Pregnancy outcome in women with Gaucher disease type 1 who had unplanned pregnancies during eliglustat clinical trials

Gaucher disease type 1 (GD1) is an inherited lysosomal storage disorder caused by deficient enzymatic activity of acid β-glucosidase, resulting in accumulation of its substrate glucosylceramide, leading to debilitating visceral, hematologic, and skeletal manifestations. Women with GD1 are at increased risk for complications during pregnancy, delivery, and postpartum. Treatment with enzyme replacement therapy is generally recommended before and during pregnancy to reduce risks. Eliglustat, an oral substrate-reduction therapy, is a first-line treatment for adults with GD1 adults who have extensive, intermediate, or poor CYP2D6-metabolizer phenotypes (>90% of patients). We report on pregnancy outcomes among women in eliglustat trials who had unplanned pregnancies and female partners of men in the trials. In four phase 2 and 3 eliglustat trials of 393 adults with GD1, women of childbearing potential were required to use contraception, have monthly pregnancy tests, and discontinue eliglustat promptly if pregnant. In phase 2 and 3 trials, 18 women had 19 pregnancies, resulting in 14 healthy infants from 13 pregnancies (one set of twins), three elective terminations, one ectopic pregnancy, one spontaneous abortion, and one in utero death. Median estimated eliglustat exposure duration during pregnancy was 38 days. In phase 1 trials (non-GD1 subjects), one woman had a spontaneous abortion. Partners of 16 eliglustat-treated men with GD1 had 18 pregnancies, all resulting in healthy infants. Eliglustat is not approved during pregnancy due to limited data. Guidelines for clinicians and patients with GD that address use of eliglustat in women of childbearing potential are needed

Adaptive morphophysiological features of neottia ovata (Orchidaceae) contributing to its natural colonization on fly ash deposits

In previous decades, some species of the Orchidaceae family have been found growing in man-made habitats. Neottia ovata is one of the most widespread orchids in Europe, however it is quite rare in Russia and is included in several regional Red Data Books. The purpose of this study was to compare the chemical composition and morphophysiological parameters of N. ovata from two forest communities of the Middle Urals, Russia: natural and transformed (fly ash dump of Verkhnetagil’skaya Thermal Power Station) for determining orchid adaptive features. The content of most of the studied metals in the underground parts (rhizome + roots) of N. ovata was considerably higher than in the leaves, which diminished the harmful effect of toxic metals on the aboveground organs. The adaptive changes in the leaf mesostructure of N. ovata such as an increase in epidermis thickness, the number of chloroplasts in the cell, and the internal assimilating surface were found for the first time. The orchids from the fly ash deposits were characterized by a higher content of chlorophyll b and carotenoids than plants from the natural forest community that evidenced the compensatory response on the decrease in chlorophyll a. The ability of N. ovata from the transformed habitat to maintain a relatively favorable water balance and stable assimilation indexes further contribute to its high viability. The study of orchid adaptive responses to unfavorable factors is necessary for their successful naturalization and introduction into a new environment. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.The reported study was partly funded by RFBR and the Government of Sverdlovsk region, project number 20-44-660011 and the Ministry of Science and Higher Education of the Russian Federation as part of state task of the Ural Federal University, FEUZ-2020-0057

A comparative study of Epipactis atrorubens in two different forest communities of the Middle Urals, Russia

