Discovery and development of lead compounds from natural sources using computational approaches

Natural products have a significant role in drug discovery. Their unique chemical structures have led to compounds in clinical use to treat different diseases. Also, natural products are significant sources of inspiration or starting points to develop new therapeutic agents. There are also unique natural products such as peptides and macrocycles that offer sources or starting points to address complex diseases. Computational approaches that used chemoinformatics and molecular modeling methods contribute to assisting and accelerating natural product-based drug discovery. Several research groups have recently used computational methodologies to organize data, interpret results, generate and test hypotheses, filter large chemical databases before the experimental screening, and design experiments. Herein, we discuss chemoinformatics and molecular modeling applications to uncover bioactive natural products. We also discuss in silico methods to optimize the biological activity and anticipate potential toxicity issues of natural products. As case studies, we discuss the role of natural products for COVID-19 drug discovery and their impact on the identification of compounds with activity against DNA methyltransferase, an epigenetic target with relevance in cancer and other diseases. © 2022 Elsevier Inc. All rights reserved.

Feelings and perceptions of Unified Health System-dependent users cured of COVID-19

Due to the whole context of pandemic and its social impacts, a fragile situation in public health is faced, and may not only cause physical illness, but especially mental suffering, which has a high chance of occurring in the general population and persisting with post-pandemic psychological symptoms. The study aimed to understand feelings and perceptions experienced by dependent UHS users affected by Coronavirus, as well as the sequelae resulting from the process of illness and cure of the virus. This is descriptive, exploratory study type with a qualitative approach. The collection was carried out in the municipality of Guarabira, PB, with 20 dependent UHS users, who were affected by COVID-19, and who had been cured for at least 1 month. Users were invited to participate in the research through social networks. The interviews were guided by the data collection instrument and conducted remotely, using digital audio and video platforms. The age range of the interviewees ranged from 20 to 63 years, and 17 (85%) were females and 3 (15%) were males. Most females had completed higher education and were single. Feelings such as fear, anxiety, anguish, and loneliness, and the presence of sequelae after the cure of COVID-19 were identified. These feelings were clearly exposed in the interviewees' statements and the most prevalent feeling was fear. The study allowed for the identification of feelings harmful to the mental health of the participants. Through the reports, the presence of important sequelae after the cure of COVID-19 was also identified. © 2022 Centro Universitario Sao Camilo. All rights reserved.

SARS-CoV-2 seroprevalence in workers from a Colombian University Hospital.

BACKGROUND: Antibody (Ab) tests for SARS-CoV-2 virus allows for the estimation of incidence, level of exposure and duration of immunity acquired by a previous infection. In health workers, the hospital setting might convey a greater risk of infection. AIMS: To describe the frequency of immunoglobulin G (IgG) Abs (IgG-Abs) to the SARS-CoV-2 virus among workers at a third-level university hospital in Colombia. METHODS: In this cross-sectional study, we included medical and non-medical personnel with at least one real-time polymerase chain reaction (RT-PCR)/antigen test between March 2020 and March 2021. In April 2021, an IgG-Ab test against SARS-CoV-2 was conducted for all participants and replicated 2 weeks later in a random sample (10%). The frequency of IgG-Abs is presented based on status (positive/negative) and time elapsed since RT-PCR/antigen test (<3 months, 3-6 months, >6 months). RESULTS: We included 1021 workers (80% women, median age 34 years (interquartile range 28-42), 73% medical personnel, 23% with previous positive RT-PCR/antigen). The overall seroprevalence was 35% (95% CI 31.6-37.4, 35% in medical and 33% in non-medical personnel). For those with a previous positive RT-PCR/antigen test, the seroprevalence was 90% (<3 months), 82% (3-6 months) and 48% (>6 months). In participants with a previous negative RT-PCR/antigen test, the seroprevalence was 17% (<3 months), 21% (3-6 months) and 29% (>6 months). CONCLUSIONS: High IgG-Ab positivity was found in hospital personnel, regardless of work activities. The prevalence of detectable Abs differed by previous RT-PCR/antigen status and time elapsed since the diagnostic test.

