Optimal alarm systems for count processes

In many phenomena described by stochastic processes, the implementation of an alarm system becomes fundamental to predict the occurrence of future events. In this work we develop an alarm system to predict whether a count process will upcross a certain level and give an alarm whenever the upcrossing level is predicted. We consider count models with parameters being functions of covariates of interest and varying on time. This article presents classical and Bayesian methodology for producing optimal alarm systems. Both methodologies are illustrated and their performance compared through a simulation study. The work finishes with an empirical application to a set of data concerning the number of sunspot on the surface of the sun

Integer-valued autoregressive processes with periodic structure

In this paper the periodic integer-valued autoregressive model of order one with period T, driven by a periodic sequence of independent Poisson-distributed random variables, is studied in some detail. Basic probabilistic and statistical properties of this model are discussed. Moreover, parameter estimation is also addressed. Specifically, the methods of estimation under analysis are the method of moments, least squares-type and likelihood-based ones. Their performance is compared through a simulation study. (C) 2009 Elsevier B.V. All rights reserved

Management of ibrutinib treatment in patients with B-cell malignancies: clinical practice in Portugal and multidisciplinary recommendations

Objectives: Ibrutinib, a potent inhibitor of the Bruton tyrosine kinase, has revolutionized the treatment of many B-cell malignancies. Ibrutinib has an established favorable toxicity profile with up to 8 years of experience in clinical trials; however, despite ibrutinib’s favorable toxicity profile, dose reductions and treatment discontinuations are becoming more evident in clinical practice, particularly in the setting of specific clinical contexts and patient characteristics. This manuscript is set to provide practical recommendations on the management of patients treated with this agent in daily practice. Methods: A group of multidisciplinary experts from Portugal met to discuss and highlight practical recommendations, supported on both literature and clinical insights, for the management of the treatment with ibrutinib. Results/discussion: Handling of both toxicities and drug–drug interactions during ibrutinib treatment poses several challenges to healthcare providers and can benefit from a multidisciplinary approach. The involvement of specialties, such as cardiology, infectiology and pharmacology, can bring an added value to patient care, not only in anticipating/managing safety issues and dose adjustments but also in enhancing adherence to treatment, ultimately improving the risk/benefit balance. Conclusion: By involving a multidisciplinary group of experts, this work provides a set of key recommendations to optimize care and outcomes for ibrutinib-treated patients. Despite not being a fully comprehensive review on the topic, it is intended as a framework to hematologists and other healthcare professionals who manage these patients in their daily clinical practice.The project received financial support from Janssen for logistics of expert meetings and editorial support. The sponsor had no influence on the opinions expressed here, which are those of the authors

Bioorthogonal Strategy for Bioprocessing of Specific-Site-Functionalized Enveloped Influenza-Virus-Like Particles

Virus-like particles (VLPs) constitute a promising platform in vaccine development and targeted drug delivery. To date, most applications use simple nonenveloped VLPs as human papillomavirus or hepatitis B vaccines, even though the envelope is known to be critical to retain the native protein folding and biological function. Here, we present tagged enveloped VLPs (TagE-VLPs) as a valuable strategy for the downstream processing and monitoring of the in vivo production of specific-site-functionalized enveloped influenza VLPs. This two-step procedure allows bioorthogonal functionalization of azide-tagged nascent influenza type A hemagglutinin proteins in the envelope of VLPs through a strain-promoted [3 + 2] alkyne-azide cycloaddition reaction. Importantly, labeling does not influence VLP production and allows for construction of functionalized VLPs without deleterious effects on their biological function. Refined discrimination and separation between VLP and baculovirus, the major impurity of the process, is achieved when this technique is combined with flow cytometry analysis, as demonstrated by atomic force microscopy. TagE-VLPs is a versatile tool broadly applicable to the production, monitoring, and purification of functionalized enveloped VLPs for vaccine design trial runs, targeted drug delivery, and molecular imaging.The authors acknowledge funding from the European Union (EDUFLUVAC project FP7-HEALTH-2013-INNOVATION), the Fundação para a Ciência e Tecnologia (FCT, Portugal; project HIVERA/0002/2013 and FCT Investigator to G.J.L.B.), EPSRC (to G.J.L.B.), the European Commission, Marie Skłodowska-Curie Actions (MSCA), and RISE project grant 644167. S. B. C., J. M. F., F. M., and D. G. acknowledge FCT for fellowships SFRH/BD/52302/2013, SFRH/BD/70423/2010, SFRH/BD/70139/2010, and SFRH/BPD/73500/2010, respectively. The authors acknowledge Ricardo Silva for all his help in fluorescence analysis implementation and fruitful discussions. The authors also acknowledge Patrícia Gomes-Alves for her help for mass spectrometry analysis. Mass spectrometry data was obtained by the Mass Spectrometry Unit (UniMS), ITQB/iBET, Oeiras, Portugal. G. J. L. B. is a Royal Society University Research Fellow and the recipient of a European Research Council Starting Grant (TagIt)

