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Delirium is a heterogeneous syndrome primarily characterized by fluctuations in attention and awareness. Sleep–wake disturbances are a common and significant feature of delirium and can manifest as circadian rhythm inversion, sleep fragmentation, and reduced rapid eye movement (REM) and slow‐wave sleep. Some literature suggests that the relationship between sleep disruption and delirium is reciprocal wherein the two reinforce one another and may share an underlying etiology. As there are no FDA‐approved medications for delirium or delirium‐related sleep disturbances, management is primarily focused on addressing underlying medical concerns and promoting physiologic circadian patterns with non‐pharmacological behavioral interventions. In practice, however, medications are often used, albeit with limited evidence to support their use. This literature review explores the pharmacology and pharmacokinetics of several medications with literature investigating their use in delirium: melatonin, ramelteon, dual orexin receptor antagonists (DORAs), and dexmedetomidine. Current evidence suggests a possible benefit of ramelteon or melatonin, dexmedetomidine for patients in the ICU setting, and DORAs as therapeutic options for the re‐regulation of sleep–wake cycle disruption in delirium. We discuss pertinent pharmacokinetic and pharmacodynamic factors that may influence clinical decision‐making regarding these interventions. [ABSTRACT FROM AUTHOR]

This paper provides a comprehensive overview of the approach taken by financial market infrastructures (FMIs) across Europe as they prepare for full implementation of the Digital Operational Resilience Act (DORA) in January 2025. With the final deadline so close, concerns are emerging that some FMIs and regulatory bodies will not be ready to meet all of DORA's requirements in time. The purpose of this paper is to examine those concerns based on current operational resilience practices in European FMIs, and to clarify the challenges and opportunities presented by greater attention to managing third-party cyber risk. The paper also covers industry perspectives and stakeholder feedback, based on interviews with industry experts (both internal and external) in fields such as banking, financial regulation and cyber security. [ABSTRACT FROM AUTHOR]

Financial institutions turn to cloud services and entrust cloud providers with increasingly important tasks. The relationship between these two groups has largely existed outside regulatory parameters, but Digital Operational Resilience Act (DORA) is set to change that dynamic when it becomes applicable in 2025. This paper tackles two issues in this context. Firstly, it identifies the legal and practical challenges that EU financial institutions may encounter while adopting and utilising cloud services under the DORA regime. Challenges during the adoption stage include the selection of providers, decisions regarding the transfer of critical or important functions, and the choice of contractual clauses. In the usage stage, data security and financial stability emerge as the most critical concerns. One overarching difficulty is concentration risk. Secondly, the question of how to address these issues arises. Fortunately, identified challenges can be mitigated if financial institutions choose appropriate cloud deployment and service models. [ABSTRACT FROM AUTHOR]

У сучасному фінансовому ландшафті, що постійно змінюється, віртуальні активи стали транс­формаційними елементами завдяки технології блокчейн. У цій статті розглядається європейська система регулювання віртуальних активів, досліджується роль, яку відіграють наднаціональні та державні органи влади у стимулюванні інновацій та зменшенні ризиків. Європейський Союз (ЄС) відреагував на виклики, пов’язані з віртуальними активами, за допомогою гармонізованої нормативно-правової бази, що включає директиви та регламенти, які формують його підхід. Ре­гуляторний ландшафт ЄС характеризується проактивною позицією Європейської комісії, яка запровадила П’яту директиву по боротьбі з відмиванням грошей (AMLD5) та Пакет цифрових фінансів, що включає такі пропозиції, як Закон про цифрову операційну стійкість (DORA) та регулювання ринків крипто-активів (MiCA). Ці ініціативи спрямовані на забезпечення комплекс­ного регулювання криптоактивів, підвищення прозорості та забезпечення операційної стійкості у фінансовому секторі. Наднаціональні організації, такі як Європейська банківська адміністра­ція (EBA) та Європейське управління з цінних паперів та ринків (ESMA), роблять свій внесок, пропонуючи рекомендації та здійснюючи нагляд за їх дотриманням. Зокрема, EBA наголошує на ризиках, пов’язаних з віртуальними валютами, і закликає споживачів не втрачати пильності. Роль ESMA поширюється на нагляд за застосуванням MiCA в державах-членах, забезпечуючи узгодже­не тлумачення нормативних актів. Національні органи влади зберігають автономію в імплемента­ції директив ЄС, транспонуючи їх у національне законодавство з урахуванням місцевих обставин. Підрозділи фінансової розвідки (ПФР) та органи пруденційного нагляду співпрацюють у боротьбі з відмиванням грошей, фінансуванням тероризму та наглядом за фінансовими установами, що займаються діяльністю з віртуальними активами. Виклики залишаються, зокрема, технологічна складність, транскордонні транзакції та фрагментація регулювання.

У сучасному фінансовому середовищі, що постійно розвивається, віртуальні активи з’явилися як трансформаційні елементи, які рухаються завдяки технології блокчейн. Ця стаття пропонує стратегічні міркування для ефективного регулювання, наголошуючи на динамічних оновленнях, глобальній координації, технологічно-агностичних підходах, посиленому нагляді, освіті зацікав­ленихсторін, регуляторних пісочницях, співпраці з гравцями галузі та не відставанні від техноло­гічних інновацій. Європейська нормативна база для віртуальних активів являє собою динамічний підхід, що розвивається. У той час як Регламент MiCA та нагляд ESMA та EBA створюють основу, співпраця між наднаціональними та державними органами залишається першорядною для ефек­тивного та збалансованого регуляторного середовища. Оскільки віртуальні активи продовжують розвиватися, регулятори повинні знайти правильний баланс між сприянням інноваціям і забезпе­ченнямцілісності ринку та захисту інвесторів у межах ЄС. У складному ландшафті віртуальних активів, стає очевидним, що передбачення та вирішення майбутніх викликів є надзвичайно важливим для ефективного загальноєвропейського регулю­вання.Динамічна природа технології блокчейн та її застосування вимагає від регуляторів про­гресивногопідходу. У прагненні до стійкої регуляторної бази виникають певні міркування, що формують майбутню траєкторію регулювання віртуальних активів. Оскільки віртуальні активи продовжують розвиватися, регулятори повинні зберігати пильність, сприяючи інноваціям і одночасно захищаючи від ризиків. Регуляторна база повинна бути гнучкою, глобально скоординованою та адаптованою до технологічного прогресу, щоб досягти правильно­го балансу між стимулюванням інновацій та забезпеченням цілісності ринку і захисту інвесторів. Співпраця між наднаціональними та державними органами влади має першорядне значення для досягнення збалансованого та ефективного регуляторного середовища, яке сприяє відповідальному та безпечному використанню віртуальних активів в межах Європейського Союзу.

