Predominance of the recombinant SARS-CoV-2 lineages XBB in Rio Grande do Sul State, Brazil: a genomic surveillance study and impact on vaccine response (preprint)

Purpose The COVID-19 pandemic has been marked by novel viral variants, posing challenges to global public health. Recombination, a viral evolution tool, is implicated in SARS-CoV-2's ongoing evolution. The XBB recombinant lineage, known for evading antibody-mediated immunity, exhibits higher transmissibility without increased disease severity. We investigated the prevalence and genomic features of XBB in SARS-CoV-2-positive cases in Rio Grande do Sul (RS), Brazil. Methods We sequenced 357 samples from epidemiological weeks (EW) 47/2022 to 17/2023, and included 389 publicly available sequences. Clinical and epidemiological data were obtained from DATASUS, e-SUS, and SIVEP GRIPE (data recording systems of the Brazilian Ministry of Health) Results Of these, 143 were classified as XBB and 586 were other Omicron lineages. The BQ.1.1 lineage was most frequent. In March 2023 (EW 10), XBB became dominant, accounting for 83·3% of cases. 97·7% of XBB-infected patients successfully recovered from the infection, with a low mortality rate. Even receiving three vaccine doses and previously infected, 59·5% of the patients experienced reinfection with XBB. However, the interval between XBB infection and the last vaccine dose exceeded a year, potentially causing antibody decline. In addition, we identified 90 mutations in RS circulating XBB, spread throughout the genome, notably in the Spike protein region associated with immune resistance. Conclusion This study provides insights into the dynamics and impact of a recombinant variant becoming predominant for the first time in the state. Continued surveillance of SARS-CoV-2 genomic evolution is crucial for effective public health management.

Efflux pump in genomic island GI-M202a mediates transfer of Polymyxin B resistance in Pandoraea pnomenusa M202 (preprint)

Background Polymyxin B was thought to be last-line therapeutic options against multidrug-resistant Gram-negative bacteria, especially in COVID-19 co-infections or other serious infections. The risk of antimicrobial resistance and its spread to the environment should be brought to the forefront.Methods P. pnomenusa M202 was isolated under selection with 8 mg/L polymyxin B from hospital sewage. The genome of M202 was sequenced by PacBio RS II and Illumina HiSeq 4000 platforms. MFS transporter recombinant E. coli strain Mrc-3 was constructed by transferring encoding gene FKQ53_RS21695, a gene in Genomic islands (GIs) of M202, to E. coli 25DN. Mating experiments were performed to evaluate transfer of MFS transporter to Escherichia coli 25DN. And influences of efflux pump inhibitors on MICs were determined. The mechanism of polymyxin B excretion mediated by FKQ53_RS21695 was investigated by Discovery Studio 2.0 based on its homologous model.Results MICs of multidrug-resistant bacterial strain P. pnomenusa M202, isolated from hospital sewage, for polymyxin B is 96 mg/L. Genomic Island GI-M202a with major facilitator superfamily (MFS) transporter encoding gene and conjugative transfer proteins encoding genes of type IV secretion system was identified in strain M202. The mating experiment between M202 and Escherichia coli 25DN reflected the transferability of polymyxin B resistant GI-M202a. Efflux pump inhibitor and heterogeneous expression assays also suggested that MFS transporter gene FKQ53_RS21695 in GI-M202a was responsible to polymyxin B resistance. Molecular docking revealed that polymyxin B fatty acyl group insert into hydrophobic region of transmembrane core with Pi-alkyl and unfavorable bump interactions, and then polymyxin B turns over around Tyr43 to left the peptide group to outside during efflux process, accompanies with conformation change of MFS transporter from inward to outward. Additionally, verapamil and CCCP demonstrated significant inhibition by competing binding sites.Conclusions These findings demonstrated that GI-M202a along with MFS transporter FKQ53_RS21695 in P. pnomenusa M202 could mediate the transmission of polymyxin B resistances.

