical bone compartments in RA patients.

The use of 3D technologies is progressing in the dental field. However, little is known about the biomechanical behavior of the additive manufacturing of full-arch fixed dental prostheses (FAFDPs) for the establishment of clinical protocols. We investigated the influence of three CAD/CAM technologies: milling (control), Selective Laser Melting (SLM) and Electron Beam Melting (EBM) for FAFDP manufacturing. Also, the effects of ceramic veneer and spark erosion on marginal misfits of FAFDPs, the stability of prosthetic screws, strain and stress on the implant-supported system, as well as the effect of chewing simulation on screw stability were evaluated. Fifteen Ti-6Al-4V alloy FAFDPs were obtained by means of CAD/CAM systems: milling, SLM and EBM (n = 5/group). The marginal misfit was analyzed according to the single-screw test protocol. Screw stability was analyzed by screw-loosening torque. Strain-gauge analysis investigated the strain on the mini-abutment analog, and photoelastic analysis investigated the stress on the peri-implant region. Subsequently, all frameworks underwent ceramic veneer and spark erosion procedures. Marginal misfit, screw-loosening and strain and stress analyses were assessed after each evaluation time: initial, ceramic veneer and spark erosion. Finally, all prostheses were subjected to 10 6 mechanical cycles (2 Hz/150 N), and screw-loosening was re-evaluated. Data were subjected to two-way ANOVA for repeated measures, and the Bonferroni test as a post hoc technique (α = 0.05). At the initial time, the milling group presented the lowest marginal misfit (p < 0.001). Ceramic veneer did not alter marginal misfit for all groups (p > 0.05); spark erosion decreased the misfit values for the SLM and EBM groups (p < 0.05). Evaluation time did not alter screw-loosening values for all groups (p = 0.191), although the milling group presented the highest screw-loosening values (p < 0.05). Ceramic veneer and spark erosion reduced strain in the components regardless of the manufacturing technology used (p < 0.05). The milling group presented the lowest stress values regardless of evaluation time (p = 0.001), and lower stress values were found after spark erosion regardless of the manufacturing group (p = 0.016). In conclusion, although milled frameworks exhibited the best biomechanical behavior, frameworks manufactured by additive technologies presented acceptable values of screw-loosening torque, strain and stress. Ceramic veneer did not negatively interfere in the biomechanical tests of the study, and clinically acceptable marginal misfit was achieved after spark erosion. Therefore, such 3D printing technologies seem to be feasible for the manufacturing of full-arch implant-supported frameworks., 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 © 2020 Elsevier Ltd. All rights reserved.)

Methods using statistical shape and appearance models have been proposed to analyze bone mineral density (BMD) in 3D from dual energy X-ray absorptiometry (DXA) scans. This paper presents a retrospective case-control study assessing the association of DXA-derived 3D measurements with osteoporotic hip fracture in postmenopausal women. Patients who experienced a hip fracture between 1 and 6 years from baseline and age-matched controls were included in this study. The 3D-SHAPER software (version 2.7, Galgo Medical, Barcelona, Spain) was used to derive 3D analysis from hip DXA scans at baseline. DXA and 3D measurements were compared between groups. Total hip areal BMD of hip fracture group as measured by DXA was 10.7% lower compared to control group. Differences in volumetric BMD (total hip) as measured by 3D-SHAPER were more pronounced in the trabecular compartment (-23.3%) than in the cortex (-8.2%). The area under the receiver operating curve was 0.742 for trabecular volumetric BMD, 0.706 for cortical volumetric BMD, and 0.712 for total hip areal BMD. Differences in the cortex were locally more pronounced at the medial aspect of the shaft, the lateral aspect of the greater trochanter, and the superolateral aspect of the neck. Marked differences in volumetric BMD were observed in the greater trochanter. This case-control study showed the association of DXA-derived 3D measurements with hip fracture. Analysis of large cohorts will be performed in future work to determine if DXA-derived 3D measurements could improve fracture risk prediction in clinical practice., (Copyright © 2020 Air Medical Journal Associates. Published by Elsevier Inc. All rights reserved.)