Knowledge About COVID-19 and Perception of Health Safety Among Mexican Dental Students

This study aimed: 1) to investigate sources of information used by students to learn about COVID-19, 2) to investigate levels of knowledge about COVID-19 and about conditions for the treatment of patients during the COVID-19 lockdown, and 3) to evaluate students' perceptions of safety regarding their return to in-person activities at the School of Dentistry. Dental students answered a questionnaire (29 items;n=371) that explored the aims of the study, based on a Likert scale (Cronbach's alpha, 0.778). Data were tested with the Mann-Whitney U test and Kendall's Tau-c. Dental students received information about COVID-19 from the Mexican Health Ministry as their first source (45.28%). Students had good knowledge about the main characteristics of COVID-19, and 59.3% of students had excellent knowledge about the factors relevant to dental treatment of patients. Half of the students said they felt safe regarding a possible return to in-person activities at the dental school, while the other half did not. Statistically significant differences were noted between the students' scholar year and their level of knowledge (P<0.001) and between their perception of safety (very unsafe, unsafe, safe, and very safe) and scholar year (P=0.000). Dental students had good knowledge about COVID-19 and about the dental care for patients during the lockdown. Half of the dental students felt unsafe about a possible return to in-person school activities. © 2023, Universidad de Costa Rica. All rights reserved.

Early Infectious Diseases Consultation and Procalcitonin-Guided Therapy Limits Unnecessary Antibiotic Use in COVID-19

Background. Antibiotic stewardship has been a central challenge of the COVID-19 pandemic. Empiric antibiotic therapy is offered in 56.6%-74.6% of inpatients with COVID-19, with microbiologically confirmed bacterial pneumonia reported in only 3.5%-16% of cases. Procalcitonin (PCT) as a biomarker for bacterial infection is of interest in improving antibiotic use. PCT-guided antibiotic stewardship initiatives have demonstrated reduction in the use of antibiotics in the COVID-19 pandemic. An Infectious Diseases (ID) consultation was obtained on most patients at our institution throughout the COVID-19 pandemic. We report a significant reduction in antibiotic use among COVID-19 patients in the setting of near-universal ID consultation in COVID-19 patients. Methods. We evaluated the records of 1346 patients with COVID-19 from March 2020 - May 2021 at four hospitals with ID consultant availability. We assessed the inclusion of an ID consultant, antibiotic indication, initiation and discontinuation, PCT levels, radiologic images, and changes to therapy decisions. A chi-square test of independence and simple logistic regression were conducted to determine whether an association exists between the PCT level and the decision to discontinue antibiotics. Results. Of 1346 patients with a confirmed COVID-19 diagnosis, 64.6% (870/ 1346) received antibiotics on admission. The most common diagnosis associated with initial antibiotic administration was bacterial pneumonia (692/870, 79.5%). An ID consultation was obtained on 97.8% (677/692) of the patients that received antibiotics for suspected bacterial pneumonia. In 48.1% (326/677) of these patients, antibiotics were discontinued within the first 48 hours of the ID consultation. A statistically significant difference was noted between the PCT level and continuation of antibiotics (X2= 67.02, p < .01). The odds of discontinuing antibiotics for the upper (PCT > 0.51) and middle (PCT = 0.26-0.50) groups were 0.22 and 0.37, respectively, when compared to the lower (PCT <= 0.25) group. Conclusion. Early consultation of an ID specialist and evaluation of PCT levels leads to significant reductions in inappropriate antibiotic use. PCT may be a useful adjunct in assisting with the decision to discontinue antibiotics.

Neutrophil Counts Related to Presentation of Covid in Autoimmune Neutropenia?

