Funnel-based Reachability Control of Unknown Nonlinear Systems using Gaussian Processes

This paper aims to synthesize a reachability controller for an unknown dynamical system. We first learn the unknown system using Gaussian processes and the (probabilistic) guarantee on the learned model. Then we use the funnel-based controller synthesis approach using this approximated dynamical system to design the controller for a reachability specification. Finally, the merits of the proposed method are shown using a numerical example.Comment: Accepted in Indian Control Conference 202

Safety and Pharmacokinetic Profiles of Phosphorodiamidate Morpholino Oligomers with Activity against Ebola Virus and Marburg Virus: Results of Two Single-Ascending-Dose Studies

Two identical single-ascending-dose studies evaluated the safety and pharmacokinetics (PK) of AVI-6002 and AVI-6003, two experimental combinations of phosphorodiamidate morpholino oligomers with positive charges (PMOplus) that target viral mRNA encoding Ebola virus and Marburg virus proteins, respectively. Both AVI-6002 and AVI-6003 were found to suppress disease in virus-infected nonhuman primates in previous studies. AVI-6002 (a combination of AVI-7537 and AVI-7539) or AVI-6003 (a combination of AVI-7287 and AVI-7288) were administered as sequential intravenous (i.v.) infusions of a 1:1 fixed dose ratio of the two subcomponents. In each study, 30 healthy male and female subjects between 18 and 50 years of age were enrolled in six-dose escalation cohorts of five subjects each and received a single i.v. infusion of active study drug (0.005, 0.05, 0.5, 1.5, 3, and 4.5 mg/kg per component) or placebo in a 4:1 ratio. Both AVI-6002 and AVI-6003 were safe and well tolerated at the doses studied. A maximum tolerated dose was not observed in either study. The four chemically similar PMOplus components exhibited generally similar PK profiles. The mean peak plasma concentration and area under the concentration-time curve values of the four components exhibited dose-proportional PK. The estimated plasma half-life of all four components was 2 to 5 h. The safety of the two combinations and the PK of the four components were similar, regardless of the target RNA sequence.Keywords: Marburg virus, Ebola virus, Single-ascending-dose studies, Phosphorodiamidate morpholino oligomer

AVI-7288 for Marburg Virus in Nonhuman Primates and Humans

BACKGROUND: AVI-7288 is a phosphorodiamidate morpholino oligomer with positive charges that targets the viral messenger RNA that encodes Marburg virus (MARV) nucleoprotein. Its safety in humans is undetermined. METHODS: We assessed the efficacy of AVI-7288 in a series of studies involving a lethal challenge with MARV in nonhuman primates. The safety of AVI-7288 was evaluated in a randomized, multiple-ascending-dose study in which 40 healthy humans (8 humans per dose group) received 14 once-daily infusions of AVI-7288 (1 mg, 4 mg, 8 mg, 12 mg, or 16 mg per kilogram of body weight) or placebo, in a 3: 1 ratio. We estimated the protective dose in humans by comparing pharmacokinetic variables in infected nonhuman primates, uninfected nonhuman primates, and uninfected humans. RESULTS: Survival in infected nonhuman primates was dose-dependent, with survival rates of 0%, 30%, 59%, 87%, 100%, and 100% among monkeys treated with 0 mg, 3.75 mg, 7.5 mg, 15 mg, 20 mg, and 30 mg of AVI-7288 per kilogram, respectively (P < 0.001 with the use of the log-rank test for the comparison of survival across groups). No safety concern was identified at doses up to 16 mg per kilogram per day in humans. No serious adverse events were reported. Drug exposure (the area under the curve) was dose-dependent in both nonhuman primates and humans; drug clearance was independent of dose but was higher in nonhuman primates than in humans. The protective dose in humans was initially estimated, on the basis of exposure, to be 9.6 mg per kilogram per day (95% confidence interval, 6.6 to 12.5) for 14 days. Monte Carlo simulations supported a dose of 11 mg per kilogram per day to match the geometric mean protective exposure in nonhuman primates. CONCLUSIONS: This study shows that, on the basis of efficacy in nonhuman primates and pharmacokinetic data in humans, AVI-7288 has potential as postexposure prophylaxis for MARV infection in humans

