Unveiling the antiviral capabilities of targeting Human Dihydroorotate Dehydrogenase against SARS-CoV-2 (preprint)

The urgent need for effective treatments against emerging viral diseases, driven by drug-resistant strains and new viral variants, remains critical. We focus on inhibiting the human dihydroorotate dehydrogenase (HsDHODH), one of the enzymes in charge of pyrimidine nucleotide synthesis. This strategy could impede viral replication without provoking resistance. We evaluated quinone-based compounds, discovering potent HsDHODH inhibition (low nanomolar IC50) and promising in vitro anti-SARS-CoV-2 activity (low micromolar EC50). These compounds exhibited low toxicity, indicating potential for further development. Additionally, we employed computational tools like molecular docking and QSAR models to analyse protein-ligand interactions. These findings represent a significant step forward in the search for effective antiviral treatments and have great potential to impact the development of new broad-spectrum antiviral drugs.

Monitoring and Tracking the Spread of SARS-CoV-2 in Asturias, Spain

Mutational analysis of SARS-CoV-2 can quantify their relative importance over time, enable the dominant mutations to be identified and facilitate near real-time detection, comparison, and tracking of evolving variants. Collected samples in Asturias an autonomous community of Spain with a large aged population, and high levels of migration and tourism was monitored and tracked from its beginning in February 2020 until its decline and stabilization in August 2021, were characterized using whole genomic sequence and single nucleotide polymorphism. Data held in the GISAID database was analyzed to establish patterns in the appearance and persistence of SARS-CoV-2 strains. Only 138 non-synonymous mutations occurring in more than 1% of the population of SARS-CoV-2 were found, identifying 10 major variants worldwide (7 arose before January 2021), 19 regional and 1 local. In Asturias only 17 different variants were found. After vaccination, no further regional majority variants were found. Only half of the defined variants circulated and no new variants were generated, indicating that infection control measures (fast diagnosis, prevention measures and vaccination) were efficient.

Time warping between main epidemic time series in epidemiological surveillance (preprint)

The most common reported epidemic time series in epidemiological surveillance are the daily or weekly incidence of new cases, the hospital admission count, the ICU admission count, and the death toll, which played such a prominent role in the struggle to monitor the Covid-19 pandemy. Based on a generalization of the renewal equation, we explore the hypothesis that each pair of such curves is related to the other one by a smooth time varying delay and by a smooth ratio generalizing the reproduction number. This hypothesis is also explored for pairs of curves measuring the same indicator in two different countries. Given two such time series, we develop, based on a signal processing approach, an efficient numerical method for computing their time varying delay and ratio curves, and we verify that its results are consistent. Indeed, they experimentally verify symmetry and transitivity requirements and we also show, using realistic simulated data, that the method is able to properly recover the time delays and ratios ground truth. Moreover, on all real examples considered, the method leads to explainable time delays and ratios. The proposed method generalizes and unifies many recent related attempts to take advantage of the plurality of these health data across regions or countries and time, providing a better understanding of the relationship between them. An implementation of the method is publicly available at the EpiInvert CRAN package

Learning from the past: a short term forecast method for the COVID-19 incidence curve (preprint)

The COVID-19 pandemy has created a radically new situation where most countries provide raw measurements of their daily incidence and disclose them in real time. This enables new machine learning forecast strategies where the prediction might no longer be based just on the past values of the current incidence curve, but could take advantage of observations in many countries. We present such a simple global machine learning procedure using all past daily incidence trend curves. Each of the 27,418 COVID-19 incidence trend curves in our database contains the values of 56 consecutive days extracted from observed incidence curves across 61 word regions and countries. Given a current incidence trend curve observed over the past four weeks, its forecast in the next four weeks is computed by matching it with the first four weeks of all samples, and ranking them by their similarity to the query curve. Then the 28 days forecast is obtained by a statistical estimation combining the values of the 28 last observed days in those similar samples. Using comparison performed by the European Covid-19 Forecast Hub with the current state of the art forecast methods, we verify that the proposed global learning method, EpiLearn, compares favorably to methods forecasting from a single past curve.

