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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.

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 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].

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.

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

Although the public's essential capacity for self-rule in the United States lies in the power of the ballot, there exist many barriers to voting, particularly for marginalized communities. These barriers cultivate less representative government and less inclusive public policy. Nonprofit and private health organizations, and in particular community health centers and safety-net hospitals, can help marginalized voting-eligible individuals overcome barriers to the ballot. With augmented, unbiased voter participation, elections would yield government that is more representative and public policy that is more equitable, while reducing costly and preventable health disparities. Health organizations can promote comprehensive, nonpartisan voter engagement through registration, mobilization, education, and protection of all voters.

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.

Background and Objective Olanzapine is an atypical antipsychotic indicated for the treatment of schizophrenia and, either as monotherapy or as an adjunct to lithium or valproate, for bipolar I disorder. Multiple daily doses of olanzapine do not affect the pharmacokinetics of lithium or valproate; therefore, concomitant olanzapine administration does not require dosage adjustment of lithium or valproate. ALKS 3831, a combination of olanzapine and the opioid receptor antagonist samidorphan (OLZ/SAM), is currently under development to provide the established antipsychotic efficacy of olanzapine while mitigating olanzapine-induced weight gain. Olanzapine is recognized as one of the most efficacious antipsychotics; however, the benefits of olanzapine are offset by its propensity to cause significant weight gain, which may lead to long-term metabolic sequelae. This study evaluated the effects of multiple daily doses of OLZ/SAM on the pharmacokinetics of lithium or valproate in healthy subjects. Methods This was an open-label, single-sequence, two-cohort study (ALKS3831-B101) conducted at a single center in the USA. Thirty-four healthy adult subjects were assigned (1:1) to receive lithium carbonate 300-mg tablets (cohort 1) or divalproex sodium 500-mg tablets (cohort 2), once every 12 h on days 1–7. Once-daily oral doses of OLZ/SAM (olanzapine 10 mg/samidorphan 10 mg) bilayer tablets were administered on days 8–18. Subjects resumed every 12-h doses of lithium or valproate concomitantly with the once-daily oral doses of OLZ/SAM on days 12–18. Plasma concentrations of lithium and valproic acid (valproate) were quantified in blood samples collected prior to and up to 12 h after lithium or valproate dose administration on days 7 and 18. Pharmacokinetic parameters of lithium and valproate, including maximum plasma concentration and area under the plasma concentration–time curve over a 12-h dosing interval, were calculated. The ratio of geometric means of maximum plasma concentration and area under the plasma concentration–time curve over a 12-h dosing interval in the presence and absence of OLZ/SAM, and its two-sided 90% confidence intervals, were derived from a mixed-effects model. Adverse events were monitored throughout the study. Results The 90% confidence intervals for the ratios of geometric means, in the presence vs. absence of OLZ/SAM, were within the equivalence interval of 80–125% for both maximum plasma concentration and area under the plasma concentration–time curve over a 12-h dosing interval of lithium and of valproate. The safety profiles of lithium or valproate co-administered with OLZ/SAM were consistent with what has been previously reported for lithium or valproate. The safety profile of OLZ/SAM was consistent with that observed in previous clinical studies with OLZ/SAM. Conclusions Consistent with previously reported findings on olanzapine, administration of multiple doses of OLZ/SAM did not have a clinically significant effect on the pharmacokinetics of lithium or valproate. Co-administration of OLZ/SAM and lithium or valproate was generally well tolerated; the safety profile of OLZ/SAM was consistent with that observed in previous clinical studies.

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.

Despite decades of investment in patient safety, unintentional patient harm remains a major challenge in the health care industry. Peer-to-peer assessment in the nuclear industry has been shown to reduce harm. The study team’s goal was to pilot and assess the feasibility of this approach in health care. The team developed tools and piloted a peer-to-peer assessment at 2 academic hospitals: Massachusetts General Hospital and Johns Hopkins Hospital. The assessment evaluated both the institutions’ organizational approach to quality and safety as well as their approach to reducing 2 specific areas of patient harm. Site visits were completed and consisted of semistructured interviews with institutional leaders and clinical staff as well as direct patient observations using audit tools. Reports with recommendations were well received and each institution has developed improvement plans. The study team believes that peer-to-peer assessment in health care has promise and warrants consideration for wider adoption.

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.

Background:ALKS 3831, a combination of olanzapine and samidorphan (OLZ/SAM) in development for schizophrenia, is intended to mitigate olanzapine-associated weight gain. This thorough QT (tQT) study evaluated OLZ/SAM effects on electrocardiogram parameters.Methods:In this randomized, double-blind, parallel-group study, 100 patients with stable schizophrenia were randomized 3:2 to either receive OLZ/SAM 10/10 mg (therapeutic dose) on days 2–4, 20/20 mg on days 5–8, and 30/30 mg (supratherapeutic dose) on days 9–13 with moxifloxacin-matching placebo on days 1 and 14, or a single dose of moxifloxacin 400 mg and matching placebo on days 1 and 14 (nested crossover design). Drug concentration relation to change from baseline in Fridericia-corrected QTc (ΔQTcF) was evaluated using a linear mixed-effect concentration-QTc (C-QTc) model. Adverse events were assessed.Results:The slope (90% CI) of the C-QTc was not significant for olanzapine or samidorphan (0.03 [−0.01, 0.08] and 0.01 [−0.01, 0.04] msec per ng/mL, respectively). Predicted placebo-corrected ΔQTcF (90% CI) was 2.33 (−2.72, 7.38) and 1.38 (−3.37, 6.12) msec at the observed geometric mean maximal concentration of olanzapine (62.6 ng/mL) and samidorphan (75.1 ng/mL), respectively, on day 13. A clinically relevant QT effect (ie, placebo-corrected ΔQTcF ≥10 msec) can be excluded for olanzapine and samidorphan concentrations up to ≈110 and ≈160 ng/mL, respectively. Assay sensitivity was confirmed by the C-QTc relationship of moxifloxacin. OLZ/SAM was well tolerated.Conclusions:OLZ/SAM, in doses and plasma concentrations up to supratherapeutic levels, was well tolerated and had no clinically relevant effects on electrocardiogram parameters, including QT interval, in patients with schizophrenia.Funding Acknowledgements:This study was funded by Alkermes, Inc.

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

The Discontinuous Deformation Analysis (DDA) method is an important tool for investigating the dynamics of systems composed of multiple discrete elements such as masonry structures and blocky rock masses. As such it has become a popular investigative tool in geotechnical and rock engineering research. In this paper dynamic verification studies of 2D and 3D-DDA performed by the rock mechanics research group at the Ben-Gurion University of the Negev, Israel (BGU), are reviewed. The analytical verifications developed and reviewed here allow critical assessment of the advantages and limitations of 2D and 3D-DDA, can be used as benchmark tests for attempted modifications to the original DDA code, for calibration of input numerical control parameters, and for quantitative and meaningful comparison with other numerical discrete element methods.