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Lien Wang,1,2 Xiaowei Chen,1 Xiaojing Gu,1 Heidi De Smedt,3 Vanina Popova,3 Dong-Jing Fu,4 Carla M Canuso,4 Wayne C Drevets,2 Guang Chen2 1Janssen Research & Development, LLC, Janssen Pharmaceutical Companies of Johnson & Johnson, Shanghai, People’s Republic of China; 2Janssen Research & Development, LLC, Janssen Pharmaceutical Companies of Johnson & Johnson, Brisbane, CA, USA; 3Janssen Research & Development, LLC, Janssen Pharmaceutical Companies of Johnson & Johnson, Beerse, Belgium; 4Janssen Research & Development, LLC, Janssen Pharmaceutical Companies of Johnson & Johnson, Raritan, NJ, USACorrespondence: Guang Chen, Janssen Fellow, Scientific Director, Translational Research, Mood DAS, Neuroscience Therapeutic Area, Janssen R & D, LLC, Janssen Pharmaceutical Companies of Johnson and Johnson, 3210 Merryfield Row, Room 1908, San Diego, CA, 92121, USA, Tel +1 (240) 602 7950, Email guangchenmd@gmail.comPurpose: This meta-analysis assessed whether atypical antipsychotics (AAPs) and esketamine nasal spray (ESK-NS), which are mechanistically distinct, differ in antidepressant outcomes.Patients and Methods: Data were extracted from 12 trials of ESK-NS or AAPs in depressed patients (4276) with inadequate response or resistance to conventional antidepressants. Montgomery-Åsberg Depression Rating Scale (MADRS) score reductions from baseline and response rates (≥ 50% reduction) were analyzed.Results: At endpoint, the estimated MADRS score reduction of pooled ESK-NS arms was greater than pooled AAP arms (+9.16 points, p < 0.0001). The reduction also was greater in the pooled control arms of the ESK-NS trials than the pooled control arms of the AAP trials (+7.57 points, p < 0.0001). The mean difference in the reductions between pooled ESK-NS and control arms was 1.87 points greater than that between pooled AAP and control arms, but this difference was not significant (95% CI: − 4.49, 0.74, p = 0.16). Relative to their respective control arms, the mean difference in response rates was 25% for the pooled ESK-NS and 9% for the pooled AAP arms; the mean response rate was 16% greater in the pooled ESK-NS studies than the pooled AAP studies (p = 0.0004). Comparisons against specific AAPs showed mean differences in the MADRS score reductions at 1 week between the experimental and control arms that were numerically larger in the ESK-NS trials than in the aripiprazole trials (mean difference of 1.71 points, p = 0.06) and the brexpiprazole trials (mean difference of 2.05 points, p = 0.02).Conclusion: The ESK-NS arms showed numerically larger MADRS score reductions at week-1 and endpoint, and a significantly larger response rate compared with AAP arms. Prospective studies involving direct comparisons are warranted to compare the relative efficacy between these treatment regimens.Keywords: major depressive disorder, treatment resistant depression, adjunctive and conjunctive treatment, atypical antipsychotics, esketamine nasal spray, rapid-acting