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Clinical writing is sometimes viewed cynically, as a way to ensure progression – through training and beyond – by demonstrating one's allegiance to received views. For candidates and faculty alike, this belief may defend against awareness of an even more troubling truth: that in writing about one's patients, one inevitably reveals a great deal about oneself. As Freud's remark on Dora's chattering fingertips implies, even writers who aspire to stay within the bounds of received wisdom may betray themselves. In this paper, I present a way of teaching Freud's first two major cases ("Dora" and "Hans") as prelude to a clinical case writing sequence at my institute. When teaching Freud, I encourage candidates to read his writing as we might hope for others to read ours: both critically and sympathetically. With perspective provided by knowledge of Freud's personal history and era, we discuss the implicit personal and political motivations that are now possible to discern between the lines of his texts. When teaching clinical writing courses, I remind candidates of our earlier, shared encounter with Freud; in writing about their patients, they too will reveal more than they can know in advance. I encourage candidates to embrace this feature of case writing, and to regard their peers and instructors as companions in a quest to understand their patients and themselves. Though I recommend including some study of Freud's cases in candidates' writing instruction, I also argue the importance of finding one's own, unique approach to teaching the practice of clinical writing, which is – for every clinician – deeply personal. [ABSTRACT FROM AUTHOR]

This paper delves into the potential impacts of the recently published Network and Information Security Directive 2 (NIS2) and Digital Operational Resilience Act (DORA) on EU cybersecurity resilience and cloud adoption. Employing a mixed method of descriptive literature review, narrative review, and thematic synthesis, we explore challenges for implementation, drawing from past data privacy regulations, notably the GDPR, which served as a basis for our analysis and has already significantly affected many organizations. We emphasize the need for efficient software solutions to assist organizations in complying with the new regulations, building upon lessons learned from the GDPR. Cloud service providers and enterprise software vendors are identified as key players to address these challenges. This paper discusses the paradox of organizations' historical reluctance to migrate to the cloud due to data privacy concerns, and how the motivation to comply with recent regulations may now drive increased modern cloud adoption.

Clozapine (CLZ) is extensively used for treatment‐resistant schizophrenia (TRS) with caution to avoid serious adverse events such as agranulocytosis and drug–drug interactions (DDIs). In the current report, we present a case of a 35‐year‐old male non‐smoking TRS patient whose steady‐state plasma trough concentrations (Ctrough) of CLZ and its active metabolite, N‐desmethylclozapine (NDMC), were significantly increased after initiating oral administration of lemborexant (LEM), a dual orexin receptor antagonist, for the treatment of insomnia. The patient experienced oversedation with sleepiness and fatigue while maintaining high levels of Ctrough of CLZ. The increased concentrations of CLZ returned to normal ranges after the discontinuation of LEM dosing, implying a pharmacokinetic DDI between CLZ and LEM. To gain insight into possible mechanisms, we performed in vitro assays of CYP1A2‐ and CYP3A4‐mediated CLZ metabolism by measuring the formations of NDMC and clozapine N‐oxide (CNO). In accordance with previous studies, the incubation of CLZ with each enzyme resulted in the production of both metabolites. LEM had only a weak inhibitory effect on CYP1A2‐ and CYP3A4‐mediated CLZ metabolism. However, the preincubation of LEM with CYP3A4 in the presence of NADPH showed a significant enhancement of inhibitory effects on CLZ metabolism with IC50 values for the formations of CNO and NDMC of 2.8 μM and 4.1 μM, respectively, suggesting that LEM exerts as a potent time‐dependent inhibitor for CYP3A4. Taken together, the results of the current study indicate that co‐medication of CLZ with LEM may lead to increase in exposure to CLZ and risks of CLZ‐related adverse events. [ABSTRACT FROM AUTHOR]

The aim of the paper is to explain what is meant by Digital Risk&Governance. For this purpose, it is important to retrace the technological evolution that has affected the last few decades: from branches to Mobile Banking, from the digitalization of transactions to the creation of Fintech, from the first process automations to Artificial Intelligence. This evolutionary journey has not only involved and still involves the birth of new technologies, but also the possibility of seizing new business opportunities and therefore necessarily of facing new types of risk, which are not always intuitive and easy to fully understand and manage. In this context, the role of the Regulator is fundamental not only to make available to companies elements for a correct and complete understanding of Digital/ICT Risk, but also to provide guidelines that allow for the construction of an organizational and governance model suitable for gaining awareness risk and to assess, manage and monitor it. A fundamental role is played by the Digital Operational Resilience Act (DORA), which certainly better defines some aspects that until recently did not find a clear place, but - even more important - which allows these aspects to be included in an organic and holistic framework. Governance and organization are essential in this panorama, the only functions capable of spreading the risk culture necessary to overcome the silo mentality and to establish the cultural paradigm change essential for managing ICT Risk. Given the extension of the perimeter that is generally included under this risk, the paper goes on to underline the most relevant aspects and suggests in a practical way the components on which companies should concentrate in order to implement and make usable an all-round management framework: from the identification of critical functions to the importance of having tools capable of certifying the correctness, completeness and quality of the data. Another high-sounding and closely related theme, which therefore could not fail to be addressed in the paper, is represented by the cyberattack and its impacts on the market. The paper then closes with a theme which, in our opinion, plays an even more stately role than the creation of an overall framework can play: the Digital Strategy, consciously accessible only through a Digital Risk&Governance framework, but which represents the ultimate goal to which companies should aspire.

