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ABSTRACT: The sequestration of CO2 in subsurface reservoirs constitutes an immediate counter‐measure to reduce anthropogenic emissions of CO2, now recognized by international scientific panels to be the single most critical factor driving the observed global climatic warming. To ensure and verify the safe geological containment of CO2 underground, monitoring of the CO2 site is critical. In the high Arctic, environmental considerations are paramount and human impact through, for instance, active seismic surveys, has to be minimized. Efficient seismic modelling is a powerful tool to test the detectability and imaging capability prior to acquisition and thus improve the characterization of CO2 storage sites, taking both geological setting and seismic acquisition set‐up into account. The unique method presented here avoids the costly generation of large synthetic data sets by employing point spread functions to directly generate pre‐stack depth‐migrated seismic images. We test both a local‐target approach using an analytical filter assuming an average velocity and a full‐field approach accounting for the spatial variability of point spread functions. We assume a hypothetical CO2 plume emplaced in a sloping aquifer inspired by the conditions found at the University of Svalbard CO2 lab close to Longyearbyen, Svalbard, Norway, constituting an unconventional reservoir–cap rock system. Using the local‐target approach, we find that even the low‐to‐moderate values of porosity (5%–18%) measured in the reservoir should be sufficient to induce significant change in seismic response when CO2 is injected. The sensitivity of the seismic response to changes in CO2 saturation, however, is limited once a relatively low saturation threshold of 5% is exceeded. Depending on the illumination angle provided by the seismic survey, the quality of the images of five hypothetical CO2 plumes of varying volume differs depending on the steepness of their flanks. When comparing the resolution of two orthogonal 2D surveys to a 3D survey, we discover that the images of the 2D surveys contain significant artefacts, the CO2‐brine contact is misplaced and an additional reflector is introduced due to the projection of the point spread function of the unresolvable plane onto the imaging plane. All of these could easily lead to a misinterpretation of the behaviour of the injected CO2. Our workflow allows for testing the influence of geological heterogeneities in the target aquifer (igneous intrusions, faults, pervasive fracture networks) by utilizing increasingly complex and more realistic geological models as input as more information on the subsurface becomes available. [ABSTRACT FROM AUTHOR]

Background: In people with OSA, excessive daytime sleepiness is a prominent symptom and can persist despite adherence to CPAP, the first-line therapy for OSA. Pitolisant was effective in reducing daytime sleepiness in two 12-week randomized controlled trials (RCTs), one in patients adherent to CPAP (BF2.649 in Patients With OSA and Treated by CPAP But Still Complaining of EDS [HAROSA 1]) and the other in patients refusing or not tolerating CPAP (BF2.649 in Patients With OSA, Still Complaining of EDS and Refusing to be Treated by CPAP [HAROSA 2])., Research Question: Does the efficacy and safety of pitolisant persist when these patients take it long-term?, Study Design and Methods: All adults included in the HAROSA 1 and HAROSA 2 RCTs (both pitolisant and placebo arms) were offered pitolisant (up to 20 mg/d) after completion of the short-term double-anonymized phase (ie, from week 13) in an open-label cohort study. The primary efficacy outcome was the change in Epworth Sleepiness Scale score between baseline and week 52. Safety outcomes were treatment-emergent adverse event(s) (TEAE[s]), serious TEAEs, and special interest TEAEs., Results: Out of 512 adults included in the two RCTs, 376 completed the 1-year follow-up. The pooled mean difference in Epworth Sleepiness Scale score from baseline to 1 year for the intention-to-treat sample was -8.0 (95% CI, -8.3 to -7.5). The overall proportions of TEAEs, serious TEAEs, and TEAEs of special interest were 35.1%, 2.0%, and 11.1%, respectively, without any significant difference between patients in the initial pitolisant and placebo arms. No cardiovascular safety issues were reported., Interpretation: Pitolisant is effective in reducing daytime sleepiness over 1 year in adults with OSA, with or without CPAP treatment. Taken for 1 year, it has a good safety profile (including cardiovascular)., Trial Registration: ClinicalTrials.gov; Nos.: NCT01071876 and NCT01072968; URL: www., Clinicaltrials: gov., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: J.