Joachim Morrens,1 Maju Mathews,2 Vanina Popova,1 Stephane Borentain,2 Benoit Rive,3 Beatriz Gonzalez Martin Moro,4 Carol Jamieson,5 Qiaoyi Zhang2 1Janssen Research & Development, Beerse, Belgium; 2Janssen Global Services, LLC, Titusville, NJ, USA; 3Janssen-Cilag, Paris, France; 4Janssen-Cilag, Madrid, Spain; 5Janssen Research & Development, LLC, Milpitas, CA, USACorrespondence: Qiaoyi Zhang, Janssen Global Services, LLC, 1125 Trenton-Harbourton Road, Titusville, NJ, 08560, USA, Tel +1 908 300 2500, Email qzhang87@its.jnj.comBackground: This post-hoc analysis evaluated the agreement between Clinical Global Impressions-Severity (CGI-S) score- and Montgomery–Åsberg Depression Rating Scale (MADRS) total score-based assessment of response in patients with treatment-resistant depression (TRD) treated with esketamine nasal spray plus a newly initiated oral antidepressant (ESK-NS + AD).Methods: Data were analyzed from a phase 3, randomized, double-blind study (TRANSFORM-2) of flexibly dosed esketamine or placebo nasal spray plus a newly initiated oral-AD in adults with moderate-to-severe TRD. Patients with ≥ 50% reduction in MADRS from baseline at the end of the 4-week acute treatment phase were defined as responders. For the CGI-S-based assessment of response, patients with ≥ 2 points decrease from baseline or a CGI-S score of ≤ 3 (mildly depressed to normal) were considered responders. Cohen’s kappa coefficient was calculated to assess level of agreement between MADRS and CGI-S-based assessments.Results: At the end of 4-week treatment, the proportion of responders among all study patients (n=201) was similar when assessed using the MADRS (61%) and CGI-S (62%) methods, with substantial agreement (Cohen’s kappa=0.76; sensitivity=92%; specificity=84%) between both methods. When restricting analysis to ESK-NS + AD-treated patients (n=101) who had a higher response rate (on MADRS: 69%; on CGI-S: 68%), the agreement remained substantial (Cohen’s kappa=0.75; sensitivity=91%; specificity=84%).Conclusion: The CGI-S may be a practical and reliable alternative to the MADRS to assess response to ESK-NS + AD in patients with TRD and can be used in real-world practice to support informed treatment decisions.Keywords: antidepressant response, Clinical Global Impressions-Severity, esketamine, Montgomery–Åsberg Depression Rating Scale, treatment-resistant depression

Stephane Borentain,1 David Williamson,2,3 Ibrahim Turkoz,4 Vanina Popova,5 William V McCall,3 Maju Mathews,1 Frank Wiegand1 1Department of Global Medical Affairs, Janssen Research & Development, LLC, Titusville, NJ, USA; 2CNS Scientific Affairs Liaisons, Janssen Scientific Affairs, LLC, Titusville, NJ, USA; 3Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta University, Augusta, GA, USA; 4Department of Clinical Statistics, Janssen Research & Development, LLC, Titusville, NJ, USA; 5Department of Neuroscience Clinical Development, Janssen Research & Development, Beerse, BelgiumCorrespondence: Stephane BorentainDepartment of Global Medical Affairs, Janssen Research & Development, LLC, 1125 Trenton-Harbourton Road, Titusville, NJ, 08560, USATel +1 609-7304420Email SBorent1@ITS.JNJ.comPurpose: To evaluate the relationship of sleep disturbance to the antidepressant effects of esketamine.Materials and Methods: Two double-blind, 4-week studies randomized adults with treatment-resistant depression (TRD) to placebo or esketamine nasal spray, each with newly initiated antidepressant. Sleep was assessed using Montgomery–Åsberg Depression Rating Scale (MADRS) item 4. Change in response (≥ 50% decrease in MADRS total score) and remission (total MADRS score ≤ 12) at day 28 was examined by presence/absence of baseline sleep disturbance using logistic regression models. Impact on reported sleep disturbance (MADRS item 4 score) was examined using ANCOVA models.Results: At baseline, most patients reported disturbed sleep – moderate/severe (65.3%, 369/565), mild (25.3%, 143/565), or none/slightly (9.4%, 53/565) – with similar distribution between treatment groups. A higher proportion of esketamine-treated patients achieved response (OR = 2.05; 95% CI: 1.40– 3.02; P < 0.001) and remission (OR = 1.81; 95% CI: 1.23– 2.66; P = 0.003) at day 28 compared to antidepressant plus placebo, regardless of presence/severity of sleep disturbance. Consistent with this, sleep (MADRS item 4 score) improved in both groups after the first dose, more so with esketamine by day 8 (between-group difference: P ≤ 0.02 at all time points). Across both treatment groups, 1-point improvement in sleep at day 8 increased the probability of antidepressant response on day 28 by 26% (OR = 1.26, 95% CI: 1.12– 1.42; P < 0.001), and remission by 28% (OR = 1.28, 95% CI: 1.14– 1.43; P < 0.001).Conclusion: Antidepressant efficacy of esketamine was demonstrated in patients with TRD, regardless of the presence of sleep disturbance. After 8 days of treatment and thereafter, significantly more esketamine-treated patients reported improvement in sleep versus antidepressant plus placebo.Keywords: esketamine, treatment-resistant depression, sleep disturbance, insomnia