The objective of this study was to compare eco-physiological and morphological parameters of a regionally endangered orchid species, Epipactis atrorubens (Hoffm. ex Bernh.) Bess., growing in two forest communities (on serpentine and granite outcrops) of the Middle Urals, Russia. Biodiversity, dominance, and phytocoenosis studies showed the colonization of a wide range of plant species on both sites. The physicochemical properties of the soil, chemical composition and morphological features of E. atrorubens, growing under technogenic conditions (asbestos deposits), on serpentine outcrops and in the natural environment of the granite massif were studied for the first time. The serpentine substrate differed from the granite one by its greater stoniness, circumneutral pH and lower contents of available nitrogen and phosphorus. Extremely high concentrations of magnesium were found in the serpentine soil, some 79 times higher than in the granite substrate. High concentrations of nickel (94 times), chromium (59 times), cobalt (17 times), and iron (4 times) were found in the serpentine substrate, higher than in the granite substrate. The differences between the sites for available metal contents and for root and shoot metal contents were significantly less. Concentrations of most of the metals in the roots were higher than in the shoots. Despite higher metal concentrations and lower nitrogen and phosphorus levels in serpentine soils, E. atrorubens had a larger population and greater viability compared to those growing on granite. Plants on serpentine outcrops were characterized by the formation of a larger number of fruits, greater root lengths and thicker leaf blades, compared to plants on granites. The well-developed orchid mycorrhizae contributed to the survival of this species under unfavorable serpentine conditions. Hence, serpentine outcrops formed due to the mining of asbestos could be a suitable substrate for the light-demanding E. atrorubens due to its capacity to adapt to dry, rocky, nutrient-depleted soils and limited competition from other plants. © 2019, The Author(s).The work was supported by the Ministry of Science and Higher Education of the Russian Federation in the framework of the State Task of UrFU No. 6.7696.2017

Parameter-Independent Strategies for pMDPs via POMDPs

Markov Decision Processes (MDPs) are a popular class of models suitable for solving control decision problems in probabilistic reactive systems. We consider parametric MDPs (pMDPs) that include parameters in some of the transition probabilities to account for stochastic uncertainties of the environment such as noise or input disturbances. We study pMDPs with reachability objectives where the parameter values are unknown and impossible to measure directly during execution, but there is a probability distribution known over the parameter values. We study for the first time computing parameter-independent strategies that are expectation optimal, i.e., optimize the expected reachability probability under the probability distribution over the parameters. We present an encoding of our problem to partially observable MDPs (POMDPs), i.e., a reduction of our problem to computing optimal strategies in POMDPs. We evaluate our method experimentally on several benchmarks: a motivating (repeated) learner model; a series of benchmarks of varying configurations of a robot moving on a grid; and a consensus protocol.Comment: Extended version of a QEST 2018 pape

The Questionnaire Survey Method in Medicine on the Example of Treatment Adherence Scales

Aim. Development, testing and validation of the original questionnaire “Adherence Scale” (AS) in the PRIORITY and ANTEY observational studies (OS).Materials and methods. The OS PRIORITY assessed adherence to statins in 298 patients with high and very high cardiovascular risk for 3 months. The OS ANTEY assessed adherence to oral anticoagulants in 201 patients with non-valvular atrial fibrillation for 1 year. Adherence was assessed using the original AS questionnaire, for which external validation was performed (with the calculation of the Cohen's Kappa coefficient). The reference methods were the validated questionnaire and direct medical interview. And internal validation was performed (consistency of questions on the AS using Spearman's correlation analysis). The sensitivity, specificity (ROC analysis) and retest reliability of the adherence scale (Cronbach's alpha) were also determined.Results. In the OS PRIORITY Cohen's kappa for the AS and the reference method of direct medical survey was 0.76 (high consistency), and for the AS and the reference method of the validated questionnaire=0.28 (low consistency). High internal consistency of the questionnaire questions (correlation coefficient=0.78, p<0.0001) confirms the internal validity of the adherence scale. Evaluation of the main characteristics of the modified AS in the OS ANTEY showed high consistency between the results of the AS and the validated questionnaire: Cohen's kappa=0.94 (high external validity of the AS). The retest reliability of the AS was 0.76 (Cronbach's alpha). The internal consistency of the questionnaire was confirmed by a strong and statistically significant correlation between the test questions: Spearman's correlation coefficient=0.80, p<0.0001. The sensitivity of the test, determined using the ROC analysis, was 89%, and the specificity was 62%.Conclusion. The developed and tested new original questionnaire (modified version) – the AS – showed high indicators of reliability, validity and sensitivity. This ensures its reliability and ease of use for assessing various types of adherence and determining the leading factors of non-adherence, and also allows its use in scientific studies and clinical practice