Objective: To describe 2 cases of autoimmune neutropenia (AIN) patients infected with Sars-Cov-2. Design/Method: Two subjects case report. Result(s): Case report 1: A girl with primary AIN since 1 year and 10 months old, maintaining severe neutropenia and mild recurrent infections. Presented to the emergency department in June/2020, at 3 years and 8 months old, with flu-like symptoms, afebrile, in good general condition. Physical examination was normal. The absolute neutrophil count (ANC) was 0.279 x 109/L. At hospital admission, Sars-Cov-2 (RT-PCR) tested positive and filgrastim (G-CSF) 5 mug/kg/day was initiated. Chest X-ray was also normal and blood culture resulted negative. She remained in great general condition, afebrile, and was discharged on the 2nd day of hospitalization, with clarithromycin (15 mg/kg/day). After G-CSF, ANC: 0.494 x 109/L (1st dose), 1.431 x 109/L (2nd dose). On outpatient follow-up, she had no long-term complications from Covid-19. Case Report 2: A man with chronic immune thrombocytopenia purpura (ITP) since 2008, autoimmune hemolytic anemia since 2013, evolved with AIN on May/2020, at 42 years old, with ANC lower than 0.5 x 109/L. On 6/1/2020, he had ANC 0.170 x 109/L. On 6/25/2020, he started flu-like symptoms, had ANC of 5.118 x 109/L, and tested positive for Sars-Cov-2 (RT-PCR). He kept high fever (102,2degreeF) and was hospitalized for 10 days without use of G-CSF. After discharge, on outpatient follow-up, he had no long-term complications from Covid-19, and presented ANC 0.338 x 109/L (Aug/2020). Discussion(s): At beginning of Covid-19 pandemic, severity infection in children was unknown. Today is known that most of them have milder clinical course, regardless of chronic diseases. In adults, in contrast, the inflammatory response tends to exacerbation, with more severe clinical conditions. Furthermore, many case reports of patients infected by SARS-CoV-2 with comorbidities literature are published. However, to date there are no reports on the impact of COVID-19 in AIN patients. Increased neutrophil counts during infectious episodes are common in AIN, which appears to be related to the benign course of most infections. We reported 2 cases of AIN patients diagnosed with Covid-19, both with favorable clinical outcomes despite heterogenic clinical course. On the first case, she presented few symptoms and ANC increased only after using G-CSF. On the second reported patient, there was a spontaneous increase of ANC and greater inflammatory response than the first case. It could suggest a correlation between inflammatory response to COVID-19 and ANC in cases of autoimmune neutropenia. Conclusion(s): In the reported cases, clinical course of disease and neutrophil count were different between adult and pediatric patients. It is not possible to state whether this difference is due to age group, individual response to infection or other variables. It is important to assess other cases of AIN infected by COVID 19 to better understand correlation between severity of infection and neutrophil count response. Copyright © 2022

[What has been done at IMSS regarding the users's mental health in the COVID-19 pandemic?]

Nowadays, mental health has acquired greater relevance and attention as a consequence mainly of the COVID-19 pandemic, to which is attributed a negative impact on the development of life, work and social coexistence of people, along with the magnitude derived from non-communicable diseases. This is why the Instituto Mexicano del Seguro Social (IMSS, Mexican Institute for Social Security) developed the Mental Health Comprehensive Program 2021-2024, whose main purpose was to establish strategies and lines of action for the prevention, early detection and timely management regarding mental health and addictions. Based on this, different actions have been carried out, for example, the identification of the material and human resources available at IMSS to meet the mental health issue;the training of healthcare professionals at the three levels of care;the integration of a census that has reported a prevalence of anxiety and depressive episodes in the users of 39.9 and 3%, respectively, as well as the evaluation of instruments for screening mental disorders. Therefore, this document describes what has been done in the IMSS in relation to the user's mental health in the context of the COVID-19 pandemic.

Digital transformation in school management: the legacy that strategic actions in the 2020s leave for future pandemics

With the outbreak of social withdrawal due to the pandemic, many countries have undergone drastic transformations in various spheres. In education, face-to-face classes were transformed into distance learning. However, this sudden change caused several problems for students and teachers. Given these events, the purpose of this article was to propose exceptional actions to improve the transition from face-to-face classes to virtual classes. For this, the elements that positively and negatively impacted education in the Covid-19 pandemic were identified in the literature. These elements were then clustered into four strategies, these being: redesign of pedagogical practices, psychological and social support, technological infrastructure in virtual teaching, and school management to cope with the pandemic scenario. The multiple case study method was used, investigating five technical schools located in the state of São Paulo (Brazil). With this, it was possible to propose 10 exceptional actions aimed at the transition from face-to-face classes to virtual classes. The main novelty of this article was the proposition of actions to motivate the school community against the impacts of the pandemic, building memory in its agents, making them more prepared for unexpected events. © 2022 Brazilian Institute for Information in Science and Technology. All rights reserved.

Impact of the COVID-19 Pandemic on a Cancer Fast-Track Programme.