-L. P. reports administrative support and APC from Bioprojet during the conduct of the study; research grants from Agiradom, Air Liquide Foundation, Astra Zeneca, Bioprojet, Jazz Pharmaceuticals, Philips, Resmed, Sefam, and Vitalaire, outside the reported work; and honoraria or consultation fees from Agiradom, Somnomed, Bioprojet, ITAMAR, Jazz Pharmaceuticals, Philips, Resmed, and SEFAM, outside the reported work. C. C. is an employee of Bioprojet. Outside the reported work, J. V. has received institutional fees and educational grants from AirLiquide, AstraZen, Bekaert Deslee Academy, Bioprojet, Desitin, Ectosense, Epilog, Fisher & Paykel, Heinen & Löwenstein, Idorsia, Inspire, Jazz Pharmaceutics, Medidis, Mediq Tefa, OSG, Philips, ResMed, Sefam, SomnoMed, Total Care, UCB Pharma, Vivisol, and Westfalen Medical. Outside the reported work, R. T. reports research grants paid to his institution (Resmed, Inspire, BioProjet); personal lecture fees from Périmetres, Philips, Resmed, Jazz Pharmaceutical, and Bioprojet; and participation in advisory boards of Narval (Resmed), Bioprojet, and Idorsia. I. L. is an employee and shareholder of Bioprojet. Y. D. reports grants from Bioprojet, during the conduct of the study; and grants and/or consulting fees from UCB, JAZZ, Takeda, Theranexus, Harmony bioscience, Avadel, Paladin, and Idorsia, outside the submitted work. P. Lehert was a consultant statistician for Bioprojet during the conduct of the study; and is a consultant statistician for Merck, Sanofi, and Aguettant Pharma, outside the submitted work. None declared (V. A., J. H., and P. Lévy)., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Narcolepsy is a life-long disorder characterised by excessive daytime sleepiness and cataplexy, often arising in childhood or adolescence. Pitolisant, a selective histamine H3 receptor inverse agonist, has been approved in Europe and USA for adults with narcolepsy with or without cataplexy, with a favourable safety profile. This phase 3 study aimed to assess the safety and efficacy of pitolisant in children with narcolepsy with or without cataplexy., Methods: For this double-blind, randomised, placebo-controlled, multisite study, we recruited patients aged 6-17 years with narcolepsy with or without cataplexy in 11 sleep centres in five countries (Italy, France, Netherlands, Russia, and Finland). Participants were required to have a Pediatric Daytime Sleepiness Scale score of 15 or greater and to have not received psychostimulants for at least 14 days before enrolment; participants who needed anticataplectics (including sodium oxybate) were required to have been on a stable dose for at least 1 month. Participants were randomly assigned to treatment with pitolisant or placebo in a 2:1 ratio at the end of screening. Randomisation was stratified by study centre and treatment was allocated using an interactive web response system. After a 4-week screening period including a 2-week baseline period, patients entered in a 4-week individual up-titration scheme from 5 mg a day to a maximum of 40 mg a day of pitolisant or placebo; treatment was administered at a stable dose for 4 weeks, followed by a 1-week placebo period. For the primary analysis, we assessed pitolisant versus placebo using change in the Ullanlinna Narcolepsy Scale (UNS) total score from baseline to the end of double-blind period in the full analysis set, defined as all randomly allocated patients who received at least one dose of treatment and who had at least one baseline UNS value. A decrease in the UNS total score reflects a reduction in both excessive daytime sleepiness and cataplexy. All adverse events were assessed in the safety population, defined as all participants who took at least one dose of study medication. An open-label follow-up is ongoing. This study is registered at ClinicalTrials.gov, NCT02611687., Findings: Between June 6, 2016, and April 3, 2021, we screened 115 participants and 110 were randomly assigned (mean age 12·9 [SD 3·0] years, 61 [55%] male, and 90 [82%] with cataplexy; 72 assigned to pitolisant and 38 to placebo); 107 (70 receiving pitolisant and 37 receiving placebo) completed the double-blind period. The mean adjusted difference in UNS total score from baseline to the end of the double-blind period was -6·3 (SE 1·1) in the pitolisant group and -2·6 (1·4) in the placebo group (least squares mean difference -3·7; 95% CI -6·4 to -1·0, p=0·007). Treatment-emergent adverse events were reported in 22 (31%) of 72 patients in the pitolisant group and 13 (34%) of 38 patients in the placebo group. The most frequently reported adverse events (affecting ≥5% of patients) in either group were headache (14 [19%] in the pitolisant group and three [8%] in the placebo group) and insomnia (five [7%] in the pitolisant group and one [3%] in the placebo