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Mobile health (mHealth) technologies have the potential to capture dense patient data on the background of real-life behavior. Merck & Co., Inc. (Kenilworth, NJ), in collaboration with Koneksa Health, conducted a phase I clinical trial to validate cardiovascular mHealth technologies for concordance with traditional approaches and to establish sensitivity to detect effects of pharmacological intervention. This two-part study enrolled 18 healthy male subjects. Part I, a 5-day study, compared mHealth measures of heart rate (HR) and blood pressure (BP) to those from traditional methods. Hypotheses of similarity, in the clinic and at home, were tested individually for HR, systolic BP, and diastolic BP, at a 2-sided 0.05 alpha level, with a prespecified criterion for similarity being the percentage differences between the 2 measurements within 15%. Part II, a 7-day, 3-period randomized balanced crossover study, evaluated the mHealth technology's ability to detect effects of bisoprolol and salbutamol. Hypotheses that the changes from baseline in HR were greater in the bisoprolol (reduction in HR) and salbutamol (increase in HR) groups compared with no treatment were tested, at a 1-sided 0.05 alpha level. Linear mixed-effects models, Pearson's correlation coefficients, summary statistics, and exploratory plots were applied to analyze the data. The mHealth measures of HR and BP were demonstrated to be similar to those from traditional methods, and sensitive to changes in cardiovascular parameters induced by bisoprolol and salbutamol.

BACKGROUND: Although the biopharmaceutical market grows rapidly, the environmental impacts of biopharmaceutical manufacturing have been hardly evaluated. The aim of the study is to comprehensively assess the environmental sustainability of a biologically‐produced active pharmaceutical ingredient (API) manufacturing process. For this purpose, an exergy analysis and an (exergetic) life cycle assessment were performed using primary (foreground system) and modeled data (background system). Infliximab, a monoclonal antibody, was considered. RESULTS: The fermentation and its raw materials' supply chain was determined to have the highest environmental impact, since the culture media requires chemicals and complex compounds such as animal‐derived materials (ADMs). The total impact per 100 mg of API produced ranged between 18.6 and 101.8 MJₑₓ and 2.0–3.1 kg CO₂‐eq, mainly as a function of the ADMs' source. A comparison of infliximab and ustekinumab, a biopharmaceutical produced without ADMs, showed that eliminating these materials can reduce the cumulative resource consumption of monoclonal antibody manufacturing by up to 7.5 times. The fermentation is the process taking the longest and the heating, ventilation and air conditioning system which support fermentation areas consumes approximately 75% of all plant electricity use. CONCLUSIONS: Culture media nutrients and cleanroom requirements are driving factors in the environmental impact of biological API manufacturing. Obtaining more precise data of the bioprocesses behind these nutrients' supply chain is crucial to corroborating this study's results. © 2019 Society of Chemical Industry

Improved understanding of cancer immunology has provided insight into the phenomenon of frequent tumor recurrence after initially successful immunotherapy. A delicate balance exists between the capacity of the immune system to control tumor growth and various resistance mechanisms that arise to avoid or even counteract the host's immune system. These resistance mechanisms include but are not limited to (i) adaptive expression of inhibitory checkpoint molecules in response to the proinflammatory environment and (ii) amplification of cancer stem cells, a small fraction of tumor cells possessing the capacity for self-renewal and mediating treatment resistance and formation of metastases after long periods of clinical remission. Several individual therapeutic agents have so far been developed to revert T-cell exhaustion or disrupt the cross-talk between cancer stem cells and the tumor-promoting microenvironment. Here, we demonstrate that a three-arm combination therapy-consisting of an mRNA-based vaccine to induce antigen-specific T-cell responses, monoclonal antibodies blocking inhibitory checkpoint molecules (PD-1, TIM-3, LAG-3), and antibodies targeting IL-6 and TGF-β-improves the therapeutic outcome in subcutaneous TC-1 tumors and significantly prolongs survival of treated mice. Our findings point to a need for a rational development of multidimensional anticancer therapies, aiming at the induction of tumor-specific immunity and simultaneously targeting multiple resistance mechanisms.

