Mobility changes following COVID-19 stay-at-home policies varied by socioeconomic measures: An observational study in Ontario, Canada (preprint)

In Canada, lower income households and essential workers and were disproportionately at risk of SARS-CoV-2. Early in the pandemic, stay-at-home restriction policies were used to limit virus transmission. There remains an evidence gap in how changes in mobility, in response to the policies, varied across socioeconomic measures in Canada. The study objective was to describe the variability in mobility change to two restrictions, by neighborhood-level income and by proportion essential workers across five regions in Ontario, Canada. The first restriction was implemented on March 17, 2020 in all five regions; and the second restriction was implemented in November 23, 2020 in two of the regions. Using cell-phone mobility data aggregated to the census tract, we compared the average mobility (% of devices that travelled outside their "primary location") three weeks before and after each restriction. We defined the adjusted mobility change via pre-restriction mobility subtracted from post-restriction, adjusted for 2019 levels. We used difference-in-differences analysis to quantify effect modification of the second restrictions effect by socioeconomic measures. With the first restriction, crude mobility fell from 77.7% to 41.6% across the five regions. The adjusted mobility change to the first restriction was largest in the highest-income neighborhoods (-43.3% versus -38.4%) and in neighborhoods with the fewest essential workers (-44.5% versus -37.6%). The overall adjusted mobility change to the second restriction was small: -0.96% (95% confidence intervals, -1.53 to -0.38%). However, there was evidence of effect modification by socioeconomic measures (less pronounced decrease in lower-income neighborhoods and more essential workers). The findings suggest a temporal saturation effect of restrictions over subsequent waves, and a saturation effect by income and occupation, leading to prevention gaps across populations by socioeconomic measures. Findings highlight the need for tailored approaches at the intersections of income and occupation when addressing epidemics of novel and resurging respiratory pathogens.

Genomic assessment of invasion dynamics of SARS-CoV-2 Omicron BA.1 (preprint)

SARS-CoV-2 variants of concern (VOCs) arise against the backdrop of increasingly heterogeneous human connectivity and population immunity. Through a large-scale phylodynamic analysis of 115,622 Omicron genomes, we identified >6,000 independent introductions of the antigenically distinct virus into England and reconstructed the dispersal history of resulting local transmission. Travel restrictions on southern Africa did not reduce BA.1 importation intensity as secondary hubs became major exporters. We explored potential drivers of BA.1 spread across England and discovered an early period during which viral lineage movements mainly occurred between larger cities, followed by a multi-focal spatial expansion shaped by shorter distance mobility patterns. We also found evidence that disease incidence impacted human commuting behaviours around major travel hubs. Our results offer a detailed characterisation of processes that drive the invasion of an emerging VOC across multiple spatial scales and provide unique insights on the interplay between disease spread and human mobility.

Frequency of thrombocytopenia in severe COVID-19 pneumonia and its effects on clinical outcomes.

To aim of the study was to determine the frequency of thrombocytopenia and its effect on clinical outcomes in South Asian patients admitted with severe COVID-19. It was a cross-sectional study conducted at the COVID intensive care unit of tertiary care government hospital of Karachi, Pakistan. 190 patients admitted in five months from 1/2/2021 till 30/6/2021 were included in the study. Platelet counts were recorded at presentation and all patients were also followed to observe if they develop thrombocytopenia during the course of hospital stay. The patient outcome and need for mechanical ventilation was assessed 28 days after admission and compared with the frequency of thrombocytopenia. Thrombocytopenia was seen in 26.8% (n=51) admitted patients. Among these, 68.6% patients had thrombocytopenia at presentation and 31.4% patients developed thrombocytopenia during the course of hospital stay. The range of platelet count in thrombocytopenic patients was 11x109 - 150x109. Mean platelets count in thrombocytopenic patients was 110x109 (SD 33). Mortality in patients who developed thrombocytopenia was 73.6% and 56.9.2% in patients without thrombocytopenia (p 0.034). Patients with thrombocytopenia were more likely to require mechanical ventilation (p 0.024). Thrombocytopenia is frequently observed in patients with severe COVID-19 and can be used as a tool for risk stratification.

