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Aim A combination of olanzapine and samidorphan (OLZ/SAM) is in development for the treatment of patients with schizophrenia or bipolar I disorder and is intended to provide the efficacy of olanzapine while mitigating olanzapine-associated weight gain. This 52-week open-label extension ( NCT02873208 ; ENLIGHTEN-2-EXT) assessed the long-term safety and tolerability of OLZ/SAM in patients with schizophrenia. Methods Patients completing the 24-week randomized, double-blind, phase 3 ENLIGHTEN-2 study ( NCT02694328 ) comparing weight change from baseline to week 24 with OLZ/SAM versus olanzapine were eligible to enroll in the 52-week ENLIGHTEN-2-EXT study. Assessments included adverse events (AEs; each visit), weight/waist circumference (every other week for the first 8 weeks, then every 4 weeks thereafter), metabolic laboratory parameters (weeks 4, 12, 24, 36, and 52), Positive and Negative Syndrome Scale (PANSS) scores (weeks 2, 4, 8, 12, 24, 36, and 52), and Clinical Global Impression-Severity (CGI-S) scores (weeks 2 and 4, then every 4 weeks thereafter through week 48, and at week 52). Analyses were based on observed results using descriptive statistics. Baseline was relative to the first OLZ/SAM dose in the extension study. Results In total, 265 patients were enrolled and received at least 1 dose of OLZ/SAM; 167 (63.0%) completed the 52-week extension study. Common AEs (≥5%) were weight decreased (n = 23; 8.7%), extra dose administered (n = 21; 7.9%), headache (n = 18; 6.8%), and weight increased (n = 16; 6.0%). At week 52, the mean (SD) change from baseline for weight and waist circumference was −0.03 (6.17) kg and − 0.35 (6.12) cm, respectively. Changes in fasting lipid and glycemic parameters were generally small and remained stable over 52 weeks. During the extension, PANSS total scores remained stable, and at week 52, 81.3% of patients had CGI-S scores of 3 or less, reflecting mild illness severity. Conclusions OLZ/SAM was generally well tolerated over 52 weeks. Weight, waist circumference, metabolic laboratory parameters, and schizophrenia symptoms remained stable throughout the study.

Background The Israeli National Health Insurance Law provides permanent residents with a basket of healthcare services through non-profit public health insurance plans, independently of the individual’s ability to pay. Since 2015, several reforms and programs have been initiated that were aimed at reinforcing public healthcare and redressing negative aspects of the health system, and specifically the constant rise in private health expenditure. These include the “From Reimbursement-to-Networks Arrangement”, the “Cooling-off Period” program and the program to shorten waiting times. The objectives of this study were to identify, describe, and analyze changes in private hospitals in 1) the volume of publicly and privately funded elective surgical procedures; and 2) private health expenditure on surgical procedures. Methods Data on the volume and funding of surgical procedures during 2013–2018 were obtained from Assuta Medical Center, Hertzelia Medical Center, the Israeli Ministry of Health and the Central Bureau of Statistics. The changes in the volume and financing sources of surgical activities in private hospitals, in the wake of the reforms were analyzed using aggregate descriptive statistics. Results Between 2013 and 2018 the volume of surgical activities in private for-profit hospitals increased by 7%. Between 2013 and 2017, the distribution of financing sources of surgical procedures in private hospitals remained stable, with most surgical procedures (75–77%) financed by the voluntary health insurance programs of the health plans (HP-VHI). In 2018, following the regulatory reforms, a significant change in the distribution of financing sources was observed: there was a sharp decline in the volume of HP-VHI-funded surgical procedures to 26%. Concurrently, the share of publicly-funded surgical procedures performed in private hospitals increased to 56% in 2018.,. During the study period, private spending on elective surgical procedures in private hospitals declined by 53% while public funding for them increased by 51%. Conclusions and policy implications In the wake of the reforms, there was a substantial shift from private to public financing of elective surgical activity in private hospitals. Private for-profit hospitals have become important providers of publicly-funded procedures. It is likely that the reforms affected the public-private mix in the financing of elective surgical procedures in those hospitals, but due to the absence of a control group, causality cannot be proven. It is also unclear whether waiting times were shortened. Health reforms must be accompanied by a clear and comprehensive set of indicators for measuring their success.

BackgroundCombination olanzapine and samidorphan (OLZ/SAM), in development for schizophrenia and bipolar I disorder, is intended to provide the efficacy of olanzapine while mitigating olanzapine-associated weight gain. OLZ/SAM safety, tolerability, and efficacy from a 52-week open-label extension study in patients with schizophrenia are reported.MethodsPatients previously completing the 4-week, double-blind ENLIGHTEN-1 study switched from OLZ/SAM, olanzapine, or placebo to OLZ/SAM. Assessments included adverse events (AEs), weight, vital signs, Positive and Negative Syndrome Scale (PANSS), and Clinical Global Impression-Severity (CGI-S) scores. Baseline was prior to first dose of OLZ/SAM in the extension study.ResultsIn total, 281 patients enrolled, 277 received ≥1 OLZ/SAM dose, and 183 (66.1%) completed 52 weeks. Reasons for discontinuation included patient withdrawal (15.5%), loss to follow-up (6.9%), AEs (5.8%), and lack of efficacy (1.8%). AEs were reported in 136 (49.1%) patients; increased weight (13%) and somnolence (8%) were most common. Ten serious AEs were reported in eight patients (2.9%); none were considered treatment related. There were no deaths. Mean (SD) baseline weight was 79.1 (17.8) kg. Mean weight change from baseline to week 52 was 1.86 kg (2.79% increase). PANSS total and CGI-S scores continued to decline over 52 weeks (mean [95% CI] changes from baseline to week 52: −16.2 [−18.5, −14.0] and −0.9 [−1.0, −0.8], respectively).ConclusionOLZ/SAM was generally well tolerated in this extension study; most patients completed the 52-week treatment period with sustained improvement in schizophrenia symptoms. Mean increases in weight stabilized by week 6 with limited subsequent change through end of treatment.