Despite the success of neural networks at solving concrete physics problems, their use as a general-purpose tool for scientific discovery is still in its infancy. Here, we approach this problem by modeling a neural network architecture after the human physical reasoning process, which has similarities to representation learning. This allows us to make progress towards the long-term goal of machine-assisted scientific discovery from experimental data without making prior assumptions about the system. We apply this method to toy examples and show that the network finds the physically relevant parameters, exploits conservation laws to make predictions, and can help to gain conceptual insights, e.g., Copernicus' conclusion that the solar system is heliocentric.

Introduction: Exercise is a protective factor for the appearance of osteoporosis, but not all physical activities have the same effect on bones. Low-impact sports, like swimming, may a have a negative or no effect. The aim of the present study is to evaluate bone mineral density (BMD, g/cm 2 ) and bone mineral content (BMC, kg) among female high performance athletes from aquatic and non-aquatic sports and to assess possible differences with sedentary controls., Methods: Participants are elite female athletes over 18 years, from the Spanish Olympic teams, with at least 12-15 h of weekly training on aquatic sports: swimming (n = 19), synchronized swimming (n = 24) and water polo (n = 14), and elite female athletes from non-aquatic sports: professional football players of Futbol Club Barcelona team (n = 92), Spanish national volleyball (n = 26) and field hockey teams (n = 29) as well as sedentary controls (n = 126). Bone mineral density scans was performed using dual-energy X-ray absorptiometry for whole body, segmental analysis, proximal femur and lumbar spine., Results: Non-aquatic female athletes have total and segments BMC and BMD values higher than those of aquatic athletes, that in turn show similar BMD values compared to controls. BMD in lumbar spine and proximal femur was higher in non-aquatic sports compared to aquatic sports athletes and both were higher than controls., Conclusion: BMD is not negatively compromised by the practice of aquatic sports at a highly competitive level. However, non-aquatic female athletes show a higher BMD. Time training out of the water improves BMD. Our findings suggest that swimming and synchronized swimming should be combined with weight-bearing, impact or strength activities, as they do not seem to be osteogenic sports., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Trabecular bone score (TBS) is a tool to improve evaluation of DXA scans, barely used in children. We proposed to evaluate TBS with bone age (BA) compared to chronological age (CA). In girls, TBS value using BA is constant until age 8, and in boys until age 10, and then starts to increase steadily. This data may help widen TBS use in pediatric populations., Introduction: Trabecular bone score (TBS) is a software-based tool for the analysis of DXA images to assess bone microarchitecture in the lumbar region. It is used widely in adults to improve evaluation of fracture risk, yet it has been rarely studied in children and no normal curves have been developed for pediatrics. The purpose of this study was to evaluate bone (skeletal) age compared to chronological age to determine which is better in the pediatric population since both bone age (BA) and trabecular density are equally susceptible to change in response to similar factors., Methods: Total body, lumbar region, and non-dominant hand scans were obtained with an iDXA device in all participants. DXA scans of lumbar region for TBS analysis and AP images of non-dominant hand-for-BA were obtained for 565 children (269 female) aged 4to 19., Results: Simple correlation was calculated and r 2 values for TBS and chronological age were obtained by linear regression, with low correlations (0.36 for boys and 0.38 for girls), and then we created Loess curves to show the change for consecutive ages. In girls, the curve forms a U shape with a nadir point at approximately age 10. We then replaced chronological age with BA, and significant change was seen in the girls' curve, where a turning point is seen at age 8. In boys, a similar trend shows a turning point at age 10. Finally, BA-corrected TBS curves were constructed using LMS, obtaining curves with percentiles., Conclusions: The use of BA in the analysis and interpretation of TBS may help widen its use in pediatric populations by enabling the appearance of normative data, but more information is needed to confirm this finding.

