PREPRINT: Vitamin B12 attenuates leukocyte inflammatory signature in COVID-19 via methyl-dependent changes in epigenetic marksby Larissa M. G. Cassiano et al.
Abstract COVID-19 induces chromatin remodeling in host immune cells, and it had previously been shown that vitamin B12 downregulates some inflammatory genes via methyl-dependent epigenetic mechanisms. In this work, whole blood cultures from moderate or severe COVID-19 patients were used to assess the potential of B12 as adjuvant drug. The vitamin normalized the expression of a panel of inflammatory genes still dysregulated in the leukocytes despite glucocorticoid therapy during hospitalization. B12 also increased the flux of the sulfur amino acid pathway, raising the bioavailability of methyl. Accordingly, B12-induced downregulation of CCL3 strongly and negatively correlated with the hypermethylation of CpGs in its regulatory regions. Transcriptome analysis revealed that B12 attenuates the effects of COVID-19 on most inflammation-related pathways affected by the disease. As far as we are aware, this is the first study to demonstrate that pharmacological modulation of epigenetic marks in leukocytes favorably regulates central components of COVID-19 physiopathology. Teaser B12 has great potential as an adjuvant drug for alleviating inflammation in COVID-19.
Primary healthcare protects vulnerable populations from inequity in COVID-19 vaccination: An ecological analysis of nationwide data from Brazilby Leonardo S.L. Bastos et al.
Summary Background There is limited information on the inequity of access to vaccination in low-and-middle-income countries during the COVID-19 pandemic. Here, we described the progression of the Brazilian immunisation program for COVID-19, and the association of socioeconomic development with vaccination rates, considering the potential protective effect of primary health care coverage. Methods We performed an ecological analysis of COVID-19 immunisation data from the Brazilian National Immunization Program from January 17 to August 31, 2021. We analysed the dynamics of vaccine coverage in the adult population of 5,570 Brazilian municipalities. We estimated the association of human development index (HDI) levels (low, medium, and high) with age-sex standardised first dose coverage using a multivariable negative binomial regression model. We evaluated the interaction between the HDI and primary health care coverage. Finally, we compared the adjusted monthly progression of vaccination rates, hospital admission and in-hospital death rates among HDI levels. Findings From January 17 to August 31, 2021, 202,427,355 COVID-19 vaccine doses were administered in Brazil. By the end of the period, 64·2% of adults had first and 31·4% second doses, with more than 90% of those aged ≥60 years with primary scheme completed. Four distinct vaccine platforms were used in the country, ChAdOx1-S/nCoV-19, Sinovac-CoronaVac, BNT162b2, Ad26.COV2.S, composing 44·8%, 33·2%, 19·6%, and 2·4% of total doses, respectively. First dose coverage differed between municipalities with high, medium, and low HDI (Median [interquartile range] 72 [66, 79], 68 [61, 75] and 63 [55, 70] doses per 100 people, respectively). Municipalities with low (Rate Ratio [RR, 95% confidence interval]: 0·87 [0·85-0·88]) and medium (RR [95% CI]: 0·94 [0·93-0·95]) development were independently associated with lower vaccination rates compared to those with high HDI. Primary health care coverage modified the association of HDI and vaccination rate, improving vaccination rates in those municipalities of low HDI and high primary health care coverage. Low HDI municipalities presented a delayed decrease in adjusted in-hospital death rates by first dose coverage compared to high HDI locations. Interpretation In Brazil, socioeconomic disparities negatively impacted the first dose vaccination rate. However, the primary health care mitigated these disparities, suggesting that the primary health care coverage guarantees more equitable access to vaccines in vulnerable locations. Funding This work is part of the Grand Challenges ICODA pilot initiative, delivered by Health Data Research UK and funded by the Bill & Melinda Gates Foundation and the Minderoo Foundation. This study was supported by the National Council for Scientific and Technological Development (CNPq), the Coordination for the Improvement of Higher Education Personnel (CAPES) - Finance Code 001, Carlos Chagas Filho Foundation for Research Support of the State of Rio de Janeiro (FAPERJ) and the Pontifical Catholic University of Rio de Janeiro. Keywords: Socioeconomic factors; Human development; Low-and-middle-income countries; Vaccine; COVID19;Primary healthcare
SARS-CoV-2, like other coronaviruses, builds a membrane-bound replication organelle (RO) to enable RNA replication1. The SARS-CoV-2 RO is composed of double membrane vesicles (DMVs) tethered to the endoplasmic reticulum (ER) by thin membrane connectors2, but the viral proteins and the host factors involved are currently unknown. Here we identify the viral non-structural proteins (NSPs) that generate the SARS-CoV-2 RO. NSP3 and NSP4 generate the DMVs while NSP6, through oligomerization and an amphipathic helix, zippers ER membranes and establishes the connectors. The NSP6ΔSGF mutant, which arose independently in the α, β, γ, η, ι, and λ variants of SARS-CoV-2, behaves as a gain-of-function mutant with a higher ER-zippering activity. We identified three main roles for NSP6: to act as a filter in RO-ER communication allowing lipid flow but restricting access of ER luminal proteins to the DMVs, to position and organize DMV clusters, and to mediate contact with lipid droplets (LDs) via the LD-tethering complex DFCP1-Rab18. NSP6 thus acts as an organizer of DMV clusters and can provide a selective track to refurbish them with LD-derived lipids. Importantly, both properly formed NSP6 connectors and LDs are required for SARS-CoV-2 replication. Our findings, uncovering the biological activity of NSP6 of SARS-CoV-2 and of other coronaviruses, have the potential to fuel the search for broad antiviral agents.
