Analysis: FDA's COVID-19 Accelerated Pathways

Current FDA programs to accelerate access In order to accelerate the product approval process, four regulatory programs currently exist to reduce development and review times for products that address unmet medical needs for the treatment of serious or life-threatening conditions. In May 2014, FDA issued a Final Guidance for Industry entitled, "Expedited Programs for Serious Conditions-Drugs and Biologics" which addresses fast track designation, breakthrough therapy designation, priority review designation and accelerated approval.3 In addition to this guidance document, under section 564 of the FD&C Act, 21 U.S.C. 360bbb3, in a situation where the Secretary of Health and Human Services (HHS) issues a declaration of emergency or threat justifying authorization of emergency use for a product caused by chemical, biological, radiological or nuclear (CBRN) agents, as well as an infectious disease, the Commissioner of the FDA may authorize an EUA of an unapproved product or an unapproved use of an approved product. In January 2017, the "Emergency Use Authorization of Medical Products and Related Authorities" guidance was finalized.4 Fast Track designation Section 112 of the Food and Drug Administration Modernization Act of 1997 (FDAMA), entitled "Expediting Study and Approval of Fast Track Drugs," mandates the facilitation of the development and processes to expedite review of therapeutics intended to treat serious or life-threatening conditions presenting with unmet medical needs. [...]a two-tiered system of review times, Standard Review and Priority Review was created.

Suicidal Risk and Depression in Pregnant Women in Times of Pandemic.

PURPOSE: Pregnancy is a risk period for the development of mental disorders. About 10% of pregnant women worldwide experience a mental disorder, mainly depression, and this percentage has been aggravated by the COVID-19 pandemic. This study aims to understand the impact of COVID-19 on the mental health of pregnant women. METHODS: Three hundred and one pregnant women in the week 21.85 ± 9.9 were recruited through social media and pregnant women forums from September 2020 to December 2020. A multiple-choice questionnaire was administered to evaluate the sociodemographic characteristics of the women, the care provided, and different aspects related to COVID-19. A Beck Depression Inventory was also delivered. RESULTS: Of the pregnant women 23.5% had seen or had considered seeing a mental health professional during pregnancy. Predictive models using multivariate logistic regression found that this fact was associated with an increased risk of depression (OR = 4.22; CI 95% 2.39-7.52; P < 0.001). Among women with moderate-severe depression, it was associated with an increased risk of having suicidal thoughts (OR = 4.99; CI 95% 1.11-27.9; P = 0.044) and age was found to be a protective variable (OR = 0.86; CI 95% 0.72-0.98; P = 0.053). CONCLUSIONS: The COVID-19 pandemic represents a major mental health challenge for pregnant women. Despite the decrease in face-to-face visits, there are opportunities for health professionals to identify the existence of psycho-pathological alterations and suicidal ideation by asking the patient if she is seeing or considering seeing a mental health professional. Therefore, it is necessary to develop tools for early identification to ensure correct detection and care.

Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is lethal in 88% of patients1, yet harbours mutation-derived T cell neoantigens that are suitable for vaccines 2,3. Here in a phase I trial of adjuvant autogene cevumeran, an individualized neoantigen vaccine based on uridine mRNA-lipoplex nanoparticles, we synthesized mRNA neoantigen vaccines in real time from surgically resected PDAC tumours. After surgery, we sequentially administered atezolizumab (an anti-PD-L1 immunotherapy), autogene cevumeran (a maximum of 20 neoantigens per patient) and a modified version of a four-drug chemotherapy regimen (mFOLFIRINOX, comprising folinic acid, fluorouracil, irinotecan and oxaliplatin). The end points included vaccine-induced neoantigen-specific T cells by high-threshold assays, 18-month recurrence-free survival and oncologic feasibility. We treated 16 patients with atezolizumab and autogene cevumeran, then 15 patients with mFOLFIRINOX. Autogene cevumeran was administered within 3 days of benchmarked times, was tolerable and induced de novo high-magnitude neoantigen-specific T cells in 8 out of 16 patients, with half targeting more than one vaccine neoantigen. Using a new mathematical strategy to track T cell clones (CloneTrack) and functional assays, we found that vaccine-expanded T cells comprised up to 10% of all blood T cells, re-expanded with a vaccine booster and included long-lived polyfunctional neoantigen-specific effector CD8+ T cells. At 18-month median follow-up, patients with vaccine-expanded T cells (responders) had a longer median recurrence-free survival (not reached) compared with patients without vaccine-expanded T cells (non-responders; 13.4 months, P = 0.003). Differences in the immune fitness of the patients did not confound this correlation, as responders and non-responders mounted equivalent immunity to a concurrent unrelated mRNA vaccine against SARS-CoV-2. Thus, adjuvant atezolizumab, autogene cevumeran and mFOLFIRINOX induces substantial T cell activity that may correlate with delayed PDAC recurrence.

Evaluating the Effect of a Telepsychiatry Educational Program on the Awareness, Knowledge, Attitude, and Skills of Telepsychiatry Among Spanish Psychiatrists during COVID-19 Pandemic.

Introduction: The COVID-19 pandemic has renewed the interest in telepsychiatry as a way to help psychiatrists care for their patients, but mental health providers' unfamiliarity and concerns may impede implementation of such services. This study aimed to determine the effect of an online educational intervention on awareness, knowledge, attitude, and skills (AKAS) of telepsychiatry among psychiatrists. Methods: The study used a pre-post-test design to compare AKAS of telepsychiatry among psychiatrists participating in an online course of practical telepsychiatry. The telemedicine AKAS questionnaire adapted to telepsychiatry was applied before and after the educational intervention, during the months of October to December 2020. Results: Responses from 213 participants were analyzed before the educational intervention and from 152 after it. The knowledge showed by Spanish psychiatrists before the educational intervention was good in 61% of participants, fair in 37%, and inadequate in 2%. With respect to attitudes toward telepsychiatry, 62% self-reported a high attitude, 33% moderate, and 5% low. With regard self-reported skills, 57% of the participating psychiatrists were highly skilled or experts, 22% moderately skilled, and 9% unskilled in handling telepsychiatry equipment. Despite the high baseline values, the educational intervention significantly improved psychiatrists' awareness, knowledge and attitudes toward telepsychiatry although not their skills. Conclusions: Online course of practical telepsychiatry was effective although future editions need to improve its focus on skills. This educational intervention represents an effort to promote the implementation of telepsychiatry as a health care alternative.

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.

Autophagy: A Key Regulator of Homeostasis and Disease: An Overview of Molecular Mechanisms and Modulators.

Autophagy is a highly conserved lysosomal degradation pathway active at basal levels in all cells. However, under stress conditions, such as a lack of nutrients or trophic factors, it works as a survival mechanism that allows the generation of metabolic precursors for the proper functioning of the cells until the nutrients are available. Neurons, as post-mitotic cells, depend largely on autophagy to maintain cell homeostasis to get rid of damaged and/or old organelles and misfolded or aggregated proteins. Therefore, the dysfunction of this process contributes to the pathologies of many human diseases. Furthermore, autophagy is highly active during differentiation and development. In this review, we describe the current knowledge of the different pathways, molecular mechanisms, factors that induce it, and the regulation of mammalian autophagy. We also discuss its relevant role in development and disease. Finally, here we summarize several investigations demonstrating that autophagic abnormalities have been considered the underlying reasons for many human diseases, including liver disease, cardiovascular, cerebrovascular diseases, neurodegenerative diseases, neoplastic diseases, cancers, and, more recently, infectious diseases, such as SARS-CoV-2 caused COVID-19 disease.