Effects of osteoporosis drugs on proximal femur cortical and trabecular bone were studied using dual-energy x-ray absorptiometry (DXA)-based 3D modeling method. Changes observed in this head-to-head study were consistent with those obtained using computed tomography in the literature., Introduction: The aim of the present study was to assess the effects of osteoporosis drugs on cortical and trabecular bone at the proximal femur using DXA-based 3D modeling., Methods: We retrospectively analyzed 155 patients stratified by treatments: naive of treatment (NAIVE), alendronate (AL), denosumab (DMAB), and teriparatide (TPTD). DXA scans were performed at baseline and after treatment, and areal bone mineral density at spine and femur were measured. A software algorithm (3D-SHAPER) was used to derive 3D models from hip DXA scans and compute: trabecular and cortical volumetric BMD (vBMD), cortical thickness (Cth), and cortical surface BMD (cortical sBMD). Changes from baseline were normalized at 24 months and evaluated in terms or percentage., Results: After 24 months, a non-significant decrease was observed for trabecular vBMD, Cortical sBMD, Cth, and cortical vBMD (- 2.3, - 0.8, - 0.3, and - 0.5%) in the NAIVE group. Under AL and DMAB, significant increases were observed in trabecular vBMD (3.8 and 7.3%), cortical vBMD (1.4 and 2.0%), and cortical sBMD (1.5 and 3.6%). An increase in Cth was observed in patients under DMAB (1.8%). Under TPTD, a significant increase in Trabecular vBMD was observed (5.9%) associated with a non-significant increase of Cth (+ 1%) concomitant with a decrease in cortical vBMD (- 1.1%)., Conclusion: Results obtained in this head-to-head study are consistent with those obtained using computed tomography in the literature. DXA-based modeling techniques could complement standard DXA examination to monitor treatment effects on trabecular and cortical compartments.

Within a global physical theory, a notion of locality allows us to find and justify information-processing primitives, like non-signalling between distant agents. Here, we propose exploring the opposite direction: to take agents as the basic building blocks through which we test a physical theory, and recover operational notions of locality from signalling conditions. First, we introduce an operational model for the effective state spaces of individual agents, as well as the range of their actions. We then formulate natural secrecy conditions between agents and identify the aspects of locality relevant for signalling. We discuss the possibility of taking commutation of transformations as a primitive of physical theories, as well as applications to quantum theory and generalized probability frameworks. This 'it from bit' approach establishes an operational connection between local actions and local observations, and gives a global interpretation to concepts like discarding a subsystem or composing local functions.This article is part of a discussion meeting issue 'Foundations of quantum mechanics and their impact on contemporary society'., (© 2018 The Authors.)

The jaw is central to the extensive variety of feeding and predatory behaviors across vertebrates. The bones of the lower but not upper jaw form around an early-developing cartilage template. Whereas Endothelin1 patterns the lower jaw, the factors that specify upper-jaw morphology remain elusive. Here, we identify Nuclear Receptor 2f genes (Nr2fs) as enriched in and required for upper-jaw formation in zebrafish. Combinatorial loss of Nr2fs transforms maxillary components of the upper jaw into lower-jaw-like structures. Conversely, nr2f5 misexpression disrupts lower-jaw development. Genome-wide analyses reveal that Nr2fs repress mandibular gene expression and early chondrogenesis in maxillary precursors. Rescue of lower-jaw defects in endothelin1 mutants by reducing Nr2f dosage further demonstrates that Nr2f expression must be suppressed for normal lower-jaw development. We propose that Nr2fs shape the upper jaw by protecting maxillary progenitors from early chondrogenesis, thus preserving cells for later osteogenesis., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Marked trabecular and cortical bone loss was observed at the proximal femur short-term after spinal cord injury (SCI). 3D-DXA provided measurement of vBMD evolution at both femoral compartments and cortical thinning, thereby suggesting that this technique could be useful for bone analysis in these patients., Introduction: SCI is associated with a marked increase in bone loss and risk of osteoporosis development short-term after injury. 3D-DXA is a new imaging analysis technique providing 3D analysis of the cortical and trabecular bone from DXA scans. The aim of this study was to assess the evolution of trabecular macrostructure and cortical bone using 3D-DXA in patients with recent SCI followed over 12 months., Methods: Sixteen males with recent SCI (< 3 months since injury) and without antiosteoporotic treatment were included. Clinical assessment, bone mineral density (BMD) measurements by DXA, and 3D-DXA evaluation at proximal femur (analyzing the integral, trabecular and cortical volumetric BMD [vBMD] and cortical thickness) were performed at baseline and at 6 and 12 months of follow-up., Results: vBMD significantly decreased at integral, trabecular, and cortical compartments at 6 months (- 8.8, - 11.6, and - 2.4%), with a further decrease at 12 months, resulting in an overall decrease of - 16.6, - 21.9, and - 5.0%, respectively. Cortical thickness also decreased at 6 and 12 months (- 8.0 and - 11.4%), with the maximal decrease being observed during the first 6 months. The mean BMD losses by DXA at femoral neck and total femur were - 17.7 and - 21.1%, at 12 months, respectively., Conclusions: Marked trabecular and cortical bone loss was observed at the proximal femur short-term after SCI. 3D-DXA measured vBMD evolution at both femoral compartments and cortical thinning, providing better knowledge of their differential contributory role to bone strength and probably of the effect of therapy in these patients.

