Inherited deficiency of the OAS-RNase L pathway in children with MIS-C

Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1, OAS2, or RNASEL in five unrelated children with MIS-C. The cytosolic dsRNA-sensing OAS1 and OAS2 generate 2'-5'-linked oligoadenylates (2-5A) that activate the ssRNA-degrading RNase L. Consistent with the absence of pneumonia in these patients, epithelial cells and fibroblasts defective for this pathway restricted SARS-CoV-2 normally. This contrasted with IFNAR1-deficient cells from patients prone to hypoxemic pneumonia without MIS-C. Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNASEL deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or SARS-CoV- 2 stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-but not RNase L- deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by MAVS deficiency. Recessive OAS-RNase L deficiencies in these patients unleash the production of SARS-CoV-2-triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C.Copyright © 2023 Elsevier Inc.

Interfering with Interferons: A Critical Mechanism for Critical COVID-19 Pneumonia.

Infection with SARS-CoV-2 results in clinical outcomes ranging from silent or benign infection in most individuals to critical pneumonia and death in a few. Genetic studies in patients have established that critical cases can result from inborn errors of TLR3- or TLR7-dependent type I interferon immunity, or from preexisting autoantibodies neutralizing primarily IFN-α and/or IFN-ω. These findings are consistent with virological studies showing that multiple SARS-CoV-2 proteins interfere with pathways of induction of, or response to, type I interferons. They are also congruent with cellular studies and mouse models that found that type I interferons can limit SARS-CoV-2 replication in vitro and in vivo, while their absence or diminution unleashes viral growth. Collectively, these findings point to insufficient type I interferon during the first days of infection as a general mechanism underlying critical COVID-19 pneumonia, with implications for treatment and directions for future research.

Evaluation of fetuin-A, CRP, and CRP/fetuin-A values in COVID-19 patients

Objectives: Fetuin-A, a glycoprotein with several functions, is also a negative acute phase reactant. The purpose of this study was to investigate levels of serum fetuin-A in coronavirus disease 2019 (COVID-19) patients, its association with disease severity, and whether it has superiority over C-reactive protein (CRP). Methods: The research comprised 56 individuals with COVID-19(+) and 30 healthy controls. The COVID-19(+) patient population was split into three subgroups: mild, moderate, and severe. All participants' serum concentrations of fetuin- A, tumor necrosis factor-alpha (TNF-a), and interleukin-6 (IL-6) were measured using ELISA commercial test kits. In addition, CRP and other biochemical values from biochemistry laboratory data were gathered, and the CRP/fetuin-A ratio was calculated. Results: The fetuin-A concentration of the COVID-19(+) patient group was shown to be statistically lower than that of the healthy control group. TNF-a and IL-6 levels were found to be significantly different in both groups. While fetuin-A had a higher area under the curve (AUC) value than CRP (0.875 and 0.800, respectively), CRP/fetuin-A had the strongest AUC (0.933). Conclusion: Low serum fetuin-A concentrations in COVID-19 patients suggest that fetuin-A is a negative acute phase reactant for severe acute respiratory syndrome coronavirus 2. Furthermore, fetuin-A alone and CRP/fetuin-A value are both contenders for being more remarkable markers than CRP.

Special Issue: Mutagenic factors in the environment impacting human and animal health. (Special Issue: Mutagenic factors in the environment impacting human and animal health.)

This special issue includes 15 articles that discuss the mutagenic effect of tobacco smoke on male fertility;environmental and occupational exposure of metals and female reproductive health;free radical biology in neurological manifestations;paternal factors in recurrent pregnancy loss;mechanical dependency of the SARS-CoV-2 virus and the renin-angiotensin-aldosterone (RAAS) axis;a perspective review on medicinal plant resources for their antimutagenic potentials;asystematic review and meta-analysis of the impacts of glyphosate on the reproductive hormones;impact of ginseng on neurotoxicity induced by cisplatin in rats.

