Six-month therapy of CGRP monoclonal antibodies in real-world clinical practice: an interim analysis of efficacy and safety data

Introduction. Migraine is one of the most common disabling neurological disorders. Recently developed monoclonal antibodies to calcitonin gene-related peptide (CGRP) or its receptor are the first targeted medication for preventive therapy of both episodic and chronic migraine. They have been thoroughly investigated in clinical trials; however, there is little data from real-world clinical practice available to date. The aim of this study is to assess the efficacy and safety of 6 months of treatment with erenumab in real-world clinical practice and investigate the effect of the drug on the patients’ sensitivity to medicines for migraine headaches relief and patient satisfaction after treatment.Materials and methods. Our observational cohort prospective study included patients in our Headache Clinic prescribed monoclonal antibodies blocking the  CGRP-receptor  – erenumab. During the  investigation, we evaluated the  previous preventive therapy and its efficacy, the number of days with migraine per month, adverse events occurring during the erenumab treatment, depression and anxiety (HADS), migraine disability (MIDAS), the presence of allodynia (ACS-12) and improved response to acute therapy after treatment. A total of 42 patients participated in the study: 6 men, 36 women, the average age was 43.9 ± 12.2. Of them, 38 patients (90%) had chronic migraine. Thirty-two patients (76%) had previously been prescribed preventive therapy, which proved ineffective, and 10 patients (24%) had not once received any type of migraine prevention.Results. Among our patients, we identified 11 patients with resistant migraine and one patient with refractory migraine. During the study, two patients dropped out due to adverse events (constipation). Thirty patients continued the administration of erenumab 70 mg for at least six months. The average number of migraine days per month before treatment was 22.8, and after six months of treatment, it dropped to 7.3. Twenty-nine patients (72.5%) also noted that the response to acute headache treatment improved after the therapy.Conclusion. The results of our study are consistent with the international experience of using erenumab and confirm its effectiveness for migraine preventive therapy, including difficult-to-treat migraine cases. However, further studies with more participants and evaluation of predictors of successful monoclonal antibody therapy are still needed

ОСНОВНЫЕ ПОКАЗАТЕЛИ МЕДИЦИНСКОЙ ПОМОЩИ ОНКОЛОГИЧЕСКИМ БОЛЬНЫМ В АМУРСКОЙ ОБЛАСТИ

Materials of the research was accepted in the Russian accounting and reporting documents of cial cancer statistics. The article presents the main indicators of medical care for cancer patients in the Amur region, where the 2014 3012 registered new cases of malignant neoplasms, which is 8.9 % more than in the previous year (2013 year – 27.67). Under medical supervision were 15997 patients, i.e. 2 % of the population. Of these, a 45.5 % male and 54.5% female. The maximum number of cases was in the age group 50–69 years. Fewer patients with I–II stages of the process, but it was more of patients with advanced forms of cancer pathology. The number of patients identi ed during preventive examinations amounted to 593 (2013 – 513). Mortality remained at the same level – 120.3 (2013 year – 129.5), whereas the incidence for the last 5 years has increased from 221.7 to in 2010 to 249.9 in 2014 (per 100 000 population). Mortality in the rst year from the time of diagnosis has decreased to 28.4 % (2013 year – 29.4 %). The proportion of patients registered for 5 years or more is 54.5 %. In the cities and districts of the region signi cantly reduced the number of oncologists (2012 year – 22; 2014 year – 13). In 2014 registered 20 cases of malignant neoplasms in children. Data on spatial features of the cancer disease are the basis for the analysis of cancer epidemiology in a speci c region and is aimed primarily at the prevention of this disease. Материалами исследования являлись общепринятые в России учетно-отчетные документы официальной онкологической статистики. Приведены основные показатели оказания медицинской помощи онкологическим больным в Амурской области, где в 2014 г. зарегистрировано 3 012 новых случаев злокачественных новообразований, что на 8,9 % больше, чем в предыдущем году (в 2013 г. – 2 767). Под диспансерным наблюдением находились 15 997 пациентов, т.е. 2 % населения области. Из них мужчин – 45,5 %, женщин – 54,5 %. Максимальное число заболевших приходилось на возрастную группу 50–69 лет. Уменьшилось количество больных с I–II стадиями процесса, но больше стало пациентов с запущенными формами онкопатологии. Количество больных, выявленных при профилактических осмотрах, – 593 (в 2013 г. – 513). Смертность снизилась в сравнении с прежним уровнем – 120,31 0/0000 (в 2013 г. – 129,5 0/0000), тогда как заболеваемость за последние 5 лет выросла с 221,74 0/0000 в 2010 г. до 249,91 0/0000 в 2014 г. Летальность на первом году с момента установления диагноза снизилась до 28,4 % (в 2013 г. – 29,4 %). Удельный вес больных, состоявших на учете 5 и более лет, – 54,5 %. В 2014 году зарегистрировано 20 случаев злокачественных новообразований у детей. Данные о территориальных особенностях онкологической патологии являются основой для анализа эпидемиологии рака в конкретном регионе.

