title: Human adenovirus among hospitalized children with respiratory tract infections in Beijing, China, 2017–2018

text: BACKGROUND: Human adenoviruses (HAdVs) cause a wide range of diseases. However, the genotype diversity and epidemiological information relating to HAdVs among hospitalized children with respiratory tract infections (RTIs) is limited. Here, we describe the epidemiology and genotype distribution of HAdVs associated with RTIs in Beijing, China. METHODS: Nasopharyngeal aspirates (NPA) were collected from hospitalized children with RTIs from April 2017 to March 2018. HAdVs were detected by a TaqMan-based quantitative real-time polymerase chain reaction (qPCR) assay, and the hexon gene was used for phylogenetic analysis. Epidemiological data were analyzed using statistical product and service solutions (SPSS) 21.0 software. RESULTS: HAdV was detected in 72 (5.64%) of the 1276 NPA specimens, with most (86.11%, 62/72) HAdV-positives cases detected among children < 6 years of age. HAdV-B3 (56.06%, 37/66) and HAdV-C2 (19.70%, 13/66) were the most frequent. Of the 72 HAdV-infected cases, 27 (37.50%) were co-infected with other respiratory viruses, most commonly parainfluenza virus (12.50%, 9/72) and rhinovirus (9.72%, 7/72). The log number of viral load ranged from 3.30 to 9.14 copies per mL of NPA, with no significant difference between the HAdV mono- and co-infection groups. The main clinical symptoms in the HAdV-infected patients were fever and cough, and 62 (86.11%, 62/72) were diagnosed with pneumonia. Additionally, HAdVs were detected throughout the year with a higher prevalence in summer. CONCLUSIONS: HAdV prevalence is related to age and season. HAdV-B and HAdV-C circulated simultaneously among the hospitalized children with RTIs in Beijing, and HAdV-B type 3 and HAdV-C type 2 were the most frequent.


title: Dynamic Transmission Modeling: A Report of the ISPOR-SMDM Modeling Good Research Practices Task Force-5

text: Abstract The transmissible nature of communicable diseases is what sets them apart from other diseases modeled by health economists. The probability of a susceptible individual becoming infected at any one point in time (the force of infection) is related to the number of infectious individuals in the population, will change over time, and will feed back into the future force of infection. These nonlinear interactions produce transmission dynamics that require specific consideration when modeling an intervention that has an impact on the transmission of a pathogen. Best practices for designing and building these models are set out in this article.


title: Non-coding yet non-trivial: a review on the computational genomics of lincRNAs

text: Long intergenic non-coding RNAs (lincRNAs) represent one of the most mysterious RNA species encoded by the human genome. Thanks to next generation sequencing (NGS) technology and its applications, we have recently witnessed a surge in non-coding RNA research, including lincRNA research. Here, we summarize the recent advancement in genomics studies of lincRNAs. We review the emerging characteristics of lincRNAs, the experimental and computational approaches to identify lincRNAs, their known mechanisms of regulation, the computational methods and resources for lincRNA functional predictions, and discuss the challenges to understanding lincRNA comprehensively.


Margaret Chan: committed to universal health coverage


title: Structure of the haemagglutinin-esterase-fusion glycoprotein of influenza C virus

text: The spike glycoproteins of the lipid-enveloped orthomyxoviruses and paramyxoviruses have three functions: to recognize the receptor on the cell surface, to mediate viral fusion with the cell membrane, and to destroy the receptor. In influenza C virus, a single glycoprotein, the haemagglutinin-esterase-fusion (HEF) protein, possesses all three functions (reviewed in ref. 1). In influenza A and B, the first two activities are mediated by haemagglutinin and the third by a second glycoprotein, neuraminidase. Here we report the crystal structure of the HEF envelope glycoprotein of influenza C virus. We have identified the receptor-binding site and the receptor-destroying enzyme (9-O -acetylesterase) sites, by using receptor analogues. The receptor-binding domain is structurally similar to the sialic acid-binding domain of influenza A haemagglutinin, but binds 9-O -acetylsialic acid. The esterase domain has a structure similar to the esterase from Streptomyces scabies and a brain acetylhydrolase(2),(3). The receptor domain is inserted into a surface loop of the esterase domain and the esterase domain is inserted into a surface loop of the stem. The stem domain is similar to that of influenza A haemagglutinin, except that the triple-stranded, α-helical bundle diverges at both of its ends, and the amino terminus of HEF2, the fusion peptide, is partially exposed. The segregation of HEF's three functions into structurally distinct domains suggests that the entire stem region, including sequences at the amino and carboxy termini of HEF1 which precede the post-translational cleavage site between HEF1 and HEF2, forms an independent fusion domain which is probably derived from an ancestral membrane fusion protein.