Adaptive Redox Reactions Promote Naturalization of Rare Orchid Epipactis atrorubens on Serpentine Dumps Post Asbestos Mining

Epipactis atrorubens (Hoffm.) Besser. is a regionally rare orchid species with highly ornamental properties due to its very beautiful bright flowers, therefore it is of considerable interest as a horticultural plant for use in botanical gardens and greenhouses. The objective of the research was to assess metal accumulation and some pro-and antioxidant reactions in E. atrorubens, colonizing serpentine dumps post asbestos mining. Additionally, some physicochemical properties of substrates, microbiotic characteristics and water status were investigated in orchids growing on two serpentine dumps and in a natural forest habitat of the Middle Urals, Russia. The dump substrates were characterized by the strong stoniness and the high content of Mg, Ni, Cr and Co (by 1.8 times on average) compared to the natural habitat. In these sites, E. atrorubens was characterized by increased mycorrhization. In the rhizome and roots of E. atrorubens the concentrations of most metals studied were considerably higher (more than 4 times on average) than in the leaves. It was found that orchids colonizing serpentine dumps produced more lipid peroxidation products (by 1.4 times on average) in the leaves which was accompanied by the more active synthesis of such non-enzymatic antioxidants as ascorbate, free proline, soluble phenolic compounds (including flavonoids) and non-protein thiols. The study suggests that non-enzymatic antioxidants increased the adaptive potential of E. atrorubens and contributed to its naturalization on serpentine dumps post asbestos mining. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.20-44-660011; Russian Foundation for Basic Research, РФФИ; Ministry of Education and Science of the Russian Federation, Minobrnauka; Ural Federal University, UrFU: FEUZ-2020-0057Funding: The reported study was partly funded by RFBR and the Government of Sverdlovsk region, project number 20-44-660011 and the Ministry of Science and Higher Education of the Russian Federation as part of state task of the Ural Federal University, FEUZ-2020-0057

Presenting signs and patient co-variables in Gaucher disease : outcome of the Gaucher Earlier Diagnosis Consensus (GED-C) Delphi initiative

© 2018 The Authors. Internal Medicine Journal by Wiley Publishing Asia Pty Ltd on behalf of Royal Australasian College of Physicians.Background: Gaucher disease (GD) presents with a range of signs and symptoms. Physicians can fail to recognise the early stages of GD owing to a lack of disease awareness, which can lead to significant diagnostic delays and sometimes irreversible but avoidable morbidities. Aim: The Gaucher Earlier Diagnosis Consensus (GED-C) initiative aimed to identify signs and co-variables considered most indicative of early type 1 and type 3 GD, to help non-specialists identify ‘at-risk’ patients who may benefit from diagnostic testing. Methods: An anonymous, three-round Delphi consensus process was deployed among a global panel of 22 specialists in GD (median experience 17.5 years, collectively managing almost 3000 patients). The rounds entailed data gathering, then importance ranking and establishment of consensus, using 5-point Likert scales and scoring thresholds defined a priori. Results: For type 1 disease, seven major signs (splenomegaly, thrombocytopenia, bone-related manifestations, anaemia, hyperferritinaemia, hepatomegaly and gammopathy) and two major co-variables (family history of GD and Ashkenazi-Jewish ancestry) were identified. For type 3 disease, nine major signs (splenomegaly, oculomotor disturbances, thrombocytopenia, epilepsy, anaemia, hepatomegaly, bone pain, motor disturbances and kyphosis) and one major co-variable (family history of GD) were identified. Lack of disease awareness, overlooking mild early signs and failure to consider GD as a diagnostic differential were considered major barriers to early diagnosis. Conclusion: The signs and co-variables identified in the GED-C initiative as potentially indicative of early GD will help to guide non-specialists and raise their index of suspicion in identifying patients potentially suitable for diagnostic testing for GD.Peer reviewedFinal Published versio

