First principles characterisation of bio-nano interface.

Nanomaterials possess a wide range of potential applications due to their novel properties and exceptionally high activity as a result of their large surface to volume ratios compared to bulk matter. The active surface may present both advantage and risk when the nanomaterials interact with living organisms. As the overall biological impact of nanomaterials is triggered and mediated by interactions at the bio-nano interface, an ability to predict those from the atomistic descriptors, especially before the material is produced, can present enormous advantage for the development of nanotechnology. Fast screening of nanomaterials and their variations for specific biological effects can be enabled using computational materials modelling. The challenge lies in the range of scales that needs to be crossed from the material-specific atomistic representation to the relevant length scales covering typical biomolecules (proteins and lipids). In this work, we present a systematic multiscale approach that allows one to evaluate crucial interactions at the bionano interface from the first principles without any prior information about the material and thus establish links between the details of the nanomaterials structure to protein-nanoparticle interactions. As an example, an advanced computational characterization of titanium dioxide nanoparticles (6 different surfaces of rutile and anatase polymorphs) has been performed. We computed characteristics of the titanium dioxide interface with water using density functional theory for electronic density, used these parameters to derive an atomistic force field, and calculated adsorption energies for essential biomolecules on the surface of titania nanoparticles via direct atomistic simulations and coarse-grained molecular dynamics. Hydration energies, as well as adsorption energies for a set of 40 blood proteins are reported.

Curvature sensing by cardiolipin in simulated buckled membranes.

Cardiolipin is a non-bilayer phospholipid with a unique dimeric structure. It localizes to negative curvature regions in bacteria and is believed to stabilize respiratory chain complexes in the highly curved mitochondrial membrane. Cardiolipin's localization mechanism remains unresolved, because important aspects such as the structural basis and strength for lipid curvature preferences are difficult to determine, partly due to the lack of efficient simulation methods. Here, we report a computational approach to study curvature preferences of cardiolipin by simulated membrane buckling and quantitative modeling. We combine coarse-grained molecular dynamics with simulated buckling to determine the curvature preferences in three-component bilayer membranes with varying concentrations of cardiolipin, and extract curvature-dependent concentrations and lipid acyl chain order parameter profiles. Cardiolipin shows a strong preference for negative curvatures, with a highly asymmetric chain order parameter profile. The concentration profiles are consistent with an elastic model for lipid curvature sensing that relates lipid segregation to local curvature via the material constants of the bilayers. These computations constitute new steps to unravel the molecular mechanism by which cardiolipin senses curvature in lipid membranes, and the method can be generalized to other lipids and membrane components as well.

Diffusion and reaction pathways of water near fully hydrated TiO2 surfaces from ab initio molecular dynamics.

Ab initio molecular dynamics simulations are reported for water-embedded TiO2 surfaces to determine the diffusive and reactive behavior at full hydration. A three-domain model is developed for six surfaces [rutile (110), (100), and (001), and anatase (101), (100), and (001)] which describes waters as "hard" (irreversibly bound to the surface), "soft" (with reduced mobility but orientation freedom near the surface), or "bulk." The model explains previous experimental data and provides a detailed picture of water diffusion near TiO2 surfaces. Water reactivity is analyzed with a graph-theoretic approach that reveals a number of reaction pathways on TiO2 which occur at full hydration, in addition to direct water splitting. Hydronium (H3O+) is identified to be a key intermediate state, which facilitates water dissociation by proton hopping between intact and dissociated waters near the surfaces. These discoveries significantly improve the understanding of nanoscale water dynamics and reactivity at TiO2 interfaces under ambient conditions.

Multiscale Modelling of Bionano Interface.

