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Objective: To study the effect of plitidepsin antiviral treatment in immunocompromised COVID-19 patients with underlying haematological malignancies or solid tumours, particularly those who have undergone anti-CD20 therapies., Design: We conducted a retrospective observational study, involving 54 adults treated with plitidepsin on compassionate use as an antiviral drug. Our analysis compared outcomes between patients with solid tumours and those with haematological malignancies, and a cohort of cases treated or not with anti-CD20 monoclonal antibodies., Results: Patients with a history of anti-CD20 therapies showed a prolonged time-to-negative RT-PCR for SARS-CoV-2 infection compared to non-treated patients (33 d (28;75) vs 15 (11;25); p  = .002). Similar results were observed in patients with solid tumours in comparison to those with haematological malignancies (13 (10;16) vs 26 (17;50); p  < .001). No serious adverse events were documented., Conclusions: Patients with haematological malignancies appear to be at a heightened risk for delayed SARS-CoV-2 clearance and subsequent clinical complications. These findings support plitidepsin as a well-tolerated treatment in this high-risk group. A phase II clinical trial (NCT05705167) is ongoing to evaluate plitidepsin as an antiviral drug in this population.KEY POINTSHaematological patients face an increased risk for severe COVID-19.Anti-CD20 therapies could increase fatal outcomes in COVID-19 patients.Persistent viral replication is increased in immunocompromised patients.Plitidepsin does not lead to new serious adverse events in immunocompromised patients.

Objectives: To evaluate the compassionate use of plitidepsin as an antiviral treatment in hospitalized immunocompromised adult patients with moderate-to-severe COVID-19., Design: Retrospective observational study of data -collected from January 01, 2021 to April 30, 2022- from 35 immunocompromised adult patients with COVID-19 non-eligible for other available antiviral treatments. Main outcome measures were time to respiratory recovery (SpFi ≥ 315); COVID-19-related 30-day-cumulative mortality after first plitidepsin infusion; and time to undetectable levels of viral RNA., Results: Thirty-three patients receiving a full course of plitidepsin (2.5 mg [n = 29] or 1.5 mg [n = 4]) were included. Most (69.7%) had a malignant hematologic disease and 27.3% had solid tumors. A total of 111 infusions were administered with lack of relevant safety events. Median time from plitidepsin initiation to SpFi ≥315 was 8 days (95% confidence interval [CI], 7-19). Median time to first negative reverse transcription-polymerase chain reaction for SARS-CoV-2 (cycle threshold >36) was 17 days (95% CI 13-25). Mortality rate was 16.3% (95% CI 3-37.3)., Conclusion: These data support plitidepsin as a well-tolerated treatment that might have potential clinical and antiviral efficacy in COVID-19 immunocompromised patients., Competing Interests: Declaration of Competing Interest JMJ holds stocks of Pangaea Oncology, has a non-remunerated role in the Scientific Advisory Board, and holds stocks of Promontory Therapeutics; and is a full-time employee and share-holder of PharmaMar, SA (Madrid, Spain), and a co-inventor of two patents for plitidepsin (WO99-42125). JAL is a full-time employee and share-holder of PharmaMar, SA (Madrid, Spain), and a co-inventor of a patent for plitidepsin (WO2008135793A1). XELE is a full-time employee of Pharma Mar, SA (Madrid, Spain). RL is a full-time employee and share-holder of PharmaMar, SA (Madrid, Spain). PGV received speaker fees from FLS Science, PharmaMar SA (Madrid, Spain) and GlaxoSmithKline (Spain); consulting fees from Angelini Pharma and PharmaMar SA; served as an advisory board member for Berlin Cures GmbH and Pharma Mar SA; and meeting grants from GlaxoSmithKline and PharmaMar SA. DCR received speaking fees from GlaxoSmithKline and Gilead Sciences. JAG received meeting grant from PharmaMar SA. PVF received speaking fee from GlaxoSmithKline (Spain) and served as an advisory board member for PharmaMar SA. MGC received meeting grant from Biomerieux. VPF received speaking fees from Janssen, Jazz Pharmaceuticals, Roche and also consultant fee from Italfarmaco SA CF (Heorfy Consulting) has received fees from Hospital Universitario Quirónsalud Madrid as a payment for statistical analysis. All remaining authors have declared no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: We aim to describe the safety and efficacy of sotrovimab in severe cases of COVID-19 in immunocompromised hosts., Methods: We used a retrospective multicenter cohort including immunocompromised hospitalized patients with severe COVID-19 treated with sotrovimab between October 2021 and December 2021., Results: We included 32 patients. The main immunocompromising conditions were solid organ transplantation (46.9%) and hematological malignancy (37.5%). Seven patients (21.9%) had respiratory progression: 12.5% died and 9.4% required mechanical ventilation. Patients treated within the first 14 days of their symptoms had a lower progression rate: 12.0% vs. 57.1%, p = 0.029. No adverse event was attributed to sotrovimab., Conclusions: Sotrovimab was safe and may be effective in its use for immunocompromised patients with severe COVID-19. More studies are needed to confirm these preliminary data.