Anosmia and negative polymerase chain reaction tests

Introduction: The COVID-19 disease caused by SARS-CoV-2 became a pandemic as of March 2020. Among the clinical manifestations of the peripheral nervous system may appear anosmia and ageusia. Objective: Demonstrate the importance of clinical and epidemiological diagnosis in the certainty criterion of COVID-19. Case presentation: 17-year-old male adolescent with loss of smell and family history of COVID-19, so he was left alone at home due to the admission in hospital of his family;he had two negative polymerase chain reaction tests in the first instance, without clinical picture of the apparent disease, until approximately 10 days after the appearance of the symptoms of the family, which begins with total loss of smell;the same test is repeated, which is negative again and he is referred to consultation for the study of anosmia. He was attended in Pediatrics service, a complete study is indicated and the interconsultation with the specialist of otolaryngology is carried out. All the complementary laboratory, microbiology and imaging tests were negative, so it was decided, due to the suspicion of COVID-19 and the family history, to perform serology for antibodies against SARS-CoV-2, which resulted in positive IgG. Conclusion: The retrospective clinical and epidemiological diagnosis allowed the certainty criterion of COVID-19 disease. © 2021, Editorial Ciencias Medicas. All rights reserved.

TELEPSIQUIATRÍA: EL FUTURO YA ES PRESENTE

Resumen Este trabajo de revisión analiza el estado de los conocimientos sobre la Telepsiquiatría (TP) tras la crisis provocada por el COVID y la consiguiente necesidad de utilizar nuevas modalidades de atención. Se abordan seis aspectos inherentes a la TP: la satisfacción de los pacientes y del personal de salud mental, la fiabilidad diagnóstica, la eficacia de la intervención de la TP, la rentabilidad en términos de coste-oportunidad (o eficiencia) y los aspectos legales inherentes a la confidencialidad y la privacidad en particular y la actitud de los profesionales hacia la TP. La satisfacción con el TP es aceptable tanto entre los pacientes como entre los profesionales, siendo estos últimos los más reacios. La fiabilidad diagnóstica está demostrada, pero requiere de más estudios que confirmen esta fiabilidad en diferentes diagnósticos y entornos sanitarios. La eficacia de los tratamientos con TP no es inferior a la atención presencial, como se ha comprobado en psicoterapias específicas. Por último, hay que destacar que la actitud del psiquiatra es el elemento más decisivo que limita o facilita la implantación del TP. This review paper analyzes the state of knowledge on Telepsychiatry (TP) after the crisis caused by COVID and the resulting need to use new modalities of care. Six essential aspects of TP are addressed: patient’s and mental health staff satisfaction, diagnostic reliability, effectiveness of TP interventions, cost-effectiveness in terms of opportunity cost (or efficiency), legal aspects inherent to confidentiality and privacy in particular and the attitude of professionals towards TP. Satisfaction with TP is acceptable among both patients and professionals, the latter being the most reluctant. Diagnostic reliability has been demonstrated, but requires further studies to confirm this reliability in different diagnoses and healthcare settings. The efficacy of TP treatments is not inferior to face-to-face care, as has been proven in specific psychotherapies. Finally, it should be noted that the attitude of the psychiatrist is the most decisive element that limits or facilitates the implementation of TP.

Role of aging in Blood–Brain Barrier dysfunction and susceptibility to SARS-CoV-2 infection: impacts on neurological symptoms of COVID-19