group)., Interpretation: Pitolisant treatment resulted in an improvement in narcolepsy symptoms in children, although the UNS was not validated for use in children with narcolepsy when our study began. The safety profile was similar to that reported in adults but further studies are needed to confirm long-term safety., Funding: Bioprojet., Competing Interests: Declaration of interests YD reports grant and consultancy fees from Bioprojet, Idorsia, Avadel, Harmony Biosciences, Takeda, and Jazz Pharmaceuticals, during the conduct of the trials. GP reports grant and consultancy fees from Bioprojet, Idorsia, Takeda, Orexia, Fidia, and Jazz Pharmaceuticals. PF reports grant and consultancy fees from Bioprojet and Jazz Pharmaceuticals. ML reports consultancy fees from Bioprojet, and Jazz Pharmaceuticals. GJL reports grant and consultancy fees from Bioprojet and Jazz Pharmaceuticals. IJ, CC, JML, and JCS are employees of Bioprojet. MP and PL declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Narcolepsy is a chronic and rare hypersomnia of central origin characterized by excessive daytime sleepiness and a complex array of symptoms as well as by several medical comorbidities. With growing pharmacological options, polytherapy may increase the possibility of a patient-centered management of narcolepsy symptoms. The aims of our study are to describe a large cohort of Italian patients with narcolepsy who were candidates for pitolisant treatment and to compare patients' subgroups based on current drug prescription (drug-naïve patients in whom pitolisant was the first-choice treatment, switching to pitolisant from other monotherapy treatments, and adding on in polytherapy)., Methods: We conducted a cross-sectional survey based on Italian data from the inclusion visits of the Post Authorization Safety Study of pitolisant, a 5-year observational, multicenter, international study., Results: One hundred ninety-one patients were enrolled (76.4% with narcolepsy type 1 and 23.6% with narcolepsy type 2). Most patients (63.4%) presented at least one comorbidity, mainly cardiovascular and psychiatric. Pitolisant was prescribed as an add-on treatment in 120/191 patients (62.8%), as switch from other therapies in 42/191 (22.0%), and as a first-line treatment in 29/191 (15.2%). Drug-naive patients presented more severe sleepiness, lower functional status, and a higher incidence of depressive symptoms., Conclusion: Our study presents the picture of a large cohort of Italian patients with narcolepsy who were prescribed with pitolisant, suggesting that polytherapy is highly frequent to tailor a patient-centered approach., (© 2022. The Author(s).)

Background: Excessive daytime sleepiness (EDS) in individuals with OSA syndrome persisting despite good adherence to CPAP is a disabling condition. Pitolisant is a selective histamine H3-receptor antagonist with wake-promoting effects., Research Question: Is pitolisant effective and safe for reducing daytime sleepiness in individuals with moderate to severe OSA adhering to CPAP treatment but experiencing residual EDS?, Study Design and Methods: In a multicenter, double-blind, randomized (3:1), placebo-controlled, parallel-design trial, pitolisant was titrated individually at up to 20 mg/day and taken over 12 weeks. The primary end point was change in the Epworth Sleepiness Scale (ESS) score in the intention-to-treat population. Key secondary end points were maintenance of wakefulness assessed by the Oxford Sleep Resistance Test, Clinical Global Impressions scale of severity, the patient's global opinion, EuroQoL quality-of-life questionnaire score, Pichot fatigue questionnaire score, and safety., Results: Two hundred forty-four OSA participants (82.8% men; mean age, 53.1 years; mean Apnea Hypopnea Index with CPAP, 4.2/h; baseline ESS score, 14.7) were randomized to pitolisant (n = 183) or placebo (n = 61). ESS significantly decreased with pitolisant compared with placebo (-2.6; 95% CI, -3.9 to -1.4; P < .001), and the rate of responders to therapy (ESS ≤ 10 or change in ESS ≥ 3) was significantly higher with pitolisant (71.0% vs 54.1%; P = .013). Adverse event occurrence (mainly headache and insomnia) was higher in the pitolisant group compared with the placebo group (47.0% and 32.8%, respectively; P = .03). No cardiovascular or other significant safety concerns were reported., Interpretation: Pitolisant used as adjunct to CPAP therapy for OSA with residual sleepiness despite good CPAP adherence significantly reduced subjective and objective sleepiness and improved participant-reported outcomes and physician-reported disease severity., Trial Registry: ClinicalTrials.gov; No.: NCT01071876; URL: www.clinicaltrials.gov; EudraCT N°: 2009-017248-14; URL: eudract.ema.europa.eu., (Copyright © 2020. Published by Elsevier Inc.)