Lifestyle, metabolic disorders and male hypogonadism - A one-way ticket?

Hypogonadism is more frequent among men with common metabolic diseases, notably obesity and type 2 diabetes. Indeed, endocrine disruption caused by metabolic diseases can trigger the onset of hypogonadism, although the underlying molecular mechanisms are not entirely understood. Metabolic diseases are closely related to unhealthy lifestyle choices, such as dietary habits and sedentarism. Therefore, hypogonadism is part of a pathological triad gathering unhealthy lifestyle, metabolic disease and genetic background. Additionally, hypogonadism harbors the potential to aggravate underlying metabolic disorders, further sustaining the mechanisms leading to disease. To what extent does lifestyle intervention in men suffering from these metabolic disorders can prevent, improve or reverse hypogonadism, is still controversial. Moreover, recent evidence suggests that the metabolic status of the father is related to the risk of inter and transgenerational inheritance of hypogonadism. In this review, we will address the proposed mechanisms of disease, as well as currently available interventions for hypogonadism

A cryo-EM grid preparation device for time-resolved structural studies

Structural biology generally provides static snapshots of protein conformations that can provide information on the functional mechanisms of biological systems. Time-resolved structural biology provides a means to visualize, at near-atomic resolution, the dynamic conformational changes that macromolecules undergo as they function. X-ray free-electron-laser technology has provided a powerful tool to study enzyme mechanisms at atomic resolution, typically in the femtosecond to picosecond timeframe. Complementary to this, recent advances in the resolution obtainable by electron microscopy and the broad range of samples that can be studied make it ideally suited to time-resolved approaches in the microsecond to millisecond timeframe to study large loop and domain motions in biomolecules. Here we describe a cryo-EM grid preparation device that permits rapid mixing, voltage-assisted spraying and vitrification of samples. It is shown that the device produces grids of sufficient ice quality to enable data collection from single grids that results in a sub-4 Å reconstruction. Rapid mixing can be achieved by blot-and-spray or mix-and-spray approaches with a delay of ∼10 ms, providing greater temporal resolution than previously reported mix-and-spray approaches

International Veterinary Epilepsy Task Force Consensus Proposal: Outcome of therapeutic interventions in canine and feline epilepsy

Common criteria for the diagnosis of drug resistance and the assessment of outcome are needed urgently as a prerequisite for standardized evaluation and reporting of individual therapeutic responses in canine epilepsy. Thus, we provide a proposal for the definition of drug resistance and partial therapeutic success in canine patients with epilepsy. This consensus statement also suggests a list of factors and aspects of outcome, which should be considered in addition to the impact on seizures. Moreover, these expert recommendations discuss criteria which determine the validity and informative value of a therapeutic trial in an individual patient and also suggest the application of individual outcome criteria. Agreement on common guidelines does not only render a basis for future optimization of individual patient management, but is also a presupposition for the design and implementation of clinical studies with highly standardized inclusion and exclusion criteria. Respective standardization will improve the comparability of findings from different studies and renders an improved basis for multicenter studies. Therefore, this proposal provides an in-depth discussion of the implications of outcome criteria for clinical studies. In particular ethical aspects and the different options for study design and application of individual patient-centered outcome criteria are considered