Development and verification of a physiologically motivated internal controller for the open-source extended Hill-type muscle model in LS-DYNA.

Nowadays, active human body models are becoming essential tools for the development of integrated occupant safety systems. However, their broad application in industry and research is limited due to the complexity of incorporated muscle controllers, the long simulation runtime, and the non-regular use of physiological motor control approaches. The purpose of this study is to address the challenges in all indicated directions by implementing a muscle controller with several physiologically inspired control strategies into an open-source extended Hill-type muscle model formulated as LS-DYNA user-defined umat41 subroutine written in the Fortran programming language. This results in increased usability, runtime performance and physiological accuracy compared to the standard muscle material existing in LS-DYNA. The proposed controller code is verified with extensive experimental data that include findings for arm muscles, the cervical spine region, and the whole body. Selected verification experiments cover three different muscle activation situations: (1) passive state, (2) open-loop and closed-loop muscle activation, and (3) reflexive behaviour. Two whole body finite element models, the 50th percentile female VIVA OpenHBM and the 50th percentile male THUMS v5, are used for simulations, complemented by the simplified arm model extracted from the 50th percentile male THUMS v3. The obtained results are evaluated additionally with the CORrelation and Analysis methodology and the mean squared error method, showing good to excellent biofidelity and sufficient agreement with the experimental data. It was shown additionally how the integrated controller allows simplified mimicking of the movements for similar musculoskeletal models using the parameters transfer method. Furthermore, the Hill-type muscle model presented in this paper shows better kinematic behaviour even in the passive case compared to the existing one in LS-DYNA due to its improved damping and elastic properties. These findings provide a solid evidence base motivating the application of the enhanced muscle material with the internal controller in future studies with Active Human Body Models under different loading conditions.

Efficient simulation strategy to design a safer motorcycle.

This work presents models and simulations of a numerical strategy for a time and cost-efficient virtual product development of a novel passive safety restraint concept for motorcycles. It combines multiple individual development tasks in an aggregated procedure. The strategy consists of three successive virtual development stages with a continuously increasing level of detail and expected fidelity in multibody and finite element simulation environments. The results show what is possible with an entirely virtual concept study-based on the clever combination of multibody dynamics and nonlinear finite elements-that investigates the structural behavior and impact dynamics of the powered two-wheeler with the safety systems and the rider's response. The simulations show a guided and controlled trajectory and deceleration of the motorcycle rider, resulting in fewer critical biomechanical loads on the rider compared to an impact with a conventional motorcycle. The numerical research strategy outlines a novel procedure in virtual motorcycle accident research with different levels of computational effort and model complexity aimed at a step-by-step validation of individual components in the future.

Role of Rotated Head Postures on Volunteer Kinematics and Muscle Activity in Braking Scenarios Performed on a Driving Simulator.

Occupants exposed to low or moderate crash events can already suffer from whiplash-associated disorders leading to severe and long-lasting symptoms. However, the underlying injury mechanisms and the role of muscle activity are not fully clear. Potential increases in injury risk of non-nominal postures, i.e., rotated head, cannot be evaluated in detail due to the lack of experimental data. Examining changes in neck muscle activity to hold and stabilize the head in a rotated position during pre-crash scenarios might provide a deeper understanding of muscle reflex contributions and injury mechanisms. In this study, the influence of two different head postures (nominal vs. rotation of the head by about 63 ± 9° to the right) on neck muscle activity and head kinematics was investigated in simulated braking experiments inside a driving simulator. The braking scenario was implemented by visualization of the virtual scene using head-mounted displays and a combined translational-rotational platform motion. Kinematics of seventeen healthy subjects was tracked using 3D motion capturing. Surface electromyography were used to quantify muscle activity of left and right sternocleidomastoideus (SCM) and trapezius (TRP) muscles. The results show clear evidence that rotated head postures affect the static as well as the dynamic behavior of muscle activity during the virtual braking event. With head turned to the right, the contralateral left muscles yielded higher base activation and delayed muscle onset times. In contrast, right muscles had much lower activations and showed no relevant changes in muscle activation between nominal and rotated head position. The observed delayed muscle onset times and increased asymmetrical muscle activation patterns in the rotated head position are assumed to affect injury mechanisms. This could explain the prevalence of rotated head postures during a crash reported by patients suffering from WAD. The results can be used for validating the active behavior of human body models in braking simulations with nominal and rotated head postures, and to gain a deeper understanding of neck injury mechanisms.

