Specific Activation of T Cells by an ACE2-Based CAR-Like Receptor upon Recognition of SARS-CoV-2 Spike Protein.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the causative agent of the Coronavirus Disease 2019 (COVID-19) pandemic, which is still a health issue worldwide mostly due to a high rate of contagiousness conferred by the high-affinity binding between cell viral receptors, Angiotensin-Converting Enzyme 2 (ACE2) and SARS-CoV-2 Spike protein. Therapies have been developed that rely on the use of antibodies or the induction of their production (vaccination), but despite vaccination being still largely protective, the efficacy of antibody-based therapies wanes with the advent of new viral variants. Chimeric Antigen Receptor (CAR) therapy has shown promise for tumors and has also been proposed for COVID-19 treatment, but as recognition of CARs still relies on antibody-derived sequences, they will still be hampered by the high evasion capacity of the virus. In this manuscript, we show the results from CAR-like constructs with a recognition domain based on the ACE2 viral receptor, whose ability to bind the virus will not wane, as Spike/ACE2 interaction is pivotal for viral entry. Moreover, we have developed a CAR construct based on an affinity-optimized ACE2 and showed that both wild-type and affinity-optimized ACE2 CARs drive activation of a T cell line in response to SARS-CoV-2 Spike protein expressed on a pulmonary cell line. Our work sets the stage for the development of CAR-like constructs against infectious agents that would not be affected by viral escape mutations and could be developed as soon as the receptor is identified.

From Cell to Symptoms: The Role of SARS-CoV-2 Cytopathic Effects in the Pathogenesis of COVID-19 and Long COVID.

Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) infection triggers various events from molecular to tissue level, which in turn is given by the intrinsic characteristics of each patient. Given the molecular diversity characteristic of each cellular phenotype, the possible cytopathic, tissue and clinical effects are difficult to predict, which determines the heterogeneity of COVID-19 symptoms. The purpose of this article is to provide a comprehensive review of the cytopathic effects of SARS-CoV-2 on various cell types, focusing on the development of COVID-19, which in turn may lead, in some patients, to a persistence of symptoms after recovery from the disease, a condition known as long COVID. We describe the molecular mechanisms underlying virus-host interactions, including alterations in protein expression, intracellular signaling pathways, and immune responses. In particular, the article highlights the potential impact of these cytopathies on cellular function and clinical outcomes, such as immune dysregulation, neuropsychiatric disorders, and organ damage. The article concludes by discussing future directions for research and implications for the management and treatment of COVID-19 and long COVID.

Epidemiology of aspergillosis in hospitalised Spanish patients-A 21-year retrospective study.

BACKGROUND: Aspergillosis is a serious infection, and in Spain, the influence of epidemiology and climate on the resulting expenses of aspergillosis is not well established. AIM: A retrospective descriptive study using the Minimum Basic Data Set was performed on records of patients admitted to hospitals of the National Health System between 1997 and 2017 with a diagnosis of aspergillosis. The weather parameters were obtained from the State Agency of Meteorology from Spain. RESULTS: A total of 32,960 patients were identified, of whom 22,383 were men (68%). The mean age (±SD) was 61.1 ± 19.1 years. The mean incidence rate for all diagnoses was 3.54 cases per 100,000 person-years (95% CI, 3.50-3.57). The incidence rate in men was twice as high as that in women, 4.89 (95% CI, 4.82-4.95) vs. 2.24 (95% CI, 2.19-2.27) cases per 100,000 person-years (p > .001). The highest incidence rates were concentrated in northern Spain. One in four patients died (8,080 cases; 25%). There was a moderate positive linear association between rainfall and incidence rate (rP  = .508; p = .026). In contrast, the Pearson's correlation coefficient indicated a moderate negative linear relationship between temperature and incidence rate (rP  = -.447; p = .050). We observed a higher incidence in the months with higher humidity and rainfall. CONCLUSIONS: Our study supports a high burden of aspergillosis in Spain, with an increase in cases in the past two decades. Additionally, the influence of climatological factors on the incidence of aspergillosis is highlighted. Despite preemptive treatment strategies, this infection still has a high mortality.

[Effectiveness of short educational intervention in patients with insomnia in primary care]. / Efectividad de una intervención educativa breve en pacientes con insomnio en atención primaria.

