Outcomes and clinical characteristics of the compassionate use of plitidepsin in COVID-19 patients with solid tumours, haematological malignancies or anti-CD20 antibody treatment.

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.

Outcomes and clinical characteristics of the compassionate use of plitidepsin for immunocompromised adult patients with COVID-19.

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.

Use of Monoclonal Antibodies in Immunocompromised Patients Hospitalized with Severe COVID-19: A Retrospective Multicenter Cohort.

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.

Endocannabinoid signalling in stem cells and cerebral organoids drives differentiation to deep layer projection neurons via CB1 receptors.

The endocannabinoid (eCB) system, via the cannabinoid CB1 receptor, regulates neurodevelopment by controlling neural progenitor proliferation and neurogenesis. CB1 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 CB1 receptors during neuronal differentiation. CB1 receptor knockdown inhibited neuronal differentiation of deep layer neurons and increased upper layer neuron generation, and this phenotype was rescued by CB1 re-expression. Pharmacological regulation with CB1 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 CB1 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 CB1 receptor, promotes mouse and human deep layer cortical neuron development.

Long-term hippocampal interneuronopathy drives sex-dimorphic spatial memory impairment induced by prenatal THC exposure.

Prenatal exposure to Δ9-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 CB1 receptors (CB1R). 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 CB1R 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 CB1R 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.

Oral administration of the cannabigerol derivative VCE-003.2 promotes subventricular zone neurogenesis and protects against mutant huntingtin-induced neurodegeneration.

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 CB1 receptors, which can elicit psychotropic effects, but other targets devoid of psychotropic activity, including CB2 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.

Contribution of Altered Endocannabinoid System to Overactive mTORC1 Signaling in Focal Cortical Dysplasia.

Alterations of the PI3K/Akt/mammalian target of rapamycin complex 1 (mTORC1) signaling pathway are causally involved in a subset of malformations of cortical development (MCDs) ranging from focal cortical dysplasia (FCD) to hemimegalencephaly and megalencephaly. These MCDs represent a frequent cause of refractory pediatric epilepsy. The endocannabinoid system -especially cannabinoid CB1 receptor- exerts a neurodevelopmental regulatory role at least in part via activation of mTORC1 signaling. Therefore, we sought to characterize the possible contribution of endocannabinoid system signaling to FCD. Confocal microscopy characterization of the CB1 receptor expression and mTORC1 activation was conducted in FCD Type II resection samples. FCD samples were subjected to single nucleotide polymorphism screening for endocannabinoid system elements, as well as CB1 receptor gene sequencing. Cannabinoid CB1 receptor levels were increased in FCD with overactive mTORC1 signaling. CB1 receptors were enriched in phospho-S6-positive cells including balloon cells (BCs) that co-express aberrant markers of undifferentiated cells and dysplastic neurons. Pharmacological regulation of CB1 receptors and the mTORC1 pathway was performed in fresh FCD-derived organotypic cultures. HU-210-evoked activation of CB1 receptors was unable to further activate mTORC1 signaling, whereas CB1 receptor blockade with rimonabant attenuated mTORC1 overactivation. Alterations of the endocannabinoid system may thus contribute to FCD pathological features, and blockade of cannabinoid signaling might be a new therapeutic intervention in FCD.

VCE-003.2, a novel cannabigerol derivative, enhances neuronal progenitor cell survival and alleviates symptomatology in murine models of Huntington's disease.

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.

Las vacunas, una herramienta fundamental para mantener y mejorar la salud de la población / No disponible

No disponible

La enfermera escolar y la enfermera de Atención Primaria. A propósito de la atención a la diabetes en la Escuela de Extremadura / The school nurse and primary health nurse, apropos the diabetes care at school in Extremadura

Los problemas crónicos de salud en estudiantes son cada vez más frecuentes (alergias alimentarias, diabetes mellitus, etc.). La existencia de una enfermera escolar en el centro educativo puede ser clave en el control y buen pronóstico de estos problemas de salud. Objetivo. Revisar el papel de la enfermera escolar a propósito de la atención a la diabetes en la escuela en Extremadura. Metodología. Revisión bibliográfica de la literatura científica y experiencia propia sobre la figura de la enfermera escolar y la atención a la diabetes en los centros educativos no universitarios. Resultados. Esta figura está establecida en muchos de los países de nuestro entorno y desarrolla actividades fundamentales en pro de la salud de los estudiantes, aunque su presencia física generalmente no es constante y requiere de algunas mejoras. Conclusiones. Se debe promover la instauración de la enfermera escolar en España, para prevenir y abordar muchos problemas de salud en edad infantil y juvenil, preferentemente con dependencia del sistema sanitario e integrada en los equipos de Atención Primaria, lo cual favorece el trabajo comunitario de enfermería (AU)