Background A randomized, controlled, phase 3b study (ALPINE) evaluated efficacy and safety of a 2-month formulation of aripiprazole lauroxil (AL) using a 1-day initiation regimen in patients hospitalized for an acute exacerbation of schizophrenia. Paliperidone palmitate (PP) was used as an active control. Exploratory endpoint assessments included severity of illness, positive and negative symptoms, quality of life, caregiver burden, and satisfaction with medication. Methods Adults were randomly assigned to AL 1064 mg q8wk or PP 156 mg q4wk as inpatients, discharged after 2 weeks, and followed through week 25. Exploratory efficacy measures included the 3 original PANSS subscales, Clinical Global Impression−Severity (CGI-S) subscale, and caregiver Burden Assessment Scale. Exploratory patient-reported outcomes (PROs) included the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) and the Medication Satisfaction Questionnaire. Within-group changes from baseline through week 25 were analyzed for AL and PP separately. PROs were summarized based on observed data. Results Of 200 patients randomized (AL, n = 99; PP, n = 101), 99 completed the study (AL, n = 56; PP, n = 43). For AL, PANSS subscale and CGI-S scores improved from baseline through week 25 (mean [SE] change from baseline at week 25: Positive, −7.5 [0.70]; Negative, −3.9 [0.46]; General, −11.8 [0.83]; CGI-S, −1.3 [0.12]). Caregiver burden also improved (mean [SD] changes from baseline at week 9: −8.4 [10.15]; week 25: −8.9 [12.36]). Most AL patients were somewhat/very satisfied with treatment at each timepoint (70.8%–74.7%); mean Q-LES-Q-SF total scores were stable in the outpatient period. For PP, results were similar: PANSS Positive, −7.3 (0.67); Negative, −3.6 (0.69); General, −10.9 (1.22); CGI-S, −1.4 (0.16); caregiver burden, week 9: −8.8 (11.89) and week 25: −9.2 (14.55); satisfaction with treatment, 64.7%–69.3%; and stable Q-LES-Q-SF scores. Conclusions ALPINE patients initiating the 2-month AL formulation using the 1-day initiation regimen as inpatients and continuing outpatient care experienced schizophrenia symptom improvement, sustained patient satisfaction with medication, stable quality of life, and reduced caregiver burden. A similar benefit pattern was observed for PP. These results support the feasibility of starting either long-acting injectable in the hospital and transitioning to outpatient treatment. Trial registration ClinicalTrials.gov identifier: NCT03345979 [trial registration date: 15/11/2017].

In the presented case the patient with highly differentiated gastric adenocarcinoma developed a rare paraneoplastic syndrome with paraproteinemia, that resulted in hemorrhagic syndrome, severe anemia, hypercoagulation and complications of compatibility tests during blood transfusion.

Background A combination of olanzapine and samidorphan (OLZ/SAM) is in development to provide the established antipsychotic efficacy of olanzapine while mitigating olanzapine-induced weight gain. Methods Two multicenter, open-label, parallel-cohort studies were performed to evaluate the effect of moderate hepatic impairment (Child-Pugh score 7-9 [class B]; study 1) and severe renal impairment (estimated glomerular filtration rate: 15-29 mL/min/1.73 m2; study 2) on the pharmacokinetics, safety, and tolerability of a single dose of OLZ/SAM 5/10 mg. Results There was a 1.67-fold increase in area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) and a 2.17-fold increase in maximum plasma concentration (Cmax) of olanzapine, and a 1.52-fold increase in AUC0-∞ and a 1.63-fold increase in Cmax of samidorphan, in subjects with moderate hepatic impairment compared with healthy control subjects. Compared with healthy control subjects, subjects with severe renal impairment had a 33% and 56% reduction in clearance, a 1.51- and 2.31-fold increase in AUC0-∞, and a 1.32- and 1.37-fold increase in Cmax of olanzapine and samidorphan, respectively. Conclusion OLZ/SAM 5/10 mg was generally well tolerated under the conditions of the studies, with a safety profile consistent with that observed in other clinical studies of OLZ/SAM.

BackgroundRecently developed software utilizing artificial intelligence for fast detection and triage of stroke cases has the potential to accelerate stroke care and improve patient outcomes. We performed this analysis to evaluate the performance and time-to-notification of one such software - RAPID LVO.MethodsWe created a database of 151 consecutive acute stroke patients for whom CT scans were processed by the RAPID LVO software over a period of eight months. The LVO notification and time to notification of the software were collected, alongside patient information and the CTA findings.ResultsRAPID LVO achieved a sensitivity of 63.6% and specificity of 85.8% for large vessel occlusion, with an average time to notification of 32.53 minutes.ConclusionsRAPID LVO has low sensitivity, moderate specificity and high time-to-notification performance. Our study data demonstrated in particular low overall sensitivity (63%) for distal occlusions (M2-3). The disparity between the observed performance and the performance reported in RAPID LVO’s FDA clearance demonstrates the importance of independent, multi-center evaluation. The gap between the performance in this study compared to published records of RAPID AI may be due to differences in imaging hardware, software implementation, connectivity or clinical definitions.