Effectiveness of a chatbot in improving the mental wellbeing of health workers in Malawi during the COVID-19 pandemic: A randomized, controlled trial (preprint)

After the deleterious effects of the COVID-19 pandemic on healthcare worker mental health, we tested the effectiveness of an interactive chatbot, Vitalk, for improving wellbeing and resilience among healthcare workers in Malawi, a country with few mental health professionals. We conducted a randomized, controlled trial (RCT) to investigate our hypothesis that Vitalk is more effective in improving mental health and resilience outcomes than passive Internet resources. For our 2-arm, 8-week, parallel RCT (ISRCTN Registry: trial ID ISRCTN16378480 ), we recruited participants from 8 professional cadres from public and private healthcare facilities. The treatment arm used Vitalk; the control arm received links to Internet resources. Of 1,584 participants, 512 completed baseline and endline assessments. Six assessments provided outcome measures for: anxiety (GAD-7); depression (PHQ-9); burnout (OLBI); loneliness (ULCA); resilience (RS-14); and resilience-building activities. We analyzed effectiveness using mixed-effects linear models, effect size estimates, and reliable change in risk levels. Results from mixed-model analyses support our hypothesis. Difference-in-differences estimators showed that Vitalk reduced: depression (-0.68 [95% CI -1.15 to -0.21]); anxiety (-0.44 [95% CI -0.88 to 0.01]); and burnout (-0.58 [95% CI -1.32 to 0.15]). Changes in resilience (1.47 [95% CI 0.05 to 2.88]) and resilience-building activities (1.22 [95% CI 0.56 to 1.87]) were significantly greater in the treatment group. We observed no treatment effect on loneliness. Our RCT produced a medium effect size. This is the first RCT of a mental health app for healthcare workers during the pandemic in Southern Africa combining multiple mental wellbeing outcomes, and measuring resilience and resilience-building activities. A significant number of participants could have benefited from mental health support (1 in 8 reported anxiety and depression; 3 in 4 suffered burnout; and 1 in 4 had low resilience). Such help is not readily available in Malawi. Vitalk has the potential to fill this gap.

Experiential COVID-19 factors predicting resilience among Spanish adults (preprint)

The pandemic caused by COVID-19 has meant for citizens a constant adaptation to health measures in order to try to stop transmission of the virus. During this adaptation process, different psychosocial aspects have caused consequences for people’s mental health to a greater or lesser extent. The objective of this research is to analyze the relationship between resilience and experiential COVID-19 factors. Sample was comprised of Spanish adults (n = 1000; age 18–79 [mean = 40.43],793 female, 201 male, and 2 non binary sex). These people participating in an online sub-study focused on the impact of COVID-19 experiences. The research has been cross-sectional, descriptive and correlational design. The instrument created for this research was a specific online questionnaire, including the “Scale of satisfaction with life” (SWLS, Diener et al., 1985, Spanish version, Atienza, et al., 2000) and “Scale of resilience” (RS, Wagnild & Young, 1993, Spanish version, Sánchez-Teruel, et al., 2015). The results obtained show how people who have been able to face the pandemic in a responsive and adaptive way have high resilience. Specifically, those participants that accepting the use of masks, vaccinations and confinement obtained high resilience. Using public funding and allocating research to the development of programs to promote resilience, adaptative beliefs and prosocial behaviors becomes basic to live in a world in constant change.

Flood Impact Assessment on Agricultural and Municipal Areas Using Sentinel-1 and 2 Satellite Images(Case study: Kermanshah province) (preprint)

Flood is one of the most destructive natural events that can be investigated as soon as possible to reduce the extent of flood damage. Floods have caused adverse impacts on agricultural lands and settlements. RS is one of the most widely applicable and fast methods in this way. In this study, the S1A, SAR data with VH descending pass and S2 during 01/03/2019 to 20/03/2019 and 25/03/2019 to 20/04/2019 were used for the before and the post-flood period in Kermanshah province. MNDWI and NDWI were applied to detect the water zones of S2 and were compared and validate the S1 images. The quality of radar images is better than optical in flood conditions where the weather is cloudy and rainy. MODIS, Hydrosheds and SRTM satellite images were used as different filters to detect land use, permanent water and areas with slope of more than 5%. The results showed that totally 36,849 ha of lands are affected by the flood. It’s containing 7073 and 4224 ha of agricultural and urban lands that are exposed to destruction in this period. The NDWI and MNDWI indices were calculated flooded area as 30,179 and 32,540 ha, respectively which are lower values compared to the results of the S1.