Objective To identify the risk of clinical hypocalcemia in the first hours after thyroidectomy. Study Design Prospective observational study. Setting Single-institution tertiary hospital in Madrid, Spain. Subjects and Methods A total of 123 patients who underwent total or completion thyroidectomy between June 2010 and March 2012 were included. Pre- and postoperative intact parathyroid hormone (iPTH) levels were obtained. Patients remain hospitalized a minimum of 48 hours until blood calcium stabilized. Calcium and/or vitamin D supplements were prescribed only when signs or symptoms of hypocalcemia developed. Receiver operating characteristic curve analysis was employed to evaluate the postoperative iPTH level and the pre- to postoperative decrease in iPTH levels. Two cutoff values were determined to stratify the risk of developing clinical hypocalcemia into 3 groups. Results The areas under the receiver operating characteristic curve were 0.991 for the postoperative iPTH and 0.998 for the decrease in iPTH. An iPTH decrease of 80% had 100% sensitivity to detect patients who developed clinical hypocalcemia, while a postoperative iPTH <3 pg/mL had 100% specificity. Thus, patients with an iPTH decrease ≤80% are at a very low risk of clinical hypocalcemia, and patients with a postoperative iPTH <3 pg/mL are at a very high risk. Patients with an iPTH decrease >80% and a postoperative iPTH ≥3 pg/mL are at intermediate risk. No significant correlation was found between the time when the sample was obtained and iPTH values. Conclusion This study stablishes a very accurate test to stratify the risk of clinical postthyroidectomy hypocalcemia based on pre- and postoperative iPTH levels.

Biogenesis and function of microRNAs can be influenced by genetic variants in the pri-miRNA sequences leading to phenotypic variability. This study aims to identify single nucleotide polymorphisms (SNPs) affecting the expression levels of bone-related mature microRNAs and thus, triggering an osteoporotic phenotype. An association analysis of SNPs located in pri-miRNA sequences with bone mineral density (BMD) was performed in the OSTEOMED2 cohort (n = 2183). Functional studies were performed for assessing the role of BMD-associated miRNAs in bone cells. Two SNPs, rs6430498 in the miR-3679 and rs12512664 in the miR-4274, were significantly associated with femoral neck BMD. Further, we measured these BMD-associated microRNAs in trabecular bone from osteoporotic hip fractures comparing to non-osteoporotic bone by qPCR. Both microRNAs were found overexpressed in fractured bone. Increased matrix mineralization was observed after miR-3679-3p inhibition in human osteoblastic cells. Finally, genotypes of rs6430498 and rs12512664 were correlated with expression levels of miR-3679 and miR-4274, respectively, in osteoblasts. In both cases, the allele that generated higher microRNA expression levels was associated with lower BMD values. In conclusion, two osteoblast-expressed microRNAs, miR-3679 and miR-4274, were associated with BMD; their overexpression could contribute to the osteoporotic phenotype. These findings open new areas for the study of bone disorders.