We present a framework for coarse-grained modelling of the interface between foreign nanoparticles (NP) and biological fluids and membranes. Our model includes united-atom presentations of membrane lipids and globular proteins in implicit solvent, which are based on all-atom structures of the corresponding molecules and parameterised using experimental data or atomistic simulation results. The NPs are modelled by homogeneous spheres that interact with the beads of biomolecules via a central force that depends on the NP size. The proposed methodology is used to predict the adsorption energies for human blood plasma proteins on NPs of different sizes as well as the preferred orientation of the molecules upon adsorption. Our approach allows one to rank the proteins by their binding affinity to the NP, which can be used for predicting the composition of the NP-protein corona for the corresponding material. We also show how the model can be used for studying NP interaction with a lipid bilayer membrane and thus can provide a mechanistic insight for modelling NP toxicity.

No difference in incidence of port-site hernia and chronic pain after single-incision laparoscopic cholecystectomy versus conventional laparoscopic cholecystectomy: a nationwide prospective, matched cohort study.

BACKGROUND: Conventional laparoscopic cholecystectomy (CLC) is regarded as the gold standard for cholecystectomy. However, single-incision laparoscopic cholecystectomy (SLC) has been suggested to replace CLC. This study aimed at comparing long-term incidences of port-site hernia and chronic pain after SLC versus CLC. METHODS: We conducted a matched cohort study based on prospective data (Jan 1, 2009-June 1, 2011) from the Danish Cholecystectomy Database with perioperative information and clinical follow-up. Consecutive patients undergoing elective SLC during the study period were included and matched 1:2 with patients subjected to CLC using pre-defined criteria. Follow-up data were obtained from the Danish National Patient Registry, mailed patient questionnaires, and clinical examination. A port-site hernia was defined as a repair for a port-site hernia or clinical hernia located at one or more port sites. RESULTS: In total, 699 patients were eligible and 147 patients were excluded from the analysis due to pre-defined criteria. The rate of returned questionnaires was 83%. Thus, 552 (SLC, n = 185; CLC, n = 367) patients were analyzed. The median observation time was 48 months (range 1-65) after SLC and 48 months (1-64) after CLC (P = 0.940). The total cumulated port-site hernia rate was 4 % and 6 % for SLC and CLC, respectively (P = 0.560). Incidences of moderate/severe chronic pain were 4 % and 5 % after SLC and CLC, respectively (P = 0.661). CONCLUSIONS: We found no difference in long-term incidence of port-site hernia or chronic pain after SLC versus CLC.

Reinforcement learning-based anatomical maps for pancreas subregion and duct segmentation.

BACKGROUND: The pancreas is a complex abdominal organ with many anatomical variations, and therefore automated pancreas segmentation from medical images is a challenging application. PURPOSE: In this paper, we present a framework for segmenting individual pancreatic subregions and the pancreatic duct from three-dimensional (3D) computed tomography (CT) images. METHODS: A multiagent reinforcement learning (RL) network was used to detect landmarks of the head, neck, body, and tail of the pancreas, and landmarks along the pancreatic duct in a selected target CT image. Using the landmark detection results, an atlas of pancreases was nonrigidly registered to the target image, resulting in anatomical probability maps for the pancreatic subregions and duct. The probability maps were augmented with multilabel 3D U-Net architectures to obtain the final segmentation results. RESULTS: To evaluate the performance of our proposed framework, we computed the Dice similarity coefficient (DSC) between the predicted and ground truth manual segmentations on a database of 82 CT images with manually segmented pancreatic subregions and 37 CT images with manually segmented pancreatic ducts. For the four pancreatic subregions, the mean DSC improved from 0.38, 0.44, and 0.39 with standard 3D U-Net, Attention U-Net, and shifted windowing (Swin) U-Net architectures, to 0.51, 0.47, and 0.49, respectively, when utilizing the proposed RL-based framework. For the pancreatic duct, the RL-based framework achieved a mean DSC of 0.70, significantly outperforming the standard approaches and existing methods on different datasets. CONCLUSIONS: The resulting accuracy of the proposed RL-based segmentation framework demonstrates an improvement against segmentation with standard U-Net architectures.