title: The Role of Human Coronaviruses in Children Hospitalized for Acute Bronchiolitis, Acute Gastroenteritis, and Febrile Seizures: A 2-Year Prospective Study

text: Human coronaviruses (HCoVs) are associated with a variety of clinical presentations in children, but their role in disease remains uncertain. The objective of our prospective study was to investigate HCoVs associations with various clinical presentations in hospitalized children up to 6 years of age. Children hospitalized with acute bronchiolitis (AB), acute gastroenteritis (AGE), or febrile seizures (FS), and children admitted for elective surgical procedures (healthy controls) were included in the study. In patients with AB, AGE, and FS, a nasopharyngeal (NP) swab and blood sample were obtained upon admission and the follow-up visit 14 days later, whereas in children with AGE a stool sample was also acquired upon admission; in healthy controls a NP swab and stool sample were taken upon admission. Amplification of polymerase 1b gene was used to detect HCoVs in the specimens. HCoVs-positive specimens were also examined for the presence of several other viruses. HCoVs were most often detected in children with FS (19/192, 9.9%, 95% CI: 6–15%), followed by children with AGE (19/218, 8.7%, 95% CI: 5.3–13.3%) and AB (20/308, 6.5%, 95% CI: 4.0–9.8%). The presence of other viruses was a common finding, most frequent in the group of children with AB (19/20, 95%, 95% CI: 75.1–99.8%), followed by FS (10/19, 52.6%, 95% CI: 28.9–75.6%) and AGE (7/19, 36.8%, 95% CI: 16.3–61.6%). In healthy control children HCoVs were detected in 3/156 (1.9%, 95% CI: 0.4–5.5%) NP swabs and 1/150 (0.7%, 95% CI: 0.02–3.3%) stool samples. It seems that an etiological role of HCoVs is most likely in children with FS, considering that they had a higher proportion of positive HCoVs results than patients with AB and those with AGE, and had the highest viral load; however, the co-detection of other viruses was 52.6%. Trial Registration: ClinicalTrials.gov NCT00987519


title: Effects of extremely low frequency electromagnetic fields (100μT) on behaviors in rats

text: Abstract Recently, extremely low frequency electromagnetic fields (ELF-EMF) have received considerable attentions for their potential pathogenicity. In the present study, we explored the effects of ELF-EMF on behaviors of adult male rats. Sixty adult male rats were randomly divided into two groups, the sham exposure group and the 50Hz/100μT ELF-EMF exposure group. During the 24 weeks exposure, body weight, as well as food and water intake were recorded. Results showed that food and water intake and the body weight of the rats were not affected by the exposure. After 24 weeks exposure, open field test and elevated plus maze were conducted to evaluate the anxiety-like behavior, the tail suspension test and forced swim test were conducted to evaluate depression-like behavior and Morris water maze and fear conditioning tests were used to evaluate the cognitive and memory ability. Exposure to ELF-EMF did not induce any anxiety-like or depression-like behaviors compared with the sham exposure. Moreover, the cognitive and memory ability was not impaired by the ELF-EMF exposure. Furthermore, ELF-EMF exposure did not affect the morphology and histology of the brain. In conclusion, 24 weeks exposure to 50Hz/100μT ELF-EMF had no effect on the behaviors of the adult male rats.