XXI ExpoPPGIm Annual Meeting of the Graduate Program in Immunology, Online, 1-3 September 2021

These proceedings contains 30 articles that covered various topics related to immunology and related fields. The conference papers presented focused on investigating the role of genetics, microbiome, and immunological pathways in disease pathogenesis and treatment. Studies presented at the conference explored the genetic factors associated with obesity in Brazilian children, the role of flavonoids in reprogramming microglia towards a neuroprotective inflammatory profile, the gut microbiome in asthmatic individuals, and the involvement of the MTOR gene and its variants in the severity of COVID-19. Other studies evaluated the immunodiagnostic potential of a protein exclusive to Corynebacterium pseudotuberculosis, genetic markers associated with alcohol dependence and asthma, and the effects of nicotine on glial cells in Parkinson's disease. The conference also presented research on the molecular mechanisms associated with the anti-glioma and immunomodulatory effects of flavonoids, the influence of Trypanosoma cruzi co-infection on the immune response and clinical outcome of patients with cutaneous leishmaniasis, and the association of metalloproteinase gene variants with periodontitis. Furthermore, the papers presented discussed the production of Zika virus singular peptide for the development of serological immunassays, and the role of genetic polymorphisms in the IL1B and IL6 genes in periodontitis. Lastly, the conference included research on the immunological response of broiler chickens fed with diet supplemented with zinc, and the modulatory effects of Agatis flavone on the glial response in an ex vivo model of brain trauma.

Genetic Ethnic Differences in Human 2'-5'-Oligoadenylate Synthetase and Disease Associations: A Systematic Review.

Recently, several studies have highlighted a skewed prevalence of infectious diseases within the African continent. Furthermore, a growing number of studies have demonstrated unique genetic variants found within the African genome are one of the contributing factors to the disease severity of infectious diseases within Africa. Understanding the host genetic mechanisms that offer protection against infectious diseases provides an opportunity to develop unique therapeutic interventions. Over the past two decades, several studies have linked the 2'-5'-oligoadenylate synthetase (OAS) family with a range of infectious diseases. More recently, the OAS-1 gene has also been associated with disease severity caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which led to a global pandemic. The OAS family serves as an antiviral factor through the interaction with Ribonuclease-Latent (RNase-L). This review explores the genetic variants observed within the OAS genes and the associations with various viral infections and how previously reported ethnic-specific polymorphisms drive clinical significance. This review provides an overview of OAS genetic association studies with a particular focus on viral diseases affecting individuals of African descent.

Associations between COVID-19 risk perceptions and mental health, wellbeing, and risk behaviours. (Special Issue: COVID-19: feeling and confronting pandemic risk challenges.)

Mental health has worsened, and substance use has increased for some people during the coronavirus (COVID-19) pandemic. Some cross-sectional studies suggest that higher COVID-19 risk perceptions are related to poorer mental health and greater risk behaviours (e.g. substance use). However, longitudinal and genetic data are needed to help to reduce the likelihood of reverse causality. We used cross-sectional, longitudinal, and polygenic risk score (PRS;for anxiety, depression, wellbeing) data from the Avon Longitudinal Study of Parents and Children (ALSPAC). We examined cross-sectional and prospective longitudinal associations between COVID-19 risk perceptions (i.e. cognitive, affective, self, other, and a combined 'holistic' measure) and mental health (i.e. anxiety, depression), wellbeing, and risk behaviours. Pandemic (April-July 2020) and pre-pandemic (2003-2017) data (ns = 233-5,115) were included. Higher COVID-19 risk perceptions (holistic) were associated with anxiety (OR 2.78, 95% confidence interval [CI] 2.20 to 3.52), depression (OR 1.65, 95% CI 1.24 to 2.18), low wellbeing (OR 1.76, 95% CI 1.45 to 2.13), and increased alcohol use (OR 1.46, 95% CI 1.24 to 1.72). Higher COVID-19 risk perceptions were also associated with self-isolating given a suspected COVID-19 infection (OR 1.74, 95% CI 1.13 to 2.68), and less face-to-face contact (OR 0.83, 95% CI 0.70 to 0.98) and physical contact (OR 0.83, 95% CI 0.68 to 1.00). Pre-pandemic anxiety (OR 1.64, 95% CI 1.29 to 2.09) and low wellbeing (OR 1.41, 95% CI 1.15 to 1.74) were associated with higher COVID-19 risk perceptions. The depression PRS (b 0.21, 95% CI 0.02 to 0.40) and wellbeing PRS (b - 0.29, 95% CI -0.48 to -0.09) were associated with higher and lower COVID-19 risk perceptions, respectively. Poorer mental health and wellbeing are associated with higher COVID-19 risk perceptions, and longitudinal and genetic data suggest that they may play a causal role in COVID-19 risk perceptions.

COVID-19 cardiac manifestations and scent perception genes in hearts of SARS-CoV-2 infected patients: a meta-analysis of gene expression data

Background: COVID-19 induced cardiac events are reported by many papers, while psychophysiology of association of the COVID-19 and cardiac attacks are not fully understood yet. Materials and Methods: Here, we compared gene expression levels of heart autopsies of SARS-Cov-2 infected patients with the cardiac organoid model of human myocardial infarction and controlled healthy cardiac organoids to identify differentially expressed genes (DEGs). Gene Ontology (GO) biological processes were enriched in DEGs.