Incipient parallel evolution of SARS-CoV-2 Deltacron variant in South Brazil (preprint)

With the coexistence of multiple lineages and increased international travel, recombination and gene flow are likely to become increasingly important in the adaptive evolution of SARS-CoV-2. This could result in the incipient parallel evolution of multiple recombinant lineages. However, identifying recombinant lineages is challenging, and the true extent of recombinant evolution in SARS-CoV-2 may be underestimated. This study describes the first SARS-CoV-2 Deltacron recombinant case identified in Brazil. We demonstrate that the recombination breakpoint is at the beginning of Spike gene (S). The 5' genome portion (circa 22 kb) resembles the AY.101 lineage (VOC Delta), and the 3' genome portion (circa 8 kb nucleotides) is most similar to the BA.1.1 lineage (VOC Omicron). Furthermore, evolutionary genomic analyses indicate that the new strain emerged after a single recombination event between lineages of diverse geographical locations in December 2021 in South Brazil. This Deltacron, named AYBA-RS, is one out of almost 30 recombinants described this year. The submission of only four sequences in the GISAID database suggests that this Brazilian lineage had a minor epidemiological impact. On the other hand, the recent emergence of this and various other Deltacron recombinant lineages (i.e., XD, XF, and XS) suggests that gene flow and recombination may play an increasingly important role in the COVID-19 pandemic. We explain the evolutionary and population genetic theory that support this assertion, and we conclude that this stresses the need for continued genomic and epidemiological surveillance. This is particularly important for countries where multiple variants are present, as well as for countries that receive significant inbound international travel.

Long COVID and Associated Factors in Individuals From Southern Brazil: a Population-based Study on COVID (preprint)

COVID-19 is an infection in which symptoms may persist after the acute phase. The aim of the present study was to verify the prevalence and factors associated with COVID-19 and to describe the main residual symptoms after 6–10 months of infection in individuals from the extreme south of Brazil. This was a cross-sectional study of 2919 individuals older than 18 diagnosed by RT‒PCR with COVID-19 in the city of Rio Grande/RS, Brazil, from December 2020 to March 2021 who were symptomatic, with data collected by telephone interview or home visit. The COVID-19 outcome was obtained from the sum of all symptoms that the individual claimed to continue having at the time of the interview, ranging from zero to 19. For the crude and adjusted analyses, we used Poisson regression with robust adjustment of variance calculating prevalence ratios (PRs) and their respective 95% confidence intervals. The adjusted analysis was performed by means of a hierarchical model built in four levels. The significance level adopted was 5%, and the analyses were performed with the statistical package Stata 16.1. The prevalence of COVID-long was 48.3% (95% CI 46.5; 50.1). The most prevalent residual symptoms were fatigue, memory loss, loss of attention, headache, loss of smell, muscle pain and loss of taste. The groups more likely to develop COVID-19 were female, exhibited anxiety, hypertension, heart problems, diabetes mellitus, musculoskeletal problems, respiratory problems, previous morbidities and hospitalization in a ward or ICU. Physical activity and self-perception of good and very good health were protective factors for the outcome. When adjusted, female gender, anxiety, morbidities and who were hospitalized remained associated with the outcome, while self-perception of good and very good health had a lower probability. This study showed that almost half of the individuals in the sample developed long COVID after 6–9 months of infection. Among the associated factors, female individuals and those with chronic conditions stand out, demanding the creation of public policies to promote integral and continued assistance to these individuals.

Assessing COVID-19 pandemic excess deaths in Brazil: years 2020 and 2021 (preprint)

We estimated the impact of the COVID-19 pandemic on mortality in Brazil for 2020 and 2021 years. We used mortality data (2015-2021) from the Health Ministry, Brazil government, to fit linear mixed models for forecasting baseline deaths under non-pandemic conditions. An advantage of the linear mixed model is the flexibility to capture year-trend while dealing with the correlations among death counts over time. Following a specified model building strategy, estimation of all-cause excess deaths at the country level and stratified by sex, age, ethnicity and region of residence, from March 2020 to August 2021. We also considered the estimation of excess deaths by specific causes. Estimated all-cause excess deaths was 199,108 (95% PI: 171,007; 227,209, P-Score=17.3%) for weeks 10-53, 2020, and 417,167 (95% PI: 372,075; 462,259, P-Score=50.1%) for weeks 1-32, 2021. P-scores ranged from 5.4% (RS, South) to 36.2% (AM, North) in 2020 and from 29.3% (AL, Northeast) to 94.9%$ (RO, North) in 2021. Differences among men (18.9%) and women (14.2%) appeared in 2020 only, and the P-scores were about 51% for both sexes in 2021. Except for youngsters (<20 years old), all adult age groups were badly hit, especially those from 40 to 79 years old. In 2020, the Indigenous+East Asian population had the highest P-score (27%), and the Black population suffered the greatest impact (61.9%) in 2021. The pandemic impact had enormous regional heterogeneity and substantial differences according to socio-demographic factors, mainly during the first wave, showing some population strata benefits from the social distancing measures when able to adhere to them. In the second wave, the burden was very high for all but extremely high for some, highlighting our society needs to tackle the health inequalities experienced by groups of different socio-demographic and economic status.