Passage of the National Health Insurance Law (NHIL) in 1995 marked a turning point in the history of the Israeli healthcare system, ensuring sustainable, high-quality medical care to all eligible Israeli residents. Over 100 amendments have been made to the law over the years, yet additional adaptations are required to ensure the law’s relevance in years to come. In honor of the 25th anniversary of the passage of the law, the 19th annual Dead Sea Conference brought together prominent figures in the Israeli healthcare system for a discussion on “25 Years to the NHIL: Suggested Changes and Adaptations”. Key topics discussed in the conference were regulatory aspects related to the healthcare system, administration of medical services, and financial aspects pertinent to the NHIL. The following meeting report summarizes the insights and recommendations from this conference.

Background The Israeli public health system has seen a steady decline in public trust and confidence, which has resulted in an increased rate of individuals holding private and commercial health insurance policies that allow more choice of various services (especially choose the surgeon’s). This study evaluated the attitudes and beliefs of Israeli adults regarding public trust, equitability and choice within the public health system. Methods A cross-sectional telephone survey conducted among a representative random sample of Israeli adults (> 25 years). Participants responded to a 27-item questionnaire. Multivariate regression analyses were performed to determine the contribution of various socio-demographic variables to the perceptions of trust and equitability in the health system and the ability to choose a surgeon, As well as a possible links among these parameters. Results Of 865 adults that responded to the survey, most were women (51.8%), Jewish (68.6%), and married (73.0%). Trust in the public health system, the perception of the system’s equitability and the public’s perception of the importance of selecting a surgeon were inter-related. The results emphasize a possible association between three meaningful factors: the trust in the public health system, the perception of the system’s equitability and the public’s perception regarding the importance of selecting a surgeon. Conclusions Public trust in the public health system is a fundamental condition for maintaining an efficient and equitable health system in Israel. The survey suggests that uncertainty regarding the identity of the surgeon who will perform a procedure in a public hospital may be linked to a sense of insecurity and distrust of the public in the public health system. This study did not examine the causal relationship between the various factors, but the study data suggests a possible link between lower trust in the system and a lower perception of its equitability, and a subsequent associated increase in the public’s desire to select a surgeon. This study suggests to recognize public trust as a central and significant tool to strengthen public health system. One of the ways to strengthen the public’s confidence in the public health system could be to provide the patient with reliable information regarding parameters such as the identity of the senior surgeon in the operating room or the surgeon’s suitability for the patient’s medical condition.

PURPOSE: Assess systemic vascular endothelial growth factor-A (VEGF) levels after treatment with intravitreous aflibercept, bevacizumab or ranibizumab. DESIGN: Comparative-effectiveness trial with participants randomly assigned to 2-mg aflibercept, 1.25-mg bevacizumab, or 0.3-mg ranibizumab following a retreatment algorithm. PARTICIPANTS: Participants with available plasma samples (N=436) METHODS: Plasma samples were collected before injections at baseline, 4-week, 52-week and 104-week visits. In a pre-planned secondary analysis, systemic free-VEGF levels from an ELISA immunoassay were compared across anti-VEGF agents and correlated with systemic side effects. MAIN OUTCOME MEASURES: Changes in the natural log (ln) of plasma VEGF levels. RESULTS: Baseline free-VEGF levels were similar across all 3 groups. At 4 weeks, mean ln(VEGF) changes were −0.30±0.61, −0.31±0.54, −0.02±0.44 pg/ml for the aflibercept, bevacizumab, and ranibizumab groups, respectively. The adjusted differences between treatment groups (adjusted CI; P-value) were −0.01 (−0.12, +0.10; P=0.89), −0.31 (−0.44, −0.18; P

ObjectiveThe randomized, controlled, phase 3b ALPINE study evaluated efficacy and safety of a 2-month formulation of aripiprazole lauroxil (AL) initiated with a 1-day regimen during hospitalization for an acute exacerbation of schizophrenia; paliperidone palmitate (PP) was included as an active control. The primary efficacy outcome, within-group change from baseline in PANSS total score at 4 weeks, was previously reported. Here we report additional exploratory PANSS subscale endpoints and patient-reported outcomes (PROs).MethodsAdults aged 18–65 years were enrolled as inpatients and randomized to AL 1064 mg q8wk or PP 156 mg q4wk and discharged after 2 weeks of study treatment if clinically stable. Patients were followed as outpatients through week 25. Exploratory efficacy endpoints were PANSS subscale (Positive, Negative, and General) and Clinical Global Impression-Severity (CGI-S) scores. The Burden Assessment Scale was administered to patients’ nonprofessional caregivers (family member or friend). Exploratory PROs (Quality of Life Enjoyment and Satisfaction Questionnaire Short Form [Q-LES-Q-SF] and Medication Satisfaction Questionnaire) were assessed during the outpatient period. Within-group changes in PANSS subscales and CGI-S scores from baseline through week 25 were analyzed for AL and PP using mixed models with repeated measures. PROs were summarized based on observed data.ResultsIn total, 200 patients were randomized (AL, n=99; PP, n=101); 99 (AL, n=56; PP, n=43) completed the 25-week study. PANSS Positive, Negative, and General subscale scores improved with AL treatment as measured by change from baseline to week 25 (least squares [LS] mean [95% CI]: Positive, −7.0 [−8.1, −6.0]; Negative, −3.7 [−4.7, −2.8]; General, −11.1 [−12.7, −9.5]), as did CGI-S scores (LS mean [95% CI] change at week 25: –1.2 [–1.4 –1.0]). Caregiver burden decreased over the treatment period, with the largest decline noted at week 9 for AL patients’ caregivers (mean change from baseline at week 9: −8.4; week 25: −8.9). Over weeks 5, 9, and 17, 70.8%−74.7% of AL-treated patients were somewhat or very satisfied with treatment. Mean Q-LES-Q-SF total scores were stable. With PP, PANSS subscale and CGI-S scores improved from baseline to study end (LS mean [95% CI] changes at week 25: Positive, −7.1 [−8.2, −5.9]; Negative, −3.5 [−4.6, −2.5]; General, −10.4 [−12.1, −8.6]; CGI-S, −1.2 [−1.5, −1.0]). Mean caregiver burden decreased (week 9: −8.8; week 25: −9.2). Most PP patients were satisfied or very satisfied with treatment (64.7%−69.3% at weeks 5, 9, and 17), and mean Q-LES-Q-SF total scores were stable.ConclusionIn ALPINE, patients who initiated AL or PP in the hospital and continued treatment during outpatient care experienced improvement in schizophrenia symptoms and reported satisfaction with medication, decreased caregiver burden, and stable quality of life.FundingAlkermes, Inc.