Global Expansion of SARS-CoV-2 Variants of Concern: Dispersal Patterns and Influence of Air Travel (preprint)

In many regions of the world, the Alpha, Beta and Gamma SARS-CoV-2 Variants of Concern (VOCs) co-circulated during 2020-21 and fueled waves of infections. During 2021, these variants were almost completely displaced by the Delta variant, causing a third wave of infections worldwide. This phenomenon of global viral lineage displacement was observed again in late 2021, when the Omicron variant disseminated globally. In this study, we use phylogenetic and phylogeographic methods to reconstruct the dispersal patterns of SARS-CoV-2 VOCs worldwide. We find that the source-sink dynamics of SARS-CoV-2 varied substantially by VOC, and identify countries that acted as global hubs of variant dissemination, while other countries became regional contributors to the export of specific variants. We demonstrate a declining role of presumed origin countries of VOCs to their global dispersal: we estimate that India contributed <15% of all global exports of Delta to other countries and South Africa <1-2% of all global Omicron exports globally. We further estimate that >80 countries had received introductions of Omicron BA.1 100 days after its inferred date of emergence, compared to just over 25 countries for the Alpha variant. This increased speed of global dissemination was associated with a rebound in air travel volume prior to Omicron emergence in addition to the higher transmissibility of Omicron relative to Alpha. Our study highlights the importance of global and regional hubs in VOC dispersal, and the speed at which highly transmissible variants disseminate through these hubs, even before their detection and characterization through genomic surveillance.

Stress, Anxiety, and Depression in Pre-Clinical Medical Students: Prevalence and Association with Sleep Disorders

Our aim was to assess sleep quality in different subgroups of preclinical medical students, and then to identify specific lifestyle factors, academic and social factors as well as Corona virus related factors that were associated with poor sleeping quality and poor psychological health. Study participants were all medical students at King Saud University of Medical Sciences in the first and second years (648 students), and the study was conducted from December 2021 to January 2022. We administered the survey on paper as well as online. We used three types of questionnaires in this study. The first was a self-administered questionnaire, the second was a validated Insomnia Severity Index (ISI) for finding sleeping problems, and the third was a validated DASS 10 for determining Depression, Anxiety, and Stress. A total of 361 pre-clinical medical students consisted of 146 (40.4%) males and 215 (59.5%) females. The majority of the students, 246 (68.1%), were in their second year. Furthermore, in the current study, students who had poor academic performance (15.8%), satisfactory academic performance (21.3%), or good academic performance (30.7%) had significant sleeping problems found (χ2 = 19.4;p = 0.001), among them poor academic performance students 21.6%, satisfactory academic performance students (29.3%), and good academic performance students (29.3%) had moderate to severe levelled sleeping problems. Similarly, poor, satisfactory, and good academic performers experienced the highest levels of anxiety (poor = 21.5%;satisfactory = 22.1%;and good = 22.8%);stress (poor = 22.4%;satisfactory = 25.2%;and good = 22.4%);and depression (poor = 40.5%;satisfactory = 40.5%;and good = 11.9%). The majority of students (64.8%) reported that during the pandemic crisis their anxiety levels were high. Additionally, students reported significantly high sleeping issues (χ2 = 10.6;p = 0.001) and also serious psychological issues (Anxiety = 34.9 (0.000);Stress = 32.5 (0.000);and Depression = 5.42 (0.01)). There was a high prevalence of sleep issues, anxiety, stress, and depression among the pre-clinical medical students, with significantly higher sleeping disorders, anxiety, stress, and depression levels among those medical students who struggle with their academic performances, poor lifestyle factor, and poor Social and COVID management.