In the world, the governments' policy decisions in response to COVID-19 were very different. Many countries, including in the Americas, political polarisation in health policies has been used as a tool for ideological dispute, draining out the debate around the right to social protection and health. During 2021, these strategies were used in vaccination policies. The consequences of the dissemination of misinformation about COVID-19 vaccines overflows distrust and hesitation into an entire public health project.
The objective of the study was to examine whether the coronavirus disease 2019 (COVID-19) pandemic altered risk of adverse pregnancy-related outcomes and whether there were differences by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection status among pregnant women. Findings suggest that in a geographically diverse U.S. cohort, the frequency of adverse pregnancy-related outcomes did not differ between those delivering before compared with during the pandemic, nor between those classified as positive compared with negative for SARS-CoV-2 infection during pregnancy.
Impact of COVID-19 pandemic on time series of maternal mortality ratio in Bahia, Brazil: analysis of period 2011-2020by Rita de Cássia Oliveira de Carvalho-Sauer et al
This study aimed to verify the relationship between the maternal mortality ratio and the incidence of COVID-19 in the State of Bahia, Brazil, 2020. The study revealed the increase in maternal mortality, and its temporal relationship with the incidence of COVID-19, in Bahia, Brazil, in 2020. The COVID-19 pandemic may be directly and indirectly related to this increase, which needs to be investigated. An urgent public health action is needed to prevent and reduce maternal deaths during this pandemic, in Brazil.
A cross-national study of factors associated with women's perinatal mental health and wellbeing during the COVID-19 pandemicby Basu et al
This international study sought to identify and measure the associations between pandemic-related information seeking, worries, and prevention behaviors on perinatal mental health during the COVID-19 pandemic. An anonymous, online, cross-sectional survey of pregnant and postpartum women was conducted in 64 countries between May 26, 2020 and June 13, 2020. Based on the study findings, public health campaigns and medical care systems need to explicitly address the impact of COVID-19 related stressors on mental health in perinatal women, as prevention of viral exposure itself does not mitigate the pandemic's mental health impact.
The objective of this study was to evaluate neonatal outcomes in relation to maternal SARS-CoV-2 test positivity in pregnancy. In a nationwide cohort of infants in Sweden, maternal SARS-CoV-2 infection in pregnancy was significantly associated with small increases in some neonatal morbidities. Given the small numbers of events for many of the outcomes and the large number of statistical comparisons, the findings should be interpreted as exploratory.
Maternal and Neonatal Morbidity and Mortality Among Pregnant Women With and Without COVID-19 Infection: The INTERCOVID Multinational Cohort Studyby Villar J. et al
The objective of the study was to evaluate the risks associated with COVID-19 in pregnancy on maternal and neonatal outcomes compared with not-infected, concomitant pregnant individuals. In this multinational cohort study, COVID-19 in pregnancy was associated with consistent and substantial increases in severe maternal morbidity and mortality and neonatal complications when pregnant women with and without COVID-19 diagnosis were compared. The findings should alert pregnant individuals and clinicians to implement strictly all the recommended COVID-19 preventive measures.
Disease Severity, Pregnancy Outcomes and Maternal Deaths among Pregnant Patients with SARS-CoV-2 Infection in Washington Stateby Lokken et al
The objective of this study was to describe disease severity and outcomes of SARS-CoV-2 infections in pregnancy across Washington State including pregnancy complications and outcomes, hospitalization, and case fatality. Findings suggest that COVID-19 hospitalization and case fatality rates in pregnant patients were significantly higher compared to similarly aged adults in Washington State. This data indicates that pregnant patients are at risk for severe or critical disease and mortality compared to non-pregnant adults, as well as preterm birth.