Synthetic electronic health records generated with variational graph autoencoders.

Data-driven medical care delivery must always respect patient privacy-a requirement that is not easily met. This issue has impeded improvements to healthcare software and has delayed the long-predicted prevalence of artificial intelligence in healthcare. Until now, it has been very difficult to share data between healthcare organizations, resulting in poor statistical models due to unrepresentative patient cohorts. Synthetic data, i.e., artificial but realistic electronic health records, could overcome the drought that is troubling the healthcare sector. Deep neural network architectures, in particular, have shown an incredible ability to learn from complex data sets and generate large amounts of unseen data points with the same statistical properties as the training data. Here, we present a generative neural network model that can create synthetic health records with realistic timelines. These clinical trajectories are generated on a per-patient basis and are represented as linear-sequence graphs of clinical events over time. We use a variational graph autoencoder (VGAE) to generate synthetic samples from real-world electronic health records. Our approach generates health records not seen in the training data. We show that these artificial patient trajectories are realistic and preserve patient privacy and can therefore support the safe sharing of data across organizations.

Determining biomembrane bending rigidities from simulations of modest size.

Thermal fluctuations of lipid orientation are analyzed to infer the bending rigidity of lipid bilayers directly from molecular simulations. Compared to the traditional analysis of thermal membrane undulations, the proposed method is reliable down to shorter wavelengths and allows for determination of the bending rigidity using smaller simulation boxes. The requisite theoretical arguments behind this analysis are presented and verified by simulations spanning a diverse range of lipid models from the literature.

Delayed dorsal scapular artery hematoma following blunt thoracic trauma: a case report and review of the literature.

BACKGROUND: The present case contributes to the limited literature on delayed chest wall hematomas following blunt trauma. The literature review provides a summary of similar previously reported cases. CASE PRESENTATION: We report the case of a 59-year-old Caucasian male who presented to the emergency department with a rapidly expanding chest wall hematoma. Six weeks earlier, he had sustained multiple rib fractures and a pneumothorax after falling 4 m from a ladder. Computed tomography angiography was used to identify two sources of active bleeding on the left dorsal scapular artery. The patient underwent surgery with evacuation of the hematoma and ligation of the artery. The patient was hospitalized for 3 days and recovered with no sequelae. CONCLUSIONS: A literature review revealed eight previously reported cases of chest wall hematomas exterior to the endothoracic fascia following blunt trauma. Most cases were initially diagnosed by computed tomography of the chest and finally by angiogram. Management options range from surgical drainage to angiographic embolization. This case is unusual regarding the delay in the development of the hematoma and illustrates the importance of considering this diagnosis even weeks after relevant trauma.

Interpretation of fluctuation spectra in lipid bilayer simulations.

Atomic resolution and coarse-grained simulations of dimyristoylphosphatidylcholine lipid bilayers were analyzed for fluctuations perpendicular to the bilayer using a completely Fourier-based method. We find that the fluctuation spectrum of motions perpendicular to the bilayer can be decomposed into just two parts: 1), a pure undulation spectrum proportional to q(-4) that dominates in the small-q regime; and 2), a molecular density structure factor contribution that dominates in the large-q regime. There is no need for a term proportional to q(-2) that has been postulated for protrusion fluctuations and that appeared to have been necessary to fit the spectrum for intermediate q. We suggest that earlier reports of such a term were due to the artifact of binning and smoothing in real space before obtaining the Fourier spectrum. The observability of an intermediate protrusion regime from the fluctuation spectrum is discussed based on measured and calculated material constants.

Determination of electron density profiles and area from simulations of undulating membranes.