I examine a speculative diagnosis made by Sigmund Freud regarding his patient's mother in his landmark 1905 paper describing a hysterical illness. Freud considered the impact of Dora's mother's mental state on her daughter, wondering whether the mother might suffer from a ‘housewife's psychosis’. Here was an emphasis on the social structures of the times and differences between the parents in terms of sexual freedom and societal limitations placed on women. Freud's description drew attention to Dora's anxieties in relation to her parents, in particular the state of their sexual relationship and the apparently sanctioned entry of another couple, Frau and Herr K, into the parental relationship. In particular, the role of syphilis in the aetiology of sexual disturbances was considered, affecting men and their sexual partners, specifically their wives, who faced lifelong risks of morbidity, inadequate treatment and psychic disturbances at this time in 19th century Vienna.

Background: Insomnia is a common disease, and the application of various types of sleeping pills for cognitive impairment is controversial, especially as different doses can lead to different effects. Therefore, it is necessary to evaluate the cognitive impairment caused by different sleeping pills to provide a theoretical basis for guiding clinicians in the selection of medication regimens. Objective: To evaluate whether various different doses (low, medium and high) of anti-insomnia drugs, such as the dual-orexin receptor antagonist (DORA), zopiclone, eszopiclone and zolpidem, induce cognitive impairment. Methods: The PubMed, Embase, Scopus, Cochrane Library, and Google Scholar databases were searched from inception to September 20th, 2022 for keywords in randomized controlled trials (RCTs) to evaluate the therapeutic effects of DORA, eszopiclone, zopiclone and zolpidem on sleep and cognitive function. The primary outcomes were indicators related to cognitive characteristics, including scores on the Digit Symbol Substitution Test (DSST) and daytime alertness. The secondary outcomes were the indicators associated with sleep and adverse events. Continuous variables were expressed as the standard mean difference (SMD). Data were obtained through GetData 2.26 and analyzed by Stata v.15.0. Results: A total of 8702 subjects were included in 29 studies. Eszopiclonehigh significantly increased the daytime alertness score (SMD = 3.00, 95 % CI: 1.86 to 4.13) compared with the placebo, and eszopiclonehigh significantly increased the daytime alertness score (SMD = 4.21, 95 % CI: 1.65 to 6.77; SMD = 3.95, 95 % CI: 1.38 to 6.51; SMD = 3.26, 95 % CI: 0.38 to 6.15; and SMD = 3.23, 95 % CI: 0.34 to 6.11) compared with zolpidemlow, zolpidemhigh, DORAlow, and eszopiclonemid, respectively. Compared with the placebo, zopiclone, zolpidemmid, and eszopiclonehigh, DORA significantly increased the TST (SMD = 2.39, 95 % CI: 1.11 to 3.67; SMD = 6.00, 95 % CI: 2.73 to 9.27; SMD = 1.89, 95 % CI: 0.90 to 2.88; and SMD = 1.70, 95 % CI: 0.42 to 2.99, respectively). Conclusion: We recommend DORA as the best intervention for insomnia because it was highly effective in inducing and maintaining sleep without impairing cognition. Although zolpidem had a more pronounced effect on sleep maintenance, this drug is better for short-term use. Eszopiclone and zopiclone improved sleep, but their cognitive effects have yet to be verified.

Objective: We aimed to compare the efficacy and safety profiles of different dosages of dual orexin receptor antagonists (DORAs) and zolpidem on insomnia and cognitive function. Methods: Databases including PubMed, Embase, Cochrane Library, Scopus, and Google Scholar were searched for relevant articles. The standard mean difference (SMD) was generated for consecutive variants. A dose‒response meta-regression model was constructed in RStudio 4.2.1 to compare the efficacy and safety of low, medium and high doses of DORAs and zolpidem on cognitive function and insomnia. Results: A total of 22 studies with 8,223 subjects were included. Compared with the placebo, low and medium doses of DORAs significantly decreased motor vehicle accidents/violations (SMD= -0.02, 95 % CI: -0.21 to 0.17 and SMD= -0.36, 95 % CI: -0.52 to -0.20, respectively), whereas medium and high doses of zolpidem significantly increased this index (SMD=0.77, 95 % CI: 0.39 to 1.16 and SMD=1.17, 95 % CI: 0.62 to 1.72, respectively). In addition, the total sleep time (TST) of low, medium, and high doses of DORAs was SMD=0.28, 95 % CI: - 0.15 to 0.70; SMD=1.36, 95 % CI: 0.87 to 1.86; and SMD=2.59, 95 % CI: 1.89 to 3.30, respectively. The TST of zolpidem at low, medium, and high doses was SMD=1.01, 95 % CI: 0.18 to 1.83; SMD=1.94, 95 % CI: 0.46 to 3.43; and SMD=1.71, 95 % CI: 0.86 to 2.56, respectively. Conclusion: We recommend DORAs as the best intervention for insomnia. DORAs were highly effective in inducing and maintaining sleep without impairing cognition. More head-to-head studies are needed to extend and consolidate our findings.

This paper is an investigation into the prominence of hysteria in Lacan's work and the enduring significance of the diagnosis for contemporary practice. Beginning with Lacan's theory of neurosis, the importance of language, and symbolic functions, we will begin to understand why the hysterical symptom is the symptomatic structure par excellence. Lacan lauds hysteria as the neurosis in direct dialogue with a given historical moment, teaching the psychoanalyst where we are in the unfolding struggle between neurosis and civilization. He returned to the case of Dora throughout his twenty-eight years of teaching to refine his work. He even saw psychoanalysis as the progressive "hystericization" of the patient and depicted himself as an hysteric walking around on a stage, not knowing what he was saying, while attempting to teach the psychoanalysts. Lacan's reading of Dora seems to mark important shifts in his own life, from his beginning to write as a psychoanalyst, to being thrown out of the IPA, to struggling with his own school and the ensuing political eruptions in France in 1968. By tracking his elaboration of Dora we can witness the evolution of Lacan's work and how he uniquely positions the analyst in the transference. [ABSTRACT FROM AUTHOR]