title: A DNA vaccine producing LcrV antigen in oligomers is effective in protecting mice from lethal mucosal challenge of plague

text: There is an urgent need to develop effective vaccines against pneumonic plague, a highly lethal and contagious disease caused by the Gram-negative bacterium Yersinia pestis. Here we demonstrate that a novel DNA vaccine expressing a modified V antigen (LcrV) of Y. pestis, with a human tissue plasminogen activator (tPA) signal sequence, elicited strong V-specific antibody responses in BALB/c mice. This tPA-V DNA vaccine protected mice from intranasal challenge with lethal doses of Y. pestis. In comparison, a DNA vaccine expressing the wild type V antigen was much less effective. Only tPA-V formed oligomers spontaneously, and elicited a higher IgG2a anti-V antibody response in immunized mice, suggesting increased T(H)1 type cellular immune response. Our data indicate that antigen engineering is effective in inducing high quality protective immune responses against conformationally sensitive antigens. These results support that optimized DNA vaccines have the potential to protect against bacterial pathogens than is generally recognized.


Impact of SARS-CoV-2 on a high volume endoscopy centre in Italy


Single-copy sensitive, field-deployable, and simultaneous dual-gene detection of SARS-CoV-2 RNA via modified RT–RPA


title: Ribosome profiling of the retrovirus murine leukemia virus

text: BACKGROUND: The retrovirus murine leukemia virus (MuLV) has an 8.3 kb RNA genome with a simple 5′-gag-pol-env-3′ architecture. Translation of the pol gene is dependent upon readthrough of the gag UAG stop codon; whereas the env gene is translated from spliced mRNA transcripts. Here, we report the first high resolution analysis of retrovirus gene expression through tandem ribosome profiling (RiboSeq) and RNA sequencing (RNASeq) of MuLV-infected cells. RESULTS: Ribosome profiling of MuLV-infected cells was performed, using the translational inhibitors harringtonine and cycloheximide to distinguish initiating and elongating ribosomes, respectively. Meta-analyses of host cell gene expression demonstrated that the RiboSeq datasets specifically captured the footprints of translating ribosomes at high resolution. Direct measurement of ribosomal occupancy of the MuLV genomic RNA indicated that ~ 7% of ribosomes undergo gag stop codon readthrough to access the pol gene. Initiation of translation was found to occur at several additional sites within the 5′ leaders of the gag and env transcripts, upstream of their respective annotated start codons. CONCLUSIONS: These experiments reveal the existence of a number of previously uncharacterised, ribosomally occupied open reading frames within the MuLV genome, with possible regulatory consequences. In addition, we provide the first direct measurements of stop codon readthrough efficiency during cellular infection. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12977-018-0394-5) contains supplementary material, which is available to authorized users.


title: “Right-to-Try” experimental drugs: an overview

text: The “Right-to-Try” experimental drugs act passed by Donald Trump in 2018 provides an opportunity of early access to experimental drugs for the treatment of life-threatening diseases and a potential boon to many young and under-capitalized biotechnology or pharmaceutical companies. The pros and cons of experimental drugs, including a number of “cutting edge” scientific, clinical, and a number of synergistic approaches such as artificial intelligence, machine learning, big data, data refineries, electronic health records, data driven clinical decisions and risk mitigation are reviewed.


Discovery of T-Cell Infection and Apoptosis by Middle East Respiratory Syndrome Coronavirus


Stress-Only CMR


title: Pediatricians are ready for COVID‐19 and other emergencies

text: In January — just as COVID‐19 was on the verge of being a worldwide pandemic — the American Academy of Pediatrics (AAP) and emergency medicine associations released a joint policy statement, “Pediatric Readiness in Emergency Medical Services Systems,” designed to bolster the emergency medical system so that children are well cared for.