Locally thermal quantum systems may contradict traditional thermodynamics: heat can flow from a cold body to a hotter one, if the two are highly entangled. We show that to recover thermodynamic laws, we must use a stronger notion of thermalization: a system S is thermal relative to a reference R if S is both locally thermal and uncorrelated with R. Considering a general quantum reference is particularly relevant for a thermodynamic treatment of nanoscale quantum systems. We derive a technical condition for relative thermalization in terms of conditional entropies. Established results on local thermalization, which implicitly assume a classical reference, follow as special cases.

Objective: To assess whether changes in antiretroviral drugs other than thymidine nucleoside reverse transcriptase inhibitors (NRTI) may have a body fat impact in HIV-infected patients with lipoatrophy., Methods: Ninety-six-week phase IV, open-label, multicentre, pilot randomized trial. HIV-infected patients with moderate/severe lipoatrophy at one or more body sites despite long-term thymidine NRTI-free therapy were randomized to continue their efavirenz (EFV)-based antiretroviral regimen or to switch from EFV to lopinavir/ritonavir (LPV/r). The primary endpoint was the absolute change in limb fat mass measured by dual X-ray absorptiometry from baseline to 96 weeks. Changes in other body fat measurements, subjective perception of lipoatrophy, subcutaneous fat gene expression and plasma lipids were also assessed., Results: Thirty-three patients (73% men, median age 52 years) were recruited. At 96 weeks, absolute limb fat mass increased in the LPV/r arm vs. the EFV arm (estimated difference +1082.1 g; 95% CI +63.7 to +2103.5; P = 0.04); this difference remained significant after adjustment by gender, age, fat mass, body mass index and CD4 cell count at baseline. Subjective lipoatrophy perception scores also improved in the LPV/r arm relative to the EFV arm. Adipogenesis, glucose and lipid metabolism, and mitochondrial gene expression increased in the LPV/r arm compared with the EFV arm at 96 weeks. HDL cholesterol decreased in the LPV/r arm relative to the EFV arm., Conclusions: Switching from EFV to LPV/r in HIV-infected patients with lipoatrophy may offer further limb fat gain beyond thymidine NRTI discontinuation, although this strategy decreased plasma HDL cholesterol and caused changes in subcutaneous fat gene expression that may be associated with increased insulin resistance., (© 2015 British HIV Association.)

Purpose: The objective of the study was to assess longitudinal effects of different osteoporosis treatments on TBS and aBMD at lumbar spine., Method: We analyzed 390 patients (men: 72; women: 318; age>40 years; mean follow-up of 20 months and BMI<37 kg/m(2)). We stratified the cohort by treatments: Naive of treatment (Naive, n=67), Calcium and Vitamin D (CaVitD, n=87), Testosterone (Te, n=36), Alendronate (AL, n=88), Risedronate (Ri, n=39), Denosumab (Dmb, n=43) and Teriparatide (PTH, n=30). The follow-up changes from baseline were normalized at 24 months., Results: After 24 months, Naive group TBS decreased by 3.1% (p<0.05) whereas a non-significant increase was observed for spine aBMD (Δ=+0.5%). Compared to the Naive group, significant improvement (p<0.05) was observed in both TBS and aBMD for Te, AL, Ri, Dmb and PTH groups and in the CaVitD group for TBS. At the end of the follow-up, significant improvement have been observed for aBMD in Te (+4.4%), AL (+4.1%), Ri (+4.8), D (+8.8%) and PTH (+8.8%) groups. Significant improvement was observed only in the AL (+1.4%), Dmb (+2.8%) and PTH (+3.6%) groups for TBS., Conclusion: As expected, TBS of Naive subjects decreased with age. As expected a TBS preservation has been observed under AL and Ri. Te and CaVitD effects on TBS were evaluated for the first time: a similar preservation effect has been observed. A significant TBS increase was observed under Denosumab and PTH. TBS could be a useful tool to monitor treatment effects., (Copyright © 2015 Elsevier Inc. All rights reserved.)