Effects of Roluperidone (MIN-101) on two dimensions of the negative symptoms factor score: Reduced emotional experience and reduced emotional expression

Recent research has suggested that negative symptoms (NS) can be considered in terms of two different dimensions: reduced expression (expressive deficit) and reduced experience (experiential deficit). Roluperidone, a compound with high affinities for 5 HT2A and sigma2 receptors, has previously shown superiority over placebo on improving NS in a prospective study in patients with schizophrenia. The objective here is to explore the effect of roluperidone compared to placebo, on the 2 domains of the Negative Symptoms. This was a multi-national Phase 2b trial that enrolled 244 symptomatically stable patients with schizophrenia who had baseline scores ≥20 on the NS subscale of the PANSS. Patients were randomized to daily monotherapy with roluperidone 32 mg, roluperidone 64 mg, or placebo in a 1:1:1 ratio. All enrolled patients were Caucasian, and 137 (56%) were male. The 3 treatment groups were balanced on all demographic and illness-related baseline characteristics. Both doses of roluperidone were superior to placebo on both domains: Reduced Experience (p ≤ .006 for the 32 mg; p ≤ .001 for the 64 mg) with persistent superiority from Week 2 for the 64 mg dose and Week 8 for the 32 mg dose; Reduced Expression (p ≤ .003 for 32 mg; p ≤ .001 for 64 mg) with similar persistence. Both doses of roluperidone previously improved PANSS negative symptoms in general and demonstrated tolerability in stable schizophrenia patients. The post hoc analysis reported here found the drug to work on both the reduced emotional experience and reduced emotional expression sub-scales empirically derived from the PANSS

Long-term effects of Roluperidone on negative symptoms of schizophrenia

Roluperidone has antagonist properties for 5-HT , sigma , α - and α -adrenergic receptors, but no dopaminergic binding affinities. In 2 randomized controlled trials (RCT), treatment improved negative symptoms of schizophrenia and social functioning among patients with moderate to severe negative symptoms. We report results of the protocol specified analysis of 2 open-label extension studies of 24 and 40 weeks investigating whether improvement of negative symptoms was sustained without significant adverse effects or worsening of psychosis. Following 12-week double-blind phase of both RCTs, patients were eligible to receive monotherapy roluperidone 32 mg/day or 64 mg/day for 24 weeks (trial 1) or 40 weeks (trial 2) in open-label extension study. Trial 1 included 244 patients of whom 142 entered 24-week open-label extension and trial 2 included 513 patients of whom 341 entered 40-week open-label extension. Trial 1 had PANSS negative factor score of Pentagonal Structure Model as primary outcome. Trial 2 had Marder Negative Symptoms Factor Score as primary outcome measure and Personal and Social Performance (PSP) Total score as secondary outcome. During open-label extensions, continued improvements in negative symptoms and on PSP were observed. Overall rate of symptomatic worsening requiring discontinuation of roluperidone and treatment with an antipsychotic was <10 %. Roluperidone was well tolerated with no meaningful changes in vital signs, laboratory values, weight gain, metabolic indices, or extrapyramidal symptoms. Results of 2 open-label extension trials support roluperidone as a treatment of negative symptoms and social functioning deficits in patients with moderate to severe negative symptoms of schizophrenia

Effet de la Paroxetine sur le sommeil de patients dépressifs analysé avec Somno-Art et la polysomnographie

Objectif: La dépression, ainsi que l’utilisation d’antidépresseurs, sont associées à une modification de l’architecture du sommeil. Somno-Art, une solution de scoring automatique du sommeil à partir de la fréquence cardiaque et du mouvement, a été validée dans diverses études incluant des sujets sains et des patients. Ici, nous nous interrogeons de la capacité de Somno-Art à détecter des modifications de l’architecture du sommeil suite à la prise d’un antidépresseur, la Paroxetine. Méthodes: Onze patients souffrant de dépression ont été enregistrés lors d’une nuit de baseline suivie d’une nuit après une dose de Paroxétine. Les stades de sommeil ont été obtenu à partir de la PSG et de l’analyse Somno-Art. Résultats: Les analyses PSG et Somno-Art montrent une augmentation significative du sommeil NREM et une diminution significative du sommeil REM après la prise de Paroxetine. Aucun autre paramètre de sommeil ne montre de variation significative, mais nous pouvons voir que les tendances observées avec la PSG sont également visibles avec l’analyse Somno-Art. Conclusion: Somno-Art montre des différences comparables à la PSG pour les principaux paramètres du sommeil. La solution permet de tirer les mêmes conclusions concernant l’effet potentiel du médicament sur le sommeil. Ainsi, Somno-Art propose une solution ambulatoire fiable pour l’évaluation des paramètres du sommeil qui pourrait avoir tout son intérêt pour des essais pharmaceutiques