The endocannabinoid (eCB) system, via the cannabinoid CB 1 receptor, regulates neurodevelopment by controlling neural progenitor proliferation and neurogenesis. CB 1 receptor signalling in vivo drives corticofugal deep layer projection neuron development through the regulation of BCL11B and SATB2 transcription factors. Here, we investigated the role of eCB signalling in mouse pluripotent embryonic stem cell-derived neuronal differentiation. Characterization of the eCB system revealed increased expression of eCB-metabolizing enzymes, eCB ligands and CB 1 receptors during neuronal differentiation. CB 1 receptor knockdown inhibited neuronal differentiation of deep layer neurons and increased upper layer neuron generation, and this phenotype was rescued by CB 1 re-expression. Pharmacological regulation with CB 1 receptor agonists or elevation of eCB tone with a monoacylglycerol lipase inhibitor promoted neuronal differentiation of deep layer neurons at the expense of upper layer neurons. Patch-clamp analyses revealed that enhancing cannabinoid signalling facilitated neuronal differentiation and functionality. Noteworthy, incubation with CB 1 receptor agonists during human iPSC-derived cerebral organoid formation also promoted the expansion of BCL11B + neurons. These findings unveil a cell-autonomous role of eCB signalling that, via the CB 1 receptor, promotes mouse and human deep layer cortical neuron development., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

Prenatal exposure to Δ 9 -tetrahydrocannabinol (THC), the most prominent active constituent of cannabis, alters neurodevelopmental plasticity with a long-term functional impact on adult offspring. Specifically, THC affects the development of pyramidal neurons and GABAergic interneurons via cannabinoid CB 1 receptors (CB 1 R). However, the particular contribution of these two neuronal lineages to the behavioral alterations and functional deficits induced by THC is still unclear. Here, by using conditional CB 1 R knockout mice, we investigated the neurodevelopmental consequences of prenatal THC exposure in adulthood, as well as their potential sex differences. Adult mice that had been exposed to THC during embryonic development showed altered hippocampal oscillations, brain hyperexcitability, and spatial memory impairment. Remarkably, we found a clear sexual dimorphism in these effects, with males being selectively affected. At the neuronal level, we found a striking interneuronopathy of CCK-containing interneurons in the hippocampus, which was restricted to male progeny. This THC-induced CCK-interneuron reduction was not evident in mice lacking CB 1 R selectively in GABAergic interneurons, thus pointing to a cell-autonomous THC action. In vivo electrophysiological recordings of hippocampal LFPs revealed alterations in hippocampal oscillations confined to the stratum pyramidale of CA1 in male offspring. In addition, sharp-wave ripples, a major high-frequency oscillation crucial for learning and memory consolidation, were also altered, pointing to aberrant circuitries caused by persistent reduction of CCK + basket cells. Taken together, these findings provide a mechanistic explanation for the long-term interneuronopathy responsible for the sex-dimorphic cognitive impairment induced by prenatal THC.