Objective:Evaluate efficacy and safety of a 2-month dose of aripiprazole lauroxil (AL) with a 1-day initiation regimen during hospitalization for an acute exacerbation of schizophrenia.Methods:In the phase 3b double-blind ALPINE study, adults with schizophrenia were randomized to AL (AL NanoCrystal® Dispersion + oral aripiprazole 30 mg day 1; AL 1064 mg day 8 and every 8 weeks) or paliperidone palmitate (PP 234 mg day 1; PP 156 mg day 8 and every 4 weeks). Patients were discharged after 2 weeks of hospitalization and followed through week 25. Primary endpoint was within-group changes in PANSS total score from baseline to week 4 (observed cases). Secondary analyses included within-group changes at weeks 9 and 25 (observed) and between-group comparisons at weeks 4, 9, and 25 (MMRM). Adverse events (AEs) were monitored throughout the study.Results:200 patients were randomized (AL, n=99; PP, n=101); 56.6% and 42.6%, respectively, completed the study. Within-group changes from baseline in PANSS were −17.4 for AL and −20.1 for PP at week 4 (both groups, PConclusions:AL and PP were effective and well-tolerated for initiating treatment of schizophrenia in the hospital and continuing in the outpatient setting.Funding Acknowledgements:This study was funded by Alkermes, Inc.

Background: ALKS 3831, a combination of olanzapine and samidorphan (OLZ/SAM), is in development for the treatment of schizophrenia and is intended to provide the antipsychotic efficacy of olanzapine while mitigating olanzapine-associated weight gain. We report the safety, tolerability, and efficacy of OLZ/SAM in patients with schizophrenia in a phase 3, 52-week, open-label extension study.Methods:Patients aged 18–70 years who completed a previous phase 3, 4-week, inpatient acute efficacy study were switched from OLZ/SAM, olanzapine, or placebo to OLZ/SAM. Study assessments included adverse events (AEs), weight, clinical laboratory testing, and Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression-Severity (CGI-S) scores.Results:281 patients were enrolled; 277 (mean age, 41.4 years) received ≥1 dose of study drug, and 183 (66.1%) completed the extension study. The most common reasons for discontinuation were withdrawal by patient (15.5%), loss to follow-up (6.9%), and AEs (5.8%). AEs were reported in 136 (49.1%) patients; most were mild in severity. The most common AEs were increased weight (13.4%), somnolence (8.3%), nasopharyngitis (4.0%), and headache (4.0%). Mean weight increase from baseline in patients completing 52 weeks of treatment was 1.86 kg, a 2.79% increase. No clinically significant changes in mean laboratory parameters were observed. Mean (SD) changes from baseline to week 52 in PANSS total score and CGI-S score were –16.2 (15.41) and –0.9 (0.92), respectively (both PDiscussion:OLZ/SAM was generally well tolerated with a safety profile that supports long-term treatment. During this 52-week extension study, there were improvements in schizophrenia symptoms.Funding Acknowledgements:This study was funded by Alkermes, Inc.

OBJECTIVE Evaluate efficacy and safety of a 2-month formulation of aripiprazole lauroxil (AL) with 1-day initiation during hospitalization for acute exacerbation of schizophrenia followed by transition to outpatient care. METHODS The phase 3b double-blind Aripiprazole Lauroxil and Paliperidone palmitate: INitiation Effectiveness (ALPINE) study was conducted from November 2017 to March 2019. Adults with acute schizophrenia according to DSM-5 criteria were randomized (1:1) to AL (AL NanoCrystal Dispersion + oral aripiprazole 30 mg, day 1; AL 1,064 mg, day 8 and every 8 weeks [q8wk]) or paliperidone palmitate (PP 234 mg, day 1; PP 156 mg, day 8 and then q4wk) for 25 weeks. Patients remained hospitalized ≥ 2 weeks after randomization per protocol. Primary endpoint was within-group change in Positive and Negative Syndrome Scale total score (PANSST) from baseline to week 4. Secondary analyses included within- and between-group changes from baseline at various time points. Adverse events (AEs) and laboratory data were monitored. RESULTS A total of 200 patients were randomized (AL, n = 99; PP, n = 101); 56.6% and 42.6%, respectively, completed the study. For AL, the mean baseline PANSST was 94.1; scores were significantly reduced from baseline at week 4 (-17.4; P < .001) and were also reduced at weeks 9 (-19.8) and 25 (-23.3). With PP, PANSST also improved significantly from baseline (94.6) at week 4 (-20.1; P < .001) and also improved at weeks 9 (-22.5) and 25 (-21.7). The 3 most common AEs over 25 weeks in the AL group were injection site pain (17.2%), increased weight (9.1%), and akathisia (9.1%). The same AEs were the most common in the PP group (injection site pain [24.8%], increased weight [16.8%], and akathisia [10.9%]). CONCLUSIONS AL and PP were efficacious and well-tolerated for initiating treatment of schizophrenia in the hospital and continuing outpatient treatment. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT03345979.