The traditional method for extracting electron density and other transmembrane profiles from molecular dynamics simulations of lipid bilayers fails for large bilayer systems, because it assumes a flat reference surface that does not take into account long wavelength undulations. We have developed what we believe to be a novel set of methods to characterize these undulations and extract the underlying profiles in the large systems. Our approach first obtains an undulation reference surface for each frame in the simulation and subsequently isolates the long-wavelength undulations by filtering out the intrinsic short wavelength modes. We then describe two methods to obtain the appropriate profiles from the undulating reference surface. Most combinations of methods give similar results for the electron density profiles of our simulations of 1024 DMPC lipids. From simulations of smaller systems, we also characterize the finite size effect related to the boundary conditions of the simulation box. In addition, we have developed a set of methods that use the undulation reference surface to determine the true area per lipid which, due to undulations, is larger than the projected area commonly reported from simulations.

Atomistic Perspective on Biomolecular Adsorption on Functionalized Carbon Nanomaterials under Ambient Conditions.

The use of carbon-based nanomaterials is tremendously increasing in various areas of technological, bioengineering, and biomedical applications. The functionality of carbon-based nanomaterials can be further broadened via chemical functionalization of carbon nanomaterial surfaces. On the other hand, concern is rising on possible adverse effects when nanomaterials are taken up by biological organisms. In order to contribute into understanding of interactions of carbon-based nanomaterials with biological matter, we have investigated adsorption of small biomolecules on nanomaterials using enhanced sampling molecular dynamics. The biomolecules included amino acid side chain analogues, fragments of lipids, and sugar monomers. The adsorption behavior on unstructured amorphous carbon, pristine graphene and its derivatives (such as few-layer graphene, graphene oxide, and reduced graphene oxide) as well as pristine carbon nanotubes, and those functionalized with OH-, COOH-, COO-, NH2-, and NH3+ groups was investigated with respect to surface concentration. An adsorption profile, that is, the free energy as a function of distance from the nanomaterial surfaces, was determined for each molecule and surface using the Metadynamics approach. The results were analyzed in terms of chemical specificity, surface charge, and surface concentration. It was shown that although morphology of the nanomaterial has a limited effect on the adsorption properties, functionalization of the surface by various molecular groups can drastically change the adsorption behavior that can be used in the design of nanosurfaces with highly selective adsorption properties and safe for human health and environment.

Stretched exponential dynamics in lipid bilayer simulations.

The decay of fluctuations in fluid biomembranes is strongly stretched and nonexponential on nanometer lengthscales. We report on calculations of structural correlation functions for lipid bilayer membranes from atomistic and coarse-grained molecular dynamics simulations. The time scales extend up to microseconds, whereas the linear size of the largest systems is around 50 nm. Thus, we can cover the equilibrium dynamics of wave vectors over two orders of magnitude (0.2-20 nm(-1)). The time correlations observed in the simulations are best described by stretched exponential functions, with exponents of 0.45 for the atomistic and 0.60 for the coarse-grained model. Area number density fluctuations, thickness fluctuations, and undulations behave dynamically in a similar way and have almost exactly the same dynamics for wavelengths below 3 nm, indicating that in this regime undulations and thickness fluctuations are governed by in-plane density fluctuations. The out-of-plane height fluctuations are apparent only at the longest wavelengths accessible in the simulations (above 6 nm). The effective correlation times of the stretched exponentials vary strongly with the wave vector. The variation fits inverse power-laws that change with wavelength. The exponent is 3 for wavelengths smaller than about 1.25 nm and switches to 1 above this. There are indications for a switch to still another exponent, 2, for wavelengths above 20 nm. Compared to neutron spin-echo (NSE) experiments, the simulation data indicate a faster relaxation in the hydrodynamic limit, although an extrapolation of NSE data, as well as inelastic neutron scattering data, is in agreement with our data at larger wave vectors.

Acute Tentorial Subdural Hematoma Caused by Rupture of the Posterior Cerebral Artery after Minor Trauma-A Case Report.