The amount of chronic health problems in students is increasing with the time (food allergies, diabetes mellitus...). The presence of a school nurse in the educational sites could be the key to control this kind of health issues. Objective. Overhaul the function of a possible nurse in the schools of our region, with the target of trying to control and prevent diabetes mellitus and other illnesses. Methodology. We have reviewed the figure of a school nurse and the diabetes care in non-university schools, using scientific sources of information and the own experience. Results. Many countries of the European environment are performing really important activities which have their benefits on the students’ health; using the figure of a school nurse. However, the presence of this person is generally not constant in the educational sites, and requires some improvements. Conclusions. We must promote the establishment of school nurses in Spain so that we can take care and prevent many health problems which mostly affect youth and childhood (AU)

Educación para la Salud. Déficit sensoriales en personas mayores / No disponible

No disponible

[THE SCHOOL NURSE AND PRIMARY HEALTH NURSE, APROPOS THE DIABETES CARE AT SCHOOL IN EXTREMADURA]. / La enfermera escolar y La enfermera de Atención Primaria: A PROPÓSITO DE LA ATENCIÓN A LA DIABETES EN LA ESCUELA EN EXTREMADURA.

UNLABELLED: The amount of chronic health problems in students is increasing with the time (food allergies, diabetes mellitus...). The presence of a school nurse in the educational sites could be the key to control this kind of health issues. OBJECTIVE: Overhaul the function of a possible nurse in the schools of our region, with the target of trying to control and prevent diabetes mellitus and other illnesses. METHODOLOGY: We have reviewed the figure of a school nurse and the diabetes care in non-university schools, using scientific sources of information and the own experience. RESULTS: Many countries of the European environment are performing really important activities which have their benefits on the students'health; using the figure of a school nurse. However, the presence of this person is generally not constant in the educational sites, and requires some improvements. CONCLUSIONS: We must promote the establishment of school nurses in Spain so that we can take care and prevent many health problems which mostly affect youth and childhood.

[Vaccines. Official calendar of vaccinations in the infancy and the adolescence]. / Vacunas. Calendario oficial de vacunaciones en la infancia y la adolescencia.

Vaccines are a key tool in disease prevention and public health. Its application through a vaccination schedule, which displayed what vaccinations and at what age should be given, it is irreplaceable for a high coverage. Nurses, working in a multidisciplinary manner are essential for successful implementation of vaccination programs.

El valor de las vacunas en el momento actual / The value of vaccines in the present moment

Las vacunas han disminuido la frecuencia de algunas enfermedades infecciosas hasta su control o erradicación. En esta situación, algunas personas olvidan sus beneficios, tienen en cuenta aspectos poco científicos o falsos y no se vacunan. Se producen «bolsas» de personas susceptibles y casos de enfermedad. La actual situación del sarampión es un ejemplo. Necesitamos «poner en valor las vacunas», difundir sus logros y llevar a cabo una promoción permanente de sus grandes beneficios y seguridad(AU)

The vaccines have decreased the frequency of infectious diseases until control or eradication. In this situation, some people forget the benefits of vaccines, they consider unscientific and false aspects and are not vaccinated. Occur «bags» of susceptible individuals and cases of disease. The current measles situation is an example. We need to «give value to vaccines», disseminate their achievements and make a permanent promotion of their great benefits and safety(AU)

Vacunas. Algunos aspectos prácticos / Vaccines. Some practical issues

Las vacunas constituyen una herramienta fundamental en la prevención de enfermedades y son claves en Salud Pública. Los profesionales de enfermería, trabajando de forma multidisciplinar, resultan imprescindibles para obtener éxito en la aplicación de los programas de vacunaciones. Repasamos algunos aspectos prácticos de utilidad en la atención de enfermería desde el ámbito clínico, con el fin de obtener mayor efectividad y eficiencia(AU)

Vaccines are a key tool in disease prevention and public health. Nurses, working in a multidisciplinary manner, are essential for successful implementation of vaccination programs. We review some practical issues, useful in the clinic. We will obtain more effective and efficient in our work(AU)

Vacunas. Calendario oficial de vacunaciones en la infancia y la adolescencia / Vaccines. Official calendar of vaccinations in the infancy and the adolescence

Las vacunas constituyen una herramienta fundamental en la prevención de enfermedades y son claves en Salud Pública. Su aplicación a través de un calendario de vacunaciones, donde se visualicen qué vacunas y a qué edad se deben administrar, resulta irreemplazable para obtener unas altas coberturas. Los profesionales de enfermería, trabajando de forma multidisciplinar, son imprescindibles para obtener éxito en la aplicación de los programas de vacunaciones(AU)

Vaccines are a key tool in disease prevention and public health. Its application through a vaccination schedule, which displayed what vaccinations and at what age should be given, it is irreplaceable for a high coverage. Nurses, working in a multidisciplinary manner, are essential for successful implementation of vaccination programs(AU)