Retinal Folds as a Clinical Feature of X-Linked Retinoschisis: A Series of Three Cases.

BACKGROUND AND OBJECTIVE: The most common clinical features of X-linked retinoschisis (XLRS) include macular schisis in a spoke wheel pattern and peripheral schisis, though other findings such as vitreous veils, vascular attenuation, and subretinal fibrosis have been described. This is the first report to describe retinal folds as a characteristic feature in patients with XLRS. PATIENTS AND METHODS: This was a case series of patients presenting to the retina service at Bascom Palmer Eye Institute with genetically confirmed XLRS. Patients included in this report underwent examination under anesthesia with multimodality imaging. RESULTS: Three patients with XLRS were found to have retinal folds, including a newly characterized "retinal scroll" seen on examination and multimodality imaging. CONCLUSIONS: The presence of a retinal fold should yield a differential diagnosis that includes XLRS in the correct clinical context. Panel-based genetic testing and multimodal imaging are useful in guiding clinical management. [Ophthalmic Surg Lasers Imaging 2022;53(6):326-331.].

SARS-CoV-2 introduction and lineage dynamics across three epidemic peaks in Southern Brazil: massive spread of P.1 (preprint)

ABSTRACT Background Genomic surveillance of SARS-CoV-2 is paramount for understanding viral dynamics, contributing to disease control. This study analyzed SARS-CoV-2 genomic diversity in Rio Grande do Sul (RS), Brazil, including the first case of each Regional Health Coordination and cases from three epidemic peaks. Methods Ninety SARS-CoV-2 genomes from RS were sequenced and analyzed against SARS-CoV-2 datasets available in GISAID for phylogenetic inference and mutation analysis. Results SARS-CoV-2 lineages among the first cases in RS were B.1 (33.3%), B.1.1.28 (26.7%), B.1.1 (13.3%), B.1.1.33 (10.0%), and A (6.7%), evidencing SARS-CoV-2 introduction by both international origin and community-driven transmission. We found predominance of B.1.1.33 (50.0%) and B.1.1.28 (35.0%) during the first epidemic peak (July–August, 2020), emergence of P.2 (55.6%) in the second peak (November–December, 2020), and massive spread of P.1 and related sequences (78.4%), such as P.1-like-II, P.1.1 and P.1.2 in the third peak (February–April, 2021). Eighteen novel mutation combinations were found among P.1 genomes, and 22 different spike mutations and/or deletions among P.1 and related sequences. Conclusions This study shows the dispersion of SARS-CoV-2 lineages in Southern Brazil, and describes SARS-CoV-2 diversity during three epidemic peaks, highlighting the spread of P.1 and the high genetic diversity of currently circulating lineages. Genomic monitoring of SARS-CoV-2 is essential to guide health authorities’ decisions to control COVID-19 in Brazil. Summary Ninety SARS-CoV-2 genomes from Rio Grande do Sul, Brazil, were sequenced, including the first cases from 15 State Health Coordination regions and samples from three epidemic peaks. Phylogenomic inferences showed SARS-CoV-2 lineages spread, revealing its genomic diversity.

Predominance of SARS-CoV-2 P.1 (Gamma) lineage inducing the recent wave in southern Brazil and the finding of an additional S: D614A mutation (preprint)

Since the first SARS-CoV-2 case in China in late 2019, this virus continues to impact many countries worldwide. Recently, the highest wave of SARS-CoV-2 epidemic was registered in Rio Grande do Sul (RS) State, Southern Brazil, considering the number of cases, deaths and hospitalization per day caused by COVID-19. In this study we described which lineages were circulating in the beginning of 2021 in southern Brazil to understand the cause of the highest health crisis caused by SARS-CoV-2 in the region, searching also possible additional SARS-CoV-2 sequence mutation. A total of 71 positive SARS-CoV-2 samples collected between December 15th, 2020, until April 23rd, 2021, were selected to sequencing. The samples were from 16 cities distributed in three RS regions. The library preparation was performed according to QIAseq® SARS-CoV-2 Primer Panel Handbook kit, and phylogenetic analysis was realized. Whole genome sequencing of 71 SARS-CoV-2 samples shows a predominance of Gamma lineage (67.14%, 47/71), followed by Zeta lineage (27.14%, 20/71) and B.1.1.28 (5,71%, 4/71). Two Gamma lineage consensus sequences presented a D614A mutation. Newly mutations could be emerging due the quick SARS-CoV-2 spreading. Thus, the greater understanding about immune protection and variants vigilance is essential to the better management of the health SARS-CoV-2 crisis.