INTRODUCTION: The COVID-19 pandemic has disrupted many aspects of clinical practice in oncology, particularly regarding early cancer diagnosis, sparking public health concerns that possible delays could increase the proportion of patients diagnosed at advanced stages. In 2009, a cancer fast-track program (CFP) was implemented at the Clinico-Malvarrosa Health Department in Valencia, Spain with the aim of shortening waiting times between suspected cancer symptoms, diagnosis and therapy initiation. OBJECTIVES: The study aimed to explore the effects of the COVID-19 pandemic on our cancer diagnosis fast-track program. METHODS: The program workflow (patients included and time periods) was analysed from the beginning of the state of alarm on March 16th, 2020 until March 15th, 2021. Data was compared with data from the same period of time from the year before (2019). RESULTS: During the pandemic year, 975 suspected cancer cases were submitted to the CFP. The number of submissions only decreased during times of highest COVID-19 incidence and stricter lockdown, and overall, referrals were slightly higher than in the previous 2 years. Cancer diagnosis was confirmed in 197 (24.1%) cases, among which 33% were urological, 23% breast, 16% gastrointestinal and 9% lung cancer. The median time from referral to specialist appointment was 13 days and diagnosis was reached at a median of 18 days. In confirmed cancer cases, treatment was started at around 30 days from time of diagnosis. In total, 61% of cancer disease was detected at early stage, 20% at locally advanced stage, and 19% at advanced stage, displaying time frames and case proportions similar to pre-pandemic years. CONCLUSIONS: Our program has been able to maintain normal flow and efficacy despite the challenges of the current pandemic, and has proven a reliable tool to help primary care physicians referring suspected cancer patients.

The role of care and the local economy in women’s labour force participation: evidence from Mexico and Colombia in the pandemic era

Women face disproportionate care burdens on their time because of traditional gender roles, lack of public policies supporting them and the lack of government services for satisfying society's care needs. This unequal distribution of care responsibilities reduces their opportunities to fully participate in labour markets. We argue that all else equal, women's physical proximity to affordable care services is key to determining their accessibility to them. In addition, services may have different effects on women's labour force participation (LFP), depending on their care responsibilities and other characteristics of their social and economic local conditions, such as size and type of economic output. We use geospatial analysis to explore the relationship between the local supply of care services and women's LFP. We use the population census and the intercensal population survey of Mexico, together with data from economic censuses and directories of care and financial services. We also develop an exploratory data analysis model for the Colombian case. We find that, given gender roles in care provision and women's accessibility to economic sectors, the supply of care services and the type of local economies are quite significant in determining their LFP, regardless of their educational level. Accordingly, mere investment in care services may not be enough since the economic output and type of activities also interfere with LFP. Besides, this effect increased considerably during the COVID-19 pandemic. © 2022 Oxfam KEDV.

Near-Full-Length Genome Sequences Representing an Event of Zooanthroponotic Transmission of SARS-CoV-2 Lineage B.1.189 in Mexico during 2020.

Here, we report three near-full-length genome sequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) obtained in Mexico City, Mexico, during the pandemic of coronavirus disease 19 (COVID-19) in 2020, representing a zooanthroponotic transmission event between humans and a dog. All three genomes belong to the B.1.189 lineage based on the pangolin classification.

Antioxidants to prevent respiratory decline in people with Duchenne muscular dystrophy and progressive respiratory decline