© 2015 International Association of Sedimentologists. Seismically induced event deposits embedded in the sedimentary infill of lacustrine basins are highly useful for palaeoseismic reconstructions. Recent well documented great megathrust earthquakes provide an ideal opportunity to calibrate seismically induced event deposits for lakes with different characteristics and located in different settings. This study used 107 short sediment cores to investigate the sedimentary impact of the 1960 Mw 9·5 Valdivia and the 2010 Mw 8·8 Maule earthquakes in 17 lakes in South Central Chile (i.e. lakes Negra Lo Encañado Aculeo Vichuquén Laja Villarrica Calafquén Pullinque Pellaifa Panguipulli Neltume Riñihue Ranco Maihue Puyehue Rupanco and Llanquihue). A combination of image analysis magnetic susceptibility and grain size analysis allows identification of five types of seismically induced event deposits: (i) mass transport deposits; (ii) in situ deformations; (iii) lacustrine turbidites with a composition similar to the hemipelagic background sediments (lacustrine turbidites type 1); (iv) lacustrine turbidites with a composition different from the background sediments (lacustrine turbidites type 2) and (v) megaturbidites. These seismically induced event deposits were compared to local seismic intensities of the causative earthquakes eyewitness reports post earthquake observations and vegetation and geomorphology of the catchment and the lake. Megaturbidites occur where lake seiches took place. Lacustrine turbidites type 2 can be the result of: (i) local near shore mass wasting; (ii) delta collapse; (iii) onshore landslides; (iv) debris flows or mudflows; or (v) fluvial reworking of landslide debris. On the contrary lacustrine turbidites type 1 are the result of shallow mass wasting on sublacustrine slopes covered by hemipelagic sediments. Due to their more constrained origin lacustrine turbidites type 1 are the most reliable type of seismically induced event deposits in quantitative palaeoseismology because they are almost exclusively triggered by earthquake shaking. Moreover they most sensitively record varying seismic shaking intensities. The number of lacustrine turbidites type 1 linearly increases with increasing seismic intensity starting with no lacustrine turbidites type 1 at intensities between V1/2 and VI and reaching 100 when intensities are higher than VII1/2. Combining different types of seismically induced event deposits allows the reconstruction of the complete impact of an earthquake.

The thymus is the organ devoted to T-cell production. The thymus undergoes multiple rounds of atrophy and redevelopment before degenerating with age in a process known as involution. This process is poorly understood, despite the influence the phenomenon has on peripheral T-cell numbers. Here we have investigated the FVB/N mouse strain, which displays premature thymic involution. We find multiple architectural and cellular features that precede thymic involution, including disruption of the epithelial-endothelial relationship and a progressive loss of pro-T cells. The architectural features, reminiscent of the human thymus, are intrinsic to the nonhematopoietic compartment and are neither necessary nor sufficient for thymic involution. By contrast, the loss of pro-T cells is intrinsic to the hematopoietic compartment, and is sufficient to drive premature involution. These results identify pro-T-cell loss as the main driver of premature thymic involution, and highlight the plasticity of the thymic stroma, capable of maintaining function across diverse interstrain architectures. ispartof: EUROPEAN JOURNAL OF IMMUNOLOGY vol:45 issue:5 pages:1535-1547 ispartof: location:Germany status: published

Dendritic cell therapy has been optimized a lot aiming to induce a strong and broad immune response in terms of the recognized epitopes by both CD8+ and CD4+ T cells and the use of the patients' complete unique set of HLA molecules. We here give an overview of our approach for antigen loading and maturation of dendritic cells and describe the consequences to evaluate the immune response after treatment as well as the Brussels experience in clinical trials.

Lago Puyehue is a glacigenic lake in the Chilean Lake District (40°S) with a complex deglaciation history. A detailed seismic–stratigraphic study of its sedimentary infill indicates a much earlier retreat of the glacier from the Lago Puyehue basin than the neighbouring glacier from the Lago Rupanco basin. Because of their close proximity, Rupanco meltwater streams played an important part in the depositional processes of Lago Puyehue. A timing discrepancy between the in-lake ages of a sediment core and the outer-lake ages of moraine deposits (re)opens the discussion on the timing of deglaciation in the Southern Hemisphere. Copyright © 2011 John Wiley & Sons, Ltd.