Spatiotemporal dissemination pattern of SARS-CoV-2 B1.1.28-derived lineages introduced into Uruguay across its southeastern border with Brazil. (preprint)

During the first nine months of the SARS-CoV-2 pandemic, Uruguay successfully kept it under control, even when our previous studies support a recurrent viral flux across the Uruguayan-Brazilian border that sourced several local outbreaks in Uruguay. However, towards the end of 2020, a remarkable exponential growth was observed and the TETRIS strategy was lost. Here, we aimed to understand the factors that fueled SARS-CoV-2 viral dynamics during the first epidemic wave in the country. We recovered 84 whole viral genomes from patients diagnosed between November, 2020 and February, 2021 in Rocha, a sentinel eastern Uruguayan department bordering Brazil. The lineage B.1.1.28 was the most prevalent in Rocha during November-December 2020, P.2 became the dominant one during January-February 2021, while the first P.1 sequences corresponds to February, 2021. The lineage replacement process agrees with that observed in several Brazilian states, including Rio Grande do Sul (RS). We observed a one to three month delay between the appearance of P.2 and P.1 in RS and their subsequent detection in Rocha. The phylogenetic analysis detected two B.1.1.28 and one P.2 main Uruguayan SARS-CoV-2 clades, introduced from the southern and southeastern Brazilian regions into Rocha between early November and mid December, 2020. One synonymous mutation distinguishes the sequences of the main B.1.1.28 clade in Rocha from those widely distributed in RS. The minor B.1.1.28 cluster, distinguished by several mutations, harbours non-synonymous changes in the Spike protein: Q675H and Q677H, so far not concurrently reported. The convergent appearance of S:Q677H in different viral lineages and its proximity to the S1/S2 cleavage site raise concerns about its functional relevance. The observed S:E484K-VOI P.2 partial replacement of previously circulating lineages in Rocha might have increased transmissibility as suggested by the significant decrease in Ct values. Our study emphasizes the impact of Brazilian SARS-CoV-2 epidemics in Uruguay and the need of reinforcing real-time genomic surveillance on specific Uruguayan border locations, as one of the key elements for achieving long-term COVID-19 epidemic control.

Cesarean section prevalence at a baby-friendly hospital in southern Brazil: current context in the face of COVID-19 (preprint)

Objective: To analyze cesarean prevalence at a baby-friendly hospital in Southern Brazil between 2017 and 2020 and possible annual and monthly changes due to the novel coronavirus (COVID-19) pandemic. Methods: Descriptive cross-sectional study using secondary data retrieved from the electronic information system of a Baby-Friendly Hospital in the municipality of Rio Grande, RS, Brazil. Data was retrieved for all hospitalizations at the obstetric center between January 1st 2017 and December 31st 2020. Data on COVID-19 deaths were obtained from the municipal government website. Annual and monthly cesarean prevalence rates were calculated in comparison to the same periods in 2017, 2018 and 2019. Differences in prevalence rates were tested using a chi-square test, taking a significance level of less than 5%. Prevalence ratios were estimated for 2018/2017, 2019/2018, and 2020/2019. Results: 7,294 childbirths were included. Cesarean prevalence was 42.6% in 2017, 44.3% in 2018, 40.2% in 2019, and 51.0% in 2020. In 2018/2017, there was no statistically significant difference in cesarean prevalence (95%CI: 0.90-1.20). Between 2019/2018, there was a reduction of approximately 20% in prevalence (95%CI: 0.69-0.93). The scenario changes between 2020/2019 with a 40% increase in cesareans (95%CI: 1.20-1.62). The period comprising July to December 2020 was the only period in which over half the deliveries were done by cesarean section, exceeding 60% in July. Conclusion: Cesarean prevalence rates increased in 2020 in relation to the three preceding years. The data highlight the need to reinforce compliance with childbirth protocols to reduce cesarean sections in baby-friendly hospitals.