Introduction in practice of therapeutic establishments in the RF of antiviral therapy of chronic viral hepatitis in the form of interferon-free schemes led to considerable increase of the frequency of the stable virologic response. Study objective: determination of virologic response predictors in CVHC patients when various therapeutic schemes are used. Materials and methods: Group 1 of CVHC 52 patients with genotype 1 of HCV received standard anti-viral therapy, Group 2 (21 subject) – interferon-free scheme (Viekira Pak+ Ribavirin). Genetic polymorphisms IL-28В rs12979860 (С>Т) and rs8099917 (Т>G) and blood interferon-γ induced protein – IP-10 were determined. Results: standard anti-viral therapy in Group 1 resulted in SVR (sustained viral response) in 29 patients (55.7%). In Group 2 that received Viekira Pak 100% SVR was achieved in spite of more frequent F3 and 4 stage of fibrosis, unsuccessful anti-viral therapy (9 persons), contraindications to IFN-α drugs (6 persons). Unfavorable genotypes IL-28B ТТ (rs12979860) and GG (rs8099917) were associated in Group 1 with lack of SVR, level of IP-10 in patients with SVR was lower than the one in non-respondents. The therapy by Viekira Pak was well tolerated and resulted in SVR despite presence of grave hepatic fibrosis/ cirrhosis, concomitant pathology, unfavourable options of IL-28B, high IP-10 protein levels. Conclusion: choice of optimal anti-viral therapy schemes for each patient with CVHC must be done taken into account all possible predictors, which allows optimizing the therapy and preventing the necessity of repeated therapy.

Aim of investigation. Nowadays the question, whether pegylated interferon should be completely abandoned in the treatment of chronic hepatitis C (CHC) is still open. Beneficial interferon properties include: absence of mutagenic capacity for hepatitis C virus and drug interaction, stimulation of host immune response. These qualities formed the basis for development of the Russian pegilated interferon-alpha 2b (Pegaltevir®, LLC «FARMAPARK», Russia) and carrying out doublestaged randomized open clinical trial: study of safety, tolerability and pharmacokinetics of Pegaltevir® at single injection of increasing doses in various groups of healthy volunteers - the I stage; studying of efficacy and safety of Pegaltevir® in comparison to PegIntron® (Schering-Plough, USA) at CHC as a part of double antiviral therapy with ribavirin (Rebetol®, Schering-Plough, USA) - the II stage. This article presents results of the II phase of investigation. Material and methods. Original study included 140 adult antiviral treatment-naive patients with CHC and compensated liver function. Patients (aged 18 to 70 years) were distributed into four groups. Group 1 (main group, Pegaltevir®/Rebetol® treatment) - 55 patients, HCV genotype 1; group 2 (comparison group, PegIntron®/Rebetol® treatment) - 20 patients, HCV genotype 1; group 3 (main group, Pegaltevir®/Rebetol® treatment) - 47 patients, non-genotype 1 (2 and 3); group 4 (comparison group, PegIntron®/ Rebetol ® treatment) with non-genotype 1 (2 and 3). Assessment of Pegaltevir® efficacy was carried out in 4 weeks (rapid virologic response, RVR) and 12 weeks of treatment (early virologic response, EVR) in groups 1 and 3 in comparison to corresponding scores in groups 2 and 4 (primary criteria of efficacy were estimated in all 140 patients enrolled in original study. The response rate at the moment of secession of antiviral therapy, the sustained virologic response (SVR), histologic response (comparison of paired liver biopsies) served as secondary efficacy criteria and were estimated in 129 patients who completed treatment. The safety analysis was carried out for each patients included in the protocol who received at least one Pegaltevir® dose in comparison to patients who received at least one dose of PegIntron®, - respectively 102 and 38 patients. Results. RVR was comparable in the Pegaltevir® and PegIntron® groups: 65,6 and 82,4% respectively (p>0,05). RVR frequency genotype one patients was 45,3% in Pegaltevir® treatment group and 66,7% in PegIntron® treatment group (p>0,1). At patients with non-genotype 1 (2 and 3): 92,5 and 100% respectively (p>0,05). RVO did not significantly differ in the studied groups: 91,6 and 97,1% for all genotypes respectively (р>0,1). RVO rate for genotype 1 patients in Pegaltevir® group was 86,8%, in PegIntron® treatment group - 94,4% (р>0,1), in non-genotype 1 patients (2 and 3) it reached 97,6 and 100% in the specified patient groups (р>0,1). Response rate at the moment of treatment secession for Pegaltevir® and PegIntron® was 87,4 and 97,1% respectively for all genotypes (р>0,05). In patients with HCV genotype 1 this score Pegaltevir® treatment group reached 79,3%, in PegIntron® group - 94,4% (р> 0,05), in non-genotype 1 patients (2 and 3) - 97,6 and 100% respectively (р>0,1). SVR rate at Pegaltevir® treatment was 82,1% (for all genotypes), PegIntron® - 82,4% (for all genotypes, p>0,1). In HCV genotype 1 patients in Pegaltevir® treatment group SVR made 73,6%, in PegIntron® treatment group - 83,3%, p>0,1, for non-genotype 1 (2 and 3) - 92,9 and 81,3%, p>0,1. No significant differences between basic and control groups at analysis of paired liver biopsies for fibrosis stage reduction rate, absence of negative changes for fibrosis severity and proportion of patients with fibrosis progression were found. Pegaltevir® and PegIntron® treatment groups were comparable safety profile, adverse events were expected, mainly of mild and moderate severity. Conclusion. The hypothesis of identical efficacy of the Russian drug Pegaltevir® tested in the protocol in comparison to PegIntron® was correct and proved. Safety of Pegaltevir® was comparable to safety of PegIntron® as well.