OBJETIVE: To evaluate the effectiveness of providing an educational intervention in primary care (PC) alongside a pharmacological treatment for insomnia. DESIGN: Single blinded non randomised clinical trial. LOCATION: Two urban primary health centers in Gijón (Asturias, Spain). PARTICIPANTS: Patients who consulted for insomnia between July 2012-January 2013 and met the inclusion criteria (n=50) were assigned systematically to the control group (CG) or intervention group (IG). All patients initiated treatment with lorazepam 1mg in the evenings and had four weekly 15 min visits plus a follow-up visit after another month. INTERVENTIONS: The IG received training for control of stimuli, sleep hygiene and respiration and relaxation techniques in the four visits. The CG had only non invasive measures taken. MEASUREMENTS: Considering as cured those who reached a Pittsburgh Sleep Quality Index PSQI <6 or a 50% reduction from baseline level. It was also analyzed the change in the PSQI from baseline to final visit and to follow-up visit, and voluntary interruption of lorazepam. Analysis by Bayesian inference. RESULTS: Twelve out of recoveries after intervention against one out of 24 among control group. Mean change in PSQI to final visit and follow-up visit was: -4.7 (95%CrI:-5.9 to -3.5) and -6,3 (95%ICred: -7.5 to -5.1) in IG; -1.8 (95%ICred: -3 to -0.5) and -1.7 (95%ICred: -2.9 to -0.4) in CG. Interruption of lorazepan: in 4 controls (16,7%) and 9 (34,6%) in IG. Twenty nine patients in GI and 17 in GC completed the trial. Per protocol analysis showed similar results. CONCLUSIONS: The educational intervention in PC improves sleep quality and reduces the need of treatment with benzodiacepines.

Three-Month Mortality in Nonhaematological Patients with Chronic Pulmonary Aspergillosis: Differences between Subtypes.

Objectives: Chronic pulmonary aspergillosis (CPA) is a fungal lung infection characterised by the slowly progressing destruction of the lung parenchyma and has four main subtypes. The objective of this work was to evaluate the epidemiology of CPA in our area and evaluate the involvement of the different subtypes in mortality. Methods: This was a descriptive longitudinal retrospective study developed in three tertiary hospitals in Spain. Among all patients admitted with a pulmonary aspergillosis diagnosis, we selected those who fulfilled the criteria for chronic aspergillosis according to the criteria of Denning, excluding those with a haematological disorder. Results: Among 409 inpatients recorded as having a pulmonary aspergillosis infection, only 76 (18.5%) fulfilled the criteria for CPA, with an estimated incidence of 0.67 cases/100,000 inhabitants/year. The subtypes detected were subacute invasive aspergillosis (SAIA) in 33 (43.4%) patients, simple aspergilloma (SA) in 25 (32.9%) patients, cavitary chronic aspergillosis (CCPA) in 13 (17.1%) patients, and chronic fibrosis (CFPA) in five (6.5%) patients. The overall three-month mortality rate was 23%, which was higher in SAIA patients. The predictors of early mortality were age > 65 years (OR 3.0 CI 95 1.0-9.5 p = 0.043) and the SAIA subtype vs. other subtypes (OR 3.1 CI 95 1.0-9.5 p = 0.042). Conclusions: The incidence rate estimated was inferior to that previously reported. The three-month mortality in patients with CPA was high, with older age and the SAIA subtype being the variable independent predictors of a worse prognosis.

Development and Validation of a Highly Sensitive Multiplex Immunoassay for SARS-CoV-2 Humoral Response Monitorization: A Study of the Antibody Response in COVID-19 Patients with Different Clinical Profiles during the First and Second Waves in Cadiz, Spain.

There is still a long way ahead regarding the COVID-19 pandemic, since emerging waves remain a daunting challenge to the healthcare system. For this reason, the development of new preventive tools and therapeutic strategies to deal with the disease have been necessary, among which serological assays have played a key role in the control of COVID-19 outbreaks and vaccine development. Here, we have developed and evaluated an immunoassay capable of simultaneously detecting multiple IgG antibodies against different SARS-CoV-2 antigens through the use of Bio-PlexTM technology. Additionally, we have analyzed the antibody response in COVID-19 patients with different clinical profiles in Cadiz, Spain. The multiplex immunoassay presented is a high-throughput and robust immune response monitoring tool capable of concurrently detecting anti-S1, anti-NC and anti-RBD IgG antibodies in serum with a very high sensitivity (94.34-97.96%) and specificity (91.84-100%). Therefore, the immunoassay proposed herein may be a useful monitoring tool for individual humoral immunity against SARS-CoV-2, as well as for epidemiological surveillance. In addition, we show the values of antibodies against multiple SARS-CoV-2 antigens and their correlation with the different clinical profiles of unvaccinated COVID-19 patients in Cadiz, Spain, during the first and second waves of the pandemic.

