Drug Repurposing in Oncology: A Systematic Review of Randomized Controlled Clinical Trials.

Quality pharmacological treatment can improve survival in many types of cancer. Drug repurposing offers advantages in comparison with traditional drug development procedures, reducing time and risk. This systematic review identified the most recent randomized controlled clinical trials that focus on drug repurposing in oncology. We found that only a few clinical trials were placebo-controlled or standard-of-care-alone-controlled. Metformin has been studied for potential use in various types of cancer, including prostate, lung, and pancreatic cancer. Other studies assessed the possible use of the antiparasitic agent mebendazole in colorectal cancer and of propranolol in multiple myeloma or, when combined with etodolac, in breast cancer. We were able to identify trials that study the potential use of known antineoplastics in other non-oncological conditions, such as imatinib for severe coronavirus disease in 2019 or a study protocol aiming to assess the possible repurposing of leuprolide for Alzheimer's disease. Major limitations of these clinical trials were the small sample size, the high clinical heterogeneity of the participants regarding the stage of the neoplastic disease, and the lack of accounting for multimorbidity and other baseline clinical characteristics. Drug repurposing possibilities in oncology must be carefully examined with well-designed trials, considering factors that could influence prognosis.

[Characterization of hospitalized patients with acute kidney injury associated with COVID-19 in Spain: Renal replacement therapy and mortality. FRA-COVID SEN Registry Data]. / Caracterización de la población con fracaso renal agudo durante la hospitalización por COVID-19 en España: tratamiento renal sustitutivo y mortalidad. Datos del Registro FRA-COVID SEN.

Background and objectives: Acute kidney injury (AKI) is common among hospitalized patients with COVID-19 and associated with worse prognosis. The Spanish Society of Nephrology created the AKI-COVID Registry to characterize the population admitted for COVID-19 that developed AKI in Spanish hospitals. The need of renal replacement therapy (RRT) therapeutic modalities, and mortality in these patients were assessed. Material and method: In a retrospective study, we analyzed data from the AKI-COVID Registry, which included patients hospitalized in 30 Spanish hospitals from May 2020 to November 2021. Clinical and demographic variables, factors related to the severity of COVID-19 and AKI, and survival data were recorded. A multivariate regression analysis was performed to study factors related to RRT and mortality. Results: Data from 730 patients were recorded. A total of 71.9% were men, with a mean age of 70 years (60-78), 70.1% were hypertensive, 32.9% diabetic, 33.3% with cardiovascular disease and 23.9% had some degree of chronic kidney disease (CKD). Pneumonia was diagnosed in 94.6%, requiring ventilatory support in 54.2% and admission to the ICU in 44.1% of cases.The median time from the onset of COVID-19 symptoms to the appearance of AKI (37.1% KDIGO I, 18.3% KDIGO II, 44.6% KDIGO III) was 6 days (4-10). A total of 235 (33.9%) patients required RRT: 155 patients with continuous renal replacement therapy, 89 alternate-day dialysis, 36 daily dialysis, 24 extended hemodialysis and 17 patients with hemodiafiltration. Smoking habit (OR 3.41), ventilatory support (OR 20.2), maximum creatinine value (OR 2.41) and time to AKI onset (OR 1.13) were predictors of the need for RRT; age was a protective factor (0.95). The group without RRT was characterized by older age, less severe AKI, shorter kidney injury onset and recovery time (p < 0.05). 38.6% of patients died during hospitalization; serious AKI and RRT were more frequent in the death group. In the multivariate analysis, age (OR 1.03), previous chronic kidney disease (OR 2.21), development of pneumonia (OR 2.89), ventilatory support (OR 3.34) and RRT (OR 2.28) were predictors of mortality while chronic treatment with ARBs was identified as a protective factor (OR 0.55). Conclusions: Patients with AKI during hospitalization for COVID-19 had a high mean age, comorbidities and severe infection. We defined two different clinical patterns: an AKI of early onset, in older patients that resolves in a few days without the need for RRT; and another more severe pattern, with greater need for RRT, and late onset, which was related to greater severity of the infectious disease. The severity of the infection, age and the presence of CKD prior to admission were identified as risk factors for mortality in these patients. In addition chronic treatment with ARBs was identified as a protective factor for mortality.

Wastewater surveillance of SARS-CoV-2 genomic populations on a country-wide scale through targeted sequencing.