A qualitative study on how older adults perceive the meaning and shaping of optimism: has the COVID-19 pandemic impacted their perceptions?

Background: Optimism is a psychosocial asset associated with healthy ageing. Coronavirus disease 2019 (COVID-19) tremendously impacts people's lives and health. This study explored what optimism means to older Australians and how the pandemic may have affected their perceptions.

Relationship between vitamin D binding protein (DBP) gene polymorphism and type 2 diabetes mellitus COVID-19 patients in Iraq

The current study has been directed to distinguish the powerful influence of the demographic characteristics changes and vitamin D binding protein (VDBP) single nucleotides polymorphism rs2282679 on patients with COVID-19 in comparison with healthy people. This study was totally covered eighty patients who were dived into groups: 60 patients with COVID-19 and 20 healthy subjects as control. As a result, the demographic characteristics of patients and control subjects were included age, gender, residency, occupation, smoking people and not, and married status. So the result was shown that mean age, gender and frequency distribution of patients have no significant difference between patients and control subjects (P = 0.277 and P = 0.299 in respectively). Furthermore, the mean and the frequency distribution of residency, occupation, and smoking were non-significant effects on patients with COVID-19 compared to the healthy group, (P = 0.093, P = 0.519) respectively, but the marital status was a significant increase (P = 0.008). However, the demographic changes in patients significantly increased COVID-19 infection. Also, chronic diseases were involved in this study, in particular, diabetes mellitus and systemic hypertension diseases were covered in relation to COVID-19, so both diseases were highly presented with significant differences rates between patients and control subjects (P = 0.001 for DM and P = 0.001 for hypertension). Moreover, the association between DBP rs2282679 polymorphism in relationship with risk of COVID-19 were studied which were displayed that heterozygous genotype AC was significantly more frequency (P = 0.01) in the COVID-19 patient's group compared to the control group, but the homozygous genotype AA was non-significant (P = 0.08) in COVID-19 patients. Afterwards, Allele A was more frequent and highly significant (P = 0.192) in the patient's group. This study was concluded that demographic changes with COVID-19 would be more increased the intensive infection, and mortality rate of disease. In the same way, diabetes mellitus and systematic hypertension diseases are the high-risk factors for COVID-19. Furthermore, VDBP rs2282679 polymorphism was clearly increased the COVID-19 infection, and heterozygous genotype AC was high frequent in patients and a risk factor for Covid-19, also allele A was absolutely a potential risk factor for Covid-19.

Collection of COVID-19 convalescent plasma in institute for transfusion medicine of republic of North Macedonia and evaluation of anti-SARS-CoV-2 antibody concentration in different donors subgroups