COVID-19, which is caused by Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2), has resulted in devastating morbidity and mortality worldwide due to lethal pneumonia and respiratory distress. In addition, the central nervous system (CNS) is well documented to be a target of SARS-CoV-2, and studies detected SARS-CoV-2 in the brain and the cerebrospinal fluid of COVID-19 patients. The blood–brain barrier (BBB) was suggested to be the major route of SARS-CoV-2 infection of the brain. Functionally, the BBB is created by an interactome between endothelial cells, pericytes, astrocytes, microglia, and neurons, which form the neurovascular units (NVU). However, at present, the interactions of SARS-CoV-2 with the NVU and the outcomes of this process are largely unknown. Moreover, age was described as one of the most prominent risk factors for hospitalization and deaths, along with other comorbidities such as diabetes and co-infections. This review will discuss the impact of SARS-CoV-2 on the NVU, the expression profile of SARS-CoV-2 receptors in the different cell types of the CNS and the possible role of aging in the neurological outcomes of COVID-19. A special emphasis will be placed on mitochondrial functions because dysfunctional mitochondria are also a strong inducer of inflammatory reactions and the “cytokine storm” associated with SARS-CoV-2 infection. Finally, we will discuss possible drug therapies to treat neural endothelial function in aged patients, and, thus, alleviate the neurological symptoms associated with COVID-19.

Familia y Tecnociencia: ¿qué nos depara el futuro inmediato?

En esta contribución abordamos el tema de la familia y la tecnociencia. Definimos la tecnociencia como un saber aplicado a todos los ámbitos de la realidad. Nos aproximamos a la cuestión de la familia nuclear y la pareja y exponemos nuestras contribuciones anteriores en torno a la biotecnología humana y la familia que actualizamos y ampliamos. Nos centramos en el impacto que la sindemia de la Covid-19 está teniendo en la vida familiar y seguidamente explicamos la repercusión de los recientes avances de la Ingeniería genética especialmente de la Edición de Genes (CRISPR). Exponemos las disputas que están generando tanto la clonación como la reciente modificación de embriones y finalmente resaltamos la necesidad de seguir investigando para lograr una relación armónica y favorable con la tecnociencia.Alternate :In this contribution we address the issue of family and technoscience. We define techno-science as knowledge applied to all areas of reality. We approach on the topic of the nuclear family and the couple and then we expose our previous contributions on family and human biotechnology and we update and expand our knowledge on it. We focus on the impact that the Covid-19 syndemic is having on family life and then we explain the impact that the latest advances in Genetic Engineering, especially Gene Editing (CRISPR) are taking into account. We expose the disputes that are generating both the cloning and the recent modification of embryos and we finally highlight the need to continue researching to achieve a harmonious and favourable relationship with techno-science.

Modeling Covid-19 incidence by the renewal equation after removal of administrative bias and noise (preprint)

The sanitary crisis of the past two years has focused the public’s attention on quantitative indicators of the spread of the COVID-19 pandemic. The daily reproduction number R t , defined by the average number of new infections caused by a single infected individual at time t , is one of the best metrics for estimating the epidemic trend. In this paper, we give a complete observation model for sampled epidemiological incidence signals obtained through periodic administrative measurements. The model is governed by the classic renewal equation using an empirical reproduction kernel, and subject to two perturbations: a time-varying gain with a weekly period and a white observation noise. We estimate this noise model and its parameters by extending a variational inversion of the model recovering its main driving variable R t . Using R t , a restored incidence curve, corrected of the weekly and festive day bias, can be deduced through the renewal equation. We verify experimentally on many countries that, once the weekly and festive days bias have been corrected, the difference between the incidence curve and its expected value is well approximated by an exponential distributed white noise multiplied by a power of the magnitude of the restored incidence curve. Simple Summary In the past two years, the COVID-19 incidence curves and reproduction number R t have been the main metrics used by policy makers and journalists to monitor the spread of this global pandemic. However, these metrics are not always reliable in the short term, because of a combination of delay in detection, administrative delays and random noise. In this article, we present a complete model of COVID-19 incidence, faithfully reconstructing the incidence curve and reproduction number from the renewal equation of the disease and precisely estimating the biases associated with periodic weekly bias, festive day bias and residual noise.