A case of Berardinelli-Seip syndrome, a congenital generalised lipodystrophy, is reported. Symptoms first appeared when the patient was 20 years old. She showed severe insulin resistance as well as micro- and macro-angiopathic complications, including chronic kidney disease, which required renal replacement therapy with peritoneal dialysis. The patient's clinical course was reviewed since paediatric age (when initial signs of the disease being already evident) to present time. Berardinelli-Seip syndrome is very uncommon, and the present case is particularly rare because it is the only case (at least as reported in the literature) in a patient receiving dialysis., (Copyright © 2015 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction: Antiphospholipid syndrome (APS) is an autoimmune disorder which causes an hypercoagulation state characterized by thrombotic events, repetitive miscarriages and the presence of antiphospholipid antibodies. APS may be an isolated disease (primary APS) or associated to systemic lupus erythematous or another autoimmune conditions (secondary APS). Neuropsychiatric manifestations accompanying APS include migraine, epilepsy, chorea, dementia or psychosis. Detailed descriptions of clinical cases are lacking, and correlations between clinical and analytical findings are far from being well known. We review literature concerning neuropsychiatric manifestations in general and psychosis in particular, in patients suffering from AFS., Case Report: A 23 years-old female who presented a primary AFS with a clinical debut consisting of neuropsychiatric manifestations characterized by psychosis (with two delusion episodes) and abnormal movements such as choreiform and hemiballistic movements, initially understood as conversive symptoms., Conclusions: We discuss the pathogenesis of the psychotic and motor manifestations. The etiology is nowadays not completely understood, but cerebral small vessel thrombosis might explain part of the manifestations. We also review the role of antipsychotic and antithrombotic medication for these patients. Currently, our patient remains asymptomatic without any antipsychotic agent, only being treated with antiagregant and antipalludic therapy.

Unlabelled: Population-based studies performed with vertebral fracture assessment (VFA) morphometric technology are lacking in postmenopausal osteoporosis. In this study, we show a lower than expected prevalence of vertebral fractures, a high prevalence of minor vertebral deformities, and a clear association with clinical and densitometric parameters indicating the usefulness of this approach., Introduction: Adequate epidemiological data on the prevalence of vertebral fractures (VF) is essential in studies of postmenopausal osteoporosis. Routine DXA-assisted VFA may be useful to determine the presence of VF. However, population-based studies performed with this technology are lacking. We aimed to assess the prevalence of VF and minor deformities in 2,968 postmenopausal women aged 59-70 years from a population-based cohort., Methods: VFA and bone mineral density (BMD) measurements were conducted, and McCloskey criteria (vertebral heights under 3 SD from reference values) confirmed with the Genant method were used to define VF. Additionally, minor vertebral deformities (vertebral heights between -2 and -2.99 SD) were evaluated., Results: The prevalence of VF was 4.3%, and 17% of the participants had minor vertebral deformities. Low BMD was frequently observed in women with VF, with 4%, and 42% of participants showing osteoporosis and osteopenia. Minor vertebral deformities were observed in nearly 40% of women with VF. Multivariate logistic regression analysis showed that age, history of previous fracture, osteoporotic BMD, receiving anti-osteoporotic treatment, and current use of glucocorticoids were significantly associated with VF., Conclusions: Although the VFA approach showed a lower than expected prevalence of VF in our cohort, its association with clinical and densitometric parameters may be useful to identify women at risk for developing fragility fractures and may therefore justify its use in longitudinal studies. The high prevalence of minor vertebral deformities detected in patients with VF indicates the need to evaluate this type of deformity as a risk factor for further skeletal fractures.