Background: Plasma collected from patients that have recovered from an infectious disease has been transfused over many decades for prophylaxis and treatment of various infectious diseases. Taking into consideration the expansion of COVID-19 pandemics, we started the COVID-19 convalescent plasma (CCP) programme. Aims: The aim of our study is to show our experience with collecting the CCP and to evaluate the SARS-CoV-2 antibody concentration in different convalescent plasma donors' subgroups. Methods: This is a prospective study performed in the Institute for Transfusion Medicine of Republic of North Macedonia since 30 April 2020 till July 2021. Antibody testing was performed at the Institute for Immunobiology and Human Genetics in Skopje using CLIA method with Snibe Maglumi SARS-CoV-2 S-RBD IgG (quantitative) with IgG cut-off larger than 5 AU/ml. All potential donor were tested for: negative RTPCR for SARSCoV-2 before donation, anti-SARS-CoV-2 antibodies, anti- HLA antibodies (where applicable), blood count, blood group, TTI and biochemistry. Preferred method for plasma collection was plasmapheresis which was performed with Terumo BCT Trima Accel and donation of whole blood, depending on the donor preference and venous access. All donors signed inform consent for donation and inclusion in the study. Results: There were 1476 potential CCP donors, but only 700(47.9%) donors fulfilled all the criteria and we obtained 793 units of CCP;639 (80.6%) units from whole blood donors and 154 (19.4%) CCP units from 61 plasmapheresis donors, 485 (69.3%) males and 215 (30.7%) females. Mean age of the donors was 40 years (range 18-63). Mean value of SARS-CoV-2 S-RBD IgG concentration was 31.05 AU/ml, (range from 5.1 AU/ml to >100 AU/ml), mean value of SARS-CoV-2 S-RBD IgG in men was 37.6 AU/ml and 28.9 AU/ml in women (p < 0.05). Distribution of CCP donors according to the ABO blood group was: 301 blood group A (43%) with median value of SARS-CoV-2 S-RBD IgG = 27.15 AU/ml, 220 blood group O (31.4%) median value of SARS-CoV-2 S-RBD IgG = 32.1 AU/ml, 116 blood group B (16.6%) median value of SARS-CoV-2 S-RBD IgG = 35.9 AU/ml and 63 donors had blood group AB (9%) median value of SARS-CoV-2 S-RBD IgG = 26.45 AU/ml. There were 69 donors that were previously hospitalized with mean value of SARS-CoV-2 S-RBD IgG = 48.6 AU/ml, and 629 that were treated at home with mean value of SARS-CoV-2 SRBD IgG = 29.1 AU/ml (p < 0.05), of which 578 had symptoms with mean value of SARSCoV- 2 S-RBD IgG = 29.1 AU/ml and 51 were asymptomatic with mean value of SARS-CoV-2 S-RBD IgG = 29.3 AU/ml. The CCP donors had the following distribution according to the age: 125 donors in the 18-29 age group with median value of SARS-CoV-2 S-RBD IgG = 23.0 AU/ml, 200 donors in the 30-39 age group with mean value of SARSCoV-2 S-RBD IgG = 28.2 AU/ml, 217 donors in the 40-49 age group with mean value of SARS-CoV-2 SRBD IgG = 32.9 AU/ml and 156 donors in the 50-63 age group mean value of SARS-CoV-2 S-RBD IgG = 38.3 AU/ml (p < 0.05). Summary/Conclusions: The collection procedures are safe and effective and collected CCP units were with high concentration and quality. The concentration of SARS-CoV-2 S-RBD IgG in CCP obtained from previously hospitalized patients was significantly larger than in ones that were treated at home. The concentration of SARS-CoV-2 S-RBD IgG was higher in men, in advanced age group and in donors with blood group B. The further studies are needed to clarify the impact of different variables on antibodies concentration/ titre in donors.

Reasons for deferral of COVID-19 convalescent plasma donors

Background: Taking into consideration historic success of convalescent plasma in prophylaxis and treatment of various infectious diseases over the century and expansion of COVID-19 pandemics, we started the COVID-19 convalescent plasma program in our country. Aims: The aim of our study was to show the reasons for deferral of the COVID-19 convalescent plasma (CCP) donors. Methods: This is a prospective study organized in the Institute for Transfusion Medicine of Republic of North Macedonia since 30 April 2020 till July 2021. CCP donors eligible for donation were donors without a history of blood transfusion, female donors who have never been pregnant, or who have been tested and found negative for anti- HLA antibodies, age 18-65, in good health that fulfil all other criteria for regular blood donors. All potential donor were tested for: negative RT-PCR for SARSCoV-2 before donation, anti-SARS-CoV-2 antibodies, anti-HLA antibodies (where applicable), blood count, blood group, TTI and biochemistry. Antibody testing was performed at the Institute for Immunobiology and Human Genetics in Skopje using CLIA method with Snibe Maglumi SARS-CoV-2 S-RBD IgG with IgG cut-off for CCP donation larger than 5 AU/ml (cut-off for regular positive result was larger than 1 AU/ml). All donors signed inform consent for donation and inclusion in the study. Results: There were 1462 potential CCP donors, of which 762(52.1%) did not fulfil criteria for CCP donation, 424(55.6%) women and 338 (44.4%) men. There were 454(59.6%) potential CCP donors that did not have enough anti-SARS-CoV-2 S-RBD IgG antibodies (Ab), of which 223(49.1%) had Ab concentration less than 1 AU/ml (29.3% of all deferred donors) and 231(50.9%) had Ab concentration between 1 and 5 AU/ml (30.3% of all deferred donors). In this subgroup of deferred donors, there were 227 women (50%) and 227 men (50%), with mean age 37.2 ± 10.1 (range 18-63). There were statistical significant correlation between the gender and the Ab concentration less than 1 AU/ml and from 1 to 5 AU/ml (Pearson Chi-square: 3.88667, df = 1, p = 0.048671). Multiple regression analysis showed that gender is independently connected with the Ab concentration, OR = 1.4495 (95%CI 1.0016-2.0976), i.e. male gender increases the chance for increased Ab concentration for one and a half times. According to the age group, the majority of deferred CCP donors, because of low Ab concentration, are in the age group from 30 till 39(39.6%), followed by age group from 40 till 49(23.8%), and least deferred donors were in 50 and above age group (13.2%). The most of these deferred donors were treated at home, 451(99.3%) and had symptoms 240(52.9%). Distribution according to blood group in CCP donors deferred due to low Ab concentration was: blood group A- 182(40.1%), blood group O-153(33.7%), blood group B-69(15.1%) and blood group AB-42(9.3%). In the whole investigated group, 65 (8.5%) potential donors were deferred because of low haemoglobin level (less than 12.5 g/dl for women and less than 13.5 g/dl for men), 26 (3.4%) were deferred because of positive TTI markers and 102 (13.4%) women of the total number of deferred donors were deferred because of presence of HLA antibodies (i.e. 24% of investigated women). Summary/Conclusions: There is large percentage of deferred CCP donors mostly because of low Ab concentration, presence of HLA antibodies and low haemoglobin level, but starting of COVID-19 convalescent plasma program was a big success for our institution and our country and helped a lot of patients.