Comparative analysis of the first wave of the COVID-19 pandemic in South Korea, Italy, Spain, France, Germany, the United Kingdom, the USA and the New-York state (preprint)

We use an exponential growth model to analyze the first wave of the COVID-19 pandemic in South Korea, Italy, Spain, France, Germany, the United Kingdom, the USA and the New-York state. This model uses the number of officially reported patients tested positive and deaths to estimate an infected hindcast of the cumulative number of patients who later tested positive or who later die. For each region, an epidemic timeline is established, obtaining a precise knowledge of the chronology of the main epidemiological events during the full course of the first wave. It includes, in particular, the time that the virus has been in free circulation before the impact of the social distancing measures were observable. The results of the study suggest that among the analyzed regions, only South Korea and Germany possessed, at the beginning of the epidemic, a testing capacity that allowed to correctly follow the evolution of the epidemic. Anticipation in taking measures in these two countries caused the virus to spend less time in free circulation than in the rest of the regions. The analysis of the growth rates in the different regions suggests that the exponential growth rate of the cumulative number of infected, when the virus is in free circulation, is around 0.250737. In addition, we also study the ability of the model to properly forecast the epidemic spread at the beginning of the epidemic outbreak when very little data and information about the coronavirus were available. In the case of France, we obtain a reasonable estimate of the peak of the new cases of patients tested positive 9 days in advance and only 7 days after the implementation of a strict lockdown.

Removing weekly administrative noise in the daily count of COVID-19 new cases. Application to the computation of Rt (preprint)

The way each country counts and reports the incident cases of SARS-CoV-2 infections is strongly affected by the "weekend effect". During the weekend, fewer tests are carried out and there is a delay in the registration of cases. This introduces an "administrative noise" that can strongly disturb the calculation of trend estimators such as the effective reproduction number R(t). In this work we propose a procedure to correct the incidence curve and obtain a better fit between the number of infected and the one expected using the renewal equation. The classic way to deal with the administrative noise is to invoke its weekly period and therefore to filter the incidence curve by a seven days sliding mean. Yet this has three drawbacks: the first one is a loss of resolution. The second one is that a 7-day mean filter hinders the estimate of the effective reproduction number R(t) in the last three days before present. The third drawback of a mean filter is that it implicitly assumes the administrative noise to be additive and time invariant. The present study supports the idea that the administrative is better dealt with as being both periodic and multiplicative. The simple method that derives from these assumptions amount to multiplying the number of infected by a correcting factor which depends on the day of the week. This correcting factor is estimated from the incidence curve itself. The validity of the method is demonstrated by its positive impact on the accuracy of an the estimates of R(t). To exemplify the advantages of the multiplicative periodic correction, we apply it to Sweden, Germany, France and Spain. We observe that the estimated administrative noise is country dependent, and that the proposed strategy manages to reduce it noise considerably. An implementation of this technique is available at www.ipol.im/ern, where it can be tested on the daily incidence curves of an extensive list of states and geographic areas provided by the European Centre for Disease Prevention and Control.

Antiviral Effect of High-Dose Ivermectin in Adults with COVID-19: A Pilot Randomised, Controlled, Open Label, Multicentre Trial (preprint)

Background: There are limited antiviral options for the treatment of patients with coronavirus disease 2019 (COVID-19) that have demonstrated clinical efficacy and none of them is an oral drug. Ivermectin (IVM), a macrocytic lactone with a wide anti-parasitary spectrum, has shown potent in vitro activity against SARS-CoV-2 in cell cultures. Methods: We completed a pilot, randomized, controlled, outcome-assessor blinded clinical trial with the goal of evaluating the antiviral activity of high dose IVM in COVID-19 patients. Eligible patients were adults (aged 18 to 69 years) with mild or moderate RT-PCR confirmed SARS-CoV-2 infection within 5 days of symptoms onset. 45 patients were randomized in a 2:1 ratio to standard of care plus oral IVM at 0·6 mg/kg/day for 5 days versus standard of care. The primary endpoint was viral load reduction in respiratory secretions at day-5. Viral load in respiratory secretions was measured through quantitative RT-PCR. Concentrations of IVM in plasma were measured on multiple treatment days.Findings: The trial run between May 18 and September 29, 2020 with 45 randomized patients (30 in the IVM group and 15 controls). There was no difference in viral load reduction between groups but a significant difference in reduction was found in patients with higher median plasma IVM levels (72% IQR 59 – 77) versus untreated controls (42% IQR 31 – 73) (p=0·004). The mean ivermectin plasma concentration levels also showed a positive correlation with viral decay rate (r:0·47, p=0·02). Adverse events were reported in 5 (33%) patients in the controls and 13 (43%) in the IVM treated group, without a relationship between IVM plasma levels and adverse events.Interpretation: A concentration dependent antiviral activity of oral high dose IVM was identified in this pilot trial at a dosing regimen that was well tolerated. Large trials with clinical endpoints are necessary to determine the clinical utility of IVM in COVID-19.Trial Registration: This trial is registered with ClinicalTrials.gov, NCT004381884.Funding Statement: This work was supported by grant IP-COVID-19-625 from Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación, Argentina and Laboratorio ELEA/Phoenix, Argentina.Declaration of Interests: AK reports grants from Laboratorio Elea/Phoenix. MAT, MDG and ES are employees of Laboratorios Elea/Phoenix. SG is a moember of the Board of Directors of Laboratorio Elea/Phoenix. All other authors declare no competing interests.Ethics Approval Statement: Ethical approval was obtained from the Institutional Independent Ethics Committees and from district and national regulatory agencies. All participating individuals provided written informed consent. The trial was done in accordance with the principles of the Declaration of Helsinki.