Rationale: Excessive daytime sleepiness is a common disabling symptom in obstructive sleep apnea syndrome. Objectives: To evaluate the efficacy and safety of pitolisant, a selective histamine H3 receptor antagonist with wake-promoting effects, for the treatment of daytime sleepiness in patients with moderate to severe obstructive sleep apnea refusing continuous positive airway pressure treatment. Methods: In an international, multicenter, double-blind, randomized (3:1), placebo-controlled, parallel-design trial, pitolisant was individually titrated at up to 20 mg/d over 12 weeks. The primary endpoint was the change in the Epworth Sleepiness Scale score. Key secondary endpoints were maintenance of wakefulness assessed on the basis of the Oxford Sleep Resistance test, safety, Clinical Global Impression of severity, patient's global opinion, EuroQol quality-of-life questionnaire, and Pichot fatigue questionnaire. Measurements and Main Results: A total of 268 patients with obstructive sleep apnea (75% male; mean age, 52 yr; apnea-hypopnea index, 49/h; baseline sleepiness score, 15.7) were randomized (200 to pitolisant and 68 to placebo) and analyzed on an intention-to-treat basis. The Epworth Sleepiness Scale score was reduced more with pitolisant than with placebo (-2.8; 95% confidence interval, -4.0 to -1.5; P  < 0.001). Wake maintenance tests were not improved. The Pichot fatigue score was reduced with pitolisant. The overall impact of pitolisant was confirmed by both physicians' and patients' questionnaires. Adverse event incidence, mainly headache, insomnia, nausea, and vertigo, was similar in the pitolisant and placebo groups (29.5% and 25.4%, respectively), with no cardiovascular or other significant safety concerns. Conclusions: Pitolisant significantly reduced self-reported daytime sleepiness and fatigue and improved patient-reported outcomes and physician disease severity assessment in sleepy patients with obstructive sleep apnea refusing or nonadherent to continuous positive airway pressure.Clinical trial registered with www.clinicaltrials.gov (NCT01072968) and EU Clinical Trials Register (EudraCT 2009-017251-94).

Study Objectives: To asses the long-term safety and efficacy of pitolisant, an histamine H3-receptor antagonist, on narcolepsy., Methods: This open-label, single-arm, pragmatic study, recruited adult patients with narcolepsy and Epworth Sleepiness Scale (ESS) score ≥12. After a titration period, patients were treated for up to 1 year with oral pitolisant once-a-day at up to 40 mg. Concomitant stimulants and anti-cataplectic agents were allowed. The primary endpoint was safety; secondary endpoints included ESS, cataplexy, and other diary parameters., Results: Patients (n = 102, 75 with cataplexy) received pitolisant, for the first time in 73 of them. Sixty-eight patients (51 with cataplexy) completed the 12-month treatment. Common treatment-emergent adverse events were headache (11.8% of patients), insomnia (8.8%), weight gain (7.8%), anxiety (6.9%), depressive symptoms (4.9%), and nausea (4.9%). Seven patients had a serious adverse effect, unrelated to pitolisant except for a possibly related miscarriage. One-third of patients stopped pitolisant, mostly (19.6%) for insufficient benefit. ESS score decreased by 4.6 ± 0.6. Two-thirds of patients completing the treatment were responders (ESS ≤ 10 or ESS decrease ≥ 3), and one third had normalized ESS (≤10). Complete and partial cataplexy, hallucinations, sleep paralysis, and sleep attacks were reduced by 76%, 65%, 54%, 63%, and 27%, respectively. Pitolisant as monotherapy (43% of patients) was better tolerated and more efficacious on ESS than on add-on, but efficacy was maintained in this last case., Conclusions: Long-term safety and efficacy of pitolisant on daytime sleepiness, cataplexy, hallucinations, and sleep paralysis is confirmed., (© Sleep Research Society 2019. Published by Oxford University Press [on behalf of the Sleep Research Society].)