HIV-1/HAART-associated lipodystrophy syndrome (HALS) has been associated with exposure to stavudine (d4T) through mitochondrial dysfunction. We performed a 48-week study to assess the effects of switching from d4T to raltegravir (RAL) on metabolic and fat molecular parameters of patients with HALS. Forty-two patients with HALS and a median exposure to d4T > 7 years were switched to RAL and followed for 48 weeks. Fasting metabolic tests, HIV RNA, CD4 cell count, and fat measured by DEXA were obtained at baseline and week 48. mtDNA and gene transcripts for PPAR gamma, adiponectin, cytochrome b, Cox IV, TNF alpha, MCP-1 and CD68 were assessed in paired subcutaneous fat tissue biopsies. Lipid parameters, fasting glucose, insulin, and HOMA-IR did not change significantly. Whole body fat (P = 0.0027) and limb fat mass (P<0.0001) increased from baseline. Trunk/limb fat ratio (P = 0.0022), fat mass ratio (P = 0.0020), fat mass index (P = 0.0011) and percent leg fat normalized to BMI (P<0.0001) improved after 48 weeks. Relative abundance of mtDNA, expression of PPAR gamma, adiponectin, Cyt b, and MCP-1 genes increased, whereas Cox IV, TNF alpha, and CD68 did not change significantly from baseline. Switching from d4T to RAL in patients with HALS is associated with an increase in limb fat mass and an improvement in markers of adipocyte differentiation and mitochondrial function in SAT.

Objective: We evaluated the safety of testosterone treatment and its efficacy on body composition in males with testosterone deficiency syndrome (TDS) over 24 months., Methods: 50 males aged 50-65 years with TDS (Aging Males Symptoms Scale [AMS] > 26 and calculated free testosterone [cFT] 250 pmol/l) were administered 50 mg testosterone gel daily for one year. During the second year, patients received 1000 mg of testosterone undecanoate every 2-3 months. Outcome measures were clinical chemistry values and total testosterone; sex hormone-binding globulin and cFT, changes in AMS and International Prostate Symptom Score; and changes in body composition measured by dual-energy-x-ray absorptiometry., Results: There were no clinically significant changes in clinical chemistry safety parameters. There were significant improvements in both total and cFT and in AMS scores after three months (p < 0.001). Lean mass increased 2.35% at 12 months and 4.5% at 24 months, but proportionally more muscle mass was gained in arms and legs than in the trunk. Fat mass decreased 4.2% at 12 months and 9.1% at 24 months., Conclusions: Testosterone treatment in males with TDS leads to body changes affecting lean and fat mass with significant improvement in AMS scores, and has an excellent safety profile.

The decline in testosterone levels found in men with testosterone deficiency syndrome (TDS) is associated with a decrease in bone mineral density (BMD). To study the safety profile and efficacy of testosterone treatment on BMD in patients with TDS. In this 2-year prospective open-label study, patients were administered 50 mg of testosterone gel daily (adjustable after 3 months up to 75-100 mg or down to 25 mg) for 12 months, followed by treatment with 1000 mg of testosterone undecanoate every 2-3 months from months 12-24. Outcome measures were as follows: (i) Changes in clinical chemistry safety parameters and total testosterone, sex hormone binding globulin and calculated free testosterone (cFT) levels; (ii) Changes in Aging Males' Symptoms Scale (AMS) and International Prostate Symptom Score scores; and (iii) Changes in lumbar spine and hip BMD. A total of 50 men aged 50-65 years with TDS (AMS >26 and cFT <0.250 nmol/mL) took part in the study. There was no significant impact of testosterone on safety. Prostate-specific antigen and haematopoietic parameters increased significantly, although the changes were not clinically significant. Total and cFT increased significantly after 3 months (p < 0.001) and there were significant improvements after 3 months in AMS scores (p < 0.001). BMD improved significantly in L2-L4 (2.90 and 4.5%), total femur (0.74 and 3%) and trochanter (1.09 and 3.2%) at 12 and 24 months respectively. Testosterone treatment in men with TDS has a good safety profile, leads to significant improvement in lumbar spine and hip BMD, and improves symptoms, as assessed by the AMS questionnaire., (© 2013 American Society of Andrology and European Academy of Andrology.)