SARS-CoV-2 surveillance of viral populations in wastewater samples is recognized as a useful tool for monitoring epidemic waves and boosting health preparedness. Next generation sequencing of viral RNA isolated from wastewater is a convenient and cost-effective strategy to understand the molecular epidemiology of SARS-CoV-2 and provide insights on the population dynamics of viral variants at the community level. However, in low- and middle-income countries, isolated groups have performed wastewater monitoring and data has not been extensively shared in the scientific community. Here we report the results of monitoring the co-circulation and abundance of variants of concern (VOCs) of SARS-CoV-2 in Uruguay, a small country in Latin America, between November 2020-July 2021 using wastewater surveillance. RNA isolated from wastewater was characterized by targeted sequencing of the Receptor Binding Domain region within the spike gene. Two computational approaches were used to track the viral variants. The results of the wastewater analysis showed the transition in the overall predominance of viral variants in wastewater from No-VOCs to successive VOCs, in agreement with clinical surveillance from sequencing of nasal swabs. The mutations K417T, E484K and N501Y, that characterize the Gamma VOC, were detected as early as December 2020, several weeks before the first clinical case was reported. Interestingly, a non-synonymous mutation described in the Delta VOC, L452R, was detected at a very low frequency since April 2021 when using a recently described sequence analysis tool (SAM Refiner). Wastewater NGS-based surveillance of SARS-CoV-2 is a reliable and complementary tool for monitoring the introduction and prevalence of VOCs at a community level allowing early public health decisions. This approach allows the tracking of symptomatic and asymptomatic individuals, who are generally under-reported in countries with limited clinical testing capacity. Our results suggests that wastewater-based epidemiology can contribute to improving public health responses in low- and middle-income countries.

Life Habits of Healthcare Professionals during the Third Wave of COVID-19: A Cross-Sectional Study in a Spanish Hospital

(1) Background: To describe sleep quality, eating behaviour and alcohol, tobacco and illicit drug use among healthcare staff in a Spanish public hospital. (2) Methods: Cross-sectional descriptive study examining sleep quality (Pittsburg Sleep Quality Index), eating behaviour (Three Factor Eating Questionnaire (R18)), tobacco and drug use (ESTUDES questionnaire) and alcohol use (Cut down, Annoyed, Guilty, Eye-opener). (3) Results: 178 people, of whom 87.1% (155) were women, with an average age of 41.59 ± 10.9 years. A total of 59.6% of the healthcare workers had sleep problems, to a greater or lesser degree. The average daily consumption was 10.56 ± 6.74 cigarettes. The most commonly used drugs included cannabis, occasionally used by 88.37%, cocaine (4.75%), ecstasy (4.65%) and amphetamines (2.33%). A total of 22.73% of participants had increased their drug use, and 22.73% had increased their consumption during the pandemic, with beer and wine accounting for 87.2% of drinks consumed during this period. (4) Conclusions: In addition to the psychological and emotional impact already demonstrated, the COVID-19 crisis has repercussions on sleep quality, eating behaviour and alcohol, tobacco and drug consumption. Psychological disturbances have repercussions on physical and functional aspects of healthcare workers. It is feasible that these alterations are due to stress, and it is necessary to act through treatment and prevention as well as promote healthy habits.

Life Habits of Healthcare Professionals during the Third Wave of COVID-19: A Cross-Sectional Study in a Spanish Hospital.

(1) Background: To describe sleep quality, eating behaviour and alcohol, tobacco and illicit drug use among healthcare staff in a Spanish public hospital. (2) Methods: Cross-sectional descriptive study examining sleep quality (Pittsburg Sleep Quality Index), eating behaviour (Three Factor Eating Questionnaire (R18)), tobacco and drug use (ESTUDES questionnaire) and alcohol use (Cut down, Annoyed, Guilty, Eye-opener). (3) Results: 178 people, of whom 87.1% (155) were women, with an average age of 41.59 ± 10.9 years. A total of 59.6% of the healthcare workers had sleep problems, to a greater or lesser degree. The average daily consumption was 10.56 ± 6.74 cigarettes. The most commonly used drugs included cannabis, occasionally used by 88.37%, cocaine (4.75%), ecstasy (4.65%) and amphetamines (2.33%). A total of 22.73% of participants had increased their drug use, and 22.73% had increased their consumption during the pandemic, with beer and wine accounting for 87.2% of drinks consumed during this period. (4) Conclusions: In addition to the psychological and emotional impact already demonstrated, the COVID-19 crisis has repercussions on sleep quality, eating behaviour and alcohol, tobacco and drug consumption. Psychological disturbances have repercussions on physical and functional aspects of healthcare workers. It is feasible that these alterations are due to stress, and it is necessary to act through treatment and prevention as well as promote healthy habits.