title: The effect of porcine epidemic diarrhea (PED) on ovarian function and reproductive performance after weaning in Berkshire sows

text: The purpose of this study was to investigate the ovarian condition at weaning and subsequent reproductive performance of Berkshire sows following an outbreak of PED. This study was conducted on a farrow-to-finish farm that experienced a PED outbreak beginning on January 6, 2014. Blood samples were collected at weaning from 19 to 20 sows every month from July 2013 until July 2014 to investigate the ovarian condition. The mean progesterone concentration was numerically higher during January 2014 than the other months, but this difference was not significant. The mean estradiol-17β concentration was higher during January 2014 than during July and October 2013 (P < 0.05). In addition, reproductive performance was compared during January, February, and March before (2013) and after (2014) the PED outbreak. Sows that farrowed in January had higher preweaning mortality in 2014 than in 2013 (P < 0.05), but sows that farrowed in February and March had similar preweaning mortality in 2013 and 2014 (P > 0.10). Sows that farrowed between January and March 2014 had 15% lower farrowing rate than those that farrowed during the same months in 2013 (P < 0.05). In conclusion, our results demonstrate poorer reproductive performance of Berkshire sows after a PED outbreak compared with before the outbreak.


title: Single-cell transcriptomic analysis of SARS-CoV-2 reactive CD4+ T cells

text: The contribution of CD4+ T cells to protective or pathogenic immune responses to SARS-CoV-2 infection remains unknown. Here, we present large-scale single-cell transcriptomic analysis of viral antigen-reactive CD4+ T cells from 32 COVID-19 patients. In patients with severe disease compared to mild disease, we found increased proportions of cytotoxic follicular helper (TFH) cells and cytotoxic T helper cells (CD4-CTLs) responding to SARS-CoV-2, and reduced proportion of SARS-CoV-2 reactive regulatory T cells. Importantly, the CD4-CTLs were highly enriched for the expression of transcripts encoding chemokines that are involved in the recruitment of myeloid cells and dendritic cells to the sites of viral infection. Polyfunctional T helper (TH)1 cells and TH17 cell subsets were underrepresented in the repertoire of SARS-CoV-2-reactive CD4+ T cells compared to influenza-reactive CD4+ T cells. Together, our analyses provide so far unprecedented insights into the gene expression patterns of SARS-CoV-2 reactive CD4+ T cells in distinct disease severities.


title: Lockdown for COVID-19 and its impact on pupil mobility in India: an analysis of the COVID-19 Community Mobility Reports, 2020

text: BACKGROUND: Coronavirus disease is a novel public health problem threatening the whole world. As an upshot, countrywide lockdown due to COVID-19 pandemic has been supportive of changing community mobility trends of various place categories including retail and recreation, groceries and pharmacies, parks, transit stations, workplaces, and residential in India. OBJECTIVE: To analyze the impact of lockdown for COVID-19 on community mobility using spatial time-series change over different states and UTs of India. Data & Methods This study has been organized based on states & union territories (UTs) wise time-series data of the daily percentage of change of community mobility from baseline in India, collected from 15(th) February to 30(th) April 2020. Conditional formatting techniques, time-series trends plotting method, spatial Inverse distance weighted (IDW) interpolation mapping techniques have been employed to show pre and post lockdown mobility trends due to COVID-19 i.e. to fulfill the objective. RESULTS: Across India, retail and recreation, grocery and pharmacy, visits to parks, transit stations, and workplaces mobility dropped by -73.4%, -51.2%, -46.3%, -66% and -56.7% respectively. Visits to residential places mobility increased by 23.8% as people mostly stayed home during the lockdown. the COVID-19 lockdown started on 24 March 2020 and just gone one day (March 25, 2020) of the beginning of lockdown, there have a decreased in percentage (-70.51% in retail and recreation mobility), (-64.26% in grocery and pharmacy mobility), (-46.17% in parks mobility), (-65.6% in transit stations mobility), (-60.03% in workplaces mobility) from baseline in compared to the pre-lockdown period and residential mobility has been increased in percentage (26.32%) from baseline due to people stayed home during the lockdown for COVID-19 pandemic in India CONCLUSION: Study figures out mobility trends over time during pre-lockdown and after lockdown period across different categories of places such as retail and recreation, groceries and pharmacies, parks, transit stations, workplaces, and residential, which can be used in public health strategies to drop the spread of COVID-19.