The increase in the risk of severity and fatality rate of covid-19 in southern Brazil after the emergence of the Variant of Concern (VOC) SARS-CoV-2 P.1 was greater among young adults without pre-existing risk conditions (preprint)

ABSTRACT Background The SARS-CoV-2 P.1 variant has been considered as variant of concern (VOC) since the end of 2020 when it was firstly identified in the Brazilian state of Amazonas and from there spread to other regions of Brazil. This variant was associated with an increase in transmissibility and worsening of the epidemiological situation in the places where it was detected. The aim of this study was to analyze the severity profile of covid-19 cases in the Rio Grande do Sul state, southern region of Brazil, before and after the emergence of the P.1 variant, considering also the context of the hospitals overload and the collapse of health services. Methods We analyzed data from the Influenza Epidemiological Surveillance Information System, SIVEP-Gripe (Sistema de Informacao de Vigilancia Epidemiologica da Gripe) and compare two epidemiological periods: the first wave comprised by cases occurred during November and December 2020 (EW 45 to 53) and the second wave with cases occurred in February 2021 (EW 5 to 8), considering that in this month there was a predominance of the new variant P.1. We calculated the proportion of severe forms among the total cases of covid-19, the case fatality rates (CFR) and hospital case fatality rate (hCFR) over both waves time set using the date of onset of symptoms as a reference. We analyzed separately the patients without pre-existing conditions of risk, by age and sex. For comparison between periods, we calculated the Risk Ratio (RR) with their respective 95% confidence intervals and the p-values. Findings We observed that in the second wave there were an increase in the proportion of severe cases and covid-19 deaths among younger age groups and patients without pre-existing conditions of risk. The proportion of people under the age of 60 among the cases that evolved to death raised from 18% (670 deaths) in November and December (1st wave) to 28% (1370 deaths) in February (2nd wave). A higher proportion of patients without pre-existing risk conditions was also observed among those who evolved to death due to covid-19 in the second wave (22%, 1,077 deaths) than in the first one (13%, 489 deaths). The CFR for covid-19 increased overall and in different age groups, in both sexes. The increase occurred in a greatest intensity in the population between 20 and 59 years old and among patients without pre-existing risk conditions. Female 20 to 39 years old, with no pre-existing risk conditions, were at risk of death 5.65 times higher in February (95%CI = 2.9 - 11.03; p <0.0001) and in the age group of 40 and 59 years old, this risk was 7.7 times higher (95%CI = 5.01-11.83; p <0.0001) comparing with November-December. Interpretation Our findings showed an increase in the proportion of young people and people without previous illnesses among severe cases and deaths in the state of RS after the identification of the local transmission of variant P.1 in the state. There was also an increase in the proportion of severe cases and in the CFR, in almost all subgroups analyzed, this increase was heterogeneous in different age groups and sex. As far as we know, these are the first evidences that the P.1 variant can disproportionately increase the risk of severity and deaths among population without pre-existing diseases, suggesting related changes in pathogenicity and virulence profiles. New studies still need to be done to confirm and deepen these findings.

Female-Male Differences in COVID Vaccine Adverse Events Have Precedence in Seasonal Flu Shots: A Potential Link to Sex-Associated Baseline Gene Expression Patterns (preprint)

Nearly 150 million doses of FDA-authorized COVID vaccines have been administered in the United States. Sex-based differences of adverse events remain poorly understood, mandating the need for real-world investigation from Electronic Health Records (EHRs) and broader epidemiological data sets. Based on an augmented curation of EHR clinical notes of 31,064 COVID-vaccinated individuals (19,321 females and 11,743 males) in the Mayo Clinic, we find that nausea and vomiting were documented significantly more frequently in females than males after both vaccine doses (nausea: RRDose 1 = 1.67, pDose 1 <0.001, RRDose 2 = 2.2, pDose 1 < 0.001; vomiting: RRDose 1 = 1.58, pDose 1 < 0.001, RRDose 2 = 1.88, pDose 1 = 3.4x10-2). Conversely, fever, fatigue, and lymphadenopathy were more common in males after the first dose vaccination (fever RR = 0.62; p = 8.65x10-3; fatigue RR = 0.86, p = 2.89x10-2; lymphadenopathy RR = 0.61, p = 3.45x10-3). Analysis of the Vaccine Adverse Events Reporting System (VAERS) database further confirms that nausea comprises a larger fraction of total reports among females than males (RR: 1.58; p<0.001), while fever comprises a larger fraction of total reports among males than females (RR: 0.84; p<0.001). Importantly, increased reporting of nausea and fever among females and males, respectively, is also observed for prior influenza vaccines in the VAERS database, establishing that these differences are not unique to the recently developed COVID-19 vaccines. Investigating the mechanistic basis underlying these clinical findings, an analysis of bulk RNA-sequencing data from 12,158 human blood samples (8626 female, 3532 male) reveals 85 genes that are not only significantly different in their gene expression between females and males at baseline, but also have established literature-based associations to COVID-19 as well as the vaccine-related adverse events of clinical consequence. The NLRP3 inflammasome and the NR3C1 glucocorticoid receptor emerge as particularly promising baseline links to sex-associated vaccine adverse events, warranting targeted investigation of these signaling pathways and associated cell types. From a public health standpoint, our clinical findings shall aid in educating patients on the sex-associated risks they should expect for COVID-19 vaccines, and promote better clinical management of vaccine-associated adverse events.Funding Statement: None to declare. Declaration of Interests: AJV, PK, ES, MS, RS, PL, EG, EL, and VS are employees of nference and have financial interests in the company and in the successful application of this research. JCO receives personal fees from Elsevier and Bates College, and receives small grants from nference, Inc, outside the submitted work. ADB is a consultant for Abbvie, is on scientific advisory boards for nference and Zentalis, and is founder and President of Splissen therapeutics. JCO, GJG, AWW, AV, MDS, and ADB are employees of the Mayo Clinic. The Mayo Clinic may stand to gain financially from the successful outcome of the research. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies. All other authors have nothing to declare. Ethics Approval Statement: This study was reviewed by the Mayo Clinic Institutional Review Board (IRB) and determined to be exempt from the requirement for IRB approval (45 CFR 46.104d, category 4).