A multiplex-NGS approach to identifying respiratory RNA viruses during the COVID-19 pandemic.

A methodological approach based on reverse transcription (RT)-multiplex PCR followed by next-generation sequencing (NGS) was implemented to identify multiple respiratory RNA viruses simultaneously. A convenience sampling from respiratory surveillance and SARS-CoV-2 diagnosis in 2020 and 2021 in Montevideo, Uruguay, was analyzed. The results revealed the cocirculation of SARS-CoV-2 with human rhinovirus (hRV) A, B and C, human respiratory syncytial virus (hRSV) B, influenza A virus, and metapneumovirus B1. SARS-CoV-2 coinfections with hRV or hRSV B and influenza A virus coinfections with hRV C were identified in adults and/or children. This methodology combines the benefits of multiplex genomic amplification with the sensitivity and information provided by NGS. An advantage is that additional viral targets can be incorporated, making it a helpful tool to investigate the cocirculation and coinfections of respiratory viruses in pandemic and post-pandemic contexts.

Consecutive deletions in a unique Uruguayan SARS-CoV-2 lineage evidence the genetic variability potential of accessory genes.

Deletions frequently occur in the six accessory genes of SARS-CoV-2, but most genomes with deletions are sporadic and have limited spreading capability. Here, we analyze deletions in the ORF7a of the N.7 lineage, a unique Uruguayan clade from the Brazilian B.1.1.33 lineage. Thirteen samples collected during the early SARS-CoV-2 wave in Uruguay had deletions in the ORF7a. Complete genomes were obtained by Illumina next-generation sequencing, and deletions were confirmed by Sanger sequencing and capillary electrophoresis. The N.7 lineage includes several individuals with a 12-nucleotide deletion that removes four amino acids of the ORF7a. Notably, four individuals underwent an additional 68-nucleotide novel deletion that locates 44 nucleotides downstream in the terminal region of the same ORF7a. The simultaneous occurrence of the 12 and 68-nucleotide deletions fuses the ORF7a and ORF7b, two contiguous accessory genes that encode transmembrane proteins with immune-modulation activity. The fused ORF retains the signal peptide and the complete Ig-like fold of the 7a protein and the transmembrane domain of the 7b protein, suggesting that the fused protein plays similar functions to original proteins in a single format. Our findings evidence the remarkable dynamics of SARS-CoV-2 and the possibility that single and consecutive deletions occur in accessory genes and promote changes in the genomic organization that help the virus explore genetic variations and select for new, higher fit changes.

COVID-19 infection and renal injury: where is the place for acute interstitial nephritis disease?

Novel coronavirus disease infection (coronavirus disease 2019, COVID-19) was declared a global pandemic in March 2020 and since then has become a major public health problem. The prevalence of COVID-19 infection and acute kidney injury (AKI) is variable depending on several factors such as race/ethnicity and severity of illness. The pathophysiology of renal involvement in COVID-19 infection is not entirely clear, but it could be in part explained by the viral tropism in the kidney parenchyma. AKI in COVID-19 infection can be either by direct invasion of the virus or as a consequence of immunologic response. Diverse studies have focused on the effect of COVID-19 on glomerulonephritis (GN) patients or the 'novo' GN; however, the effect of COVID-19 in acute tubulointerstitial nephritis (ATIN) has been scarcely studied. In this article, we present five cases with different spectrums of COVID-19 infection and ATIN that may suggest that recent diagnosis of ATIN is accompanied by a worse clinical prognosis in comparison with long-term diagnosed ATIN.

Transmission cluster of COVID-19 cases from Uruguay: emergence and spreading of a novel SARS-CoV-2 ORF6 deletion.