Ivermectin repurposing for COVID-19 therapy: Safety and pharmacokinetic assessment of a novel nasal spray formulation in a pig model (preprint)

High ivermectin (IVM) concentrations suppress in vitro SARS-CoV-2 replication. Nasal IVM spray (NIVM spray) administration may contribute to attaining high drug concentrations in nasopharyngeal (NP) tissue, a primary site of virus entrance/replication. The safety and pharmacokinetic performance of a new NIVM spray formulation in a piglet model were assessed. Crossbred piglets (10/12 kg) were treated with either one or two (12 h apart) doses of N IVM spray (2 mg, 1 puff/nostril) or orally (0.2 mg/kg). The overall safety of NIVM-spray was assessed (clinical, haematological, serum biochemical determinations), and histopathology evaluation of the application site tissues performed. The IVM concentration profiles measured in plasma and respiratory tract tissues (nasopharynx and lungs) after the nasal spray treatment (one and two applications) were compared with those achieved after the oral administration. Animals tolerated well the novel NIVM spray formulation. No local/systemic adverse events were observed. After nasal administration, the highest IVM concentrations were measured in NP and lung tissues. Significant increases in IVM concentration profiles in both NPtissue and lungs were observed after the 2 dose nasal administrations. The nasal/oral IVM concentration ratios in NP and lung tissues (at 6 h postdose) markedely increased by repeating the spray application. The fast attainment of high and persistent IVM concentrations in NP tissue is the main advantage of the nasal over the oral route. These original results are encouraging to support the undertaking of further clinical trials to evaluate the safety/efficacy of the nasal IVM spray application in the treatment and/or prevention of COVID-19.

Evidence for ZAP-independent CpG reduction in SARS-CoV-2 genome, and pangolin coronavirus origin of 5'UTR (preprint)

SARS-CoV-2, the causative agent of COVID-19, has an RNA genome, which is, overall, closely related to the bat coronavirus sequence RaTG13. However, the ACE2-binding domain of this virus is more similar to a coronavirus isolated from pangolin. In addition to this unique feature, the genome of SARS-CoV-2 (and its closely related coronaviruses) has a low CpG content. This has been postulated to be signature of an evolutionary pressure exerted by the host antiviral protein ZAP. Here, we analyzed the sequences of a wide range of viruses using both alignment-based and alignment free approaches to investigate the origin of SARS-CoV-2 genome. Our analyses revealed a high level of similarity between the 5UTR of SARS-CoV-2 and that of a Guangdong pangolin coronavirus. These data suggest that not only ACE2, but also the 5UTR of SARS-CoV-2 likely has a pangolin coronavirus origin. Additionally, we performed a detailed analysis of viral genome compositions as well as expression and RNA binding data of ZAP to show that the low CpG abundance in SARS-CoV-2 is not related to an evolutionary pressure from ZAP.