A predictive model is presented which allows estimating six-month-risk of cardiovascular disease in patients discharged from hospital after acute coronary syndrome. A database, that has been collected from 16 medical centers in seven Russian cities during seven years, was used to create the model. The database contains a wide range of clinical, biochemical and genetic characteristics. The approaches based on the use of optimal partitioning, such as the method of optimal valid partitioning (OVD) and the modified method of statistically weighted syndromes (MSWS), were used in order to create the predictive model. The accuracy of the model is quite well and is estimated by the value of AUC=0.72. This model shows the better predictive ability in comparison with the most widely used methods such as logistic regression, usage of decision trees, neural networks etс.

Aim . To assess the condition of adhesion function of endothelium in various clinical variants of primary mitral valve prolapse (MVP). Material and methods. Totally, 91 patient studied with primary MVP at the age 21 (19-24) y. First grade mitral regurgitation was found in 45,1% and II — in 54,9% patients. MVP was solitary variant (6,6%) and comorbid with 1-3 minor anomalies of the heart (93,4%). Doppler-echocardiography was done on Vivid07 equipment (Israel). The grade of systemic involvement of connective tissue was 2 (1,5-4,0) points. Controls were 10 healthy persons, matched by age, sex, smoking, body mass index. By the immune enzyme method we checked plasmatic concentrations of L-, E-, Р-selectins, ICAM-1, VCAM-1, PECAM-1 (Bender MedSystems GmbH, Austria). Findings are presented as mediana (25-75 percentiles). Results . In MVP patients the levels of Е-selectin — 43,0 (33,7-54,8) ng/ mL, ICAM-1 — 669,9 (546,4-883,3) ng/mL and VCAM-1 — 925,0 (707,5- 1215,0) ng/mL, were significantly higher, and the level of РЕСАМ-1 — 49,8 (40,4-63,2) ng/mL, in opposite, lower than in control group. L- and P-selectins levels in MVP group were measured as relevant to controls values (p>0,05). In regurgitation cases of II degree, the level of E-selectin and ICAM-1 were maximal (p

Background Patients with schizophrenia are known to experience many problems across the 24-hour sleep-wake cycle (SWC), including lower daytime physical activity levels, as well as a range of problems in nighttime sleep quality. However, self-report assessment of these parameters is challenging because of recall bias and confounding with other schizophrenia symptoms (eg, cognitive and negative symptoms). Quantitative measures such as sleep lab assessments are useful but may be prohibitively expensive and impractical for routine use, and do not represent sleep behavior in a real-world setting. Wearable digital measures such as actigraphy hold promise, but data on feasibility of longitudinal assessment of SWC are limited in schizophrenia outpatients. In this exploratory analysis, we evaluated feasibility and utility of wrist actigraphy to measure key activity and sleep parameters within a randomized, double-blind clinical trial. This trial followed recently stabilized schizophrenia outpatients on a fixed dose of a long-acting injectable (LAI) antipsychotic. Methods Exploratory actigraphy assessments were carried out in a 25-week, prospective, randomized, controlled trial (RCT) primarily designed to evaluate safety and effectiveness of aripiprazole lauroxil (AL) for treatment of schizophrenia (1-day initiation regimen and a 2-month dose interval). Paliperidone palmitate (PP) was included as an active control. Patients were enrolled and randomized as inpatients during an acute exacerbation of schizophrenia, were discharged after 2 weeks, and were followed as outpatients for the remainder of the 25 weeks. Actigraphy was used to assess SWC during the outpatient part of the study, with patients being offered wrist-worn Axivity AX3 (Axivity Ltd) accelerometers for continuous wear on the nondominant hand in two 2-week sessions. The first session started at week 3 (cycle 1) and the second at week 9 (cycle 2). Upon return of the accelerometers to the study site, data were uploaded to a central data management system (TrialTracker™, IXICO plc) and were evaluated in 24-hour increments to exclude periods of non-wear; cycles were analyzed individually. Actigraphy parameters included total sleep time (TST; average total time asleep over 24 hours), sleep efficiency (proportion of time asleep when resting), activity (circadian rhythm MESOR; average activity level over 24 hours), and other common actigraphic variables. Results The mean Positive and Negative Syndrome Scale (PANSS) total score in the population of patients remaining in the study at week 3 (n=162) was 75.7. Of these 162 patients, 145 received an actigraphy device and 126 provided ≥1 valid 24-hour recording interval in cycle 1 (n=113) and/or cycle 2 (n=81). Within-subject actigraphy profiles from cycle 1 and cycle 2 were consistent, allowing the analysis to be based on the combined data from the 2 cycles. For AL (n=61) and PP (n=65), values for mean±SD TST were 10.2±2.5 hours and 11.7±2.8 hours, sleep efficiency were 80.0%±9.4% and 82.8%±8.1%, and average activity (MESOR) were 122.0±33.5 counts/min and 104.0±36.0 counts/min, respectively. As baseline actigraphy was not collected prior to randomization in this study, conclusions regarding comparability between treatment groups are limited. Discussion This exploratory analysis demonstrates that actigraphy monitoring is feasible in stabilized patients with schizophrenia in an outpatient setting. This dataset offers some evidence on the relative stability of SWC for individual patients over time, as well as possible group differences based on demographic, symptom, or treatment factors. Data from this analysis can provide guidance for future actigraphy studies in schizophrenia.