Documenting research software in engineering science.

The reuse of research software needs good documentation, however, the documentation in particular is often criticized. Especially in non-IT specific disciplines, the lack of documentation is attributed to the lack of training, the lack of time or missing rewards. This article addresses the hypothesis that scientists do document but do not know exactly what they need to document, why, and for whom. In order to evaluate the actual documentation practice of research software, we examined existing recommendations, and we evaluated their implementation in everyday practice using a concrete example from the engineering sciences and compared the findings with best practice examples. To get a broad overview of what documentation of research software entailed, we defined categories and used them to conduct the research. Our results show that the big picture of what documentation of research software means is missing. Recommendations do not consider the important role of researchers, who write research software, whose documentation takes mainly place in their research articles. Moreover, we show that research software always has a history that influences the documentation.

Implementation and validation of the extended Hill-type muscle model with robust routing capabilities in LS-DYNA for active human body models.

BACKGROUND: In the state of the art finite element AHBMs for car crash analysis in the LS-DYNA software material named *MAT_MUSCLE (*MAT_156) is used for active muscles modeling. It has three elements in parallel configuration, which has several major drawbacks: restraint approximation of the physical reality, complicated parameterization and absence of the integrated activation dynamics. This study presents implementation of the extended four element Hill-type muscle model with serial damping and eccentric force-velocity relation including [Formula: see text] dependent activation dynamics and internal method for physiological muscle routing. RESULTS: Proposed model was implemented into the general-purpose finite element (FE) simulation software LSDYNA as a user material for truss elements. This material model is verified and validated with three different sets of mammalian experimental data, taken from the literature. It is compared to the *MAT_MUSCLE (*MAT_156) Hill-type muscle model already existing in LS-DYNA, which is currently used in finite element human body models (HBMs). An application example with an arm model extracted from the FE ViVA OpenHBM is given, taking into account physiological muscle paths. CONCLUSION: The simulation results show better material model accuracy, calculation robustness and improved muscle routing capability compared to *MAT_156. The FORTRAN source code for the user material subroutine dyn21.f and the muscle parameters for all simulations, conducted in the study, are given at https://zenodo.org/record/826209 under an open source license. This enables a quick application of the proposed material model in LS-DYNA, especially in active human body models (AHBMs) for applications in automotive safety.

Diagnosis of hypersplenism with the epinephrine stimulation test - 23 years of experience at a tertiary care hospital.

PRINCIPLES: Hypersplenism can be defined by thrombocytopenia and/or neutropenia resulting from blood cell sequestration in an enlarged spleen. In multimorbid patients the differential diagnosis of cytopenia is challenging and currently there is no established test for diagnosing hypersplenism. METHODS: The epinephrine stimulation test (EST) measures changes in platelets, neutrophil counts and spleen size following a subcutaneous epinephrine injection. We retrospectively analysed the results of EST in 228 patients. RESULTS: Increases in neutrophils and platelets after epinephrine injection were significantly greater in patients with enlarged than in patients with normal size spleens. Using cutoffs of low, intermediate and high confidence EST was positive in 69.8% vs. 41.3% (low confidence), 49.6% vs. 17.4% (intermediate confidence) and 38.8% vs. 10.9% (high confidence) in patients with enlarged vs. normal size spleens. Changes in platelet and neutrophil counts correlated with each other and with changes in spleen size, confirming cell release from the spleen during EST. When stratified according to the underlying diagnosis, patients with liver disease had the strongest response to EST, patients with malignant haematological diseases the weakest. In addition the response to EST was significantly related to changes in platelet and neutrophil counts after splenectomy, confirming the validity of our test. No serious side effects occurred during EST. CONCLUSION: When used in a large patient cohort, EST is a safe and simple diagnostic test. In this exploratory study EST is of value in evaluating patients with cytopenia and a positive EST argues strongly for hypersplenism. Future studies should prospectively evaluate EST for the management of patients with splenomegaly.

High Prevalence of Iron Deficiency among Educated Hospital Employees in Switzerland.

