Results of the non-interventional observational program: Influence of Novel COroNavirus on the condition of patients with liver and gastrointestinal Tract diseases and the effect of Ursodeoxycholic acid drugs and Rebamipide on the course of COVID-19 infection (CONTUR)

Intriduction. The course and outcome of COVID-19 infection in patients with liver and gastrointestinal tract diseases remain poorly understood. The article presents a multicenter non-interventional observational program conducted by the Russian Society for the Study of the Liver.Aim. To study the relationship between COVID-19 and injuries of gastrointestinal tract and liver, to assess the effect of therapy with UDCA and Rebamipide on the course and outcome of COVID-19 infection. Materials and methods. 460 patients were enrolled in the study, of which 46% were patients with gastrointestinal and liver diseases. Some patients received Rebamipide and UDCA at a dose of 15 mg/kg body weight, followed by assessment of the clinical and laboratory parameters.Results. In the study group, more severe lung injury and the course of infection were observed. The investigators detected three phenotypes of gastrointestinal tract injury: dyspeptic, diarrheal and painful. The latter was more common in patients with gastrointestinal diseases. Liver injury occurred in 87% of patients with COVID-19 (of which 44% had a history of liver disease). Increased ALT and AST were more often recorded in patients with obesity and diabetes mellitus and correlated with the severity of the infection. An inverse relationship was found between the albumin level and death and transfer to mechanical ventilation. At least 5-day Rebamipide therapy leads to reduction of diarrhea and abdominal pain (p < 0.00001 and p = 0.002), decrease in the levels of systemic inflammatory markers (CRP and ferritin, p<0.00001). The use of UDCA leads to a decrease of the systemic inflammation markers: ferritin and is associated with a significant decrease/normalization of ALT levels (p < 0.00001).Conclusions. In patients with diseases of the gastrointestinal tract and liver, COVID-19 develops in a more severe form and symptoms of gastrointestinal tract injury may prevail in the clinical picture. The severity of liver injury correlates with the severity of COVID-19 and a poor prognosis. Rebamipide reduces diarrhea and abdominal pain. UDCA prevents or reduces liver injury in COVID-19 infection. Both drugs reduce the level of systemic inflammation markers.

Cosmology at high redshift — a probe of fundamental physics

An observational program focused on the high redshift (2<z<6) Universe has the opportunity to dramatically improve over upcoming LSS and CMB surveys on measurements of both the standard cosmological model and its extensions. Using a Fisher matrix formalism that builds upon recent advances in Lagrangian perturbation theory, we forecast constraints for future spectroscopic and 21-cm surveys on the standard cosmological model, curvature, neutrino mass, relativistic species, primordial features, primordial non-Gaussianity, dynamical dark energy, and gravitational slip. We compare these constraints with those achievable by current or near-future surveys such as DESI and Euclid, all under the same forecasting formalism, and compare our formalism with traditional linear methods. Our Python code FishLSS — used to calculate the Fisher information of the full shape power spectrum, CMB lensing, the cross-correlation of CMB lensing with galaxies, and combinations thereof — is publicly available.

No evidence for loss of natalizumab effectiveness with every-6-week dosing: a propensity score–matched comparison with every-4-week dosing in patients enrolled in the Tysabri Observational Program (TOP)

Background: Extended interval dosing of natalizumab is associated with significantly lower progressive multifocal leukoencephalopathy risk compared with every-4-week (Q4W) dosing in patients with relapsing-remitting multiple sclerosis. Previous studies have suggested that natalizumab effectiveness is maintained in patients who switch from Q4W to extended interval dosing but have been limited by a lack of well-matched patient cohorts. Methods: Tysabri Observational Program (TOP) data as of November 2019 were used to identify patients with relapsing-remitting multiple sclerosis treated with natalizumab Q4W and those with a single physician-indicated dosing change from Q4W to every-6-week (Q6W) dosing after ⩾1 year of Q4W treatment. Patients were propensity score matched at the time of the switch from Q4W to Q6W dosing. Clinical outcomes (annualized relapse rate and probability of remaining relapse free or free of 24-week confirmed disability worsening) and safety outcomes were assessed for the two cohorts. Results: This study included 219 pairs of propensity score–matched Q6W and Q4W patients. Annualized relapse rates were similar for Q6W (0.150) and Q4W (0.157) patients. The probability of remaining relapse free [hazard ratio = 1.243 (95% confidence interval = 0.819–1.888); p = 0.307] and of remaining free of 24-week confirmed disability worsening [hazard ratio = 0.786 (95% confidence interval = 0.284–2.176); p = 0.644] did not differ significantly between Q6W and Q4W patients. Summarized safety results for the matched Q6W and Q4W patients are also presented. Conclusion: These real-world findings in well-matched patient cohorts from TOP demonstrate that natalizumab effectiveness is maintained in patients who switch to Q6W dosing after ⩾1 year of Q4W dosing. ClinicalTrials.gov identifier: NCT00493298