Analysis of total tissue composition and, particularly, body fat measurements has become progressively important in the diagnosis and follow-up of patients with different clinical conditions. Dual-energy X-ray absorptiometry (DXA) fan-beam scanners are widely used to measure body composition, but the development of translational equations to be able to compare data of different scanning systems is necessary. The aim of this study was to assess the extent of agreement for regional measurements of body composition among the following 3 fan-beam DXA scanners: (1) Hologic Discovery (Hologic, Inc., Waltham, MA), (2) Lunar iDXA (GE Healthcare, Madison, WI), and (3) Lunar Prodigy Advance (GE Healthcare, Madison, WI). The study population consisted of 91 adult healthy volunteers (40 males and 51 females; mean age 48.5±14.4yr) who underwent DXA evaluation of the lumbar spine, hip, and whole body in each machine on the same day. Agreement among the 3 scanners was evaluated according to the Bland-Altman method and Lin's concordance correlation coefficient. Results showed a better agreement and concordance for the Lunar iDXA scanner than for any of them with the Hologic scanner. Differences were higher for any tissue or region than for the whole tissue mass. Translational equations were developed to ensure comparability of body composition measurements obtained with each of these 3 scanners., (Copyright © 2013 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

Intragastric infection mimics the natural route of infection of Chlamydia abortus (etiological agent of ovine enzootic abortion). In the mouse model, intragastric experimental infection induces very mild signs of infection followed by late term abortions, as it is shown by the natural ovine host. In order to evaluate the immune mechanisms associated to the dissemination of the pathogen from the gastrointestinal tract, we have administered an intragastric dose of C. abortus to pregnant mice. Systemic and local expression of cytokines, tissue colonization and excretion of bacteria after parturition were monitored during pregnancy. Susceptible CBA/J mice showed a higher bacterial colonization of the placenta and excretion of live bacteria after parturition that were related to a higher local IL-10 expression. By contrast, resistant C57BL/6 mouse strain had higher local IFN-γ mRNA expression in the placenta just before parturition and a transient bacterial colonization of the reproductive tract, with no excretion of C. abortus after parturition. In summary, intragastric infection not only mimics the natural route of infection of C. abortus, but can also be useful in order to understand the immunopathogenesis of chlamydial abortion in the mouse., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

This cross-sectional study evaluated the distribution of serum cross-linked C-telopeptides of collagen type I (βCTXs) in postmenopausal women, the characteristics of bone remodeling, and the factors influencing this bone marker, especially the use of anti-osteoporotic drugs. Women (n = 4,175) aged 59-70 years randomly selected from the community were invited to participate, measuring βCTXs and lumbar and femoral bone mineral density at recruitment. Risk factors for osteoporosis and the use of anti-osteoporotic treatment were collected with a structured questionnaire. We evaluated the percentage of women with increased (βCTXs >0.620 ng/mL) and decreased bone turnover (βCTXs <0.100 ng/mL) and those reaching the so-called treatment target (values of βCTXs within the lower half of the reference range for healthy young premenopausal women). Two thousand nine hundred sixty-eight women (70 %) participated (2,405 non-treated and 563 treated). Increased and decreased bone turnover was observed in 16.4 and 1.8 %, respectively, of non-treated women with significant differences compared with treated women (9.7 and 14.2 %, respectively, p < 0.001); 28 % of non-treated osteoporotic individuals had increased bone turnover versus 14 % of osteopenic participants and 8.8 % of women with normal bone density (p < 0.001). Women receiving bisphosphonates presented the highest percentages of decreased bone turnover (27 %) and βCTXs (43 %) within the treatment target. Increased bone turnover is observed in 16.4 % of non-treated postmenopausal women and is more frequent in individuals with osteoporosis, whereas decreased bone turnover is unusual. Most participants taking bisphosphonates had values within the treatment target, but nearly one quarter had decreased bone turnover.