Iron deficiency is known to cause symptoms such as fatigue, depression and restless legs syndrome resulting in impaired quality of life and working capacity. We sought to examine the iron status of reportedly healthy individuals by a framed study design in 58 highly educated Swiss hospital employees and to compare the use of non invasive tests for assessing iron deficiency (ID). A structured interview was used to assess health status, nutritional intake and potential blood loss, blood counts as well as parameters proposed to diagnose iron deficiency were determined. All subjects felt well and were working at their maximum capacity. The male subjects were neither anaemic nor had decreased iron parameters however 50% (23/46) of the women had a serum ferritin of below 22 µg/L, still 33% (15/46) of the women had a ferritin value below the more stringent cut off value of 15 µg/L. In 15% (7/46) of the women we diagnosed iron deficient anaemia. Red meat consumption correlated with ferritin values as did the menstrual blood loss which was estimated by asking the amount of tampons used. Of the additionally analysed iron parameters only the percentage of hypochromic erythrocytes, soluble transferrin receptor and transferrin values were significantly correlated with ferritin and reached an AUCROC of ≥0.7 indicating good predictive tests. Nevertheless neither soluble transferrin receptor nor transferrin showed diagnostic advantages for the diagnosis of ID compared to ferritin alone or together with erythrocyte parameters. Working in a hospital environment and having access to health education does not seem to correlate with prevention of ID or ID anaemia in female hospital employees.

Long-term follow-up of interferon-alpha induction and low-dose maintenance therapy in hairy cell leukemia.

OBJECTIVE: Interferon-alpha (IFNalpha) was the first effective pharmacologic treatment of hairy cell leukemia (HCL). Since 1990 purine analogs replaced IFNalpha because of higher rates of complete remission and an invariable disease recurrence after cessation of IFNalpha. However, there are only limited data about long-term maintenance treatment with IFNalpha and none about dose finding in this phase. PATIENTS AND METHODS: Fifty-two consecutive patients treated at our institution for HCL are included in this retrospective analysis. Forty (77%) patients received IFNalpha and 35 patients continue on long-term IFNalpha maintenance therapy. The initial dose of IFNalpha was 3 Mio IU three times per week and was tapered 6 months after initiation to doses as low as 3 Mio IU/12 wk. Dose adaptation was performed by repeated measurement of soluble Interleukin 2 receptor (sIL2R) together with peripheral blood values. RESULTS: The median follow-up of patients in the long-term IFNalpha group was 13.6 +/- 7.5 yr. Long-term IFNalpha was in general well tolerated and only in six (17%) patients the treatment had to be changed to purine analogs in the long-term IFNalpha group because of side effects. There are no deaths directly related to HCL. CONCLUSIONS: IFNalpha is still an effective and well tolerated therapeutic option. By repeated measurements of sIL2R together with the peripheral blood values, IFNalpha doses can be tapered to the minimal effective dose. The advantages and disadvantage of IFNalpha in regards to the standard treatment in HCL patients are discussed.

G-CSF-induced remission in two cases of acute myeloid leukemia.

We report on two elderly patients with newly diagnosed acute myeloid leukemia (AML) who were treated in palliative intention because of comorbidities and intermediate or poor risk cytogenetics. Both received G-CSF to reduce the risk of infection related to neutropenia. Interestingly, one patient achieved a full hematological remission and the other a peripheral remission with dramatic reduction of the bone marrow blast count. Although a direct therapeutic effect of myeloid growth factors seems to be unusual in AML, the use of G-CSF or GM-CSF may be recommended in patients such as elderly patients who are not suited for intensive chemotherapy.

Retinal microangiopathy and rapidly fatal cerebral edema in a patient with adult-onset Still's disease and concurrent macrophage activation syndrome.

Hemophagocytic lymphohistiocytosis (HLH) is a complex inflammatory disease with multiple diagnostic and therapeutic pitfalls. The congenital form, referred to as familial hemophagocytic lymphohistiocytosis (FHL), is often associated with cerebromeningeal involvement, whereas neurological complications are not characteristic of the adult form of secondary HLH (sHLH). Here we report the case of a 20-year-old woman with adult-onset Still's disease (AOSD), retinal microangiopathy and concurrent macrophage activation syndrome (MAS), in the context of sHLH. Following treatment with etanercept, ibuprofen, methylprednisolone, and phenylbutazone for 3 weeks, MAS deteriorated and fatal cerebral edema occurred within only 24 h. The clinical signs and neuropathological findings are discussed with special emphasis on possible relationships between the aggravation of MAS and therapeutic interventions for AOSD. In conclusion, even the slightest sign of mental decline in a patient with AOSD must be considered central nervous system MAS which can be rapidly fatal.