Results of the Russian Multi-Center Cooperative Prospective-Retrospective Observational Program for Hodgkin’s Lymphoma Treatment RNWOHG-HD1

Aim. The observational program was aimed at obtaining data on classical Hodgkin’s lymphoma (cHL) incidence in the Russian Federation, therapy options, and clinical outcomes of treatment. The aim of the prospective part of the program was to standardize the approaches to therapy and to compare its outcomes with off-protocol treatment. Materials & Methods. The prospective-retrospective observational program for Hodgkin’s lymphoma treatment engaged 32 regional and federal centers. It included 218 patients, 21 out of them were included into the prospective part of the RNWOHG-HD1 (Russian North-West Oncology and Hematology Group - Hodgkin Disease Study 1) program. The median age was 36 years (range 22-87 years). cHL stages I/II were identified in 48 % of patients, III/IV stages were reported in 52 % of patients. The prospective part of the program used escalating protocol in patients with stages I/IIA and without risk factors and de-escalating protocol in patients with advanced stages. Overall (OS) and progression-free (PFS) survivals were analyzed in 160 and 152 patients, respectively. PET-CT was used to assess the response in 33 % of patients. Results. The study used the following first-line chemotherapy regimens: ABVD in 42 %, BEACOPPst in 11 %, BEACOPP-14 in 17 %, BEACOPPesc in 25 %, and EACOPP in 1 % of cases. After the completion of first-line therapy objective response rate was 91 % including 61 % of complete responses. Response structure did not significantly differ in the groups of non-intensive therapy (ABVD and BEACOPPst), intensified regimens (BEACOPP-14, BEACOPPesc, and EACOPP), and treatment according to the RNWOHG-HD1 protocol (91 %, 92 %, and 96 %, respectively; p = 0.7226). In the total cohort the 3-year OS was 97 % (95% confidence interval [95% CI] 94-99 %), PFS was 87 % (95% CI 80-92 %). The 3-year PFS did not differ in ABVD, BEACOPPst, BEACOPP-14, BEACOP-Pesc, and RNWOHG-HD1 recipients (р = 0.37). International Prognostic Score (IPS) yielded significant results in PFS prediction for patients with IPS score of 5-6, but not for those with IPS score of 1-4 (p = 0.0028). Conclusion. The observational program showed that the majority of participating centers use the risk-adapted ABVD/ BEACOPPesc approach which explains no difference in PFS being found with the use of these chemotherapy options. The study demonstrated the need for PET-CT to assess the response since the CT alone cannot distinguish between complete and partial responses in a considerable number of patients. The prospective unified program for cHL treatment may well be implemented in the Russian Federation.

Monitoring clumpy wind accretion in supergiant fast-X-ray transients with XMM-Newton

Supergiant fast-X-ray transients (SFXTs) are a sub-class of supergiant high-mass X-ray binaries hosting a neutron star accreting from the stellar wind of a massive OB companion. Compared to the classical systems, SFXTs display a pronounced variability in X-rays that has long been (at least partly) ascribed to the presence of clumps in the stellar wind. Here, we report on the first set of results of an ongoing XMM-Newton observational program searching for spectroscopic variability during the X-ray flares and outbursts of the SFXTs. The goal of the paper is to present the observational program and show that the obtained results are in agreement with expectations, with a number of flares (between one and four) generally observed per source and per observation (20 ks-long, on average). We base our work on a systematic and uniform analysis method optimized to consistently search for spectral signatures of a variable absorption column density, as well as other parameters of the spectral continuum. Our preliminary results show that the program is successful and the outcomes of the analysis support previous findings that most of the X-ray flares seem associated to the presence of a massive structure approaching and being accreted by the compact object. However, we cannot rule out that other mechanisms are at work together with clumps to enhance the X-ray variability of SFXTs. This is expected according to current theoretical models. The success of these observations shows that our observational program can be a powerful instrument to deepen our understanding of the X-ray variability in SFXTs. Further observations will help us to obtain a statistically robust sample. This will be required to conduct a systematic analysis of the whole SFXT class with the ultimate goal being to disentangle the roles of the different mechanisms giving rise to these events.