Shortcomings in the area of open-access publishing are repeatedly criticized and discussed in the scientific community. Meanwhile, there are initiatives such as the DORA declaration, which aim to implement improvement and sustainability at specific points of the system. Regrettably, it can be observed at the same time that corresponding intentions are only partially realized. Simultaneously, status groups such as Ph.D. students, which are comparatively low in the science system, bear a burden or dilemma: All too often, they have to choose between improving their own career prospects and what can be called sustainable and good scientific practice. However, such decisions should not be imposed on those who hold a lower and insecure position in the scientific system. Rather, decision-makers at scientific institutions must finally begin to implement the DORA recommendations consistently or renounce them. [ABSTRACT FROM AUTHOR]

This paper delves into the potential impacts of the recently published Network and Information Security Directive 2 (NIS2) and Digital Operational Resilience Act (DORA) on EU cybersecurity resilience and cloud adoption. Employing a mixed method of descriptive literature review, narrative review, and thematic synthesis, we explore challenges for implementation, drawing from past data privacy regulations, notably the GDPR, which served as a basis for our analysis and has already significantly affected many organizations. We emphasize the need for efficient software solutions to assist organizations in complying with the new regulations, building upon lessons learned from the GDPR. Cloud service providers and enterprise software vendors are identified as key players to address these challenges. This paper discusses the paradox of organizations' historical reluctance to migrate to the cloud due to data privacy concerns, and how the motivation to comply with recent regulations may now drive increased modern cloud adoption. [ABSTRACT FROM AUTHOR]

I examine a speculative diagnosis made by Sigmund Freud regarding his patient's mother in his landmark 1905 paper describing a hysterical illness. Freud considered the impact of Dora's mother's mental state on her daughter, wondering whether the mother might suffer from a 'housewife's psychosis'. Here was an emphasis on the social structures of the times and differences between the parents in terms of sexual freedom and societal limitations placed on women. Freud's description drew attention to Dora's anxieties in relation to her parents, in particular the state of their sexual relationship and the apparently sanctioned entry of another couple, Frau and Herr K, into the parental relationship. In particular, the role of syphilis in the aetiology of sexual disturbances was considered, affecting men and their sexual partners, specifically their wives, who faced lifelong risks of morbidity, inadequate treatment and psychic disturbances at this time in 19th century Vienna. [ABSTRACT FROM AUTHOR]

The Journal Impact Factor and other indicators that assess the average citation rate of articles in a journal are consulted by many academics and research evaluators, despite initiatives against overreliance on them. Undermining both practices, there is limited evidence about the extent to which journal impact indicators in any field relate to human judgements about the quality of the articles published in the field's journals. In response, we compared average citation rates of journals against expert judgements of their articles in all fields of science. We used preliminary quality scores for 96,031 articles published 2014–18 from the UK Research Excellence Framework 2021. Unexpectedly, there was a positive correlation between expert judgements of article quality and average journal citation impact in all fields of science, although very weak in many fields and never strong. The strength of the correlation varied from 0.11 to 0.43 for the 27 broad fields of Scopus. The highest correlation for the 94 Scopus narrow fields with at least 750 articles was only 0.54, for Infectious Diseases, and there was only one negative correlation, for the mixed category Computer Science (all), probably due to the mixing. The average citation impact of a Scopus-indexed journal is therefore never completely irrelevant to the quality of an article but is also never a strong indicator of article quality. Since journal citation impact can at best moderately suggest article quality it should never be relied on for this, supporting the San Francisco Declaration on Research Assessment. [ABSTRACT FROM AUTHOR]

The impact of tau pathology on sleep microarchitecture features, including slow oscillations, spindles, and their coupling, has been understudied, despite the proposed importance of these electrophysiological features toward learning and memory. Dual orexin receptor antagonists (DORAs) are known to promote sleep, but whether and how they affect sleep microarchitecture in the setting of tauopathy is unknown. In the PS19 mouse model of tauopathy MAPT (microtubule-associated protein tau) P301S (both male and female), young PS19 mice 2–3 months old show a sleep electrophysiology signature with markedly reduced spindle duration and power and elevated slow oscillation (SO) density compared with littermate controls, although there is no significant tau hyperphosphorylation, tangle formation, or neurodegeneration at this age. With aging, there is evi)dence for sleep disruption in PS19 mice, characterized by reduced REM duration, increased non-REM and REM fragmenta)tion, and more frequent brief arousals at the macrolevel and reduced spindle density, SO density, and spindle-SO coupling at the microlevel. In ;33% of aged PS19 mice, we unexpectedly observed abnormal goal-directed behaviors in REM, including mastication, paw grasp, and forelimb/hindlimb extension, seemingly consistent with REM behavior disorder (RBD). Oral administration of DORA-12 in aged PS19 mice increased non-REM and REM duration, albeit with shorter bout lengths, and increased spindle density, spindle duration, and SO density without change to spindle–SO coupling, power in either the SO or spindle bands, or the arousal index. We observed a significant effect of DORA-12 on objective measures of RBD, thereby encouraging future exploration of DORA effects on sleep-mediated cognition and RBD treatment. [ABSTRACT FROM AUTHOR]

Background: Systematic comparisons of the doses of the Food and Drug Administration (FDA)-approved dual orexin receptor antagonists (DORAs) for people with insomnia are limited. Methods: PubMed, Embase, Cochrane Library, and Clinicaltrials. gov were systematically searched to identify relevant studies published before 31 October 2022. We assessed the certainty of evidence using the confidence in network meta-analysis (CINeMA) framework. Results: We pooled 7257 participants from 9 randomized controlled trials (RCTs). Moderate to high certainty evidence demonstrated suvorexant (20 and 40 mg) and daridorexant (10 and 50 mg) as the most effective in latency to persistent sleep (LPS) reduction. Lemborexant at 5 and 10 mg was the most effective in subjective sleep onset time (sTSO) reduction. For wake time after sleep onset (WASO), all drugs except daridorexant 5mg were more effective than placebo. Lemborexant 5mg was among the best in subjective WASO (sWASO) (moderate to high certainty) and had the highest surface under the curve ranking area (SUCRA) values for sWASO (100%). For total sleep time (TST), suvorexant and daridorexant, except the respective minimum doses, were more effective than placebo, while suvorexant 40 mg and lemborexant 10 mg may have been the most effective for subjective TST (sTST) (low to very low certainty). Suvorexant 40 mg (RR 1.09), suvorexant 80 mg (RR 1.65), and daridorexant 25 mg (RR 1.16) showed a higher safety risk than placebo. Conclusion: Suvorexant 20 mg, lemborexant 5 mg, lemborexant 10 mg, and daridorexant 50 mg represent suitable approaches for insomnia. [ABSTRACT FROM AUTHOR]