Abstracts from the 54th European Society of Human Genetics (ESHG) Conference

The proceedings contain 1623 papers. The topics discussed include: the COVID-19 host genetics initiative - an international, open science effort to identify genetic risk factors for COVID19 severity and susceptibility;clinical implementation of RNA sequencing for Mendelian disease diagnostics;local gene co-expression measurements in single-cells highlight inter-individual specificity;a cross-disorder dosage sensitivity map of the human genome;biallelic ATG7 variants impair autophagy leading to neurological disease;epilepsy polygenic risk scores in >269k individuals with and without epilepsy;machine learning methods for prioritizing genetic variants;Mendel Lecture - Cell-free DNA in plasma: coming in different sizes and shapes;imaging the accessible genome at nanometer scale;retrotransposition in brain: does LINE activity in the central nervous system matter?;activation of transposons in neurological disorders;how to transfer genomic data internationally in compliance with the GDPR;mutational signatures of environmental agents and chemotherapeutics in human cellular models;and the art, science and practice of implementing genomics in clinical care.

Innate and Adaptive Immune Responses in the Upper Respiratory Tract and the Infectivity of SARS-CoV-2.

Increasing evidence shows the nasal epithelium to be the initial site of SARS-CoV-2 infection, and that early and effective immune responses in the upper respiratory tract (URT) limit and eliminate the infection in the URT, thereby preventing infection of the lower respiratory tract and the development of severe COVID-19. SARS-CoV-2 interferes with innate immunity signaling and evolves mutants that can reduce antibody-mediated immunity in the URT. Recent genetic and immunological advances in understanding innate immunity to SARS-CoV-2 in the URT, and the ability of prior infections as well as currently available injectable and potential intranasal COVID-19 vaccines to generate anamnestic adaptive immunity in the URT, are reviewed. It is suggested that the more detailed investigation of URT immune responses to all types of COVID-19 vaccines, and the development of safe and effective COVID-19 vaccines for intranasal administration, are important needs.

Implementation of telemedicine-based pediatric genetics care at the Children’s Hospital of Philadelphia

Background: The COVID-19 pandemic has necessitated an unprecedented increase in the use of telemedicine, the distribution of healthcare services using communication technology which allows for physical separation of the patient and provider. In Pediatric Genetics, there has been a longstanding interest in implementing telemedicine-based care to increase access to diagnostic testing, patient counseling and medical management of rare inherited diseases. In response to COVID-19, the Division of Human Genetics at the Children’s Hospital of Philadelphia rapidly transitioned to telemedicine-based care. Objective/Aim:We sought to understand howthe use of telemedicine affected medical care for patients with suspected or confirmed genetic conditions. In addition to assessing the immediate impact of telemedicine on Pediatric Genetics care, we asked if this new care model could provide long-term benefit in increasing our effectiveness and efficiency, improving patient outcomes and reducing healthcare disparities. Methods:We initiated a quality improvement project to evaluate the utility of telemedicine pre-pandemic and during the pandemic. This included 3869 outpatient encounters in the Division of Human Genetics from March 1, 2020 to November 30, 2020 and 3228 outpatient encounters from the same time period in 2019. Visit types, diagnosis codes, patient demographics and laboratory procedure codes were pulled from Epic, and patient satisfaction was assessed using Press Ganey scores. This project was undertaken as a Quality Improvement Initiative and as such does not constitute human subjects research. Results: Of the encounters in 2020, 75% (n = 2895) were virtual, compared to 3% (n = 81) of the encounters in 2019. Using primarily telemedicine-based appointments in 2020, we saw nearly 20% more patients than were seen using primarily in-person appointments in the same time period in 2019. Genetic counselor-only appointments more than doubled, with 312 encounters (8% of all appointments) in 2020, and 149 encounters (5% of all appointments) in 2019. The distribution of visit types was similar in both time periods, with new patient appointments comprising 56% of appointments in 2020 compared to 53% in 2019, and follow-up appointments comprising 44% of appointments in 2020 compared to 47% in 2019. Press Ganey scores indicated improved rates of overall patient satisfaction (84.3% in 2020 vs. 80.1% in 2019) as well as satisfaction with access (76.0% in 2020 vs. 62.1% in 2019) and moving through the visit (67.7% in 2020 vs. 56.4% in 2019). Conclusion: The Division of Human Genetics at the Children’s Hospital of Philadelphia seamlessly transitioned to telemedicine in the midst of a global pandemic. Using telemedicine, there was increased patient access and patient satisfaction. Long-term use of telemedicine may result in increased access to care and improved efficiency in care delivery.