Domestic violence and its relationship with quality of life in pregnant women during the outbreak of COVID-19 diseaseby Somayyeh Naghizadeh et al
This study aimed to investigate the prevalence of domestic violence and its relationship with quality of life in pregnant women during the COVID-19 pandemic. The findings of this study indicate a high prevalence of domestic violence and its relationship with a low quality of life during the COVID-19 pandemic. Therefore, the findings signify the importance of screening pregnant women in terms of domestic violence in respective centers as well as the necessity of conducting proper interventions to address domestic violence to improve the quality of life in women.
Number of Childhood and Adolescent Vaccinations Administered Before and After the COVID-19 Outbreak in Coloradoby Sean T. O’Leary et al
In this report, the authors assessed the number of childhood and adolescent vaccinations administered in the months before and after the start of the COVID-19 outbreak in Colorado. Findings suggest that since the onset of the COVID-19 pandemic, vaccination uptake in children and adolescents has shown a significant decrease in Colorado. While the clinical implications of our observation are not yet known, public health advocates should consider addressing this drop to avoid the potential for vaccine-preventable diseases.
Changes in Preterm Birth Phenotypes and Stillbirth at 2 Philadelphia Hospitals During the SARS-CoV-2 Pandemic, March-June 2020by Handley et al
Given differences in preterm birth across populations, the authors examined a diverse urban cohort in the US to determine if preterm birth, spontaneous preterm birth, medically indicated preterm birth, and stillbirth rates have changed during the SARS-CoV-2 pandemic. This study did not detect significant changes in preterm or stillbirth rates during the SARS-CoV-2 pandemic in a racially diverse urban cohort from 2 Philadelphia hospitals. Although these data allow for disaggregation of spontaneous and medically indicated preterm births, no differences in overall rates of these phenotypes were detected.
This study assessed the National Health Service hospital admissions in England from April 1, 2019, to June 30, 2020, using annual Hospital Episode Statistics (HES) data (April 1, 2019, to March 31, 2020) and monthly data available as Secondary Uses Service (April 1 to June 30, 2020). Findings suggest that there was no evidence of any increase in stillbirths regionally or nationally during the COVID-19 pandemic in England when compared with the same months in the previous year and despite variable community SARS-CoV-2 incidence rates in different regions.
Pregnant women with severe or critical COVID-19 have increased composite morbidity compared to non-pregnant matched controlsby DeBolt et al
The authors aim to describe the outcomes of severe and critical COVID-19 infection in pregnant versus non-pregnant reproductive aged women. Findings suggest that pregnant women with severe and/or critical COVID-19 are at increased risk for certain morbidities when compared to non-pregnant controls. Despite the higher comorbidities of diabetes and hypertension in the non-pregnant controls, the pregnant cases were at increased risk for composite morbidity, intubation, mechanical ventilation and ICU admission. These findings suggest that pregnancy may be associated with a worse outcome in women with severe and critical COVID-19. The study suggests that similar to other viral infections such as SARS-CoV and MERS-CoV, pregnant women may be at risk for greater morbidity and disease severity.
Characteristics and outcomes of neonatal SARS-CoV-2 infection in the UK: a prospective national cohort study using active surveillanceby Gale et al
The authors aimed to describe the incidence, characteristics, transmission, and outcomes of SARS-CoV-2 infection in neonates who received inpatient hospital care in the UK. The findings suggest that neonatal SARS-CoV-2 infection is uncommon in babies admitted to hospital. Infection with neonatal admission following birth to a mother with perinatal SARS-CoV-2 infection was unlikely, and possible vertical transmission rare, supporting international guidance to avoid separation of mother and baby. The high proportion of babies from Black, Asian, or minority ethnic groups requires investigation.
Impact of COVID-19 mitigation measures on the incidence of preterm birth: a national quasi-experimental studyby Been et al
The study aimed to study the impact of the COVID-19 mitigation measures implemented in the Netherlands in a stepwise fashion on March 9, March 15, and March 23, 2020, on the incidence of preterm birth. In this national quasi-experimental study, initial implementation of COVID-19 mitigation measures was associated with a substantial reduction in the incidence of preterm births in the following months, in agreement with preliminary observations elsewhere. Integration of comparable data from across the globe is needed to further substantiate these findings and start exploring underlying mechanisms.