Insomnia is the most prevalent sleep disorder, affecting millions worldwide and taking a heavy toll on patient health with significant social and economic impact. Even though there are multiple different types of insomnia medications and behavioral therapies, there are still many individuals for whom treatment remains ineffective. The objective of this retrospective study was to analyze the effectiveness of daridorexant in a cohort of chronic insomnia patients largely transitioned from GABA-A positive allosteric modulators (benzodiazepines, zolpidem or eszopiclone) or other frequently prescribed insomnia medications (including trazodone, atypical antipsychotics or tricyclic antidepressants). A total of 86 patients were treated in the course of ordinary practice and the primary analytic endpoint was the change in Insomnia Severity Index (ISI) score following ≥ 30 nights of treatment with daridorexant. Results from 80 of the 86 patients with full data (65% female, mean age 53.5 years, 18.8% with comorbid obstructive sleep apnea, 91.3% transitioned from a different medication) showed a mean improvement in ISI score of 7.0 ± 0.54 points (SEM) (p < 0.0001) from 18.0 to 11.0. Overall, 78% of the cohort demonstrated a clinically meaningful improvement as defined by at least a six-point drop in ISI. Total sleep time increased by 54 ± 1.0 min (SEM) (p < 0.0001) from 6.0 h to 6.9 h. Mean sleep latency decreased by 23.9 ± 2.4 min (SEM) (p < 0.0001) from 58.8 min to 34.9 min. Wake after sleep onset decreased by 31.6 ± 3.2 min (SEM) (p < 0.001) from 42.8 min to 11.3 min. Sleep efficiency improved by 10.5 ± 1.1% (SEM) (p < 0.0001) from 79.3% to 89.8%. No significant adverse events were noted during the study duration. Keeping in mind this study's limitations, these data suggest that for insomnia patients with an incomplete response to current therapy, switching to daridorexant is safe and may be an effective alternative treatment. [ABSTRACT FROM AUTHOR]

Lemborexant (LEM) is a novel dual orexin receptor antagonist (DORA), recently approved for the treatment of insomnia. As with other DORAs, LEM has potential of abuse and therefore placed in Schedule IV class by the United States Drug Enforcement Administration (USDEA). In this study, a sensitive and accurate UPLC-MS/MS assay was developed for the quantification of LEM in human plasma sample using losartan as an internal standard (IS). The chromatographic separation was performed by using gradient elution of mobile phase, comprising of 10 mM ammonium acetate and acetonitrile with a flow rate of 0.3 mL/min. An Acquity UPLC BEH C18 (1.7 μm, 2.1 × 50 mm) column was used for separation of LEM and IS by maintaining the oven temperature of 40 °C. The electrospray ionization in positive mode was used for sample ionization. The precursor to product ion transition of 411.12 > 175.09 (qualifier) and 411.1 > 287.14 (quantifier) was used for detection and quantification of LEM, respectively, in multiple reaction monitoring mode. Being a drug of abuse, the assay was validated according to "Scientific Working Group for Toxicology" (SWGTOX) guidelines, including limit of detection (LOD), limit of quantification (LOQ), precision and bias, calibration model, interferences, carry-over effects, matrix effects, and stability parameters. The LOD and LOQ of the assay were 0.35 and 1.0 ng/mL, respectively. The linear range was between 1–300 ng/mL with correlation coefficient of ≥0.995. The method was also cross validated in rat plasma samples with acceptable ranges of precision and accuracy before its application for pharmacokinetic study in rats. [ABSTRACT FROM AUTHOR]

Daridorexant is a new sleep medication with a different mode of action than, for instance, benzodiazepine. Daridorexant is a so-called dual orexin receptor antagonist (DORA), which within the complex process of falling asleep is said to reduce wakefulness and increase somnolence. Hardly any research has been conducted into the efficacy of daridorexant compared with non-medicinal treatments, like cognitive behavioural therapy, or treatment with benzodiazepine agonists. It is unclear, for instance, whether it results in less daytime sleepiness than the benzodiazepine agonists, but it does affect driving performance on the day after administration of a single dose. The question is whether this new sleeping pill nevertheless has any added value over existing treatments. [ABSTRACT FROM AUTHOR]

Failure to recover from repeated hypercapnia and hypoxemia (HH) challenges caused by severe GCS and postictal apneas may contribute to sudden unexpected death in epilepsy (SUDEP). Our previous studies found orexinergic dysfunction contributes to respiratory abnormalities in a preclinical model of SUDEP, Kcna1 −/− mice. Here, we developed two gas challenges consisting of repeated HH exposures and used whole body plethysmography to determine whether Kcna1 −/− mice have detrimental ventilatory responses. Kcna1−/− mice exhibited an elevated ventilatory response to a mild repeated hypercapnia-hypoxia (HH) challenge compared to WT. Moreover, 71% of Kcna1−/− mice failed to survive a severe repeated HH challenge, whereas all WT mice recovered. We next determined whether orexin was involved in these differences. Pretreating Kcna1−/− mice with a dual orexin receptor antagonist rescued the ventilatory response during the mild challenge and all subjects survived the severe challenge. In ex vivo extracellular recordings in the lateral hypothalamus of coronal brain slices, we found reducing pH either inhibits or stimulates putative orexin neurons similar to other chemosensitive neurons; however, a significantly greater percentage of putative orexin neurons from Kcna1−/−mice were stimulated and the magnitude of stimulation was increased resulting in augmentation of the calculated chemosensitivity index relative to WT. Collectively, our data suggest that increased chemosensitive activity of orexin neurons may be pathologic in the Kcna1−/− mouse model of SUDEP, and contribute to elevated ventilatory responses. Our preclinical data suggest that those at high risk for SUDEP may be more sensitive to HH challenges, whether induced by seizures or other means; and the depth and length of the HH exposure could dictate the probability of survival. • Kcna1 −/− mice have altered ventilatory responses and succumb to severe HH tests. • Orexinergic blockade improves ventilation and survival in Kcna1 −/− mice during HH. • Kcna1 −/− putative orexin neurons have greater chemosensitive activity. [ABSTRACT FROM AUTHOR]