Viral infections during pregnancy - optimization of therapy

The article presents the results of a clinical study of a comparative assessment of the therapeutic efficacy, safety and tolerability of the drug Panavir, a solution for intravenous administration of 0.04 mg / ml with the preparations of the basic complex therapy of IVI in pregnant women in the II and III trimesters. The study revealed that the inclusion of the drug "Panavir" in the complex therapy of viral infections during pregnancy effectively reduces the risk of developing amnionitis, placenta and infection of the fetus; is safe for both the mother and the fetus and is not accompanied by side effects and undesirable phenomena.В статье представлены результаты клинического исследования сравнительной оценки лечебной эффективности, безопасности и переносимости препарата «Панавир», раствора для внутривенного введения 0,04 мг/мл с препаратами базовой комплексной терапии ВУИ у беременных во II и III триместрах. В результате исследования выявлено, что включение препарата «Панавир» в комплексную терапию вирусных инфекций во время беременности эффективно снижает риск развития амнионита, плацентита и инфицирование плода; безопасно как для матери, так и для плода и не сопровождается побочными эффектами и нежелательными явлениями

Phenotypic Variation and Bistable Switching in Bacteria

Microbial research generally focuses on clonal populations. However, bacterial cells with identical genotypes frequently display different phenotypes under identical conditions. This microbial cell individuality is receiving increasing attention in the literature because of its impact on cellular differentiation, survival under selective conditions, and the interaction of pathogens with their hosts. It is becoming clear that stochasticity in gene expression in conjunction with the architecture of the gene network that underlies the cellular processes can generate phenotypic variation. An important regulatory mechanism is the so-called positive feedback, in which a system reinforces its own response, for instance by stimulating the production of an activator. Bistability is an interesting and relevant phenomenon, in which two distinct subpopulations of cells showing discrete levels of gene expression coexist in a single culture. In this chapter, we address techniques and approaches used to establish phenotypic variation, and relate three well-characterized examples of bistability to the molecular mechanisms that govern these processes, with a focus on positive feedback.

Evolution of response dynamics underlying bacterial chemotaxis

© 2011 Soyer and Goldstein; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background: The ability to predict the function and structure of complex molecular mechanisms underlying cellular behaviour is one of the main aims of systems biology. To achieve it, we need to understand the evolutionary routes leading to a specific response dynamics that can underlie a given function and how biophysical and environmental factors affect which route is taken. Here, we apply such an evolutionary approach to the bacterial chemotaxis pathway, which is documented to display considerable complexity and diversity.Results: We construct evolutionarily accessible response dynamics starting from a linear response to absolute levels of attractant, to those observed in current-day Escherichia coli. We explicitly consider bacterial movement as a two-state process composed of non-instantaneous tumbling and swimming modes. We find that a linear response to attractant results in significant chemotaxis when sensitivity to attractant is low and when time spent tumbling is large. More importantly, such linear response is optimal in a regime where signalling has low sensitivity. As sensitivity increases, an adaptive response as seen in Escherichia coli becomes optimal and leads to 'perfect' chemotaxis with a low tumbling time. We find that as tumbling time decreases and sensitivity increases, there exist a parameter regime where the chemotaxis performance of the linear and adaptive responses overlap, suggesting that evolution of chemotaxis responses might provide an example for the principle of functional change in structural continuity.Conclusions: Our findings explain several results from diverse bacteria and lead to testable predictions regarding chemotaxis responses evolved in bacteria living under different biophysical constraints and with specific motility machinery. Further, they shed light on the potential evolutionary paths for the evolution of complex behaviours from simpler ones in incremental fashion

Dependence of Bacterial Chemotaxis on Gradient Shape and Adaptation Rate

Simulation of cellular behavior on multiple scales requires models that are sufficiently detailed to capture central intracellular processes but at the same time enable the simulation of entire cell populations in a computationally cheap way. In this paper we present RapidCell, a hybrid model of chemotactic Escherichia coli that combines the Monod-Wyman-Changeux signal processing by mixed chemoreceptor clusters, the adaptation dynamics described by ordinary differential equations, and a detailed model of cell tumbling. Our model dramatically reduces computational costs and allows the highly efficient simulation of E. coli chemotaxis. We use the model to investigate chemotaxis in different gradients, and suggest a new, constant-activity type of gradient to systematically study chemotactic behavior of virtual bacteria. Using the unique properties of this gradient, we show that optimal chemotaxis is observed in a narrow range of CheA kinase activity, where concentration of the response regulator CheY-P falls into the operating range of flagellar motors. Our simulations also confirm that the CheB phosphorylation feedback improves chemotactic efficiency by shifting the average CheY-P concentration to fit the motor operating range. Our results suggest that in liquid media the variability in adaptation times among cells may be evolutionary favorable to ensure coexistence of subpopulations that will be optimally tactic in different gradients. However, in a porous medium (agar) such variability appears to be less important, because agar structure poses mainly negative selection against subpopulations with low levels of adaptation enzymes. RapidCell is available from the authors upon request