RBD-Specific Polyclonal F(ab´) 2 Fragments of Equine Antibodies in Patients with Moderate to Severe COVID-19 Disease: A Randomized, Double-Blind, Placebo-Controlled, Adaptive Phase 2/3 Clinical Trial (preprint)

Background: Passive immunotherapy is a therapeutic alternative for patients with COVID-19. Equine polyclonal antibodies (EpAbs) could represent a source of easily scaled up neutralizing antibodies against SARS-CoV-2.Methods: We conducted a double-blind, randomized, placebo-controlled trial of EpAbs (INM005) in hospitalized adult patients with moderate and severe COVID-19 pneumonia in 19 hospitals of Argentina. Primary endpoint was improvement in at least two categories in WHO ordinal clinical scale at day 28 (ClinicalTrials.gov number NCT04494984).Findings: Enrolled patients were assigned to receive two doses of INM005 (n=118) or placebo (n=123). Median age was 54 years old, 65·1% were male and 61% had moderate disease at baseline. The median time from the onset of COVID-19 symptoms to the administration of the first dose of intervention was 6 days (interquartile range 5 to 8 days). At day 28 no significant difference was noted between study groups on primary endpoint (odds ratio, 1·61%, 95% confidence interval [95%CI] 0·71 to 3·63 p=0·34); however, overall variation in ordinal clinical status during the 28 days follow up period favored INM005. Improvement in at least two categories was significantly higher in INM005 at days 7, 14 and 21 of follow up. A significant difference was noted in time to improvement in at least two ordinal categories or hospital discharge: 14·2 (± 0·7) days in the INM005 group and 16·3 (± 0·7) days in the placebo group. Pre-specified subgroup analyses showed a more pronounced effect of the intervention over severe patients and with no antibody response at baseline. Overall mortality was 6·8% the INM005 group and 11·4% in the placebo group.Interpretation: Albeit not having reached the primary endpoint, we found clinical improvement of hospitalized patients with SARS-CoV-2 pneumonia, particularly those with severe disease. Funding: Funded by Inmunova and grants from the Ministries of Science and Production of Argentina.Trial Registration: ClinicalTrials.gov number NCT04494984Declaration of Interests: MC, SS, VZ, LM, LS, FG received grants from Ministerio de Desarrollo Productivo “Programa soluciona. reactivación de la economía del conocimiento” and Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación del Ministerio de Ciencia, Tecnología e Innovación. MD, JF, GV, AB, FC, MFA, LB, RT, SL, DS, MI, VS, RS, PC, MMC, LA, HLL, AC, DC declare reimbursement for conduction of clinical trial as investigator of the study. PC, OS, YK report other funds from Inmunova. EN, GL, WHB, SPLL report personal fees from Inmunova. AP, B de M, SM, Gabriel L declare no competing interests. SPLL declare personal fees from Movement Disorders Society, Laboratorio Elea and Merck pharmaceuticals.Ethics Approval Statement: The study protocol was approved by the Institutional Review Boards of all participant clinical sites as well as regional or jurisdictional Ethics Committees as applicable. The Argentinean National Administration of Medicines, Food and Medical Technology (ANMAT) also approved the study protocol.