Body flexibility is of ever-increasing importance in multibody simulation. The current state-of-the-art simulation techniques typically have difficulties with systems in which flexible bodies can be loaded in many degrees of freedom (DOFs). However, in many applications, loading is possible in many DOFs but only few are loaded simultaneously at any given moment, such that at any moment only a low-dimensional part of the reduced body flexibility description contributes to the solution. Static Modes Switching, the methodology proposed in this paper, exploits this by judiciously choosing the body flexibility mode set and at any moment only including those modes that contribute to the solution. Static Modes Switching does not improve simulation accuracy; however, it can significantly reduce simulation times. In a numerical experiment, results using Static Modes Switching match results for a conventional model using the same mode set. The approximation errors are negligible compared to the accuracy loss encountered when using a mode set without compensation for the quasi-static response of the high-frequency dynamics, while both simulation results are obtained at a comparable computational cost. Static Modes Switching numerically introduces discontinuities when removing a mode from the mode set. This is overcome by time integration schemes exhibiting high-frequency numerical damping. Copyright © 2011 John Wiley & Sons, Ltd.

The double-edged nature of modern technology, continuously balancing between risks and opportunities, manifests itself clearly in an emerging societal problem known as cyberbullying. To analyse the extent and nature of the issue in Belgium, 1318 adolescents were questioned explicitly about their involvement in cyberbullying, as well as implicitly about their experience with specific types of cyberbullying-related behaviour. This alternate questioning revealed higher victimisation and perpetration rates. The study also provides better insight into predictors associated with victimisation or perpetration in cyberbullying. Especially past involvement in cyberbullying and engaging in online risk behaviour increase the likelihood of victimisation; non-rejection of cyberbullying and online identity experimentation augment the likelihood of perpetration. Girls are more likely to become victims of cyberbullying, whereas boys are more inclined to engage in electronic bullying. Moreover, the incidence of cyberbullying increases slightly with age. Finally, teens spending much time on the Internet, reporting higher ICT expertise and owning a computer with privileged online access share an increased likelihood of online bullying behaviour. � 2009 The Author(s). Children & Society � 2009 National Children’s Bureau and Blackwell Publishing Limited.

Flexible multibody systems are governed by sets of non-linear differential-algebraic equations (DAE). The number of degrees of freedom (DOFs) required for accurate body flexibility modeling, as well as the presence of the algebraic constraint equations limit the simulation speed. Body-level model reduction and general-purpose system-level model reduction techniques do not result in optimal model dimension reduction and do not necessarily transform the DAE-set into a cheaper to solve set of ordinary differential equations, as opposed to model reduction techniques, such as Global Modal Parameterization (GMP), which are based on describing the system motion by the contribution of its dominant (configuration-dependent) system-level modal patterns. Their use as a simulation tool has not been thoroughly investigated. This paper investigates the influence of the modal content of the configuration-dependent mode set on the simulation accuracy through numerical experiments. By including the dynamically excited eigenmodes and static deformation patterns for DOFs in which the system is externally loaded, the system can be accurately represented by a very limited number of DOFs. Phenomena such as mode veering and mode crossing, in which the modal content of eigenmodes rapidly varies, can be expected to be problematic for such a description, which is confirmed with numerical experiments. Copyright © 2010 John Wiley & Sons, Ltd.

Recently a new model reduction technique for flexible multibody systems has been introduced, namely the Global Modal Parameterization (GMP). This method uses a system-level model reduction, in which the reduction is parameterized by the rigid position of the system and a small flexible deformation superposed on this rigid position. Because of the non-linearity, the projection base for reduction is position dependent. This position dependence leads to strongly non-linear inertial terms, with associated increased storage requirements and computational load. This paper gives a short overview of the GMP-method and focuses predominantly on the derivation of the reduced inertial forces. Three different approximations for the inertial terms are presented and numerically validated. It is shown that a substantial reduction in storage requirements, while maintaining accurate results, is possible through these approximations. Copyright © 2010 John Wiley & Sons, Ltd.