Biomarker Candidates for Alzheimer’s Disease Unraveled through In Silico Differential Gene Expression Analysis

Alzheimer’s disease (AD) is neurodegeneration that accounts for 60–70% of dementia cases. Symptoms begin with mild memory difficulties and evolve towards cognitive impairment. The underlying risk factors remain primarily unclear for this heterogeneous disorder. Bioinformatics is a relevant research tool that allows for identifying several pathways related to AD. Open-access databases of RNA microarrays from the peripheral blood and brain of AD patients were analyzed after background correction and data normalization;the Limma package was used for differential expression analysis (DEA) through statistical R programming language. Data were corrected with the Benjamini and Hochberg approach, and genes with p-values equal to or less than 0.05 were considered to be significant. The direction of the change in gene expression was determined by its variation in the log2-fold change between healthy controls and patients. We performed the functional enrichment analysis of GO using goana and topGO-Limma. The functional enrichment analysis of DEGs showed upregulated (UR) pathways: behavior, nervous systems process, postsynapses, enzyme binding;downregulated (DR) were cellular component organization, RNA metabolic process, and signal transduction. Lastly, the intersection of DEGs in the three databases showed eight shared genes between brain and blood, with potential use as AD biomarkers for blood tests.

Reflexiones de niños preescolares, familiares y maestros de educación especial durante la pandemia

Palabras clave: aislamiento educativo, educación especial, edad preescolar, problemas en el desarrollo, atención educativa en línea The educational isolation caused by the Covid-19 pandemic has consequences in the teaching and learning process of preschool children with special needs, their parents, and teachers. [...]we created and applied online semi-structured interactive interviews for children, parents, and teachers in special education from public institutions. The study participants were ten preschool children with special needs, ten parents, and 25 special education teachers from Tlaxcala, Mexico. The conclusions establish that all preschool children wish to return to a face-toface modality of education and special attention, which corresponds to the needs of psychological development of this age.

Areas of Interest and Social Consideration of Antidepressants on English Tweets: A Natural Language Processing Classification Study.

BACKGROUND: Antidepressants are the foundation of the treatment of major depressive disorders. Despite the scientific evidence, there is still a sustained debate and concern about the efficacy of antidepressants, with widely differing opinions among the population about their positive and negative effects, which may condition people's attitudes towards such treatments. Our aim is to investigate Twitter posts about antidepressants in order to have a better understanding of the social consideration of antidepressants. METHODS: We gathered public tweets mentioning antidepressants written in English, published throughout a 22-month period, between 1 January 2019 and 31 October 2020. We analysed the content of each tweet, determining in the first place whether they included medical aspects or not. Those with medical content were classified into four categories: general aspects, such as quality of life or mood, sleep-related conditions, appetite/weight issues and aspects around somatic alterations. In non-medical tweets, we distinguished three categories: commercial nature (including all economic activity, drug promotion, education or outreach), help request/offer, and drug trivialization. In addition, users were arranged into three categories according to their nature: patients and relatives, caregivers, and interactions between Twitter users. Finally, we identified the most mentioned antidepressants, including the number of retweets and likes, which allowed us to measure the impact among Twitter users. RESULTS: The activity in Twitter concerning antidepressants is mainly focused on the effects these drugs may have on certain health-related areas, specifically sleep (20.87%) and appetite/weight (8.95%). Patients and relatives are the type of user that most frequently posts tweets with medical content (65.2%, specifically 80% when referencing sleep and 78.6% in the case of appetite/weight), whereas they are responsible for only 2.9% of tweets with non-medical content. Among tweets classified as non-medical in this study, the most common subject was drug trivialization (66.86%). Caregivers barely have any presence in conversations in Twitter about antidepressants (3.5%). However, their tweets rose more interest among other users, with a ratio 11.93 times higher than those posted by patients and their friends and family. Mirtazapine is the most mentioned antidepressant in Twitter (45.43%), with a significant difference with the rest, agomelatine (11.11%). CONCLUSIONS: This study shows that Twitter users that take antidepressants, or their friends and family, use social media to share medical information about antidepressants. However, other users that do not talk about antidepressants from a personal or close experience, frequently do so in a stigmatizing manner, by trivializing them. Our study also brings to light the scarce presence of caregivers in Twitter.