title: Quantification of the Middle East Respiratory Syndrome-Coronavirus RNA in Tissues by Quantitative Real-Time RT-PCR

text: Since the emergence of the Middle East respiratory syndrome-coronavirus (MERS-CoV) in 2012, more than 2280 confirmed human infections and 800 associated deaths had been reported to the World Health Organization. MERS-CoV is a single-stranded RNA virus that belongs to the Coronaviridae family. MERS-CoV infection leads to a variety of clinical outcomes in humans ranging from asymptomatic and mild infection to severe acute lung injury and multi-organ failure and death. To study the pathogenesis of MERS-CoV infection and development of medical countermeasures (MCMs) for MERS, a number of genetically modified mouse models have been developed, including various versions of transgenic mice expressing the human DPP4 viral receptor. Tracking and quantifying viral infection, among others, in permissive hosts is a key endpoint for studying MERS pathogenesis and evaluating the efficacy of selected MCMs developed for MERS. In addition to quantifying infectious progeny virus which requires high-containment biosafety level (BSL)-3 laboratory, here we outlined an established real-time quantitative RT-PCR (RT-qPCR)-based procedure to unequivocally quantify MERS-CoV-specific RNAs within the lungs of infected human DPP4 (hDPP4, transgenic (hDPP4 Tg) mice under a standard BSL-2 laboratory.


title: COVID-19 pathophysiology: A review

text: Abstract In December 2019, a novel coronavirus, now named as SARS-CoV-2, caused a series of acute atypical respiratory diseases in Wuhan, Hubei Province, China. The disease caused by this virus was termed COVID-19. The virus is transmittable between humans and has caused pandemic worldwide. The number of death tolls continues to rise and a large number of countries have been forced to do social distancing and lockdown. Lack of targeted therapy continues to be a problem. Epidemiological studies showed that elder patients were more susceptible to severe diseases, while children tend to have milder symptoms. Here we reviewed the current knowledge about this disease and considered the potential explanation of the different symptomatology between children and adults.


title: Chapter 6 Developing a Framework for Investor Analysis of Hedge Fund Governance

text: Abstract This chapter provides an investor framework for analyzing hedge fund governance. It discusses the relationship between the increased focus on operational due diligence and governance. The efforts of institutional investors such as the California Public Employees’ Retirement System (“CalPERS”) in promoting governance analysis are discussed. This chapter also outlines techniques for performing due diligence on fund directors including interview techniques and background investigations. Other topics covered in this chapter include the relationship of separately managed accounts with investor governance analysis and governance considerations for investor financial statement analysis.


title: Arf Family G Proteins and their regulators: roles in membrane transport, development and disease

text: Members of the ADP-ribosylation factor (ARF) family of guanine-nucleotide-binding (G) proteins, including the ARF-like (ARL) proteins and SAR1, regulate membrane traffic and organelle structure by recruiting cargo-sorting coat proteins, modulating membrane lipid composition, and interacting with regulators of other G proteins. New roles of ARF and ARL proteins are emerging, including novel functions at the Golgi complex and in cilia formation. Their function is under tight spatial control, which is mediated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) that catalyse GTP exchange and hydrolysis, respectively. Important advances are being gained in our understanding of the functional networks that are formed not only by the GEFs and GAPs themselves but also by the inactive forms of the ARF proteins.