Necrobiotic xanthogranuloma successfully treated with autologous stem cell transplantation.

Paraproteinemia can be complicated by necrobiotic xanthogranuloma. Therapeutic options for this progressive disease are limited, and there is no agreement on a single best strategy. We report the case of a patient with a massive periorbital infiltration narrowing the palpebral fissure and blinding the patient. Conventional myeloma therapy had only limited benefit in our patient. However, he was successfully treated with high-dose chemotherapy followed by autologous stem cell transplantation, rendering the patient free of symptoms. This is the first report of autologous stem cell transplantation in a patient with necrobiotic xanthogranuloma.

Novel, semi-automated, 60-min-assay to determine von Willebrand factor cleaving activity of ADAMTS-13.

INTRODUCTION: The clinical entity of idiopathic thrombotic thrombocytopenic purpura (TTP) has been closely associated with a severe deficiency of the von Willebrand factor (vWF)-cleaving protease (ADAMTS-13). Levels below 5% are highly specific for TTP basically excluding hemolytic uremic syndrome (HUS). Deficiency of ADAMTS-13 can either be inherited or caused by inhibitory IgG autoantibodies to ADAMTS-13. Diagnosis of TTP is often difficult since it often manifests oligosymptomatic exhibiting only laboratory signs of thrombocytopenia and hemolysis or involving atypical organs. In such cases rapid knowledge of the ADAMTS-13 activity is very useful in helping to establish a correct diagnosis rapidly and to initiate the appropriate therapy. METHODS AND RESULTS: We have therefore designed a rapid, sensitive and simple assay for the determination of ADAMTS-13 activity and ADAMTS-13 inhibitors. The test is based on the measurement of the ristocetin-cofactor activity of purified, urea-denaturated vWF concentrate after incubation with diluted patient plasma that has been preactivated with barium chloride. While this assay has already previously been established, we have further modified and simplified the test thereby improving markedly the sensitivity, accuracy and turn-around time. A major improvement proved to be the change from buffer to heat-treated and vWF-replenished plasma as diluent for making the serial dilutions of normal pool plasma (NPP) for the calibration curve. Set up as a semi-automated assay the test is performed in only 50 to 60 min. Tested in 15 patients with ADAMTS-13 deficiency this new assay compared favorably and even more accurately with the classic electrophoretic ADAMTS-13 assay, especially in the low range below 10%. Mixing studies with patient plasma and NPP (ratio 1:1) revealed that a relatively short period of only 30 min at room temperature is sufficient for most samples to detect an inhibitor. With a single mixing experiment it is possible to discriminate inhibitor levels in the range of 0.5-4 Bethesda units. CONCLUSION: Using this novel assay, determination of ADAMTS-13 activity and ADAMTS-13 inhibitors can be performed easily, rapidly (less than 2 h), and accurately, providing rapid information about the severity of ADAMTS-13 deficiency and the presence of an inhibitor. In addition, the test is suitable for full automation enabling to screen large populations and, thus, help to get further insights into the clinical significance of ADAMTS-13 deficiency in other diseases.

Functional expression of the CD163 scavenger receptor on acute myeloid leukemia cells of monocytic lineage.

The hemoglobin-haptoglobin (Hb-Hp) scavenger receptor CD163 is a monocyte/macrophage-restricted surface antigen, whose expression is strongly up-regulated by glucocorticoids. We have previously shown that CD163 is expressed by acute myeloid leukemia (AML) cells of monocytic lineage. Herein, we expand this finding by demonstrating constitutive and glucocorticoid-enhanced CD163 expression on French-American-British M4/M5 AML cells, and leukemic blasts of other AML subtypes and normal hematopoietic progenitor cells do not express CD163. We provide evidence that the functional characteristics of CD163 are preserved on malignant cells by showing the capability of types M4/M5 blast cells to internalize Hb-Hp by a CD163-mediated mechanism. Together, our results identify CD163 as a potential target for therapeutic intervention. It is important that CD163 does not appear to be released from leukemic blasts under noninflammatory conditions, thus reducing the probability of off-target side-effects as a result of competitive binding of potential therapeutic ligands to nonmembrane-bound CD163.