Inferring the true number of SARS-CoV-2 infections in Japan (preprint)

Introduction. In Japan, as of December 31, 2021, more than 1.73 million laboratory-confirmed cases have been reported. However, the actual number of infections is likely to be under-ascertained due to the epidemiological characteristics such as mild and subclinical infections and limited testing availability in the early days of the pandemic. In this study, we infer the true number of infections in Japan between January 16, 2020, and December 31, 2021 , using a statistical modelling framework that combines data on reported cases and fatalities. Methods. We used reported daily COVID-19 deaths stratified into 8 distinct age-groups and age-specific infection fatality ratios (IFR) to impute the true number of infections. Estimates of IFR were informed from published studies as well seroprevalence studies conducted in Japan. To account for the uncertainty in IFR estimates, we sampled values from relevant distributions. Results. We estimated that as of December 31, 2021, 2.90 million (CrI: 1.77 to 4.27 million) people had been infected in Japan, which is 1.68 times higher than the 1.73 million reported cases. Our meta-analysis confirmed that these findings were consistent with the intermittent seroprevalence studies conducted in Japan. Conclusions. We have estimated that a substantial number of COVID-19 infections in the country were unreported, particularly in adults. Our approach provides a more realistic assessment of the true underlying burden of COVID-19. The results of this study can be used as fundamental components to strengthen population health control and surveillance measures.

Regional connectivity drove bidirectional transmission of SARS-CoV-2 in the Middle East during travel restrictions (preprint)

Regional connectivity and land-based travel have been identified as important drivers of SARS-CoV-2 transmission. However, the generalizability of this finding is understudied outside of well-sampled, highly connected regions such as Europe. In this study, we investigated the relative contributions of regional and intercontinental connectivity to the source-sink dynamics of SARS-CoV-2 for Jordan and the wider Middle East. By integrating genomic, epidemiological and travel data we show that the source of introductions into Jordan was dynamic across 2020, shifting from intercontinental seeding from Europe in the early pandemic to more regional seeding for the period travel restrictions were in place. We show that land-based travel, particularly freight transport, drove introduction risk during the period of travel restrictions. Consistently, high regional connectivity and land-based travel also disproportionately drove Jordan's export risk to other Middle Eastern countries. Our findings emphasize regional connectedness and land-based travel as drivers of viral transmission in the Middle East. This demonstrates that strategies aiming to stop or slow the spread of viral introductions (including new variants) with travel restrictions need to prioritize risk from land-based travel alongside intercontinental air travel to be effective.

Context-specific emergence and growth of the SARS-CoV-2 Delta variant (preprint)

The Delta variant of concern of SARS-CoV-2 has spread globally causing large outbreaks and resurgences of COVID-19 cases. The emergence of Delta in the UK occurred on the background of a heterogeneous landscape of immunity and relaxation of non-pharmaceutical interventions. Here we analyse 52,992 Delta genomes from England in combination with 93,649 global genomes to reconstruct the emergence of Delta, and quantify its introduction to and regional dissemination across England, in the context of changing travel and social restrictions. Through analysis of human movement, contact tracing, and virus genomic data, we find that the focus of geographic expansion of Delta shifted from India to a more global pattern in early May 2021. In England, Delta lineages were introduced >1,000 times and spread nationally as non-pharmaceutical interventions were relaxed. We find that hotel quarantine for travellers from India reduced onward transmission from importations; however the transmission chains that later dominated the Delta wave in England had been already seeded before restrictions were introduced. In England, increasing inter- regional travel drove Delta's nationwide dissemination, with some cities receiving >2,000 observable lineage introductions from other regions. Subsequently, increased levels of local population mixing, not the number of importations, was associated with faster relative growth of Delta. Among US states, we find that regions that previously experienced large waves also had faster Delta growth rates, and a model including interactions between immunity and human behaviour could accurately predict the rise of Delta there. Delta's invasion dynamics depended on fine scale spatial heterogeneity in immunity and contact patterns and our findings will inform optimal spatial interventions to reduce transmission of current and future VOCs such as Omicron.