Variabilité interscoreurs entre 5 centres de sommeil comparé à une analyse cardio-actimétrique

Introduction: Health literacy is the ability to understand the basic health information and to receive and manage health services that allow an individual to make appropriate healthcare decisions. Within medicine, the recommendation is for patient education materials to be written at no higher than fifth grade. However, most materials have been found to be written at greater than eighth grade literacy. The health literacy of a patient with head and neck cancer (HNC) has an ability to affect cancer treatment and outcomes. We evaluated the health literacy and the associated factors in patients diagnosed with HNC. Methods: This was a retrospective chart review of patients with HNC who presented for pretreatment evaluation with an embedded psych-oncologist in Otolaryngology department of an academic medical center from 2018 to 2021. The outcome variable was health literacy which was measured using the Rapid Evaluation of Adult Literacy in Medicine (REALM-SF) tool. The REALM-SF, a validated instrument, is a 7‐item word recognition test which provides scores of zero to seven. Zero points correlate to third grade and below, one to three points correlate to between fourth and sixth grade, four to six points correlate to seventh to eighth grade, and seven points correlate to high school reading level. In this study, adequate health literacy was defined as having a score of seven. Independent variables assessed included sociodemographic factors (age, sex, race, education level, employment status), smoking status, and psychosocial factors (relationship status, social support). Multivariable logistic regression model was used to examine the association between sociodemographic factors, smoking status and psychosocial factors, and health literacy. Results: A total of 421 patients were included in the study, of which 65.6% (n=276) had adequate health literacy. The average age of patients was 63.4 years (SD=10.9); and majority of patients were male (72.4%), white race (74.6%), married (64.7%), and had emotional support (73.3%). Approximately 43% of patients had a high school diploma or less, and 30% were current smokers. In the adjusted analyses, sex, race, education, and emotional support were associated with health literacy. Compared to females, males (aOR=0.34; 95% CI: 0.14–0.82) were less likely to have adequate health literacy, as were Blacks (aOR=0.26; 95% CI: 0.11–0.65) compared with Whites. Patients who had a high school diploma or less were 89% less likely to have adequate health literacy compared to those with college degree or higher (aOR=0.11; 95% CI: 0.04–0.33). Patients who had no emotional support (aOR=4.25; 95% CI: 1.40–12.91) were more likely to have adequate health literacy compared to those with emotional support. Conclusion: Males, Blacks, and patients with lower education were more likely to have inadequate health literacy. Future investigation in quantifying these gaps is needed to ensure these patients are receiving adequate knowledge support throughout their treatment to improve shared decision making and outcomes

Cognitive Effects of MIN-101 in Patients With Schizophrenia and Negative Symptoms

Current dopamine-blocking antipsychotic drugs have little impact on the cognitive deficits associated with schizophrenia. We evaluated whether MIN-101, a molecule that combines sigma-2 antagonism and 5-HT2A antagonism, might improve cognitive deficits in individuals with moderate to severe negative symptoms in schizophrenia. Individuals (N = 244) aged 18 to 60 years with stable symptoms of DSM-5-defined schizophrenia and moderate to severe negative symptoms were randomized to placebo (n = 83), MIN-101 32 mg (n = 78), or MIN-101 64 mg (n = 83) in a 12-week, phase 2b, prospective, double-blind, placebo-controlled, parallel-group trial between May 2015 and December 2015. In a post hoc analysis, mean z and T score changes from baseline at 12 weeks of treatment in the cognitive composite score and individual tests on the Brief Assessment of Cognition in Schizophrenia (BACS) Battery were compared between MIN-101 and placebo. A total of 79 patients (95.2%) from the placebo group, 76 (97.4%) from the MIN-101 32 mg group, and 79 (95.2%) from the MIN-101 64 mg group completed the BACS at baseline. The BACS token motor (P = .04), verbal fluency (P = .01), and composite z scores (P = .05) showed significant improvements in the MIN-101 32 mg group compared to the placebo group. At week 4, the clinical improvements from baseline in the Positive and Negative Syndrome Scale (PANSS) negative factor showed a significant correlation with improvements from baseline on the BACS composite in the 64 mg group (r = -0.292, P = .020). At week 12, improvement in the PANSS negative factor showed significant correlations with improvements in the BACS composite (r = -0.408, P = .002), Trail Making Test (r = -0.394, P = .003), and verbal memory (r = -0.322, P = .017) for the 64 mg group. Results suggest a possible benefit of MIN-101 on cognitive performance in individuals with schizophrenia with stable positive symptoms and concurrent clinically significant negative symptoms. EU Clinical Trials Register identifier: 2014-004878-42​