Genetic susceptibility to viral disease in humans.

BACKGROUND: During the past decades, studies on patients with severe viral infections have revealed rare inborn errors of immunity (IEIs) underlying these diseases. This has led to important new insights into the molecular genetics and immunological mechanisms governing susceptibility to viral infection in humans. OBJECTIVES: Herein, the current knowledge on major IEIs predisposing to severe or chronic viral infections are described and discussed, and the clinical implications of these findings for individualized prophylaxis and treatment are outlined. SOURCES: The review is based on a broad literature search, including relevant studies primarily based on patients, supported by experimental molecular models in vitro or in mice, to characterize the pathophysiological mechanism governing these disease conditions. CONTENT: Current concepts and principles of genetic predisposition to viral infections in humans are described with a major focus on defects related to innate immune responses and new concepts of constitutive immune mechanisms. The topic therefore spans from seminal studies on the human genetics of herpesvirus infections in the central nervous system, severe influenza, and disease after vaccination with live attenuated viral vaccines, to genetic resistance to viral infection. IMPLICATIONS: Past and present studies of patients with IEIs conferring vulnerability to viral infections have taught us important lessons on protective innate and adaptive antiviral immunity in humans. Such knowledge also has important clinical implications, allowing development of prophylactic and therapeutic solutions to prevent or dampen the clinical consequences of insufficient or dysregulated antiviral immunity in patients. Collectively, such measures are likely to improve patient management at an individualized level and help societies reduce the disease burden from viral infections.

Stay at home: implementation and impact of virtualising cancer genetic services during COVID-19.

The COVID-19 pandemic has led to the rapid adoption of virtual clinic processes and healthcare delivery. Herein, we examine the impact of virtualising genetics services at Canada's largest cancer centre. A retrospective review was conducted to evaluate relevant metrics during the 12 weeks prior to and during virtual care, including referral and clinic volumes, patient wait times and genetic testing uptake. The number of appointments and new patients seen were maintained during virtual care. Likewise, there was a significant increase in the number of patients offered testing during virtual care who did not provide a blood sample (176/180 (97.7%) vs 180/243 (74.1%); p<0.001), and a longer median time from the date of pretest genetic counselling to the date a sample was given (0 vs 11 days; p<0.001). Referral volumes significantly decreased during virtual care (35 vs 22; p<0.001), which was accompanied by a decreased median wait time for first appointment (55 days vs 30 days; p<0.001). The rapid virtualisation of cancer genetic services allowed the genetics clinic to navigate the COVID-19 pandemic without compromising clinical volumes or access to genetic testing. There was a decrease in referral volumes and uptake of genetic testing, which may be attributable to pandemic-related clinical restrictions.

Network-Driven Drug Discovery.

We describe an approach to early stage drug discovery that explicitly engages with the complexities of human biology. The combined computational and experimental approach is formulated on a conceptual framework in which network biology is used to bridge between individual molecular entities and the cellular phenotype that emerges when those entities interact in a network. Multiple aspects of early stage discovery are addressed including the data-driven elucidation of biological processes implicated in disease, target identification and validation, phenotypic discovery of active molecules and their mechanism of action, and extraction of genetic target support from human population genetics data. Validation is described via summary of a number of discovery projects and details from a project aimed at COVID-19 disease.