Context-specific emergence and growth of the SARS-CoV-2 Delta variant (preprint)

The Delta variant of concern of SARS-CoV-2 has spread globally causing large outbreaks and resurgences of COVID-19 cases. The emergence of Delta in the UK occurred on the background of a heterogeneous landscape of immunity and relaxation of non-pharmaceutical interventions. Here we analyse 52,992 Delta genomes from England in combination with 93,649 global genomes to reconstruct the emergence of Delta, and quantify its introduction to and regional dissemination across England, in the context of changing travel and social restrictions. Through analysis of human movement, contact tracing, and virus genomic data, we find that the focus of geographic expansion of Delta shifted from India to a more global pattern in early May 2021. In England, Delta lineages were introduced >1,000 times and spread nationally as non-pharmaceutical interventions were relaxed. We find that hotel quarantine for travellers from India reduced onward transmission from importations; however the transmission chains that later dominated the Delta wave in England had been already seeded before restrictions were introduced. In England, increasing inter-regional travel drove Delta's nationwide dissemination, with some cities receiving >2,000 observable lineage introductions from other regions. Subsequently, increased levels of local population mixing, not the number of importations, was associated with faster relative growth of Delta. Among US states, we find that regions that previously experienced large waves also had faster Delta growth rates, and a model including interactions between immunity and human behaviour could accurately predict the rise of Delta there. Delta’s invasion dynamics depended on fine scale spatial heterogeneity in immunity and contact patterns and our findings will inform optimal spatial interventions to reduce transmission of current and future VOCs such as Omicron.

The value of HRCT chest in diagnosis of COVID 19 and its correlation with RT-PCR

Objective: Aim of the study is to correlate CT findings of pulmonary involvement in COVID-19 positive patients with clinical findings and to investigate the role of CT Score in predicting result of patients. Study Design: Single-centered retrospective analysis Place and Duration of Study: The study has been conducted from June to November, 2020. Research has been carried out in District Headquarter Teaching Hospital, Sargodha. Methodology: From June to November 2020, 138 COVID-19 patients who appeared positive for reverse transcriptase polymerase chain reaction were registered for chest CT analysis and clinical examination. Based on the range of lobular involvement quantitative CT scores were considered. Data was correlated with clinical findings.

Travel-driven emergence and spread of SARS-CoV-2 lineage B.1.620 with multiple VOC-like mutations and deletions in Europe (preprint)

Many high-income countries have met the SARS-CoV-2 pandemic with overwhelming sequencing resources and have identified numerous distinct lineages, including some with notably altered biology. Over a year into the pandemic following unprecedented reductions in worldwide human mobility, distinct introduced lineages of SARS-CoV-2 without sequenced antecedents are increasingly discovered in high-income countries as a result of ongoing SARS-CoV-2 genomic surveillance initiatives. We here describe one such SARS-CoV-2 lineage, carrying many mutations and deletions in the spike protein shared with widespread variants of concern (VOCs), including E484K, S477N and deletions HV69del, Y144del, and LLA241/243del. This lineage - designated B.1.620 - is known to circulate in Lithuania and has now been found in several European states, but also in increasing numbers in central Africa owing to important recent increases in genome sequencing efforts on the continent. We provide evidence of likely ongoing local transmission of B.1.620 in Lithuania, France, Germany, Spain, Belgium and the Central African Republic. We describe the suite of mutations this lineage carries, its potential to be resistant to neutralising antibodies, travel histories for a subset of the European cases, and evidence of local B.1.620 transmission in Europe. We make a case for the likely Central African origin of this lineage by providing travel records as well as the outcomes of carefully crafted phylogenetic and phylogeographic inference methodologies, the latter of which is able to exploit individual travel histories recorded for infected travellers having entered different European countries.