Psychological Impact and Risk of Suicide in Hospitalized COVID-19 Patients, During the Initial Stage of the Pandemic: A Cross-Sectional Study.

OBJECTIVES: This study aimed to assess the psychological impact and risk of suicide in patients hospitalized for COVID-19. METHODS: A cross-sectional study was conducted on a representative sample of patients hospitalized for COVID-19 at the "San Cecilio" University Hospital (Granada, Spain) between March and May 2020. Sociodemographic and clinical variables were collected. All participants were evaluated using the Gijon's Social-Familial Evaluation Scale to assess social problems, the Impact of Event Scale-6 and the Hospital Anxiety-Depression Scale to assess psychological impact, the Columbia Suicide Severity and Beck Hopelessness scales to assess risk of suicide, and the List of Threatening Experiences questionnaire to control for confounding bias. RESULTS: Thirty-six COVID-19 patients were evaluated. Of them, 33.3% had a significant psychological impact; 13.9% showed symptoms of anxiety, 13.9% showed symptoms of depression, and 47.2% showed symptoms of anxiety-depression. Moderate and severe risk of suicide were found in 75% and 2.8% of the patients, respectively. Suicidal ideation was observed in 16.7% and suicide behaviors in 5.6% of the patients. Psychological impact was associated with previous psychological treatment, a greater degree of functional dependency, and increased social-familial risk. In addition, the risk of suicide was mainly associated with active treatment of a psychiatric illness and active smoking. No significant correlation was found between psychological impact and risk of suicide. CONCLUSIONS: Psychological impact and risk of suicide were significant in patients admitted for COVID-19. Although the risk of suicide was not associated with increased psychological impact, both should be assessed, especially in patients at higher risk based on significantly associated factors.

Sexual Dysfunction and Atopic Dermatitis: A Systematic Review.

Atopic dermatitis (AD) is a chronic inflammatory disease of the skin whose main symptom is pruritus and may affect all age ranges. Regarding the prevalence, it has been estimated at around 10% of the world population. Many concomitant diseases have been associated with AD, but the causal relationship between AD and psychological impairment has not been clearly established. Scientific literature studying the probable association between male or female sexual dysfunction and dermatological pathology is limited, even more so in AD. This systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines and the Cochrane Collaboration methodology for systematic reviews. All relevant articles in English were identified through a search from inception to 10 December 2020, including the following databases: Medline (via PubMed), Scopus, Web of Science Core Collection, and SciELO. The results of the search were compiled using the COVIDENCE software for systematic reviews. The methodological quality of the included studies was done using the "Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies" and the "Quality Assessment of Case-Control Studies" developed by the National Heart, Lung, and Blood Institute, National Institutes of Health (NIH). Our search yielded potentially relevant studies. Five studies that evaluated the prevalence of sexual dysfunction in atopic dermatitis were retrieved after applying the selection criteria. The present systematic review achieved data from 8088 patients with atopic dermatitis from four articles. Sample sizes for atopic dermatitis patients ranged from 266 to 3997. We identified one cohort study with four years of follow-up, three studies with a cross-sectional design, and one case-control study. Three studies reported data disaggregated by the severity of atopic dermatitis. Two studies included healthy controls with a total sample size of 1,747,755 subjects. Two studies compared data with other dermatological conditions such as psoriasis. In conclusion, we can establish that unlike other psychological comorbidities such as anxiety and depression, sexual dysfunction is a field scarcely explored in the literature. This sexual dysfunction focuses on the male sex in large population studies and in clinical diagnoses without exploring it through specific and validated questionnaires in this regard. Further studies focused on both genders are needed. It is important to correlate this sexual dysfunction with the severity of the disease, previous treatments, and cardiovascular comorbidities.