The studies of the meadow-chernozem soil of the Omsk region, showed that biological products are effective when used for spring wheat by seed treatment. When comparing their action, it was noted that a greater effect was obtained from the use of the variants Azotobacterin+Phosphobacterin and Azotobacterin+Phosphobacterin+Humate K. The improvement of the nutritional conditions of plants when applying biological fertilizers and biological products has a positive effect on the content of the number of amino acids in the grain, which without fertilizers increases from 9.59% up to a maximum of 9.92% with Humat K.

This article considers the development of N. O. Lossky’s concept of intuitivism in the context of the translation of Kant’s works and revision of Kant’s epistemology. The development of Lossky as an independent philosopher required overcoming Kant’s scepticism, which was not consistent with the ideal-realist’s belief in the cognoscibility of transsubjective world given us in the original. The means necessary to overcome it determined the key characteristics of the new system of intuitivism, which emerged in a discussion of Kant’s epistemological system. The author identifies the key themes of transcendental philosophy that drew special attention of Lossky. These include the fundamental logical issues of the essence of logical connection, the nature of judgement and inference, and that of the synthetic and analytic. The article addresses the interpretation of the concept of ‘intuition’ by Lossky and the influence of this interpretation on the translation of Kant’s Anschauung.The author identifies a number of reasons that inspired the intuitivist to translate the CPR. Fol¬lowing Kant’s philosophy, Lossky had sufficient arguments in the game played in the field of his teacher and opponent, the Russian Kantian A. I. Vvedensky; moreover, he proved the inconsistency of Vvedensky’s interpretation of transcendental philosophy. It is shown that the experience of translating CPR and the critical analysis of Kant’s epistemology helped Lossky to overcome the complications that emerged in the history of philosophy and develop his own complete and organic worldview. Moreover, there arose an objective need for a new CPR translation, since some intellectuals were not satisfied with that made by N. M. Sokolov. The article contains excerpts from reviews of Sokolov’s and Lossky’s translations of CPR by G. G. Shpet

The concepts of style and topos in their cultural studies interpretation by Yu. V. Rozhdestvensky are applied to the analysis of some fragments of N. O. Lossky's philosophical concept pertaining to the features of Russian culture in general and the originality of Russian philosophy in particular. The topic is developed through comparative digressions into the field of anthropological aspects of I. Kant's philosophy.

Atrial fibrillation (AF) is one of the most frequent cardiac arrhythmias and leads to heart failure. Excessive sympathetic activity aggravates arrhythmogenic processes at the cellular and tissue levels. Hypersympathicotonia leads to desensitization of β1-adrenoreceptors (β1-AR), and negative regulation develops until the synthesis of new receptors stops. Desensitization processes may be indirectly reflected in an increase or decrease in the expression of the ADRB1 gene encoding β1-AR. The level of relative expression of the β1-AP ADRB1 gene in leukocytes of 52 patients with different forms of AF was analyzed in dynamics: before treatment, 3 days, and 3 and 12 months after ablation. Before ablation, expression was reduced in patients with persistent AF compared to groups with other forms of AF (р = 0.026). The study of dynamics revealed a significant decrease in the level of expression in patients with paroxysmal AF at the point of 3 days compared with the level before ablation (p = 0.003), with a further increase in values to the baseline at the point of 12 months (p = 0.021) relative to the point of 3 days. In patients with persistent AF, the expression level significantly increased 3 months after ablation (p = 0.046) compared to the level before surgery. Patients with long-term persistent AF after ablation had a tendency toward a decrease in expression. [ABSTRACT FROM AUTHOR]