Emergence of an early SARS-CoV-2 epidemic in the United States (preprint)

The emergence of the early COVID-19 epidemic in the United States (U.S.) went largely undetected, due to a lack of adequate testing and mitigation efforts. The city of New Orleans, Louisiana experienced one of the earliest and fastest accelerating outbreaks, coinciding with the annual Mardi Gras festival, which went ahead without precautions. To gain insight into the emergence of SARS-CoV-2 in the U.S. and how large, crowded events may have accelerated early transmission, we sequenced SARS-CoV-2 genomes during the first wave of the COVID-19 epidemic in Louisiana. We show that SARS-CoV-2 in Louisiana initially had limited sequence diversity compared to other U.S. states, and that one successful introduction of SARS-CoV-2 led to almost all of the early SARS-CoV-2 transmission in Louisiana. By analyzing mobility and genomic data, we show that SARS-CoV-2 was already present in New Orleans before Mardi Gras and that the festival dramatically accelerated transmission, eventually leading to secondary localized COVID-19 epidemics throughout the Southern U.S.. Our study provides an understanding of how superspreading during large-scale events played a key role during the early outbreak in the U.S. and can greatly accelerate COVID-19 epidemics on a local and regional scale.

Establishment & lineage dynamics of the SARS-CoV-2 epidemic in the UK (preprint)

The UK's COVID-19 epidemic during early 2020 was one of world's largest and unusually well represented by virus genomic sampling. Here we reveal the fine-scale genetic lineage structure of this epidemic through analysis of 50,887 SARS-CoV-2 genomes, including 26,181 from the UK sampled throughout the country's first wave of infection. Using large-scale phylogenetic analyses, combined with epidemiological and travel data, we quantify the size, spatio-temporal origins and persistence of genetically-distinct UK transmission lineages. Rapid fluctuations in virus importation rates resulted in >1000 lineages; those introduced prior to national lockdown were larger and more dispersed. Lineage importation and regional lineage diversity declined after lockdown, whilst lineage elimination was size-dependent. We discuss the implications of our genetic perspective on transmission dynamics for COVID-19 epidemiology and control.

Host transcriptional responses and SARS-CoV-2 isolates from the nasopharyngeal samples of Bangladeshi COVID-19 patients (preprint)

As the COVID-19 pandemic progresses, fatality and cases of new infections are also increasing at an alarming rate. SARS-CoV-2 follows a highly variable course and it is becoming more evident that individuals immune system has a decisive influence on the progression of the disease. However, the detailed underlying molecular mechanisms of the SARS-CoV-2 mediate disease pathogenesis are largely unknown. Only a few host transcriptional responses in COVID-19 have been reported so far from the Western world, but no such data has been generated from the South-Asian region yet to correlate the conjectured lower fatality around this part of the globe. In this context, we aimed to perform the transcriptomic profiling of the COVID-19 patients from Bangladesh along with the reporting of the SARS-CoV-2 isolates from these patients. Moreover, we performed a comparative analysis to demonstrate how differently the various SARS-CoV-2 infection systems are responding to the viral pathogen. We detected a unique missense mutation at 10329 position of ORF1ab gene, annotated to 3C like proteinase, which is found in 75% of our analyzed isolates; but is very rare globally. Upon the functional enrichment analyses of differentially modulated genes, we detected a similar host induced response reported earlier; this response was mainly mediated by the innate immune system, interferon stimulation, and upregulated cytokine expression etc. in the Bangladeshi patients. Surprisingly, we did not perceive the induction of apoptotic signaling, phagosome formation, antigen presentation and production, hypoxia response within these nasopharyngeal samples. Furthermore, while comparing with the other SARS-CoV-2 infection systems, we spotted that lung cells trigger the more versatile immune and cytokine signaling which was several folds higher compared to our reported nasopharyngeal samples. We also observed that lung cells did not express ACE2 in a very high amount as suspected, however, the nasopharyngeal cells are found overexpressing ACE2. But the amount of DPP4 expression within the nasal samples was significantly lower compared to the other cell types. Surprisingly, we observed that lung cells express a very high amount of integrins compared to the nasopharyngeal samples, which might suggest the putative reasons for an increased amount of viral infections in the lungs. From the network analysis, we got clues on the probable viral modulation for the overexpression of these integrins. Our data will provide valuable insights in developing potential studies to elucidate the roles of ethnicity effect on the viral pathogenesis, and incorporation of further data will enrich the search of an effective therapeutics.