Behavioural Difficulties in Children and Adolescents with Mental Disorders under Extreme Situations.

In 2020, the Governments of many countries maintained different levels of confinement of the population due to the pandemic that produced the COVID-19. There are few studies published on the psychological impact in the child and adolescent population diagnosed with mental disorders, especially during the home confinement stage. Explanatory models based on socio-demographic and clinical variables provide an approximation to level changes in different dimensions of behavioural difficulties. A categorical-response logistic ordinal regression model, based on a cross-sectional study with 139 children and adolescents diagnosed with mental disorders is performed for each dimension under analysis. Most of the socio-demographic and clinical explanatory variables considered (24 of 26) were significant at population level for at least one of the four dimensions of behavioural difficulties (15 response variables) under analysis. Odds-ratios were interpreted to identify risk or protective factors increasing or decreasing severity in the response variable. This analysis provides useful information, making it possible to more readily anticipate critical situations due to extreme events, such as a confinement, in this population.

Intubation timing as determinant of outcome in patients with acute respiratory distress syndrome by SARS-CoV-2 infection.

PURPOSE: To determine whether time-to-intubation was associated with higher ICU mortality in patients with COVID-19 on mechanical ventilation due to respiratory insufficiency. MATERIALS AND METHODS: We conducted an observational, prospective, single-center study of patients with confirmed SARS-CoV-2 infection hospitalized with moderate to severe ARDS, connected to mechanical ventilation in the ICU between March 17 and July 31, 2020. We examined their general and clinical characteristics. Time-to-intubation was the time from hospital admission to endotracheal intubation. RESULTS: We included 183 consecutive patients; 28% were female, and median age was 62 years old. Eighty-eight patients (48%) were intubated before 48 h (early) and ninety-five (52%) after 48 h (late). Patients intubated early had similar admission PaO2/FiO2 ratio (123 vs 99; p = 0.179) but were younger (59 vs 64; p = 0.013) and had higher body mass index (30 vs 28; p = 0.006) compared to patients intubated late. Mortality was higher in patients intubated late (18% versus 43%), with admission PaO2/FiO2 ratio < 100 mmHg (OR 5.2; p = 0.011), of older age (OR 1.1; p = 0.001), and with previous use of ACE inhibitors (OR 4.8; p = 0.026). CONCLUSIONS: In COVID-19 patients, late intubation, Pafi <100, older age, and previous ACE inhibitors use were associated with increased ICU mortality.

Elucidating the Neuropathologic Mechanisms of SARS-CoV-2 Infection.

The current pandemic caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a public health emergency. To date, March 1, 2021, coronavirus disease 2019 (COVID-19) has caused about 114 million accumulated cases and 2.53 million deaths worldwide. Previous pieces of evidence suggest that SARS-CoV-2 may affect the central nervous system (CNS) and cause neurological symptoms in COVID-19 patients. It is also known that angiotensin-converting enzyme-2 (ACE2), the primary receptor for SARS-CoV-2 infection, is expressed in different brain areas and cell types. Thus, it is hypothesized that infection by this virus could generate or exacerbate neuropathological alterations. However, the molecular mechanisms that link COVID-19 disease and nerve damage are unclear. In this review, we describe the routes of SARS-CoV-2 invasion into the central nervous system. We also analyze the neuropathologic mechanisms underlying this viral infection, and their potential relationship with the neurological manifestations described in patients with COVID-19, and the appearance or exacerbation of some neurodegenerative diseases.

Clinical characterization of brief psychotic disorders triggered by the COVID-19 pandemic: a multicenter observational study.

