Importance Severe coronavirus disease 2019 (COVID-19) can occur in younger, predominantly male, patients without preexisting medical conditions. Some individuals may have primary immunodeficiencies that predispose to severe infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Objective To explore the presence of genetic variants associated with primary immunodeficiencies among young patients with COVID-19. Design, Setting, and Participants Case series of pairs of brothers without medical history meeting the selection criteria of young (age Exposure Severe COVID-19. Main Outcome and Measures Results of rapid clinical whole-exome sequencing, performed to identify a potential monogenic cause. Subsequently, basic genetic and immunological tests were performed in primary immune cells isolated from the patients and family members to characterize any immune defects. Results The 4 male patients had a mean age of 26 years (range, 21-32), with no history of major chronic disease. They were previously well before developing respiratory insufficiency due to severe COVID-19, requiring mechanical ventilation in the ICU. The mean duration of ventilatory support was 10 days (range, 9-11); the mean duration of ICU stay was 13 days (range, 10-16). One patient died. Rapid clinical whole-exome sequencing of the patients and segregation in available family members identified loss-of-function variants of the X-chromosomalTLR7.In members of family 1, a maternally inherited 4-nucleotide deletion was identified (c.2129_2132del; p.[Gln710Argfs*18]); the affected members of family 2 carried a missense variant (c.2383G>T; p.[Val795Phe]). In primary peripheral blood mononuclear cells from the patients, downstream type I interferon (IFN) signaling was transcriptionally downregulated, as measured by significantly decreased mRNA expression ofIRF7,IFNB1, andISG15on stimulation with the TLR7 agonist imiquimod as compared with family members and controls. The production of IFN-γ, a type II IFN, was decreased in patients in response to stimulation with imiquimod. Conclusions and Relevance In this case series of 4 young male patients with severe COVID-19, rare putative loss-of-function variants of X-chromosomalTLR7were identified that were associated with impaired type I and II IFN responses. These preliminary findings provide insights into the pathogenesis of COVID-19.

/pdf/presence-of-genetic-variants-among-young-men-with-severe-2y02wt9l1h.pdf

Presence of Genetic Variants Among Young Men With Severe COVID-19.

The presence of SARS-CoV-2 was officially documented in Europe at the end of February 2020. Despite many observations, the real impact of COVID-19 in the European Union (EU), its underlying factors and their contribution to mortality and morbidity outcomes were never systematically investigated. The aim of the present work is to provide an overview and a meta-analysis of main predictors and of country differences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-associated mortality rate (MR) in hospitalized patients. Out of 3714 retrieved articles, 87 studies were considered, including 35,486 patients (mean age 60.9 ± 8.2 years) and 5867 deaths. After adjustment for confounders, diabetes mellitus was the best predictors of MR in an age- and sex-dependent manner, followed by chronic pulmonary obstructive diseases and malignancies. In both the US and Europe, MR was higher than that reported in Asia (25[20;29] % and 20[17;23] % vs. 13[10;17]%; both p < 0.02). Among clinical parameters, dyspnea, fatigue and myalgia, along with respiratory rate, emerged as the best predictors of MR. Finally, reduced lymphocyte and platelet count, along with increased D-dimer levels, all significantly contributed to increased mortality. The optimization of glucose profile along with an adequate thrombotic complications preventive strategy must become routine practice in diseased SARS-CoV-2 infected patients.

/pdf/diabetes-is-most-important-cause-for-mortality-in-covid-19-4jyjns702c.pdf

Diabetes is most important cause for mortality in COVID-19 hospitalized patients: Systematic review and meta-analysis.

While COVID-19 spreads aggressively and rapidly across the globe, many societies have also witnessed the spread of other viral phenomena like misinformation, conspiracy theories, and general mass suspicions about what is really going on. This study investigates how exposure to and trust in information sources, and anxiety and depression, are associated with conspiracy and misinformation beliefs in eight countries/regions (Belgium, Canada, England, Philippines, Hong Kong, New Zealand, United States, Switzerland) during the COVID-19 pandemic. Data were collected in an online survey fielded from May 29, 2020 to June 12, 2020, resulting in a multinational representative sample of 8,806 adult respondents. Results indicate that greater exposure to traditional media (television, radio, newspapers) is associated with lower conspiracy and misinformation beliefs, while exposure to politicians and digital media and personal contacts are associated with greater conspiracy and misinformation beliefs. Exposure to health experts is associated with lower conspiracy beliefs only. Higher feelings of depression are also associated with greater conspiracy and misinformation beliefs. We also found relevant group- and country differences. We discuss the implications of these results.