Perversely expressed long noncoding RNAs can alter host response and viral proliferation in SARS-CoV-2 infection (preprint)

BackgroundSince December 2019, the world is experiencing an unprecedented crisis due to a novel coronavirus, SARS-CoV-2. Owing to poor understanding of pathogenicity, the virus is eluding treatment and complicating recovery. Regulatory roles of long non-coding RNAs (lncRNAs) during viral infection and associated antagonism of host antiviral immune responses has become more evident in last decade. To elucidate possible functions of lncRNAs in the COVID-19 pathobiology, we have utilized RNA-seq dataset of SARS-CoV-2 infected lung epithelial cells. ResultsOur analyses uncover 21 differentially expressed lncRNAs whose functions are broadly involved in cell survival and regulation of gene expression. By network enrichment analysis we find that these lncRNAs can directly interact with differentially expressed protein-coding genes ADAR, EDN1, KYNU, MALL, TLR2 and YWHAG; and also AKAP8L, EXOSC5, GDF15, HECTD1, LARP4B, LARP7, MIPOL1, UPF1, MOV10 and PRKAR2A, host genes that interact with SARS-CoV-2 proteins. These genes are involved in cellular signaling, metabolism, immune response and RNA homeostasis. Since lncRNAs have been known to sponge microRNAs and protect expression of upregulated genes, we also identified 9 microRNAs that are induced in viral infections; however, some lncRNAs are able to block their usual suppressive effect on overexpressed genes and consequently contribute to host defense and cell survival. ConclusionsOur investigation determines that deregulated lncRNAs in SARS-CoV-2 infection are involved in viral proliferation, cellular survival, and immune response, ultimately determining disease outcome and this information could drive the search for novel RNA therapeutics as a treatment option.

SARS-CoV-2 mutations altering regulatory properties: deciphering host's and virus's perspectives (preprint)

Since the first recorded case of the SARS-CoV-2, it has acquired several mutations in its genome while spreading throughout the globe. However, apart from some changes in protein coding, functional importance of these mutations in disease pathophysiology are still largely unknown. In this study, we investigated the significance of these mutations both from the hosts and viruss perspective by analyzing the host miRNA binding and viruss internal ribosome entry site (IRES), respectively. Strikingly, we observed that due to the acquired mutations, host miRNAs bind differently compared to the reference; where few of the miRNAs lost and few gained the binding affinity for targeting the viral genome. Moreover, functional enrichment analysis suggests that targets of both of these gained and lost miRNAs might be involved in various host immune signaling pathways. Also, we sought to shed some insights on the impacts of mutations on the IRES structure of SARS-CoV-2. Remarkably, we detected that three particular mutations in the IRES can disrupt its secondary structure which can further make the virus less functional. These results could be valuable in exploring the functional importance of the mutations of SARS-CoV-2 and could provide novel insights into the differences observed different parts of the world.

SARS-CoV-2 proteins exploit host's genetic and epigenetic mediators for the annexation of key host signaling pathways that confers its immune evasion and disease pathophysiology (preprint)