Stochastic dynamics and mean field approach in a system of three interacting species

The spatio-temporal dynamics of three interacting species, two preys and one predator, in the presence of two different kinds of noise sources is studied. To describe the spatial distributions of the species we use a model based on Lotka-Volterra equations. A correlated dichotomous noise acts on \beta, the interaction parameter between the two preys, and a multiplicative white noise affects directly the dynamics of each one of the three species. We study the time behaviour of the three species in single site for different values of the multiplicative noise intensity, finding noise-induced oscillations of the three species densities with an anticorrelated behaviour of the two preys. Afterwards, by considering a spatially extended system formed by a two-dimensional lattice with N sites and applying a mean field approach, we get the corresponding moment equations in Gaussian approximation. Within this formalism we obtain the time behaviour of the first and second order moments for different values of multiplicative noise intensity, with \beta(t) subject to the same dichotomous noise source. Finally, we compare our results with those obtained by using a coupled map lattice model, consisting of a time discrete version of the Lotka-Volterra equations.Comment: 21 pages, 7 figures. Submitted to Centr. Eur. J. Phy

Signatures of a globally optimal searching strategy in the three-dimensional foraging flights of bumblebees

Simulated annealing is a powerful stochastic search algorithm for locating a global maximum that is hidden among many poorer local maxima in a search space. It is frequently implemented in computers working on complex optimization problems but until now has not been directly observed in nature as a searching strategy adopted by foraging animals. We analysed high-speed video recordings of the three-dimensional searching flights of bumblebees (Bombus terrestris) made in the presence of large or small artificial flowers within a 0.5 m3 enclosed arena. Analyses of the three-dimensional flight patterns in both conditions reveal signatures of simulated annealing searches. After leaving a flower, bees tend to scan back-and forth past that flower before making prospecting flights (loops), whose length increases over time. The search pattern becomes gradually more expansive and culminates when another rewarding flower is found. Bees then scan back and forth in the vicinity of the newly discovered flower and the process repeats. This looping search pattern, in which flight step lengths are typically power-law distributed, provides a relatively simple yet highly efficient strategy for pollinators such as bees to find best quality resources in complex environments made of multiple ephemeral feeding sites with nutritionally variable rewards

Advancing microbial sciences by individual-based modelling

Remarkable technological advances have revealed ever more properties and behaviours of individual microorganisms, but the novel data generated by these techniques have not yet been fully exploited. In this Opinion article, we explain how individual-based models (IBMs) can be constructed based on the findings of such techniques and how they help to explore competitive and cooperative microbial interactions. Furthermore, we describe how IBMs have provided insights into self-organized spatial patterns from biofilms to the oceans of the world, phage-CRISPR dynamics and other emergent phenomena. Finally, we discuss how combining individual-based observations with IBMs can advance our understanding at both the individual and population levels, leading to the new approach of microbial individual-based ecology (μIBE)

KEY INDICATORS OF MEDICAL CARE FOR CANCER PATIENTS IN THE AMUR REGION

Materials of the research was accepted in the Russian accounting and reporting documents of cial cancer statistics. The article presents the main indicators of medical care for cancer patients in the Amur region, where the 2014 3012 registered new cases of malignant neoplasms, which is 8.9 % more than in the previous year (2013 year – 27.67). Under medical supervision were 15997 patients, i.e. 2 % of the population. Of these, a 45.5 % male and 54.5% female. The maximum number of cases was in the age group 50–69 years. Fewer patients with I–II stages of the process, but it was more of patients with advanced forms of cancer pathology. The number of patients identi ed during preventive examinations amounted to 593 (2013 – 513). Mortality remained at the same level – 120.3 (2013 year – 129.5), whereas the incidence for the last 5 years has increased from 221.7 to in 2010 to 249.9 in 2014 (per 100 000 population). Mortality in the rst year from the time of diagnosis has decreased to 28.4 % (2013 year – 29.4 %). The proportion of patients registered for 5 years or more is 54.5 %. In the cities and districts of the region signi cantly reduced the number of oncologists (2012 year – 22; 2014 year – 13). In 2014 registered 20 cases of malignant neoplasms in children. Data on spatial features of the cancer disease are the basis for the analysis of cancer epidemiology in a speci c region and is aimed primarily at the prevention of this disease