Background: Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder characterised by progressive muscle weakness beginning in early childhood. Respiratory failure and weak cough develop in all patients as a consequence of muscle weakness leading to a risk of atelectasis, pneumonia, or the need for ventilatory support. There is no curative treatment for DMD. Corticosteroids are the only pharmacological intervention proven to delay the onset and progression of muscle weakness and thus respiratory decline in DMD. Antioxidant treatment has been proposed to try to reduce muscle weakness in general, and respiratory decline in particular. Objectives: To assess the effects of antioxidant agents on preventing respiratory decline in people with Duchenne muscular dystrophy during the respiratory decline phase of the condition. Search methods: We searched CENTRAL, MEDLINE, Embase, and two trials registers to 23 March 2021, together with reference checking, citation searching, and contact with study authors to identify additional studies. Selection criteria: We included randomised controlled trials (RCTs) and quasi-RCTs that met our inclusion criteria. We included male patients with a diagnosis of DMD who had respiratory decline evidenced by a forced vital capacity (FVC%) less than 80% but greater than 30% of predicted values, receiving any antioxidant agent compared with other therapies for the management of DMD or placebo. Data collection and analysis: Two review authors screened studies for eligibility, assessed risk of bias of studies, and extracted data. We used standard methods expected by Cochrane. We assessed the certainty of the evidence using the GRADE approach. The primary outcomes were FVC and hospitalisation due to respiratory infections. Secondary outcomes were quality of life, adverse events, change in muscle function, forced expiratory volume in the first second (FEV1), and peak expiratory flow (PEF). Main results: We included one study with 66 participants who were not co-treated with corticosteroids, which was the only study to contribute data to our main analysis. We also included a study that enrolled 255 participants treated with corticosteroids, which was only available as a press release without numerical results. The studies were parallel-group RCTs that assessed the effect of idebenone on respiratory function compared to placebo. The trial that contributed numerical data included patients with a mean (standard deviation) age of 14.3 (2.7) years at the time of inclusion, with a documented diagnosis of DMD or severe dystrophinopathy with clinical features consistent with typical DMD. The overall risk of bias across most outcomes was similar and judged as 'low'. Idebenone may result in a slightly less of a decline in FVC from baseline to one year compared to placebo (mean difference (MD) 3.28%, 95% confidence interval (CI) -0.41 to 6.97;64 participants;low-certainty evidence), and probably has little or no effect on change in quality of life (MD -3.80, 95% CI -10.09 to 2.49;63 participants;moderate-certainty evidence) (Pediatric Quality of Life Inventory (PedsQL), range 0 to 100, 0 = worst, 100 = best quality of life). As a related but secondary outcome, idebenone may result in less of a decline from baseline in FEV1 (MD 8.28%, 95% CI 0.89 to 15.67;53 participants) and PEF (MD 6.27%, 95% CI 0.61 to 11.93;1 trial, 64 participants) compared to placebo. Idebenone was associated with fewer serious adverse events (RR 0.42, 95% CI 0.09 to 2.04;66 participants;low-certainty evidence) and little to no difference in non-serious adverse events (RR 1.00, 95% CI 0.88 to 1.13;66 participants;low-certainty evidence) compared to placebo. Idebenone may result in little to no difference in change in arm muscle function (MD -2.45 N, 95% CI -8.60 to 3.70 for elbow flexors and MD -1.06 N, 95% CI -6.77 to 4.65 for elbow extensors;both 52 participants) compared to placebo. We found no studies evaluating the outcome hospitalisation due to respiratory infection. The second trial, involving 255 participants

Highly Specific Sigma Receptor Ligands Exhibit Anti-Viral Properties in SARS-CoV-2 Infected Cells.

(1) Background: There is a strong need for prevention and treatment strategies for COVID-19 that are not impacted by SARS-CoV-2 mutations emerging in variants of concern. After virus infection, host ER resident sigma receptors form direct interactions with non-structural SARS-CoV-2 proteins present in the replication complex. (2) Methods: In this work, highly specific sigma receptor ligands were investigated for their ability to inhibit both SARS-CoV-2 genome replication and virus induced cellular toxicity. This study found antiviral activity associated with agonism of the sigma-1 receptor (e.g., SA4503), ligation of the sigma-2 receptor (e.g., CM398), and a combination of the two pathways (e.g., AZ66). (3) Results: Intermolecular contacts between these ligands and sigma receptors were identified by structural modeling. (4) Conclusions: Sigma receptor ligands and drugs with off-target sigma receptor binding characteristics were effective at inhibiting SARS-CoV-2 infection in primate and human cells, representing a potential therapeutic avenue for COVID-19 prevention and treatment.

Extreme thrombocytosis during acute pyelonephritis. Collateral consequence of the Coronavirus (COVID-19) pandemic

A young woman with extreme (>1,000x109/L) thrombocytosis during Escherichia coli pyelonephritis is presented. Diagnosis of pyelonephritis was delayed after several teleconsultations for atypical symptoms during the COVID-19 pandemic. Virtual clinic models can lead to protracted courses and bizarre manifestations of infectious disease.