Acute subdural hematoma (aSDH) is a common pathology encountered after head trauma. Only a minority of aSDHs have an arterial source. In this article, we report a case of aSDH originating from a traumatic pseudoaneurysm of the distal segment of posterior cerebral artery (PCA), diagnosed several days after the initial minor trauma and successfully treated with endovascular coiling. This case emphasizes the importance of searching for vascular pathology when the localization, severity or relapsing course of the intracranial hemorrhage does not fully correspond to the severity of initial trauma and when the bleeding has a delayed onset. Characteristics, diagnostics and treatment possibilities of traumatic cerebral aneurysms, an important cause of arterial aSDH, are described in the article.

Dynamic structure factors from lipid membrane molecular dynamics simulations.

Dynamic structure factors for a lipid bilayer have been calculated from molecular dynamics simulations. From trajectories of a system containing 1024 lipids we obtain wave vectors down to 0.34 nm(-1), which enables us to directly resolve the Rayleigh and Brillouin lines of the spectrum. The results confirm the validity of a model based on generalized hydrodynamics, but also improves the line widths and the position of the Brillouin lines. The improved resolution shows that the Rayleigh line is narrower than in earlier studies, which corresponds to a smaller thermal diffusivity. From a detailed analysis of the power spectrum, we can, in fact, distinguish two dispersive contributions to the elastic scattering. These translate to two exponential relaxation processes in separate time domains. Further, by including a first correction to the wave-vector-dependent position of the Brillouin lines, the results agree favorably to generalized hydrodynamics even up to intermediate wave vectors, and also yields a 20% higher adiabatic sound velocity. The width of the Brillouin lines shows a linear, not quadratic, dependence to low wave vectors.

Sarcopenia predicts 90-day mortality in elderly patients undergoing emergency abdominal surgery.

PURPOSE: Image-based measurement of sarcopenia is an established predictor of a decreased outcome for a large variety of surgical procedures. Sarcopenia in elderly patients undergoing emergency abdominal surgery has not been well studied. This study aims to investigate the association between the total psoas area (TPA) and postoperative mortality after 90 days in a group of elderly emergency laparotomy patients. METHODS: We retrospectively reviewed the emergency CT-scans of 150 elderly patients from a consecutive cohort undergoing emergency abdominal surgery at our surgical center. TPA was measured manually at the level of L3 and indexed to patient height. Sarcopenia was defined as having a TPA index below the first quartile for gender in the cohort. Other collected variables were age, vital status/date of death, ASA-score, surgical procedure, and WHO performance score. RESULTS: Overall 90-day mortality was 42.7%. Sarcopenic patients had a higher 90-day mortality (60.5%) than non-sarcopenic patients (36.6%), corresponding to an odds ratio of 2.66 (95% confidence interval 1.2-5.7, p = 0.01). Sarcopenic patients had an increased mortality compared with non-sarcopenic patients (p = 0.0009, Log-rank test), with a clear separation of the two groups within 30 days postoperatively. In a multivariate logistic regression model, with age, ASA-score, and WHO performance score as covariates, sarcopenia was independently associated with 90-day mortality. CONCLUSION: Manual measurement of TPA on an abdominal CT-scan is a relevant risk factor for postoperative mortality in elderly patients undergoing high-risk emergency abdominal surgery. Incorporation of sarcopenia in postoperative risk-prediction models in emergency abdominal surgery should be considered.

Computing Curvature Sensitivity of Biomolecules in Membranes by Simulated Buckling.

Membrane curvature sensing, where the binding free energies of membrane-associated molecules depend on the local membrane curvature, is a key factor to modulate and maintain the shape and organization of cell membranes. However, the microscopic mechanisms are not well understood, partly due to absence of efficient simulation methods. Here, we describe a method to compute the curvature dependence of the binding free energy of a membrane-associated probe molecule that interacts with a buckled membrane, which has been created by lateral compression of a flat bilayer patch. This buckling approach samples a wide range of curvatures in a single simulation, and anisotropic effects can be extracted from the orientation statistics. We develop an efficient and robust algorithm to extract the motion of the probe along the buckled membrane surface, and evaluate its numerical properties by extensive sampling of three coarse-grained model systems: local lipid density in a curved environment for single-component bilayers, curvature preferences of individual lipids in two-component membranes, and curvature sensing by a homotrimeric transmembrane protein. The method can be used to complement experimental data from curvature partition assays and provides additional insight into mesoscopic theories and molecular mechanisms for curvature sensing.