Background: The administration of certain cannabinoids provides neuroprotection in models of neurodegenerative diseases by acting through various cellular and molecular mechanisms. Many cannabinoid actions in the nervous system are mediated by CB 1 receptors, which can elicit psychotropic effects, but other targets devoid of psychotropic activity, including CB 2 and nuclear PPARγ receptors, can also be the target of specific cannabinoids., Methods: We investigated the pro-neurogenic potential of the synthetic cannabigerol derivative, VCE-003.2, in striatal neurodegeneration by using adeno-associated viral expression of mutant huntingtin in vivo and mouse embryonic stem cell differentiation in vitro ., Results: Oral administration of VCE-003.2 protected striatal medium spiny neurons from mutant huntingtin-induced damage, attenuated neuroinflammation and improved motor performance. VCE-003.2 bioavailability was characterized and the potential undesired side effects were evaluated by analyzing hepatotoxicity after chronic treatment. VCE-003.2 promoted subventricular zone progenitor mobilization, increased doublecortin-positive migrating neuroblasts towards the injured area, and enhanced effective neurogenesis. Moreover, we demonstrated the proneurogenic activity of VCE-003.2 in embryonic stem cells. VCE-003.2 was able to increase neuroblast formation and striatal-like CTIP2-mediated neurogenesis., Conclusions: The cannabigerol derivative VCE-003.2 improves subventricular zone-derived neurogenesis in response to mutant huntingtin-induced neurodegeneration, and is neuroprotective by oral administration., Competing Interests: Animal studies were approved by ethics committee of Complutense University and Cordoba University (Spain). Consent to participate is not applicable.Not applicable.EM is scientific advisors of Emerald Health Pharmaceuticals.

Cannabinoids have shown to exert neuroprotective actions in animal models by acting at different targets including canonical cannabinoid receptors and PPARγ. We previously showed that VCE-003, a cannabigerol (CBG) quinone derivative, is a novel neuroprotective and anti-inflammatory cannabinoid acting through PPARγ. We have now generated a non-thiophilic VCE-003 derivative named VCE-003.2 that preserves the ability to activate PPARγ and analyzed its neuroprotective activity. This compound exerted a prosurvival action in progenitor cells during neuronal differentiation, which was prevented by a PPARγ antagonist, without affecting neural progenitor cell proliferation. In addition, VCE-003.2 attenuated quinolinic acid (QA)-induced cell death and caspase-3 activation and also reduced mutant huntingtin aggregates in striatal cells. The neuroprotective profile of VCE-003.2 was analyzed using in vivo models of striatal neurodegeneration induced by QA and 3-nitropropionic acid (3NP) administration. VCE-003.2 prevented medium spiny DARPP32(+) neuronal loss in these Huntington's-like disease mice models improving motor deficits, reactive astrogliosis and microglial activation. In the 3NP model VCE-003.2 inhibited the upregulation of proinflammatory markers and improved antioxidant defenses in the brain. These data lead us to consider VCE-003.2 to have high potential for the treatment of Huntington's disease (HD) and other neurodegenerative diseases with neuroinflammatory traits.

This paper studies the proportion of the population reached by the programme of universal vaccination against Hepatitis B for children of 13 during the first year since its introduction in Extremadura (Spain). A reach of 96.04% is considered satisfactory and higher than that achieved in other pilot programmes, and even higher than that of other childhood vaccines. This is attributed to the energetic organization of the programme within those activities aimed at children of school age, to the information and participation by the various social and institutional bodies involved, to the work of the Extremaduran Health Education Board, and to the ongoing work of teams of health workers and doctors. There are no significant differences between urban and rural Health Clinics. These differences are to be found in those areas where the aforementioned teams and the traditional model have begun to operate. Given the existing health system in this country and the widespread nature of the illness, it is assumed that the most effective method of vaccination would be that aimed at the high-risk population, the children of mothers who are carriers, and universal vaccination of school-age children.

In the cross section study of a sample of 1,915 newly diagnosed cases of hypertension and 8,043 healthy individuals, a comparative analysis is made of different risk factors which can influence blood pressure counts. An association among the statistics for an excessive salt intake, stress, when the analysis is made according to age, in those over 45 years of age and regular physical exercise is shown. To the contrary, this association is not found with the use of oral contraceptives nor among the smoking population, even among those smoking over 20 cigarettes a day. For each one of these variables, the relative inequalities and their respective reliability intervals are studied. In the population studied, the factor of greatest importance is an excessive salt intake, revealing a risk twice that of diets in which no salt is added.