Universal Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV-2) Testing Uptake in the Labor and Delivery Unit: Implications for Health Equityby Kernberg et al
The objective of the study was to understand severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing uptake in the labor and delivery unit and rationales for declining testing, and to institute a process to increase equitable testing uptake. Findings suggest that universal SARS-CoV-2 testing uptake significantly increased through a rapid-cycle improvement initiative. Aligning hospital policy with patient-centered approaches led to nearly universally acceptable testing.
Mapping Inequity among COVID Cases in Sindh, Punjab and Balochistan: Assessment of Characteristics and associations among COVID-19 Cases to Inform Equitable COVID Responseby Das et al
The broader goal of this study is to assess any association between individual and demographic characteristics of the COVID-19 patients and the risk and severity of the diseases. This cross-sectional study will synthesize the COVID-19 surveillance data and actively collect data on additional variables. The sample would comprise of all the reported cases irrespective of age and gender of COVID-19 in Sindh, Punjab and Balochistan.
Characteristics of Women of Reproductive Age With Laboratory-Confirmed SARS-CoV-2 Infection by Pregnancy Status - United States, January 22-June 7, 2020by Ellington et al
The objective of the study was to assess the prevalence and severity of COVID-19 among pregnant U.S. women and determine whether signs and symptoms differ among pregnant and nonpregnant women. Findings suggest that among women of reproductive age with COVID-19, pregnant women are more likely to be hospitalized and at increased risk for ICU admission and receipt of mechanical ventilation compared with nonpregnant women, but their risk for death is similar. To reduce occurrence of severe illness from COVID-19, pregnant women should be counseled about the potential risk for severe illness from COVID-19, and measures to prevent infection with SARS-CoV-2 should be emphasized for pregnant women and their families
Clinical Findings and Disease Severity in Hospitalized Pregnant Women With Coronavirus Disease 2019 (COVID-19)by Savasi et al
The objective of this study was to investigate the clinical evolution of coronavirus disease 2019 (COVID-19) in hospitalized pregnant women and potential factors associated with severe maternal outcomes. In the study cohort, one in five women hospitalized with COVID-19 infection delivered urgently for respiratory compromise or were admitted to the ICU. None, however, died. Increased pregestational BMI and abnormal heart and respiratory rates on admission were associated with severe disease.
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection in Children and Adolescents A Systematic Reviewby Riccardo Castagnoli et al
The objective of this study was to evaluate currently reported pediatric cases of SARS-CoV-2 infection. A total of 815 articles were identified. Eighteen studies with 1065 participants (444 patients were younger than 10 years, and 553 were aged 10 to 19 years) with confirmed SARS-CoV-2 infection were included in the final analysis. All articles reflected research performed in China, except for 1 clinical case in Singapore. Children at any age were mostly reported to have mild respiratory symptoms, namely fever, dry cough, and fatigue, or were asymptomatic. Bronchial thickening and ground-glass opacities were the main radiologic features, and these findings were also reported in asymptomatic patients. Among the included articles, there was only 1 case of severe COVID-19 infection, which occurred in a 13-month-old infant. No deaths were reported in children aged 0 to 9 years. Available data about therapies were limited.
Facing a Pandemic While Pregnant
This study aims to observe the clinical features and outcomes of pregnant women who have been confirmed with COVID-19. Findings suggest that the clinical symptoms and laboratory indicators are not obvious for asymptomatic and mild COVID-19 pregnant women. Pulmonary CT scan plus blood routine examination are more suitable for finding pregnancy women with asymptomatic or mild COVID-19 infection, and can be used screening COVID-19 pregnant women in the outbreak area of COVID-19 infection.
Clinical features and obstetric and neonatal outcomes of pregnant patients with COVID-19 in Wuhan, China: a retrospective, single-centre, descriptive studyby Yu et al
This study aimed to clarify the clinical features and obstetric and neonatal outcomes of pregnant patients with COVID-19. In this retrospective, single-centre study, the authors included all pregnant women with COVID-19 who were admitted to Tongji Hospital in Wuhan, China. Clinical features, treatments, and maternal and fetal outcomes were assessed. Findings suggest that the maternal, fetal, and neonatal outcomes of patients who were infected in late pregnancy appeared very good, and these outcomes were achieved with intensive, active management that might be the best practice in the absence of more robust data. The clinical characteristics of these patients with COVID-19 during pregnancy were similar to those of non-pregnant adults with COVID-19 that have been reported in the literature.