How Has the Aspergillosis Case Fatality Rate Changed over the Last Two Decades in Spain?

(1) Background: Aspergillus produces high morbidity and mortality, especially in at-risk populations. In Spain, the evolution of mortality in recent years due to this fungus is not well established. The aim of this study was to estimate the case fatality rate of aspergillosis in inpatients from 1997 to 2017 in Spain. (2) Methodology: A retrospective descriptive study was conducted with records of inpatients admitted to the National Health System with a diagnosis of aspergillosis. (3) Principal findings: Of 32,960 aspergillosis inpatients, 24.5% of deaths were registered, and 71% of the patients who died were men. The percentage of deaths increased progressively with age. The case fatality rate progressively decreased over the period, from 25.4 and 27.8% in 1997-1998 to values of 20.6 and 20.8% in 2016 and 2017. Influenza and pneumonia occurrence/association significantly increased case fatality rates in all cases. (4) Conclusions: Our study shows that lethality significantly decreased in the last two decades despite the increase in cases. This highlights the fact that patients with solid and/or hematological cancer do not have a much higher mortality rate than the group of patients with pneumonia or influenza alone, these two factors being the ones that cause the highest CFRs. We also need studies that analyze the causes of mortality to decrease it and studies that evaluate the impact of COVID-19.

Solubilization in vitro of tea tree oil and first results of antifungal effect in onychomycosis.

INTRODUCTION: Onychomycosis is the main cause of nail alteration. Hepatotoxicity, interference and low adherence to pharmacological treatment are associated. Therefore, our objective was to assess the in vitro effectiveness of tea tree essential oil (less harmful) against main causative agents of these infections. MATERIAL AND METHODS: Thrichophyton rubrum and Thrichophyton mentagrophytes were isolated and inoculated at a concentration of 3 × 105 CFU/mL in potato agar dextrose and tea tree essential oil at different concentrations to assess its effect by counting colony forming units and radial growth. RESULTS: Trichophyton rubrum growth inhibition was obtained at concentrations higher than 0.04% of the essential tea tree oil (p = 0.004). In the case of Thrichophyton mentagrophytes, inhibition was obtained at 0.02% (p = 0.017), and even complete inhibition at a final concentration of the oil at 0.07%. CONCLUSIONS: Tea tree essential oil inhibits the in vitro growth of the fungus and may be a less harmful alternative to the onychomycosis treatment.

Solubilization in vitro of tea tree oil and first results of antifungal effect in onychomycosis. / Solubilización in vitro del aceite de árbol de té y primeros resultados de su efecto antifúngico en onicomicosis.

INTRODUCTION: Onychomycosis is the main cause of nail alteration. Hepatotoxicity, interference and low adherence to pharmacological treatment are associated. Therefore, our objective was to assess the in vitro effectiveness of tea tree essential oil (less harmful) against main causative agents of these infections. MATERIAL AND METHODS: Trichophyton rubrum and Trichophyton mentagrophytes were isolated and inoculated at a concentration of 3x105 CFU / mL in potato agar dextrose and tea tree essential oil at different concentrations to assess its effect by counting colony forming units and radial growth. RESULTS: Trichophyton rubrum growth inhibition was obtained at concentrations higher than 0.04% of the essential tea tree oil (p = 0.004). In the case of Trichophyton mentagrophytes, inhibition was obtained at 0.02% (p = 0.017), and even complete inhibition at a final concentration of the oil at 0.07%. CONCLUSIONS: Tea tree essential oil inhibits the in vitro growth of the fungus and may be a less harmful alternative to the onychomycosis treatment.

I Can Not Wear My Sunglasses: An Unusual Sarcoidosis Presentation.

A 39-year-old Caucasian man was referred to University Hospital Salamanca from a primary care unit due to the presence of an erythematous violaceous nodule at the superior portion of his nose. Physical examination indicated that the firm, fixed erythematous violaceous nodule measured approximately 2 cm in diameter and was located inferior to a scar on the nasal bridge. Cutaneous involvement in sarcoidosis occurs in 25% of cases. A wide range of clinical presentations of cutaneous sarcoidosis is recognized. Skin lesions are classified as either non-specific, of which erythema nodosum is the most representative and specific, or as granulomatous, which includes maculopapular nodules, plaques, infiltrated scars, lupus pernio, ulcerations, warty lesions and erythroderma. Scar sarcoidosis is a type of cutaneous sarcoidosis.