Цель. Определить взаимосвязь нарушений сердечного ритма с ремоделированием миокарда и экспрессией молекул адгезии у молодых пациентов с пролапсом митрального клапана (ПМК). Материал и методы. Обследован 61 пациент (48 мужчин, 13 женщин, средний возраст 21,1±3,5 года) с первичным ПМК и нарушениями сердечного ритма. Степень пролабирования клапанов и клапанной регургитации – II и менее. Нарушения сердечного ритма были представлены синусовой аритмией, миграцией водителя ритма по предсердиям, наджелудочковой и желудочковой экстрасистолией, пароксизмальной наджелудочковой и желудочковой тахикардией, пароксизмальной фибрилляцией предсердий, синдромами и феноменами предвозбуждения желудочков, синдромом ранней реполяризации желудочков, синоатриальной блокадой II степени, атриовентрикулярной блокадой I–II степеней, блокадой правой ножки пучка Гиса. Группы сравнения сформировали 17 пациентов с первичным ПМК без аритмического синдрома и 10 здоровых людей, сопоставимых по полу и возрасту. Исследование структурно-функциональных показателей сердца проводили с помощью эхокардиографии (ЭхоКГ) в М-, Ви допплеровском режимах («Vivid-7», Израиль). Плазменные концентрации L-, E-, Р-селектинов, молекул адгезии 1-го типа – межклеточной (ICAM-1), тромбоцитарно-эндотелиальной (PECAM-1) и сосудистой (VCAM-1) были определены методом иммуноферментного анализа («Bender MedSystems GmbH», Австрия). Результаты. Пациенты с ПМК независимо от наличия аритмии характеризовались более высокими показателями ударного индекса, что свидетельствовало об объемной перегрузке, обусловленной митральной регургитацией. Наличие легкой и умеренной митральной регургитации не оказывало заметного влияния на возникновение аритмий. В случаях нарушений сердечного ритма при ПМК выявлена гиперэкспрессия ICAM-1 и VCAM-1. Риск клинически значимых аритмий увеличивался при индексе конечного диастолического объема более 61,7 мл/м2 (относительный риск (ОР) 3,9, 95% доверительный интервал (ДИ) 1,9–7,7), индексе конечного систолического объема более 24,3 мл/м2 (ОР 4,2, 95% ДИ 2,1–8,2), ударном индексе более 45,4 мл/м2 (ОР 3,3, 95% ДИ 1,7–6,7), концентрации VCAM-1 более 1588,8 нг/мл (ОР 2,3, 95% ДИ 1,1–4,9). Заключение. У молодых пациентов с ПМК и нарушениями сердечного ритма имеются структурнофункциональное ремоделирование миокарда и нарушения процессов межклеточного взаимодействия. Установлена взаимосвязь процессов ремоделирования и уровня молекулы VCAM-1 с тяжестью аритмического синдрома. Ключевые слова: пролапс митрального клапана; аритмии; ремоделирование миокарда; молекулы адгезии.

BACKGROUND: ALKS 3831, currently under development for the treatment of schizophrenia, is composed of a flexible dose of olanzapine and a fixed dose of 10 mg of samidorphan. Samidorphan is intended to mitigate weight gain associated with olanzapine treatment alone. Here, we report the safety, tolerability and efficacy of ALKS 3831 in subjects with schizophrenia that were enrolled in a phase 3, 52 week open-label extension study. Subjects had completed a phase 3, 4-week, double-blind, inpatient acute efficacy study of ALKS 3831 compared to olanzapine or placebo. METHODS: Subjects were switched from either ALKS 3831, olanzapine or placebo from the previous study to receive treatment with ALKS 3831 10/10 (10 mg olanzapine/10 mg samidorphan) as investigators were blinded to previous treatment. Subsequently, treatment could be increased to 15/10 or 20/10 at any time during the study at the discretion of the Investigator. Study assessments included adverse event monitoring, clinical laboratory testing, evaluation of extrapyramidal symptoms, PANSS and CGI-S rating scales (last observed on treatment visit), and weight (observed case). Sites were located in the United States, Ukraine, Serbia and Bulgaria. RESULTS: In total, 281 patients were enrolled in this extension study and 277 subjects received at least 1 dose of study drug with the majority of subjects being male (58.1%), a mean (SD) age of 41.4 (11.31) years, and white (78.7%). The baseline weight of all 277 subjects was 79.1 kg (SD=17.8 kg). A total of 183 (66.1%) subjects completed the treatment period. Overall, the most common reasons for early termination were withdrawal by subject (15.5%), lost to follow-up (6.9%) and adverse event (5.8%). 1.8% of subjects discontinued due to lack of efficacy. Treatment emergent adverse events (TEAEs) were reported in 136 (49.1%) subjects. Serious adverse events were reported in 8 (2.9%) subjects and none were considered related to study drug. No deaths were reported. Most of the TEAEs were mild in severity. The common TEAEs (≥4%) were weight increase (13%), somnolence (8%), nasopharyngitis (4%), and headache (4%). The mean weight increase from baseline was 2.79%. There was a statistically significant improvement in PANSS and CGI-S scores with a 14.0 (SE=1.11; p