This study aimed to characterize the clinical profile of patients with brief psychotic disorders (BPD) triggered by the psychosocial distress derived from the COVID-19 crisis. A multicenter study was conducted from March 14 to May 14, 2020 (the peak weeks of the pandemic in Europe). All consecutive patients presenting non-affective psychotic episodes with a duration of untreated psychosis of less than 1 month and whose onset was related to the COVID-19 crisis were recruited, but only those patients meeting Diagnostic Statistical Manual 5th edition (DSM-5) criteria for "BPD with marked stressors" (DSM-5 code: 298.8) during follow-up were finally included. Patients' sociodemographic and clinical characteristics were collected at baseline and summarized with descriptive statistics. During the study period, 57 individuals with short-lived psychotic episodes related to the emotional stress of the COVID-19 pandemic were identified, of whom 33 met DSM-5 criteria for "BPD with marked stressors". The mean age was 42.33 ± 14.04 years, the gender distribution was almost the same, and the majority were rated as having good premorbid adjustment. About a quarter of the patients exhibited suicidal symptoms and almost half presented first-rank schizophrenia symptoms. None of them were COVID-19 positive, but in more than half of the cases, the topic of their psychotic features was COVID-19-related. The coronavirus pandemic is triggering a significant number of BPD cases. Their risk of suicidal behavior, their high relapse rate, and their low temporal stability make it necessary to closely monitor these patients over time.

Early versus deferred anti-SARS-CoV-2 convalescent plasma in patients admitted for COVID-19: A randomized phase II clinical trial.

BACKGROUND: Convalescent plasma (CP), despite limited evidence on its efficacy, is being widely used as a compassionate therapy for hospitalized patients with COVID-19. We aimed to evaluate the efficacy and safety of early CP therapy in COVID-19 progression. METHODS AND FINDINGS: The study was an open-label, single-center randomized clinical trial performed in an academic medical center in Santiago, Chile, from May 10, 2020, to July 18, 2020, with final follow-up until August 17, 2020. The trial included patients hospitalized within the first 7 days of COVID-19 symptom onset, presenting risk factors for illness progression and not on mechanical ventilation. The intervention consisted of immediate CP (early plasma group) versus no CP unless developing prespecified criteria of deterioration (deferred plasma group). Additional standard treatment was allowed in both arms. The primary outcome was a composite of mechanical ventilation, hospitalization for >14 days, or death. The key secondary outcomes included time to respiratory failure, days of mechanical ventilation, hospital length of stay, mortality at 30 days, and SARS-CoV-2 real-time PCR clearance rate. Of 58 randomized patients (mean age, 65.8 years; 50% male), 57 (98.3%) completed the trial. A total of 13 (43.3%) participants from the deferred group received plasma based on clinical aggravation. We failed to find benefit in the primary outcome (32.1% versus 33.3%, odds ratio [OR] 0.95, 95% CI 0.32-2.84, p > 0.999) in the early versus deferred CP group. The in-hospital mortality rate was 17.9% versus 6.7% (OR 3.04, 95% CI 0.54-17.17 p = 0.246), mechanical ventilation 17.9% versus 6.7% (OR 3.04, 95% CI 0.54-17.17, p = 0.246), and prolonged hospitalization 21.4% versus 30.0% (OR 0.64, 95% CI, 0.19-2.10, p = 0.554) in the early versus deferred CP group, respectively. The viral clearance rate on day 3 (26% versus 8%, p = 0.204) and day 7 (38% versus 19%, p = 0.374) did not differ between groups. Two patients experienced serious adverse events within 6 hours after plasma transfusion. The main limitation of this study is the lack of statistical power to detect a smaller but clinically relevant therapeutic effect of CP, as well as not having confirmed neutralizing antibodies in donor before plasma infusion. CONCLUSIONS: In the present study, we failed to find evidence of benefit in mortality, length of hospitalization, or mechanical ventilation requirement by immediate addition of CP therapy in the early stages of COVID-19 compared to its use only in case of patient deterioration. TRIAL REGISTRATION: NCT04375098.