Modeling the COVID-19 dissemination in the South Region of Brazil and testing gradual mitigation strategies (preprint)

This study aims to understand the features of the COVID-19 spread in the South Region of Brazil by estimating the Effective Reproduction Number (ERN) for the states of Parana (PR), Rio Grande do Sul (RS), and Santa Catarina (SC). We used the SIRD (Susceptibles-Infectious-Recovered-Dead) model to describe the past data and to simulate strategies for the gradual mitigation of the epidemic curve by applying non-pharmacological measures. Besides the SIRD model does not include some aspects of COVID-19, as the symptomatic and asymptomatic subgroups of individuals and the incubation period, for example, in this work we intend to use a classical and easy to handle model to introduce a thorough method of adjustment that allows us to achieve reliable fitting for the real data and to obtain insights about the current trends for the pandemic in each locality. Our results demonstrate that for localities for which the ERN is about 2, only rigid measures are efficient to avoid overwhelming the health care system. These findings corroborate the relevance of keeping the value of the ERN below 1 and applying containment measures early.

Insufficient social distancing may be related to a future COVID-19 outbreak in Ijui-Brazil: Predictions of further social interventions. (preprint)

The coronavirus disease that initiates in 2019 (COVID-19) has proven to be highly contagious since it became pandemic quickly and nowadays presents higher transmission rates worldwide, including small Brazilian cities, as Ijui. Located in the northwestern of the State of Rio Grande do Sul (RS) with 83,475 inhabitants, Ijui was selected to receive a population-based survey divided into four steps separated by 15 days each that involved 1,750 subjects. Subjects were tested for the presence of antibodies against coronavirus (SARS CoV-2) and answered questions about social distance adherence, daily routine, comorbidities, and sociodemographic characteristics. In parallel, the local government registered the official COVID-19 cases in Ijui. In this study, we demonstrated the levels of social distancing adherence and the beginning of COVID-19 community transmission in Ijui and showed some predictions for cases, hospitalization, and deaths. We concluded that the insufficient social distancing registered in the population-based study might be related to the rapid increase of COVID-19 cases in Ijui. Our study predicts a closer outbreak of community infection of COVID-19, which could be avoided or attenuated if the levels of the social distancing in the population increase in the next weeks.

Molecular modelling predicts SARS-CoV-2 ORF8 protein and human complement Factor 1 catalytic domain sharing common binding site on complement C3b (preprint)

Pathogens are often known to use host factor mimicry to take evolutionary advantage. As the function of the non-structural ORF8 protein of SARS-CoV-2 in the context of host-pathogen relationship is still obscure, we investigated its role in host factor mimicry using computational protein modelling techniques. Modest sequence similarity of ORF8 of SARS-CoV-2 with the substrate binding site within the C-terminus serine-protease catalytic domain of human complement factor 1 (F1; PDB ID: 2XRC), prompted us to verify their resemblance at the structural level. The modelled ORF8 protein was found to superimpose on the F1 fragment. Further, protein-protein interaction simulation confirmed ORF8 binding to C3b, an endogenous substrate of F1, via F1-interacting region on C3b. Docking results suggest ORF8 to occupy the binding groove adjacent to the conserved arginine-serine (RS) F1-mediated cleavage sites on C3b. Comparative H-bond interaction dynamics indicated ORF8/C3b binding to be of higher affinity than the F1/C3b interaction. Hence, ORF8 is predicted to inhibit C3b proteolysis by competing with F1 for C3b binding using molecular mimicry with a possibility of triggering unregulated complement activation. This could offer a mechanistic premise for the unrestrained complement activation observed in large number of SARS-CoV-2 infected patients.

Depression and anxiety during 2019 coronavirus disease pandemic in Saudi Arabia: a cross-sectional study (preprint)

Background: COVID 19 outbreak in 2020 was associated with a high rate of depression and anxiety among individuals in the affected countries. The aim of this study is to explore the influence of the COVID 19 epidemic on the psychological distress of residents of the Kingdom of Saudi Arabia. Methods: A cross sectional study using an online survey was conducted in Saudi Arabia between 27th of March and 27th of April 2020. The Patient Health Questionnaire (PHQ 9) and Generalized Anxiety Disorder-7 (GAD 7) were used to assess depression and anxiety. Logistic regression analysis was used to identify predictors of depression and anxiety. Results: The prevalence of depression and anxiety among the entire study participants was 9.4% and 7.3%, respectively. Non-Saudi residents, aged 50 years and above, divorced, retired, university students, and those with income (2000 to 10,000 RS) were at higher risk of developing depression. Saudi individuals, married, unemployed, and those with high income (> 10,000 RS) were at higher risk of developing anxiety. Conclusions: There is a wide range of the Saudi residents who are at higher risk of mental illness during COVID 19 pandemic. Policymakers and mental healthcare providers are advised to provide continuous monitoring of the psychological consequences during this pandemic, and provide mental support.