SARS-CoV-2 RBD mutations, ACE2 genetic polymorphism, and stability of the virus-receptor complex: The COVID-19 host-pathogen nexus. (preprint)

We herein report a computational study on the implications of SARS-CoV-2 RBD mutations and the Angiotensin Converting Enzyme 2 (ACE2) receptor genetic variations on the stability of the virus-host association. In silico analysis of the complex between the virus mutated forms and ACE2 isoform 1 showed that out of 351 RBD point mutations, 83% destabilizes the complex, while 17% have mild stabilizing effect. Study of the complex SARS-CoV-2 Wuhan strain RBD region /ACE2 isoform 1, 6LZG PDB 3D model revealed 18 contact residues. Interestingly, mutations occurring in 15 out of these residues show variations in the patterns of polar and hydrophobic interactions as compared to the original complex. Similarly, comparison of the effect on the complex stability of different ACE2 variants showed that the pattern of molecular interactions and the virus-receptor complex stability varies also according to ACE2 polymorphism. This could explain the large inter-individual variation of disease susceptibility and/or severity. The observation of a high variability in the interactions patterns highlights the complexity of the molecular interplay between SARS-CoV-2 and the ACE2 receptor. We infer that it is important to consider both ACE2 genetic variants and SARS-CoV-2 RBD mutations to assess the stability of the virus-receptor association and evaluate the infectivity of circulating SARS-CoV-2. These findings point toward the importance of individuals genetic typing of the circulating viral form as well as the ACE2 receptor. This will offer a good molecular ground to adjust the mitigation efforts for a better control of the virus spreading.

QT interval measurement with portable device during COVID-19 outbreak.

Coronavirus Disease 2019 continues to spread and to date, no definitive treatment is available. Overcrowded and under-resourced healthcare centres have had to design different strategies to treat these patients, what includes the control of the electrocardiogram (ECG), as some drugs that have been used to treat this disease may prolong the QT interval as a side effect. During the COVID-19 outbreak, we designed a protocol for monitoring the QT interval using a portable device with Bluetooth connectivity. After a validation study with 50 patients, we found a very good correlation between the QT interval measured both with this device and with the conventional body surface ECG. In this article, we provide a brief overview of the protocol and then analyse the QT changes observed in a group of patients during their hospitalization and treatment for SARS-CoV-2 infection. 81 patients with confirmed SARS-CoV-2 infection were enrolled in the protocol (age 63.4 SD 17.2 years; 70.3% men), while being treated with lopinavir/ritonavir, azithromycin and hydroxychloroquine, both individually or combined. Ten patients developed long drug-related QT interval, and the QT prolongation was statically significant for all treatment schemes. All patients with drug induced QT prolongation corrected the QT interval following the indications of the protocol, and no patients died of arrhythmic causes after its implementation. In our experience, a protocol for the electrocardiographic monitoring of these patients minimizes the risk of iatrogenic QT interval prolongation and consequently reduces sudden death events, and for that purpose, portable devices like the one used in this protocol may constitute a useful tool to minimize the contact with such patients.

A variational model for computing the effective reproduction number of SARS-CoV-2 (preprint)

We propose a variational model for computing the effective reproduction number (ERN) of SARS-CoV-2 from the daily count of incident cases. This computation only requires the knowledge of the serial interval. The ERN estimate is made through the minimization of a functional that includes: (i) the adjustment of the incidence curve using an epidemiological model, (ii) the regularity of the estimation of the ERN and, (iii) the adjustment of the initial value to an initial estimate of R_0 obtained from the initial exponential growth of the epidemic. The model does not assume any statistical distribution for the ERN and, more importantly, does not require truncating the serial interval when its distribution contains negative days. A comparative study has been carried out with the standard EpiEstim method. For a particular choice of the parameters of the variational model and of the serial interval, a good agreement has been obtained between the estimate provided by the variational model and a 7 days shifted estimate obtained by EpiEstim. This backward shift suggests that our estimate is closer to present than that of EpiEstim. We also examine how to forecast the value of the ERN and the number of infected in the short term by two different extrapolation techniques. An implementation of the model is available online at www.ipol.im/ern.