Insights into Functionalization of Metal-Organic Frameworks Using In Situ NMR Spectroscopy.

Postsynthetic reactions of metal-organic frameworks (MOFs) are versatile tools for producing functional materials, but the methods of evaluating these reactions are cumbersome and destructive. Here we demonstrate and validate the use of in situ NMR spectroscopy of species in the liquid state to examine solvent-assisted ligand exchange (SALE) and postsynthetic modification (PSM) reactions of metal-organic frameworks. This technique allows functionalization to be monitored over time without decomposing the product for analysis, which simplifies reaction screening. In the case of SALE, both the added ligand and the ligand leaving the framework can be observed. We demonstrate this in situ method by examining SALE and PSM reactions of the robust zirconium MOF UiO-67 as well as SALE with the aluminum MOF DUT-5. In situ NMR spectroscopy provided insights into the reactions studied, and we expect that future studies using this method will permit the examination of a variety of MOF-solute reactions.

Traumatic separation of osseous segments in a double-layered patella.

INTRODUCTION: Double-layered patella is a rare intra-articular disorder associated with multiple epiphyseal dysplasia. PRESENTATION OF CASE: We present a case of a 40-year old man with acute pain in his left knee after a tackle during soccer play. DISCUSSION: Clinical examination and radiographs confirmed the diagnosis of a bilateral double-layered patella with traumatic separation of the osseous segments on the afflicted left side. Surgical management comprised of open arthrotomy and debridement of the bony interface. Stabilization was performed with tension cerclage, supported by a lag screw with excellent outcome at 12 months follow-up. CONCLUSION: It is possible that micromovement in a double-layered patella can dispose to a traumatic coronal segment displacement. Osseous fusion of traumatic patellar segments can be achieved.

Nonpeptide and peptide growth hormone secretagogues act both as ghrelin receptor agonist and as positive or negative allosteric modulators of ghrelin signaling.

Two nonpeptide (L692,429 and MK-677) and two peptide [GH-releasing peptide (GHRP)-6 and ghrelin] agonists were compared in binding and in signal transduction assays: calcium mobilization, inositol phosphate turnover, cAMP-responsive element (CRE), and serum-responsive element (SRE) controlled transcription, as well as arrestin mobilization. MK-677 acted as a simple agonist having an affinity of 6.5 nm and activated all signal transduction systems with similar high potency (0.2-1.4 nm). L-692,429 also displayed a very similar potency in all signaling assays (25-60 nm) but competed with a 1000-fold lower apparent affinity for ghrelin binding and surprisingly acted as a positive allosteric receptor modulator by increasing ghrelin's potency 4- to 10-fold. In contrast, the potency of GHRP-6 varied 600-fold (0.1-61 nm) depending on the signal transduction assay, and it acted as a negative allosteric modulator of ghrelin signaling. Unexpectedly, the maximal signaling efficacy for ghrelin was increased above what was observed with the hormone itself during coadministration with the nonendogenous agonists. It is concluded that agonists for the ghrelin receptor vary both in respect of their intrinsic agonist properties and in their ability to modulate ghrelin signaling. A receptor model is presented wherein ghrelin normally only activates one receptor subunit in a dimer and where the smaller nonendogenous agonists bind in the other subunit to act both as coagonists and as either neutral (MK-677), positive (L-692,429), or negative (GHRP-6) modulators of ghrelin function. It is suggested that an optimal drug candidate could be an agonist that also is a positive modulator of ghrelin signaling.