• DORA and CoARA are redefining academic evaluation standards. • Europe is adopting narrative scientific assessment methods. • Narrative CVs have originated a new field of evaluation. • Narrative Bibliometrics is a new discipline for mapping scientific evidence through data. • Narrative Bibliometrics is a research method adaptable and scalable to any evaluation. The document 'Foundations of Narrative Bibliometrics' provides an analysis of the evolution of scientific assessment, highlighting the influence of manifestos such as DORA and CoARA in shaping ethical and responsible practices in academia, as well as their assimilation by Spanish scientific policies. It connects this context with the contributions of evaluative bibliometrics, emphasising the transition towards a more integrative approach that advocates for a balance between quantitative and qualitative methods in research evaluation. Furthermore, it underscores how the Narrative Curriculum has emerged as one of the fundamental tools in new evaluation processes, as it allows for the description of the complexity and context of academic achievements. Narrative Bibliometrics is proposed, defined as the use of bibliometric indicators to generate stories that support the defence and exposition of a scientific curriculum and/or its individual contributions within the framework of a scientific evaluation process, which demands narratives. To introduce the reader, it presents, in a non-exhaustive manner, sources, indicators, and practical cases for effectively applying Narrative Bibliometrics in various scientific evaluation contexts. Hence, this document contributes to the responsible use of bibliometric indicators, serving as a tool for evaluators and researchers. [ABSTRACT FROM AUTHOR]

BackgroundAbout one-third of adults have trouble sleeping, ranging from occasional difficulty to chronic insomnia, along with difficulty maintaining sleep. Many studies reported that the long-term use of hypnotics can cause brain dysfunction and damage cognition.ObjectiveThe objective of the study is to evaluate whether low, medium, and high doses of orexin dual receptor antagonists (DORA), zopiclone (ZOP), eszopiclone (ESZ), and zolpidem (ZST) can impair cognition.MethodsFrom the beginning through September 20, 2022, PubMed, Embase, Scopus, the Cochrane Library, and Google Scholar were searched. Randomized controlled trials (RCTs) assessing the therapeutic effects of DORA, eszopiclone, and zopiclone for sleep and cognitive function were included. The primary outcomes were indices related to the cognitive profile, including memory, alertness, execution and control function, and attention and orientation. The secondary outcomes were indices related to sleep and adverse events. The standard mean difference (SMD) was generated for continuous variables. Certain data were captured from figures by GetData 2.26 and analyzed using RStudio 4.2.ResultsFinally, a total of 8,702 subjects were included in 29 studies. Compared with the placebo, the DSST (Digit Symbol Substitution Test) scores of low, medium, and high doses of DORA were SMD = 0.77; 95% CI: 0.33–1.20; SMD = 1.58; 95% CI: 1.11–2.05; and SMD = 0.85; 95% CI: 0.33–1.36, respectively. The DSST scores of zolpidem at low, medium, and high doses were SMD = −0.39; 95% CI: 0.85–0.07; SMD = −0.88, 95% CI: −2.34–0.58; and SMD = −0.12, 95% CI: −0.85–0.60, respectively. Zopiclone's DSST scale score was SMD = −0.18; 95% CI: −0.54–0.18. In addition, the total sleep time (TST) of low, medium, and high doses of DORA was SMD = 0.28, 95% CI: −0.15–0.70; SMD = 1.36, 95% CI: 0.87–1.86; and SMD = 2.59, 95% CI: 1.89–3.30, respectively. The TST of zolpidem with low, medium, and high doses was SMD = 1.01, 95% CI: 0.18–1.83; SMD = 1.94, 95% CI: 0.46–3.43; and SMD = 1.71, 95% CI: 0.86–2.56, respectively. The TST of low, medium, and high doses of eszopiclone was relatively SMD = 2.03, 95% CI: −0.21–4.27; SMD = 2.38, 95% CI: 1.35–3.42; and SMD = 1.71, 95% CI: 0.60–2.82. Zopiclone's TST was SMD = 2.47, 95% CI: 1.36–3.58.ConclusionWe recommend DORA as the best intervention for insomnia because it is highly effective in inducing and maintaining sleep without impairing cognition. Although zolpidem has a more pronounced effect on maintaining sleep, it is best to reduce its use because of its side effects. Eszopiclone and zopiclone improved sleep quality, but their safety in cognition remains to be verified.

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Insomnia affects 4.4–4.8% of the world's population, but because the effect of hypnotic drugs is limited and may cause harmful side-effects, scientists are turning their attention to developing drugs that act on the orexin system. Daridorexant, a selective dual-orexin receptor antagonist (DORA), has exhibited promising results in both animal and human studies. Its activity was evaluated based on the physiology-based pharmacodynamic and pharmacokinetic model. The use of daridorexant is considered safe, with no clinically significant side-effects including deprivation of next-morning residual effects. In this manuscript we conducted a comprehensive review of daridorexant including pharmacodynamics, animal and human research, pharmacokinetics and safety. [ABSTRACT FROM AUTHOR]