Prevalence of prominent and predominant negative symptoms across different criteria for negative symptom severity and minimal positive symptoms: A comparison of different criteria

Negative symptoms are a source of disability in schizophrenia, but criteria for identifying patients for clinical trials are in flux. Minimum severity for negative symptoms is paired with a definition of minimal psychosis to identify predominant negative symptoms. Two previous successful negative symptoms treatment studies used very different severity and selection criteria. We compared the prevalence of participants meeting those two criteria in a large outpatient sample of participants with schizophrenia. Data from 867 outpatients with schizophrenia who participated in one of four NIMH-funded studies were analyzed. Common data elements included diagnoses, the PANSS, and an assessment of everyday functioning. We compared previous criterion for premoninant negative symptoms based on low levels of agitation and psychosis and different cut-offs for negative symptoms severity. 57 % of the participants met the agitation-based criteria for low scores and 33 % met the psychosis-based criteria. 18 % met total PANSS score ≥ 20 and 8 % met ≥24 prominent negative symptoms criteria. 14 % met low agitation and PANSS≥20 and 2 % met the low psychosis and negative symptoms ≥24 criteria. Participants who met all predominant criteria had more impairments in social functioning (all p  0.37). Criteria for predominant negative symptoms from previous clinical trials identify widely different numbers of cases, with criteria for negative symptom severity and low symptoms both impacting. All criteria yield the expected profile of relatively specific social deficits. Even in unselected populations who participated in complex research protocols, 14 % meet low- agitation based criteria for predominant negative symptoms and many more participants would be expected to meet criteria with enrichment for the presence of negative symptoms

Performance of Somno-Art Software compared to polysomnography interscorer variability: A multi-center study

The visual scoring of gold standard polysomnography (PSG) is known to present inter- and intra-scorer variability. Previously, Somno-Art Software, a cardiac based sleep scoring algorithm, has been validated in comparison to 2 expert visual PSG scorers. The goal of this research is to evaluate the performances of the algorithm against a pool of scorers. Sixty PSG and actimetry recording nights, representative of clinical practice (healthy subjects and patients suffering from obstructive sleep apnea [OSA], insomnia or major depressive disorder), were scored by 5 different sleep scoring centers and by the Somno-Art Software. Intra-class correlation coefficient (ICC) and Wilcoxon Signed-Rank Test were calculated between each scorer and the average value of the 6 scorers, including Somno-Art Software. In addition, epoch-by-epoch agreement between scorers were analyzed. Somno-Art Software estimation of sleep efficiency, wake, N1+N2, N3 and REM sleep fit within the interscorer range for the full dataset and the subgroups, except for underestimating N3 sleep in OSA patients. Additionally, Somno-Art Software overestimated sleep latency compared to the average scoring for insomniacs (+4.7 ± 1.6min). On the full dataset, Somno-Art Software had good (0.75 \u3c ICC\u3c0.90) or excellent (ICC\u3e0.90) ICC scores for all sleep parameters except N3 sleep (moderate score, 0.50 \u3c ICC\u3c0.75). For the 4-stages epoch-by-epoch agreement, Somno-Art Software was slightly below that of the visual scorers except for the healthy sub-group where an overlap was demonstrated. Somno-Art Software sleep scoring shows a good interscorer reliability in the range of the 5 visual polysomnography scorers