Clinical evaluation of an aerolysin-based screening test for paroxysmal nocturnal haemoglobinuria.

BACKGROUND: Recently, a toxin produced by Aeromonas hydrophila was demonstrated to bind directly to the glycosyl-phosphatidyl-inositol (GPI) anchor. After coupling it to a fluorescent dye and applying it in fluorescence-activated cell scanning (FACS), this property was exploited to detect GPI-negative cells in the diagnosis of paroxysmal nocturnal haemoglobinuria (PNH). METHODS: We used this reagent according to a very simple staining protocol followed by single-colour FACS and compared the results in patients with PNH and normal controls with those obtained with antibody-mediated detection of cells lacking GPI-anchored proteins. RESULTS: We observed very good concordance between the two methods, with correlation coefficients (R2) of quantified GPI-deficient cell populations ranging from 0.952 to 0.969. The lower limit of detection was determined at 0.50% GPI-negative cells, which was in the range obtained with double-colour staining with antibodies (0.20-1.00%, depending on the antibody). A significant correlation was observed between the fraction of GPI-negative granulocytes and laboratory parameters of haemolysis, with the erythrocyte creatine having the best correlation (R2 = 0.671, P < 0.0001). CONCLUSIONS: Using this protocol, we were able to reliably diagnose PNH with a high sensitivity. The test allows the identification of GPI-negative granulocyte populations as small as 0.5%.

Soluble hemoglobin-haptoglobin scavenger receptor CD163 as a lineage-specific marker in the reactive hemophagocytic syndrome.

Reactive hemophagocytic syndrome (RHS) is a disease of overwhelming macrophage activity triggered by infection, malignancy or autoimmune disorders. Currently used laboratory markers for the quantitative assessment of monocyte/macrophage activation lack lineage-restricted expression patterns and thus specificity. Serum levels of the macrophage specific scavenger receptor CD163 were determined by enzyme-linked immunosorbent assay (ELISA) and were found to be highly increased in patients with RHS (median 39.0 mg/L). Significantly lower levels were determined in patients with sepsis (median 9.1 mg/L), acute mononucleosis (median 8.2 mg/L), Leishmania infection (median 6.7 mg/L) and healthy controls (median 1.8 mg/L). Follow-up of patients with a relapsing course of the disease revealed close correlations of sCD163 with clinical disease activity, serum ferritin and other markers of macrophage activity. Large sinusoidal accumulations of CD163 expressing macrophages actively engaged in phagocytosis of blood cells were detected in spleen sections of RHS patients. Our data suggests sCD163 to be a macrophage-specific marker in patients with disorders of inappropriate macrophage activation.

A new highly unstable alpha chain variant causing alpha(+)-thalassemia: Hb Zurich Albisrieden [alpha59(E8)Gly-->Arg (alpha2)].

A new alpha-globin mutation causing persistent mild hypochromic microcytosis and erythrocytosis is described. Hb Zurich Albisrieden [alpha59(E8)Gly-->Arg (alpha2)] is not detected at the protein level and leads to alpha(+)-thalassemia (thal).

Analysis of cyclin D1 expression by quantitative real-time reverse transcription-polymerase chain reaction in the diagnosis of mantle cell lymphoma.

Mantle cell lymphoma (MCL) is characterized by typical morphologic features and the CD5+, CD23-immunophenotype. However, some morphologically typical MCLs are CD23+. A t(11;14)(q13;q32) translocation is frequently found in MCL, leading to overexpression of cyclin D1. We studied the expression of cyclin D1 in 50 small cell non-Hodgkin lymphomas by real-time reverse transcription-polymerase chain reaction. Most cases with typical MCL morphologic features and immunophenotype gave a strong signalfor cyclin D1, whereas most typical chronic lymphocytic leukemias/small lymphocytic lymphomas (CLLs/SLLs) gave weak or no signals. Based on these results, we determined a threshold value for the diagnosis of cyclin D1-overexpressing MCL. Cyclin D1 expression in 17 lymphomas with conflicting data from morphologic examination and immunophenotyping was variable. The concordance of cyclin D1 measurements with morphologic features and immunophenotype in typical cases proves the usefulness of the method. Unexpectedly high values were found in few CLL/SLL cases and in many CD23+ lymphomas with MCL morphologic features.