Fifty Years of Atmospheric Boundary-Layer Research at Cabauw Serving Weather, Air Quality and Climate

An overview is given of 50-year Cabauw observations and research on the structure and dynamics of the atmospheric boundary layer. It is shown that over time this research site with its 200-m meteorological tower has grown into an atmospheric observatory with a comprehensive observational program encompassing almost all aspects of the atmospheric column including its boundary conditions. This is accomplished by the Cabauw Experimental Site for Atmospheric Research (CESAR) a consortium of research institutes. CESAR plays an important role in the educational programs of the CESAR universities. The current boundary-layer observational program is described in detail, and other parts of the CESAR observational program discussed more briefly. Due to an open data policy the CESAR datasets are used by researchers all over the world. Examples are given of the use of the long time series for model evaluation, satellite validation, and process studies. The role of tall towers is discussed in relation to the development of more and better ground-based remote sensing techniques. CESAR is now incorporated into the Ruisdael observatory, the large-scale atmospheric research infrastructure in the Netherlands. With Ruisdael the embedding of the Dutch atmospheric community in national policy landscape, and in the European atmospheric research infrastructures is assured for the coming decade.

Fixed-dose combination of amlodipine/indapamide/perindopril arginine — a rational and safe choice for blood pressure control in actual clinical setting: data of an observational program DOKAZATEL`STVO

Aim. To analyze the efficacy and tolerability of amlodipine/indapamide/perindopril arginine (Triplixam) in a subgroup of 790 people participating in the Russian observational program DOKAZATEL`STVO without use of other antihypertensive agents.Material and methods. The analysis included 790 patients with hypertension (HTN) (men — 37,9%, mean age — 60,0±10,2 years). The drug was administrated in one of 4 recommended dosages for 3 months. We assessed the dynamics of office and home blood pressure (BP) from visit 1 to visit 4 and the frequency of achieving the target BP <140/90 mm Hg in 3 months.Results. After 3 months, office systolic BP (SBP) decreased from 163,4±14,0 to 127,2±7,8 mm Hg, diastolic BP (DBP) — from 95,7±9,5 to 78,3±6,2 mm Hg (p 0,001). Home SBP in the morning decreased from 145,9±12,3 to 128,3±7,8 mm Hg, DBP — from 86,2±7,7 to 78,4±5,6 mm Hg (p<0,001). After 3 months, target office BP (<140/90 mm Hg) was achieved in 88,4% of subjects, home BP (<135/85 mm Hg) — 73%.Conclusion. The administration of Triplixam without additional antihypertensive agents results in a significant BP decrease by 36/17 mm Hg and rapid achievement of BP control in most patients. The combination is safe and well tolerated.

The RONO (Rank-Order-Normalization) Procedure for Power-Spectrum Analysis of Datasets with Non-Normal Distributions

Standard (Lomb-Scargle, likelihood, etc.) procedures for power-spectrum analysis provide convenient estimates of the significance of any peak in a power spectrum, based—typically—on the assumption that the measurements being analyzed have a normal (i.e., Gaussian) distribution. However, the measurement sequence provided by a real experiment or a real observational program may not meet this requirement. The RONO (rank-order normalization) procedure generates a proxy distribution that retains the rank-order of the original measurements but has a strictly normal distribution. The proxy distribution may then be analyzed by standard power-spectrum analysis. We show by an example that the resulting power spectrum may prove to be quite close to the power spectrum obtained from the original data by a standard procedure, even if the distribution of the original measurements is far from normal. Such a comparison would tend to validate the original analysis.

Real-world disability improvement in patients with relapsing–remitting multiple sclerosis treated with natalizumab in the Tysabri Observational Program

Background: Natalizumab has been associated with disability improvement as indicated by a confirmed Expanded Disability Status Scale (EDSS) score decrease. Objective: The aim of this study was to characterize disability improvement in patients in the Tysabri Observational Program (TOP), an ongoing observational study of relapsing–remitting multiple sclerosis patients initiating natalizumab in clinical practice. Methods: TOP data as of November 2018 were included. Confirmed disability improvement (CDI) was defined as a decrease ⩾1.0 confirmed 24 weeks later from a baseline EDSS score ⩾2.0. Confirmed functional system (FS) improvement was defined as a decrease ⩾1.0 confirmed 24 weeks later from a baseline score ⩾1.0 in that FS. Results: Of 5384 patients, 1287 (23.9%) had CDI; 51.8% experienced CDI in the first treatment year. Among patients with CDI, 56.6% had CDI ⩾1.5 points; 34.4% had CDI ⩾2.0 points. The cumulative probability of maintaining improvement 8 years after the CDI event was 52.6%. At treatment initiation, 5363 patients (85.2%) had impairment in ⩾1 FS. At 8 years, the cumulative probability of confirmed improvement in any FS was 88.8% and ranged from 38.3% to 58.6% in individual FS. Conclusion: These results highlight disability improvement as a potential benefit of natalizumab treatment. Improvements across all FS demonstrate the range of functional improvement.