In his marking of the consequential vicissitudes that attend the more primary instincts, Freud articulates history as the discursive operation of the psychoanalytic undertaking. But his ambivalence toward the requisite writing of that articulated history comes through when he introduces the narrative genre of the case study. The first part of this article examines Freud's implicit proposition that psychoanalysis is a complex articulation of history in that symptoms are noted and inscribed as consequential, present indicators of causal instincts (Triebe) that have been variously and "fatefully" rerouted. The second part reads Freud's defensive presentation of the first case history, the "broken fragment" of Dora and her hysteria, considering Freud's ambivalence toward his own historiographic operation. Freud's ambivalence in relation to his new genre of narrative writing illustrates the more general productive ambivalence of historiography as outlined by Michel de Certeau. [ABSTRACT FROM AUTHOR]

There has been much debate around the role of metrics in scholarly communication, with particular focus on the misapplication of journal metrics, such as the impact factor in the assessment of research and researchers. Various initiatives have advocated for a change in this culture, including the Declaration on Research Assessment (DORA), which invites stakeholders throughout the scholarly communication ecosystem to sign up and show their support for practices designed to address the misuse of metrics. This case study provides an overview of the process undertaken by a large academic publisher (Taylor & Francis Group) in signing up to DORA and implementing some of its key practices in the hope that it will provide some guidance to others considering becoming a signatory. Our experience suggests that research, consultation and flexibility are crucial components of the process. Additionally, approaching signing with a project mindset versus a ‘sign and forget’ mentality can help organizations to understand the practical implications of signing, to anticipate and mitigate potential obstacles and to support cultural change.

This text discusses and denounces the growing trend of “bibliometric denialism,” which rejects the utility of bibliometric indicators in scientific evaluation. This denialism is evident in the decision to dispense with metrics, a practice encouraged by the Declaration on Research Assessment (Dora) and, especially, upon the signing of the Agreement on Reforming Research Assessment promovido promoted by the Coalition for Advancing Research Assessment (Coara). Both advocate for a more qualitative approach, primarily based on peer review. However, we argue that these qualitative approaches have been adopted without considering their limitations and ignoring the principles and methods of evaluative bibliometrics. [ABSTRACT FROM AUTHOR]

There has been much debate around the role of metrics in scholarly communication, with particular focus on the misapplication of journal metrics, such as the impact factor in the assessment of research and researchers. Various initiatives have advocated for a change in this culture, including the Declaration on Research Assessment (DORA), which invites stakeholders throughout the scholarly communication ecosystem to sign up and show their support for practices designed to address the misuse of metrics. This case study provides an overview of the process undertaken by a large academic publisher (Taylor & Francis Group) in signing up to DORA and implementing some of its key practices in the hope that it will provide some guidance to others considering becoming a signatory. Our experience suggests that research, consultation and flexibility are crucial components of the process. Additionally, approaching signing with a project mindset versus a 'sign and forget' mentality can help organizations to understand the practical implications of signing, to anticipate and mitigate potential obstacles and to support cultural change. [ABSTRACT FROM AUTHOR]

Lemborexant (LEM) is a novel dual orexin receptor antagonist (DORA), recently approved for the treatment of insomnia. As with other DORAs, LEM has potential of abuse and therefore placed in Schedule IV class by the United States Drug Enforcement Administration (USDEA). In this study, a sensitive and accurate UPLC-MS/MS assay was developed for the quantification of LEM in human plasma sample using losartan as an internal standard (IS). The chromatographic separation was performed by using gradient elution of mobile phase, comprising of 10 mM ammonium acetate and acetonitrile with a flow rate of 0.3 mL/min. An Acquity UPLC BEH C18 (1.7 μm, 2.1 × 50 mm) column was used for separation of LEM and IS by maintaining the oven temperature of 40 °C. The electrospray ionization in positive mode was used for sample ionization. The precursor to product ion transition of 411.12 > 175.09 (qualifier) and 411.1 > 287.14 (quantifier) was used for detection and quantification of LEM, respectively, in multiple reaction monitoring mode. Being a drug of abuse, the assay was validated according to “Scientific Working Group for Toxicology” (SWGTOX) guidelines, including limit of detection (LOD), limit of quantification (LOQ), precision and bias, calibration model, interferences, carry-over effects, matrix effects, and stability parameters. The LOD and LOQ of the assay were 0.35 and 1.0 ng/mL, respectively. The linear range was between 1–300 ng/mL with correlation coefficient of ≥0.995. The method was also cross validated in rat plasma samples with acceptable ranges of precision and accuracy before its application for pharmacokinetic study in rats.

Universities and research institutions have to assess individuals when making decisions about hiring, promotion and tenure, but there are concerns that such assessments are overly reliant on metrics and proxy measures of research quality that overlook important factors such as academic rigor, data sharing and mentoring. These concerns have led to calls for universities and institutions to reform the methods they use to assess research and researchers. Here we present a new tool called SPACE that has been designed to help universities and institutions implement such reforms. The tool focuses on five core capabilities and can be used by universities and institutions at all stages of reform process.

Insomnia affects 4.4–4.8% of the world’s population, but because the effect of hypnotic drugs is limited and may cause harmful side-effects, scientists are turning their attention to developing drugs that act on the orexin system. Daridorexant, a selective dual-orexin receptor antagonist (DORA), has exhibited promising results in both animal and human studies. Its activity was evaluated based on the physiology-based pharmacodynamic and pharmacokinetic model. The use of daridorexant is considered safe, with no clinically significant side-effects including deprivation of next-morning residual effects. In this manuscript we conducted a comprehensive review of daridorexant including pharmacodynamics, animal and human research, pharmacokinetics and safety.