The constant rise of the death toll and cases of COVID-19 has made this pandemic a serious threat to human civilization. Understanding of host-SARS-CoV-2 interaction in viral pathogenesis is still in its infancy. In this study we aimed to correlate how SARS-CoV-2 utilizes its proteins for tackling the host immune response; parallelly, how host epigenetic factors might play a role in this pathogenesis was also investigated. We have utilized a blend of computational and knowledgebase approach to elucidate the interplay between host and SARS-CoV-2. Integrating the experimentally validated host interactome proteins and differentially expressed host genes due to SARS-CoV-2 infection, we have taken a blend of computational and knowledgebase approach to delineate the interplay between host and SARS-CoV-2 in various signaling pathways. Also, we have shown how host epigenetic factors are involved in the deregulation of gene expression. Strikingly, we have found that several transcription factors and other epigenetic factors can modulate some immune signaling pathways, helping both host and virus. We have identified miRNA hsa-miR-429 whose transcription factor was also upregulated and targets were downregulated and this miRNA can have pivotal role in suppression of host immune responses. While searching for the pathways in which viral proteins interact with host proteins, we have found pathways like-HIF-1 signaling, autophagy, RIG-I signaling, Toll-like receptor signaling, Fatty acid oxidation/degradation, Il-17 signaling etc significantly associated. We observed that these pathways can be either hijacked or suppressed by the viral proteins, leading to the improved viral survival and life-cycle. Moreover, pathways like-Relaxin signaling in lungs suggests aberration by the viral proteins might lead to the lung pathophysiology found in COVID-19. Also, enrichment analyses suggest that deregulated genes in SARS-CoV-2 infection are involved in heart development, kidney development, AGE-RAGE signaling pathway in diabetic complications etc. might suggest why patients with comorbidities are becoming more prone to SARS-CoV-2 infection. Our results suggest that SARS-CoV-2 integrates its proteins in different immune signaling pathway and other cellular signaling pathways for developing efficient immune evasion mechanisms, while leading the host to more complicated disease condition. Our findings would help in designing more targeted therapeutic interventions against SARS-CoV-2.

Epigenetic regulator miRNA pattern differences among SARS-CoV, SARS-CoV-2 and SARS-CoV-2 world-wide isolates delineated the mystery behind the epic pathogenicity and distinct clinical characteristics of pandemic COVID-19 (preprint)

Detailed molecular mechanism of SARS-CoV-2 pathogenesis is still elusive to address its deadlier nature and to design effective theraputics. Here, we present our study elucidating the interplay between the SARS-CoV and SARS-CoV-2 viruses; and hosts miRNAs, an epigenetic regulator, as a mode of pathogenesis, and enlightened how the SARS-CoV and SARS-CoV-2 infections differ in terms of their miRNA mediated interactions with host and its implications in the disease complexity. We have utilized computational approaches to predict potential host and viral miRNAs, and their possible roles in different important functional pathways. We have identified several putative host antiviral miRNAs that can target the SARS viruses, and also SARS viruses encoded miRNAs targeting host genes. In silico predicted targets were also integrated with SARS infected human cells microarray and RNA-seq gene expression data. Comparison of the host miRNA binding profiles on 67 different SARS-CoV-2 genomes from 24 different countries with respective countrys normalized death count surprisingly uncovered some miRNA clusters which are associated with increased death rates. We have found that induced cellular miRNAs can be both a boon and a bane to the host immunity, as they have possible roles in neutralizing the viral threat, parallelly, they can also function as proviral factors. On the other hand, from over representation analysis, interestingly our study revealed that although both SARS-CoV and SARS-CoV-2 viral miRNAs could target broad immune signaling pathways; only some of the SARS-CoV-2 miRNAs are found to uniquely target some immune signaling pathways like-autophagy, IFN-I signaling etc, which might suggest their immune-escape mechanisms for prolonged latency inside some hosts without any symptoms of COVID-19. Further, SARS-CoV-2 can modulate several important cellular pathways which might lead to the increased anomalies in patients with comorbidities like-cardiovascular diseases, diabetes, breathing complications, etc. This might suggest that miRNAs can be a key epigenetic modulator behind the overcomplications amongst the COVID-19 patients. Our results support that miRNAs of host and SARS-CoV-2 can indeed play a role in the pathogenesis which can be further concluded with more experiments. These results will also be useful in designing RNA therapeutics to alleviate the complications from COVID-19.