/pdf/beliefs-in-conspiracy-theories-and-misinformation-about-5bz1r0lcj3.pdf

Beliefs in Conspiracy Theories and Misinformation About COVID-19: Comparative Perspectives on the Role of Anxiety, Depression and Exposure to and Trust in Information Sources

Echo chambers in online social networks, in which users prefer to interact only with ideologically-aligned peers, are believed to facilitate misinformation spreading and contribute to radicalize political discourse. In this paper, we gauge the effects of echo chambers in information spreading phenomena over political communication networks. Mining 12 million Twitter messages, we reconstruct a network in which users interchange opinions related to the impeachment of the former Brazilian President Dilma Rousseff. We define a continuous political leaning parameter, independent of the network’s structure, that allows to quantify the presence of echo chambers in the strongly connected component of the network. These are reflected in two well-separated communities of similar sizes with opposite views of the impeachment process. By means of simple spreading models, we show that the capability of users in propagating the content they produce, measured by the associated spreading capacity, strongly depends on their attitude. Users expressing pro-impeachment leanings are capable to transmit information, on average, to a larger audience than users expressing anti-impeachment leanings. Furthermore, the users’ spreading capacity is correlated to the diversity, in terms of political position, of the audience reached. Our method can be exploited to identify the presence of echo chambers and their effects across different contexts and shed light upon the mechanisms allowing to break echo chambers.

/pdf/quantifying-echo-chamber-effects-in-information-spreading-1t9ur9njc4.pdf

Quantifying echo chamber effects in information spreading over political communication networks

Background: The adverse events reported from the COVID-19 mRNA vaccines have varied from very mild, such as pain near the vaccination site, to more severe, with occasional anaphylaxis. Details of age-specific gender differences for the adverse effects are not well documented. Methods: Age and gender disaggregated data on reports of adverse events following two or three doses of the Pfizer-BioNTech COVID-19 vaccine were obtained from four cross-sectional studies. The first was from reports submitted to the Israel Ministry of Health national adverse events database (for ages 16 and above). The second was from a national cross-sectional survey based on an internet panel (for ages 30 and above), and the third and fourth were from cross-sectional surveys among employees of a large company (for ages 20–65) using links to a self-completed questionnaire. Results: In all studies, the risks of adverse events were higher following the second dose and consistently higher in females at all ages. The increased risk among females at all ages included local events such as pain at the injection site, systemic events such as fever, and sensory events such as paresthesia in the hands and face. For the combined adverse reactions, for the panel survey the female-to-male risk ratios (RRs) were 1.89 for the first vaccine dose and 1.82 for the second dose. In the cross-sectional workplace studies, the female-to-male RRs for the first, second and third doses exceeded 3.0 for adverse events, such as shivering, muscle pain, fatigue and headaches. Conclusions: The consistent excess in adverse events among females for the mRNA COVID-19 vaccine indicates the need to assess and report vaccine adverse events by gender. Gender differences in adverse events should be taken into account when determining dosing schedules.

/pdf/gender-differences-in-adverse-events-following-the-pfizer-rs9d4b1v.pdf

Gender Differences in Adverse Events Following the Pfizer-BioNTech COVID-19 Vaccine

BACKGROUND: Early in the COVID-19 pandemic, it was noted that males seemed to have higher case-fatality rates than females. We examined the magnitude and consistency of the sex differences in age-specific case-fatality rates (CFRs) in seven countries. METHODS: Data on the cases and deaths from COVID-19, by sex and age group, were extracted from the national official agencies from Denmark, England, Israel, Italy, Spain, Canada and Mexico. Age-specific CFRs were computed for males and females separately. The ratio of the male to female CFRs were computed and meta-analytic methods were used to obtained pooled estimates of the male to female ratio of the CFRs over the seven countries, for all age-groups. Meta-regression and sensitivity analysis were conducted to evaluate the age and country contribution to differences. RESULTS: The CFRs were consistently higher in males at all ages. The pooled M:F CFR ratios were 1.71, 1.88, 2.11, 2.11, 1.84, 1.78 and 1.49, for ages 20-29, 30-39, 40-49, 50-59, 60-69, 70-79, 80+ respectively. In meta-regression, age group and country were associated with the heterogeneity in the CFR ratios. CONCLUSIONS: The sex differences in the age-specific CFRs are intriguing. Sex differences in the incidence and mortality have been found in many infectious diseases. For COVID-19, factors such as sex differences in the prevalence of underlying diseases may play a part in the CFR differences. However, the consistently greater case-fatality rates in males at all ages suggests that sex-related factors impact on the natural history of the disease. This could provide important clues as to the mechanisms underlying the severity of COVID-19 in some patients.

