Opportunistic hip fracture risk prediction in Men from X-ray: Findings from the Osteoporosis in Men (MrOS) Study

Osteoporosis is a common disease that increases fracture risk. Hip fractures, especially in elderly people, lead to increased morbidity, decreased quality of life and increased mortality. Being a silent disease before fracture, osteoporosis often remains undiagnosed and untreated. Areal bone mineral density (aBMD) assessed by dual-energy X-ray absorptiometry (DXA) is the gold-standard method for osteoporosis diagnosis and hence also for future fracture prediction (prognostic). However, the required special equipment is not broadly available everywhere, in particular not to patients in developing countries. We propose a deep learning classification model (FORM) that can directly predict hip fracture risk from either plain radiographs (X-ray) or 2D projection images of computed tomography (CT) data. Our method is fully automated and therefore well suited for opportunistic screening settings, identifying high risk patients in a broader population without additional screening. FORM was trained and evaluated on X-rays and CT projections from the Osteoporosis in Men (MrOS) study. 3108 X-rays (89 incident hip fractures) or 2150 CTs (80 incident hip fractures) with a 80/20 split were used. We show that FORM can correctly predict the 10-year hip fracture risk with a validation AUC of 81.44 +- 3.11% / 81.04 +- 5.54% (mean +- STD) including additional information like age, BMI, fall history and health background across a 5-fold cross validation on the X-ray and CT cohort, respectively. Our approach significantly (p < 0.01) outperforms previous methods like Cox Proportional-Hazards Model and \frax with 70.19 +- 6.58 and 74.72 +- 7.21 respectively on the X-ray cohort. Our model outperform on both cohorts hip aBMD based predictions. We are confident that FORM can contribute on improving osteoporosis diagnosis at an early stage.Comment: Accepted at MICCAI 2022 Workshop (PRIME

Endolithic Algae Affect Modern Coral Carbonate Morphology and Chemistry

While burial diagenetic processes of tropical corals are well investigated, current knowledge about factors initiating early diagenesis remains fragmentary. In the present study, we focus on recent Porites microatolls, growing in the intertidal zone. This growth form represents a model organism for elevated sea surface temperatures (SSTs) and provides important but rare archives for changes close to the seawater/atmosphere interface with exceptional precision on sea level reconstruction. As other coral growth forms, microatolls are prone to the colonization by endolithic green algae. In this case, the algae can facilitate earliest diagenetic alteration of the coral skeleton. Algae metabolic activity not only results in secondary coral porosity due to boring activities, but may also initiate reprecipitation of secondary aragonite within coral pore space, a process not exclusively restricted to microatoll settings. In the samples of this initial study, we quantified a mass transfer from primary to secondary aragonite of around 4% within endolithic green algae bands. Using δ 18 O, δ 13 C, Sr/Ca, U/Ca, Mg/Ca, and Li/Mg systematics suggests that the secondary aragonite precipitation followed abiotic precipitation principles. According to their individual distribution coefficients, the different isotope and element ratios showed variable sensitivity to the presence of secondary aragonite in bulk samples, with implications for microatoll-based SST reconstructions. The secondary precipitates formed on an organic template, presumably originating from endolithic green algae activity. Based on laboratory experiments with the green algae Ostreobium quekettii, we propose a conceptual model that secondary aragonite formation is potentially accelerated by an active intracellular calcium transport through the algal thallus from the location of dissolution into coral pore spaces. The combined high-resolution imaging and geochemical approach applied in this study shows that endolithic algae can possibly act as a main driver for earliest diagenesis of coral aragonite starting already during a coral’s life span

Lipid-Iron Nanoparticle with a Cell Stress Release Mechanism Combined with a Local Alternating Magnetic Field Enables Site-Activated Drug Release

Simple Summary A novel active release system magnetic sphingomyelin-containing liposome encapsulated with indocyanine green, fluorescent marker, or the anticancer drug cisplatin was evaluated. The liposomal sphingomyelin is a target for the sphingomyelinase enzyme, which is released by stressed cells. Thus, sphingomyelin containing liposomes behave as a sensitizer for biological stress situations. In addition, the liposomes were engineered by adding paramagnetic beads to act as a receiver of outside given magnetic energy. The enzymatic activity towards liposomes and destruction caused by the applied magnetic field caused the release of the content from the liposomes. By using these novel liposomes, we could improve the drug release feature of liposomes. The improved targeting and drug-release were shown in vitro and the orthotopic tongue cancer model in mice optical imaging. The increased delivery of cisplatin prolonged the survival of the targeted delivery group versus free cisplatin. Most available cancer chemotherapies are based on systemically administered small organic molecules, and only a tiny fraction of the drug reaches the disease site. The approach causes significant side effects and limits the outcome of the therapy. Targeted drug delivery provides an alternative to improve the situation. However, due to the poor release characteristics of the delivery systems, limitations remain. This report presents a new approach to address the challenges using two fundamentally different mechanisms to trigger the release from the liposomal carrier. We use an endogenous disease marker, an enzyme, combined with an externally applied magnetic field, to open the delivery system at the correct time only in the disease site. This site-activated release system is a novel two-switch nanomachine that can be regulated by a cell stress-induced enzyme at the cellular level and be remotely controlled using an applied magnetic field. We tested the concept using sphingomyelin-containing liposomes encapsulated with indocyanine green, fluorescent marker, or the anticancer drug cisplatin. We engineered the liposomes by adding paramagnetic beads to act as a receiver of outside magnetic energy. The developed multifunctional liposomes were characterized in vitro in leakage studies and cell internalization studies. The release system was further studied in vivo in imaging and therapy trials using a squamous cell carcinoma tumor in the mouse as a disease model. In vitro studies showed an increased release of loaded material when stress-related enzyme and magnetic field was applied to the carrier liposomes. The theranostic liposomes were found in tumors, and the improved therapeutic effect was shown in the survival studies.Peer reviewe