The results of a study of the GdAlO3–SrO section, which is one of the internal sections of the Gd2O3–SrO–Al2O3 ternary system, are presented. In the GdAlO3–SrO section three triple compounds, Gd2SrAl2O7, GdSrAlO4, and GdSr2AlO5, crystallizing in the tetragonal system, are synthesized. The data on the mechanism of their solid-phase formation are systematized. The results of the thermal stability of perovskite-like phases in the GdAlO3–SrO system are presented in a wide temperature range of 1100–1800°C in air. The congruent character of the melting of Gd2SrAl2O7, GdSrAlO4, and GdSr2AlO5 complex oxides is established and their melting temperatures are determined. [ABSTRACT FROM AUTHOR]

Актуальність. У хворих із вперше виявленим цукровим діабетом 2-го типу (ЦД2) спостерігається невелике, але статистично вірогідне зниження абсолютного числа природних клітин-кілерів (СD56+) у периферичній крові (ПК), особливо виражене при супутньому ожирінні. У зв’язку з вищевикладеним метою дослідження було подальше вивчення ролі NK-клітин у пацієнтів із вперше виявленим ЦД2, у тому числі ускладненим ожирінням. Для цього використовували комбінацію методів проточної цитометрії зі скануючою та трансмісійною електронною мікроскопією для визначення кількості та функції CD56+ клітин у ПК хворих із ЦД2. Матеріали та методи. Обстежено 144 особи обох статей із вперше виявленим ЦД2 віком 40–70 років, які не мали інших гострих та хронічних захворювань і раніше не приймали гіпоглікемічних препаратів. Контрольну групу становили 50 здорових людей із нормоглікемією віком 40–65 років, які не хворіли на COVID-19. Результати. Наші дослідження встановили, що в нелікованих пацієнтів із вперше діагностованим ЦД2 порівняно зі здоровими особами спостерігається дуже невелике статистично значуще зниження абсолютної кількості клітин CD56+ у ПК. При поєднанні проточної цитометрії (FACS методом) і супутніх трансмісійної та скануючої електронної мікроскопії у хворих на ЦД2 було виявлено значні зміни в ультраструктурі СD56+ клітин. Це вказує на зниження їхньої функції, а саме збільшення кількості клітин із більш гладенькою поверхнею клітинної мембрани, різке зменшення кількості азурофільних гранул у цитоплазмі, які вважаються основним продуцентом цитокінів і перфоринів, появу паралельно-трубчастих структур, біомаркерів зниження функцій клітин, порушення структури апарату Гольджі, гранулярного ендоплазматичного ретикулума та ін. Отримані дані свідчать про те, що у хворих на ЦД2, особливо на початковій стадії розвитку, спостерігається виражене послаблення функції NК-клітин, а отже, природного імунного захисту організму, й пояснюють підвищену схильність пацієнтів із діабетом до захворювання на різні віруси та інфекції, у тому числі COVID-19, а також тяжчий клінічний перебіг й підвищену смертність. Висновки. Проведені дослідження показують, що у хворих на початковій стадії ЦД2 спостерігається різке порушення субмікроскопічної організації CD56+ — найважливішого клітинного елемента природного імунітету, що свідчить про ослаблення функції природного імунного захисту. Це основна причина підвищеної чутливості хворих на діабет до інфікування різними патогенами, включаючи вірус SARS-CoV-2, а також більш тяжкого клінічного перебігу та підвищення рівня смертності. [ABSTRACT FROM AUTHOR]