Natural Forest Colonisation and Soil Formation on Ash Dump in Southern Taiga

Ash dumps occupy significant areas around the world and make a negative influence on the environment. This effect is decreased by their natural colonisation determined by the bioclimatic conditions of the area. The purpose of the current study was to identify the structure of the forest communities and the initial stages of soil formation on the ash dump in southern taiga. This study was carried out on three sites in the forest phytocoenosis formed in the process of revegetation of the Verkhniy Tagil Power Station ash dump over 50 years, as well as on two background forest sites in the Middle Urals. Complex geobotanical and soil studies were carried out. The results of the study show that forest phytocoenoses with a predominance of hardwood species (Betula pendula Roth and Populus tremula L.) and a small admixture of coniferous species can form on the non-recultivated ash dump within 50 years in a boreal zone. In total, the studied mixed forest phytocoenoses are similar in composition to zonal secondary forests, but differ by having lower height and diameter of the stand, as well as herb–shrub layer coverage. Their species density and floristic richness are also lesser. The study proved that the process of soil formation is also proceeding according to the zonal type in the ash substrate under forest communities. The results of the study can be applied to justifying the forecasts of ecosystem restoration on the technogenic substrate, as well as for the species selecting for their recultivation in the studied area and similar to it. © 2020 by the Committee on Forestry Sciences and Wood Technology of the Polish Academy of Sciences and the Forest Research Institute in S´kocin Stary

The problem of obesity «through the eyes» of patients (results of the survey of patients of the outpatient registry)

Aim. To assess, based on the results of the questionnaire, patients' awareness of the presence, possible causes and health effects of overweight /obesity; to determine patients' self-assessment of their own weight, information about the methods used to treat the disease, adherence to therapy.Material and methods. The survey of patients of the outpatient registry was carried out as part of a face-to-face visit of inclusion in the observational study of EVA using a specially designed questionnaire. Out of 582 patients of the PROFILE registry who came for a visit in the period from 08.04.2019 to 24.03.2020, 295 people with a body mass index (BMI) were included in the study>25 kg/m2.Results. According to the BMI values, the patients of the study cohort were divided into 4 groups: 108 (36.6%) with pre-obesity, 124 (42.1%) with class I obesity, 42 (14.2%) with class II obesity, 21 (7.1%) with class III obesity. With an increase in the class of obesity, the number of patients who admit the presence of this pathology in self-assessment increases (p<0.0001): 26.6% of patients with grade I obesity, 47.6% with grade II obesity and 81% of patients with grade III obesity gave correct answers. Among the possible causes of overweight/obesity, every third patient of the study indicated physical inactivity (31.3%) and every fifth specified excessive nutrition (20.8%). The majority of patients, 244 (82.7%), believe that being overweight worsens their health, the same number of patients, 255 (86.4%), are sure that they need to lose weight. The most common (70% of responses) for weight loss patients used various dietary restrictions, fasting, only 17% of patients increased the level of physical activity. Frequent violation of the principles of rational nutrition was revealed (insufficient amount of fruits and vegetables in the diet, salting food, eating a large amount of easily digestible carbohydrates. One hundred and thirty nine (47.1%) patients noted that it was difficult for them to observe any restrictions in food, to adhere to a diethalf of all patients and 70% of patients with class III obesity experience a constant feeling of hunger. Of the 25 patients to whom pharmacotherapy was recommended, 21 (84%) people were adherent.Conclusion. Overweight and obese patients are not always critical of self-assessment of their body weight, and the main reasons for being overweight or obese considered to be inactivity and various violations of the principles of rational nutrition. The patients of the study cohort were characterized by eating disorders and half of the patients showed signs of food addiction. Recommendations for the pharmacotherapy of obesity were received by less than 10% of patients in the study cohort, while the patients' adherence to drug therapy was high