Genome-Wide Association Study and Functional Characterization Identifies Candidate Genes for Insulin-Stimulated Glucose Uptake

Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in \u3e55,000 participants from three ancestry groups. We identified ten new loci (P \u3c 5 × 10-8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits

Evaluation of the degradation behavior of resorbable metal implants for in vivo osteosynthesis by synchrotron radiation based x-ray tomography and histology

Magnesium(Mg)-alloys are promising candidates as temporary implants for orthopedic and cranio-facial applications. They can sustain tissues during healing, thanks to favorable mechanical properties, and then they slowly degrade into biocompatible products, avoiding the need of a second surgery for implant removal. They have the potential to benefit a vast number of patients, especially children and elderly patients. However, to be able to tailor their degradation to match the speed of tissue regeneration it is crucial to understand how they actually degrade in the living organism. We utilized high-resolution synchrotron-based tomography at the beamline P05 operated by HZG at the storage ring PETRA III at DESY to study the degradation of 3 novel Mg-alloys in rat bone and the consequent bone response. On threedimensional reconstructions of the bone-implant explants we were able to follow the dynamic transformation that the materials underwent at different healing times and on the basis of absorption coefficients we could distinguish and quantify the amount of remaining implants, the corrosion layers and the new bone. This was a great advantage compared to laboratory CT, for which the limitation in contrast and in resolution made impossible to discriminate between original alloy, degradation products and bone, leading to inaccurate determination of the materials degradation rates. The same samples imaged by tomography were used for non-decalcified histology. The combination of histological and tomographical images provided new insight on the nature of the bone-to-implant interface and of the degradation products, which appeared to have great similarities to the host bone

Assessment of Bone Fragility in Patients With Multiple Myeloma Using QCT-Based Finite Element Modeling

Multiple myeloma (MM) is a malignant plasma cell disease associated with severe bone destruction. Surgical intervention is often required to prevent vertebral body collapse and resulting neurological complications; however, its necessity is determined by measuring lesion size or number, without considering bone biomechanics. Finite element (FE) modeling, which simulates the physiological loading, may improve the prediction of fragility. To test this, we developed a quantitative computed tomography (QCT)-based FE model of the vertebra and applied it to a dataset of MM patients with and without prevalent fracture. FE models were generated from vertebral QCT scans of the T-12 (T-11 if T-12 was fractured) of 104 MM patients, 45 with fracture and 59 without, using a low-dose scan protocol (1.5mm slice thickness, 4.0 to 6.5 mSv effective dose). A calibration phantom enabled the conversion of the CT Hounsfield units to FE material properties. Compressive loading of the vertebral body was simulated and the stiffness, yield load, and work to yield determined. To compare the parameters between fracture and nonfracture groups, t tests were used, and standardized odds ratios (sOR, normalized to standard deviation) and 95% confidence intervals were calculated. FE parameters were compared to mineral and structural parameters using linear regression. Patients with fracture showed lower vertebral stiffness (-15.2%; p=0.010; sOR=1.73; 95% CI, 1.11 to 2.70), yield force (-21.5%; p=0.002; sOR=2.09; 95% CI, 1.27 to 3.43), and work to yield (-27.4%; p=0.001; sOR=2.28; 95% CI, 1.33 to 3.92) compared to nonfracture patients. All parameters correlated significantly with vBMD (stiffness: R-2=0.57, yield force: R-2=0.59, work to yield: R-2=0.50, p < 0.001), BV/TV (stiffness: R-2=0.56, yield force: R-2=0.58, work to yield: R-2=0.49, p < 0.001), and Tb.Sp (stiffness: R-2=0.51, yield force: R-2=0.53, work to yield: R-2=0.45, p < 0.001). FE modeling identified MM patients with compromised mechanical integrity of the vertebra. Higher sOR values were obtained for the biomechanical compared to structural or mineral measures, suggesting that FE modeling improves fragility assessment in these patients. (c) 2016 American Society for Bone and Mineral Research