The aim of this study was to investigate an association of polymorphic markers G(-308)A of TNF gene and Thr26Asn of LTA gene with the frequency of poor outcomes in patients with the history of acute coronary syndrome.Methods. A total of 1145 patients admitted to cardiological hospitals of Moscow, St. Petersburg, Kazan, Chelyabinsk, Perm, Stavropol, and Rostov-on-Don with ischemic heart disease exacerbation were examined. The maximum follow up time was 3.2 years. The identification of polymorphic marker allele was carried out by hybridization-fluorescent analysis using real-time polymerase chain reaction.Results. In case of Thr26Asn polymorphic marker of LTA gene we have not found any association with the frequency of poor outcomes in patients with the history of acute coronary syndrome. However, in case of G(-308)A polymorphic marker of TNF gene we have found the reliable association. The carriers of GA and AA genotypes has higher frequency of poor outcomes in comparison with the carriers of GG genotypes. The survival time to the endpoint for carriers of the GA and AA genotypes was 43.3 months (95% CI = 40.04 - 46.56) vs. 49.6 months (95% CI = 47.38 - 51.82) for carriers of theGG genotype (χ2 = 15.4; р < 0.001).The results of our study allow to make a conclusion that the G(-308)A polymorphic marker of TNF gene is significantly associated with hereditary predisposition to unfavourable outcome in patients with history of acute coronary syndrome.

Aim. To study the selected mediators of intracellular interactions and endothelial function in patients with myxomatous mitral valve prolapse (MVP). Material and methods. In total, 25 patients with myxomatous MVP, aged 18–29 years, were examined. The comparison groups included patients with MVP but no echocardiographic signs of myxomatosis and healthy individuals. The blood levels of the following mediators were measured: interleukin 1

В проспективном когортном исследовании изучено влияние полиморфизма -455G-А гена фибриногена B и уровня фибриногена плазмы крови на риск развития инсульта и системных тромбоэмболий у 102 пациентов с неклапанной формой ФП (83,3 % мужчин, средний возраст 52,9±8,4 года) в течение 24 месяцев. Определение полиморфизма -455G-A гена фибриногена В может быть рекомендовано с целью индивидуализации тактики антикоагулянтной терапии у больных с фибрилляцией предсердий., In a prospective cohort study the effect of the fibrinogen β-chain gene polymorphism -455G-A and fibrinogen plasma levels on the risk of stroke and systemic thromboembolism in 102 patients (83.3 % men, mean age 52.9±8.4 yrs) with non-valvular atrial fibrillation. Identification of fibrinogen B gene 455G-A polymorphism can be useful to customize the anticoagulation strategy in patients with atrial fibrillation.

Определялось клиническое значение сывороточных уровней интерферон-g индуцированного протеина (IP10) в прогнозировании устойчивого вирусологического ответа (SVR) на противовирусную терапию (ПВТ) хронического вирусного гепатита С (ХВГС) у 107 больных (50 женщин и 57 мужчин), средний возраст 43,0±1,1 лет. У 75 был диагностирован генотип 1 HCV (G1), у 32 пациентов не-1 генотип HCV (G2 или G3). Содержание IP-10 в сыворотке крови определяли методом ELISA. Содержание IP-10 в крови больных ХВГС значительно превышало показатели здоровых и зависело от активности аминотрансфераз и стадии фиброза печени. Стандартная ПВТ препаратами ПегИФН-а и рибавирином у 52 пациентов с G1 (SVR 54,9 %) и 27 с G2 или G3 (SVR 75 %) показала, что у больных, достигших SVR, исходный уровень IP-10 был ниже, чем у нон-респондеров. Определен прогностический уровень IP-10, выше которого вероятность достижения SVR при ПВТ ПегИФН-а и рибавирином сомнительна: < 403 пг/мл при G1 и < 433 пг/мл при G2 или G3. У 18 больных, получивших тройную ПВТ: ПегИФН-а/рибавирин + ингибиторы вирусных протеаз (УВО 77,7 %), исходное содержание IP-10 при разных результатах противовирусной терапии не различалось. Таким образом, при ХВГС уровень в крови IP-10 повышен и зависит от активности цитолиза и выраженности стадии печеночного фиброза. Содержание белка IP-10 при ХВГС может быть использовано в качестве предиктора исходов стандартной ПВТ., Clinical values were identified for serum levels of g interferon-induced protein (IP-10) to be employed in forecasting SVR to AVT for CHC, which was carried out involving 107 patients (50 females and 57 males); mean age 43.0±11 yrs. 75 of the patients were diagnosed with genotype 1 HCV (G1), while 32 patients were identified as having non-1 genotype HCV (G2 or G3). The IP-10 levels in blood serum were detected with the ELISA method. Patients with CHC had significantly higher blood IP-10 levels compared to healthy people, and that depended on the aminotransferases’ activity as well as on the stage of hepatic fibrosis. A standard AVT with pegIFN-а medications and ribavirin given to 52 patients with G1 (SVR 54.9 %) and 27 with G2 or G3 (SVR 75 %), showed that the patients who had reached SVR had their initial levels of IP-10 below that of non-responders. The prognostic level of IP-10 was detected, above which the likelihood of ending up at SVR in case of AVT with pegIFN-а and ribavirin was questionable: < 403 pg/ml for G1 and < 433 pg/ml for G2 or G3. In 18 patients who were given triple AVT pegIFN-а + ribavirin + viral proteases inhibitors (SVR 77.7 %) the initial levels of IP-10 at various outcomes of AVT were the same. Therefore, in case of CHC, the levels of blood IP-10 are elevated and depend on cytolysis activity and the degree of hepatic fibrosis. The levels of IP-10 protein in case of CHC may be used as a predictor regarding the standard AVT outcomes.