In this examination of Freud's Dora, I show that Freud insisted that Dora's comments and gestures reflected her underlying sexual motivations, despite her repeated denials and objections. The main point is that, just as Freud "ruled in" certain ways of talking, defining Dora's sexual fantasies and dreams as acceptable and valid representations of her feelings, so also, Freud "ruled out" other kinds of talking, in particular, Dora's accounts of nonsexual motivation. In treating those accounts as false and meaningless, as so much cover for her "true" sexual feelings, Freud not only imposed his vision of sexuality onto a patient, he showed an entire historical period how to read sexuality into everything people say and do. [ABSTRACT FROM AUTHOR]

The pressure to distinguish high quality from lower quality law journals is intensifying. To contribute to this debate, citation-based and peer review-based ranking of law journals are paralleled in the paper, using qualitative and quantitative analysis. It is found that all law journals that are considered as journals of the highest quality by legal experts are also ranked highly in Web of Science (WoS) and that 40% of the law journals categorised as 'internationally leading' by the peers are not listed in WoS. This paper explores what the editors of some of the internationally leading law journals that are not listed in the WoS think about applying to be listed in it. The paper offers data to support the contention that legal scholarship is characterised by regionalism in academic publishing and citation patterns. It is submitted that there is no perfect indicator of quality, and that no evaluation system will ever convince every legal scholar in the world of its value. WoS could be adopted as a rigorous and internationally recognised index for law journals only if it were aligned more closely with the Leiden Manifesto. [ABSTRACT FROM AUTHOR]

This letter is a call to the Spanish scientific authorities to abandon current research evaluation policies, which are based on an excessive and indiscriminate use of bibliometric indicators for nearly all areas of scientific activity. This narrow evaluation focus is especially applied to assess the individual performance of researchers. To this end, we first describe the contexts in which the journal impact factor (JIF) and other bibliometric indicators are being used. We then consider the toxic effects of this abuse of indicators. Finally, we outline some significant transformations and initiatives being introduced in various academic fields and regions of the world. These international initiatives offer alternatives to bibliometrics that can improve evaluation processes, and we urge political leaders in Spain to adopt and develop them. [ABSTRACT FROM AUTHOR]

Information technology (IT) as a regulatory object is defined and viewed differently across various domains of European IT security law. However, common definitions and methods for the demarcation and separation of operational information technology can contribute to coherence in the historically grown body of regulation. This paper identifies three different general approaches for the treatment of information technology within the existing body of law: information technology as a means, as a service and as a product. Furthermore, we compile a general definition of information technology , which consists of three logical subentities: components, systems , and services. Additionally, steps for the practical identification of the operational information technology addressed by material law requirements are shown. First, all services that affect an articulated protected good must be identified. Within the identification of the systems used to realize those services , two dimensions must be considered. There is the functional dimension as well as the control and power of the disposal dimension. An identified weakness of the current state of IT security law is a lack of clearly formulated protected goods within the existing regulations, which contributes to the difficulties of addressing information technology in general. Furthermore, this paper discusses which actors are responsible for a demarcated piece of information technology and what responsibilities are assigned to them. This section also elaborates on the difficulty of appropriately addressing commercial and non-commercial actors. [ABSTRACT FROM AUTHOR]

The use of cloud services by financial institutions has become increasingly prevalent due to its economic benefits. However, this comes with the inherent drawbacks of increased security risks and potential financial stability risks from the cloud market concentration. The EU has introduced specific legal instruments that place responsibilities on financial institutions to mitigate these risks. This paper analyses how the regulation of cloud service providers in the EU financial sector has evolved from the regulation of operational risk to the regulation of systemic risk. The Digital Operational Resilience Act, adopted in December 2022 and effective from January 17, 2025, plays a key role in enabling this transformation by recognizing the systemic risk aspect of the use of cloud service providers. It responds to this risk by creating a new oversight regime of critical cloud service providers. However, new oversight of critical cloud service providers brings about novel problems, particularly concerning the ne bis in idem principle in the case of overlapping oversight and enforcement by different authorities responsible for respective legislative instruments in cybersecurity and data protection. The overlapping oversight shall respect the principle. This paper evaluates to what extent the overlapping regime respects the principle under Article 50 of the Charter of Fundamental Rights of the European Union by analysing the Digital Operational Resilience Act and provides suggestions to improve coordination among different competent authorities in the case of overlapping supervision and enforcement to respect the principle. [ABSTRACT FROM AUTHOR]

The article is devoted to the consideration of key scientometric platforms, which are widely used in Ukraine. The practice of application of such platforms as Web of Science, Scopus, Google Scholar, Russian index of scientific citation, Index Copernicus, Journal's International Compliance Index, Ukrainian index of scientific citation, "Scientists of Ukraine" is analyzed. Key parametric tools that the above-mentioned platforms use to determine proposed scientometric indicators are identified and critically analyzed. In particular, attention is paid to the possibilities of evaluating the Hirsch-index for ranking scientific publications on the importance and value. The key shortcomings inherent in the Hirsch-index are revealed. Also, the practice of using the impact factor for assessing the quality of scientific publications is considered. Advantages and disadvantages of the practice of using these scientometric platforms for assessing the quality of the publication activity of institutions, publications and scientists are being studied. The key strengths and weaknesses of Web of Science, Scopus and Google Scholar have been identified. The possibility of using along with the above science-based platforms and such as: the Russian index of scientific citation and the Journal's International Compliance Index is being proved. The incorrectness of using the Index Copernicus platform for assessing the quality of scientific work and the inadequacy of the tools of the Ukrainian Index of Scientific Citation to the evaluation of the quality of scientific and publishing activity are justified. The inconsistency of using scientometric tools exclusively for assessing the quality of scientific work is being proved. The necessity of transforming the practice of assessing the quality of science through the prism of scientometric indicators, by changing the editorial policy (DORA) and the introduction of new parametric tools (R-factor) with another philosophy for the evaluation of scientific works is substantiated.

The article raises a few issues -- essential in the author's view -- which are related to the place of scientific journals in the system of science, with special emphasis laid on the publishing practice of scholars representing the social sciences. The practice of overusing bibliometric indices with which individual journals are assigned -- especially in evaluation procedures -- is taken into account and subjected to criticism. The author strongly supports DORA (the declaration on research assessment) when it comes to the common practice of replacing peer review with a simpler and more effective procedure of using bibliometric indices (also to assess the performance of individual scholars). When employers (for instance, universities) exert pressure on scientists to obtain points from publications, this results in a number of pathological phenomena: the emergence of predatory journals and the appearance of 'virtual' teams of authors only pretending to collaborate. The article ends with the author's recommendations for young scientists on how to design their careers -- including how to publish wisely in scientific journals. [ABSTRACT FROM AUTHOR]