/pdf/sex-differences-in-the-case-fatality-rates-for-covid-19-a-1jtxeu8z6c.pdf

Sex differences in the case-fatality rates for COVID-19-A comparison of the age-related differences and consistency over seven countries.

Background Crude case-fatality rates (CFRs) for COVID-19 vary widely between countries. There are serious limitations in the CFRs when making comparisons. We examined how the age distribution of the cases is responsible for the COVID-19 CFR differences between countries. Methods COVID-19 cases and deaths, by ten-year age-groups, were available from the reports of seven countries. The overall and age-specific CFRs were computed for each country. The age-adjusted CFRs were computed by the direct method, using the combined number of cases in all seven countries in each age group as the standard population. A meta-analytic approach was used to obtain pooled age-specific CFRs. Findings The crude overall CFRs varied between 0.82% and 14.2% in the seven countries and the variation in the age-specific CFRs were much smaller. There was wide variation in the age distribution of the cases between countries. The ratio of the crude CFR for the country with the highest CFR to that with the lowest (6.28) was much lower for the age-adjusted CFRs rates (2.57). Conclusions The age structure of the cases explains much of differences in the crude CFRs between countries and adjusting for age substantially reduces this variation. Other factors such as the definition of cases, coding of deaths and the standard of healthcare are likely to account for much of the residual variation. It is misleading to compare the crude COVID-19 CFRs between countries and should be avoided. At the very least, age-specific and age-adjusted CFRs should be used for comparisons.

/pdf/the-confounded-crude-case-fatality-rates-cfr-for-covid-19-4rz5da8pcc.pdf

The confounded crude case-fatality rates (CFR) for COVID-19 hide more than they reveal-a comparison of age-specific and age-adjusted CFRs between seven countries.

Background Transfusion guidelines advocate restrictive rather than liberal use of red blood cells (RBC) and are based mostly on randomized trials in intensive care and surgical departments. We aimed to study RBC transfusion practice in the medical patients' population. Methods The data in this study were collected from patients over the age of 18 years admitted to an Internal Medicine department between 2009 and 2014 who received at least one unit of packed red blood cells (RBC). In addition, data on demographics, patients' diagnoses, laboratory tests and number of transfused RBC units were extracted from the electronic health records. Results One thousand three hundred and twenty eight patients were included, having mean age of 75 ± 14 years. The median hemoglobin (Hb) trigger for RBC transfusion was 8.0 g/dl (IQR 7.3–8.7g/dl), and most patients received either one (43.4%) or two (33.4%) RBC units. There was no significant difference in Hb trigger between males and females (Hb 8.0 g/dl and 7.9 g/dl, respectively, p = 0.098), and a weak correlation with age (r = 0.108 p = 0.001). Patients with cardiovascular and lung diseases had a statistically significant higher Hb trigger compared to patients without those diagnoses, however the median difference between them was 0.5 g/dl or less. Conclusions These "real world" data we collected show a Hb trigger compliant with the upper limit of published guidelines and influenced by medical patients' common diagnoses. Prospective trials addressing patients hospitalized in internal medicine departments could further contribute to transfusion decision algorithms.

/pdf/hemoglobin-transfusion-trigger-in-an-internal-medicine-hshltbrzeq.pdf

Hemoglobin transfusion trigger in an internal medicine department - A "real world" six year experience.

Consistent, Excess Viral Meningitis Incidence Rates in Young Males: A Multi-country, Multi-year, Meta-analysis of National Data. The Importance of Sex as a Biological Variable.

Victoria Peer

Papers

Gender Differences in Adverse Events Following the Pfizer-BioNTech COVID-19 Vaccine

Sex differences in the case-fatality rates for COVID-19-A comparison of the age-related differences and consistency over seven countries.

The confounded crude case-fatality rates (CFR) for COVID-19 hide more than they reveal-a comparison of age-specific and age-adjusted CFRs between seven countries.

Hemoglobin transfusion trigger in an internal medicine department - A "real world" six year experience.

Consistent, Excess Viral Meningitis Incidence Rates in Young Males: A Multi-country, Multi-year, Meta-analysis of National Data. The Importance of Sex as a Biological Variable.