Lung biopsy cells transcriptional landscape from COVID-19 patient stratified lung injury in SARS-CoV-2 infection through impaired pulmonary surfactant metabolism (preprint)

Clinical management of COVID-19 is still complicated due to the lack of therapeutic interventions to reduce the breathing problems, respiratory complications and acute lung injury - which are the major complications of most of the mild to critically affected patients and the molecular mechanisms behind these clinical features are still largely unknown. In this study, we have used the RNA-seq gene expression pattern in the COVID-19 affected lung biopsy cells and compared it with the effects observed in typical cell lines infected with SARS-CoV-2 and SARS-CoV. We performed functional overrepresentation analyses using these differentially expressed genes to signify the processes/pathways which could be deregulated during SARS-CoV-2 infection resulting in the symptomatic impairments observed in COVID-19. Our results showed that the significantly altered processes include inflammatory responses, antiviral cytokine signaling, interferon responses, and interleukin signaling etc. along with downmodulated processes related to lungs functionality like-responses to hypoxia, lung development, respiratory processes, cholesterol biosynthesis and surfactant metabolism. We also found that the viral protein interacting hosts proteins involved in similar pathways like: respiratory failure, lung diseases, asthma, and hypoxia responses etc., suggesting viral proteins might be deregulating the processes related to acute lung injury/breathing complications in COVID-19 patients. Protein-protein interaction networks of these processes and map of gene expression of deregulated genes revealed that several viral proteins can directly or indirectly modulate the host genes/proteins of those lung related processes along with several host transcription factors and miRNAs. Surfactant proteins and their regulators SPD, SPC, TTF1 etc. which maintains the stability of the pulmonary tissue are found to be downregulated through viral NSP5, NSP12 that could lead to deficient gaseous exchange by the surface films. Mitochondrial dysfunction owing to the aberration of NDUFA10, NDUFAF5, SAMM50 etc. by NSP12; abnormal thrombosis in lungs through atypical PLAT, EGR1 functions by viral ORF8, NSP12; dulled hypoxia responses due to unusual shift in HIF-1 downstream signaling might be the causative elements behind the acute lung injury in COVID-19 patients. Our study put forward a distinct mechanism of probable virus induced lung damage apart from cytokine storm and advocate the need of further research for alternate therapy in this direction.

Global trends in air travel: implications for connectivity and resilience to infectious disease threats (preprint)

Background: Increased connectivity via air travel can facilitate the geographic spread of infectious diseases. The number of travelers alone does not explain risk; passenger origin and destination will also influence risk of disease introduction and spread. We described trends in international air passenger numbers and connectivity between countries with different capacities to detect and respond to infectious disease threats. Methods: We used the Fragile States Index (FSI) as an annual measure of country-level resilience and capacity to respond to infectious disease events. Countries are categorized as: Sustainable, Stable, Warning, or Alert, in order of increasing fragility. We included data for 177 sovereign states for the years 2007 to 2016. Annual inbound and outbound international air passengers for each country were obtained for the same time period. We examined trends in FSI score, trends in worldwide air travel, and the association between a state's FSI score and air travel. Results: Among countries included in the FSI rankings, the total number of passengers increased from 0.791 billion to 1.28 billion between 2007 and 2016. Increasing fragility was associated with a decrease in travel volumes, with a 2.9% (95% CI: 2.3-3.5%) reduction in passengers per 1-unit increase in FSI score. Overall, travel between countries of different FSI categories either increased or remained stable. The greatest increase was observed for travel to Warning countries from Warning countries, with an annual increase of 8,967,623 passengers (95%CI: 6,546,494 to 11,388,753) over the study period. Conclusions: The world's connectivity via air travel has increased dramatically over the past decade. There has been notable growth in travel from Warning and Stable countries, which comprise more than three-quarters of international air travel passengers. These countries may have suboptimal capacity to detect and respond to infectious disease threats that emerge within their borders.