BACKGROUND: Evolutionary changes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) include indels in non-structural, structural, and accessory open reading frames (ORFs) or genes. OBJECTIVES: We track indels in accessory ORFs to infer evolutionary gene patterns and epidemiological links between outbreaks. METHODS: Genomes from Coronavirus disease 2019 (COVID-19) case-patients were Illumina sequenced using ARTIC_V3. The assembled genomes were analysed to detect substitutions and indels. FINDINGS: We reported the emergence and spread of a unique 4-nucleotide deletion in the accessory ORF6, an interesting gene with immune modulation activity. The deletion in ORF6 removes one repeat unit of a two 4-nucleotide repeat, which shows that directly repeated sequences in the SARS-CoV-2 genome are associated with indels, even outside the context of extended repeat regions. The 4-nucleotide deletion produces a frameshifting change that results in a protein with two inserted amino acids, increasing the coding information of this accessory ORF. Epidemiological and genomic data indicate that the deletion variant has a single common ancestor and was initially detected in a health care outbreak and later in other COVID-19 cases, establishing a transmission cluster in the Uruguayan population. MAIN CONCLUSIONS: Our findings provide evidence for the origin and spread of deletion variants and emphasise indels' importance in epidemiological studies, including differentiating consecutive outbreaks occurring in the same health facility.

Cannabis Use and Emotional Intelligence in Adolescents during COVID-19 Confinement: A Social Network Analysis Approach

Confinement by COVID-19 had negative consequences on adolescent mental health, including increased cannabis use. Cannabis is related to variables that influence health and well-being. Emotional Intelligence is associated with adaptive coping styles, peer relationships, and social–emotional competencies. In adolescence, peer selection plays a unique role in the initiation of substance use. However, there are no studies during a confinement stage that analyse the relationships between networks, Emotional Intelligence, and cannabis use. The aim of this paper is to describe and analyse the consumption and friendship networks of an adolescent classroom and their relationship with Emotional Intelligence, cannabis use, and gender during COVID-19 confinement. Participants completed different questionnaires for Emotional Intelligence, cannabis use, and the consumption and friendship network. The sample consisted of 21 students from 10th grade, of which 47.6% were consumers. The friendship network correlates with the consumption network, and significant associations between emotional repair and being a cannabis user. The regression model points to the friendship network as a significant variable in predicting the classroom use network. This study highlights the role of the Social Network Analysis in predicting consumption networks during a COVID-19 confinement stage and serves as a tool for cannabis use prevention interventions in a specific population.

A deletion in SARS-CoV-2 ORF7 identified in COVID-19 outbreak in Uruguay.

The analysis of genetic diversity in SARS-CoV-2 is the focus of several studies, providing insights into how the virus emerged and evolves. Most common changes in SARS-CoV-2 are single or point nucleotide substitutions; meanwhile, insertions and deletions (indels) have been identified as a less frequent source of viral genetic variability. Here, we report the emergence of a 12-nucleotide deletion in ORF7a, resulting in a 4-amino acid in-frame deletion. The Δ12 variant was identified in viruses from patients of a single outbreak and represents the first report of this deletion in South American isolates. Phylogenetic analysis revealed that Δ12 strains belong to the lineage B.1.1 and clustered separated from the remaining Uruguayan strains. The ∆12 variant was detected in 14 patients of this outbreak by NGS sequencing and/or two rapid and economic methodologies: Sanger amplicon sequencing and capillary electrophoresis. The presence of strong molecular markers as the deletion described here are useful for tracking outbreaks and reveal a significant aspect of the SARS-CoV-2 evolution on the robustness of the virus to keep its functionality regardless loss of genetic material.

Genome Sequences of SARS-CoV-2 P.1 (Variant of Concern) and P.2 (Variant of Interest) Identified in Uruguay.

Two severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants associated with increased transmission and immune evasion, P.1 and P.2, emerged in Brazil and spread throughout South America. Here, we report genomes corresponding to these variants that were recently detected in Uruguay. These P.1 and P.2 genomes share all substitutions that are characteristic of these variants.

Leveraging a public-public partnership in Los Angeles County to address COVID-19 for children, youth, and families in underresourced communities.

There is growing concern about the mental health and social impact of COVID-19 on underresourced children, youth, and families given widespread social disruption, school closures, economic impact, and loss of lives. In this commentary we describe how an existing public-public partnership between a large county mental health department and a state university responded to COVID-19. This partnership, originally designed to address workforce needs, rapidly pivoted to support providers through a trauma- and resilience-informed approach to mitigating adverse mental health effects among youth and families in Los Angeles County. (PsycInfo Database Record (c) 2020 APA, all rights reserved).