The launch of the first product is an important event for start-ups, because it takes the new venture closer to growth, profitability, and financial independence. The new product development (NPD) literature mainly focuses its attention on NPD processes in large firms. In this article insights on the antecedents on innovation speed in large firms are combined with resource-based theory and insights from the entrepreneurship literature to develop hypotheses concerning the antecedents of innovation speed in start-ups. In particular, tangible assets such as starting capital and the stage of product development at founding and intangible assets such as team tenure, experience of founders, and collaborations with third parties are considered as important antecedents for innovation speed in start-ups. A unique data set on research-based start-ups (RBSUs) was collected, and event-history analyses were used to test the hypotheses. The rich qualitative data on the individual companies are used to explain the statistical findings. This article shows that RBSUs differ significantly in their starting conditions. The impact of starting conditions on innovation speed differs between software and other companies. Although intuition suggests that start-ups that are further in the product development cycle at founding launch their first product faster, our data indicate that software firms starting with a beta version experience slower product launch. The amount of initial financing has no significant effect on innovation speed. Next, it is shown that team tenure and experience of founders leads to faster product launch. Contrary to expectations, alliances with other firms do not significantly affect innovation speed, and collaborations with universities are associated with longer development times.

Several clinical and laboratory studies have demonstrated electromagnetic interaction between implantable medical devices like pacemakers and cell phones being operated in close proximity. Those devices are largely now immune to phone interaction or procedures have been established to limit their interaction. The use of cell phones near people with implanted neural stimulators has not been studied. This research was initiated to investigate electromagnetic interaction between current cell phone technology and specific models of Cyberonics neural stimulators. Out of 1080 test runs conducted for this study, no interactions were observed, and it was concluded that the phone technologies examined in this study did not adversely affect the Cyberonics NeuroStar (Model 102) NeuroCybernetic Prosthesis (NCP) System. This article provides details on the experimental procedure that was used, which can also be used to test other neural stimulators and test technologies, and the results obtained.

Follicular lymphoma (FL) cells have inherited an activated hypermutation mechanism from their origin of germinal centre B cells. Based on today's knowledge of the intrinsic properties related to this mechanism and the VH base composition, reconsideration of previous reports should be made on a broader range of samples. The present study examined the mutation pattern of the VH genes expressed by 55 cases of FL. FL VH genes showed evidence of antigenic selection in 30% of cases with 88% carrying a functional sIg and 78.2% showing intraclonal variation. VH family and gene segment utilization was found to be roughly similar to that of normal B lymphocytes. FL VH genes revealed extensive variations. 17% of the VH exons harboured a total of five deletions, three duplications and two insertions as compared to the most homologous germline counterpart. The VH genes of one tumour displayed three populations with varying CDR3 length at diagnosis. At relapse, emergence of a differently mutated gene, additional mutations reminiscent of ongoing mutations or no variation was prominent. From this study the heterogeneity of FLs is well established and ongoing mutations are seen in the scope of the activated status of the hypermutation mechanism rather than antigen-stimulated tumour growth.

Recently it was reported that Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) infects bone marrow (BM) dendritic cells (DC) in multiple myeloma (MM) patients and therefore might play a role in MM development. Because of the use of myeloid growth factors like GM-CSF and G-CSF for the mobilization of peripheral blood progenitor cells (PBPC), the subsequent increase of DC precursors might imply a risk for KSHV contamination in PBPC grafts. Therefore, in this study leukapheresis products and ex vivo cultured CD34+ cell suspensions were analysed. KSHV DNA could not be amplified in any of them.

The present study aims at exploring which factors predict the willingness of adolescents to disclose personal information in response to online marketing requests. Our analyses show that especially privacy concerns and perceived benefits explain a considerable portion of variance in both willingness to disclose profile data (e.g. age, hobbies, favourite products) and contact data (e.g. phone number, e-mail address, home address). An interesting interrelationship was found between profile data and contact data disclosure. Contrary to our expectations, parental mediation strategies were only a weak predictor of teenagers’ willingness to disclose contact information. Policy implications that emerge from the central findings of this study are discussed.