title: A planarian nidovirus expands the limits of RNA genome size

text: RNA viruses are the only known RNA-protein (RNP) entities capable of autonomous replication (albeit within a permissive host environment). A 33.5 kilobase (kb) nidovirus has been considered close to the upper size limit for such entities; conversely, the minimal cellular DNA genome is in the 100–300 kb range. This large difference presents a daunting gap for the transition from primordial RNP to contemporary DNA-RNP-based life. Whether or not RNA viruses represent transitional steps towards DNA-based life, studies of larger RNA viruses advance our understanding of the size constraints on RNP entities and the role of genome size in virus adaptation. For example, emergence of the largest previously known RNA genomes (20–34 kb in positive-stranded nidoviruses, including coronaviruses) is associated with the acquisition of a proofreading exoribonuclease (ExoN) encoded in the open reading frame 1b (ORF1b) in a monophyletic subset of nidoviruses. However, apparent constraints on the size of ORF1b, which encodes this and other key replicative enzymes, have been hypothesized to limit further expansion of these viral RNA genomes. Here, we characterize a novel nidovirus (planarian secretory cell nidovirus; PSCNV) whose disproportionately large ORF1b-like region including unannotated domains, and overall 41.1-kb genome, substantially extend the presumed limits on RNA genome size. This genome encodes a predicted 13,556-aa polyprotein in an unconventional single ORF, yet retains canonical nidoviral genome organization and expression, as well as key replicative domains. These domains may include functionally relevant substitutions rarely or never before observed in highly conserved sites of RdRp, NiRAN, ExoN and 3CLpro. Our evolutionary analysis suggests that PSCNV diverged early from multi-ORF nidoviruses, and acquired additional genes, including those typical of large DNA viruses or hosts, e.g. Ankyrin and Fibronectin type II, which might modulate virus-host interactions. PSCNV's greatly expanded genome, proteomic complexity, and unique features–impressive in themselves–attest to the likelihood of still-larger RNA genomes awaiting discovery.


title: Rapid Multiplex Testing for Upper Respiratory Pathogens in the Emergency Department: A Randomized Controlled Trial

text: BACKGROUND: Acute upper respiratory tract infections are a common cause of emergency department (ED) visits and often result in unnecessary antibiotic treatment. METHODS: We conducted a randomized clinical trial to evaluate the impact of a rapid, multipathogen respiratory panel (RP) test vs usual care (control). Patients were eligible if they were ≥12 months old, had symptoms of upper respiratory infection or influenza-like illness, and were not on antibiotics. The primary outcome was antibiotic prescription; secondary outcomes included antiviral prescription, disposition, and length of stay (ClinicalTrials.gov# NCT02957136). RESULTS: Of 191 patients enrolled, 93 (49%) received RP testing; 98 (51%) received usual care. Fifty-three (57%) RP and 7 (7%) control patients had a virus detected and reported during the ED visit (P = .0001). Twenty (22%) RP patients and 33 (34%) usual care patients received antibiotics during the ED visit (–12%; 95% confidence interval, –25% to 0.4%; P = .06/0.08); 9 RP patients received antibiotics despite having a virus detected. The magnitude of antibiotic reduction was greater in children (–19%) vs adults (–9%, post hoc analysis). There was no difference in antiviral use, length of stay, or disposition. CONCLUSIONS: Rapid RP testing was associated with a trend toward decreased antibiotic use, suggesting a potential benefit from more rapid viral tests in the ED. Future studies should determine if specific groups are more likely to benefit from testing and evaluate the relative cost and effectiveness of broad testing, focused testing, and a combined diagnostic and antimicrobial stewardship approach.


title: Comparison of risk factors for seropositivity to feline immunodeficiency virus and feline leukemia virus among cats: a case-case study

text: BACKGROUND: Feline immunodeficiency virus (FIV) and feline leukemia virus (FeLV) are reported to have similar risk factors and similar recommendations apply to manage infected cats. However, some contrasting evidence exists in the literature with regard to commonly reported risk factors. In this study, we investigated whether the known risk factors for FIV and FeLV infections have a stronger effect for either infection. This retrospective study included samples from 696 cats seropositive for FIV and 593 cats seropositive for FeLV from the United States and Canada. Data were collected during two cross sectional studies, where cats were tested using IDEXX FIV/FeLV ELISA kits. To compare the effect of known risk factors for FIV infection compared to FeLV, using a case-case study design, random intercept logistic regression models were fit including cats’ age, sex, neuter status, outdoor exposure, health status and type of testing facility as independent variables. A random intercept for testing facility was included to account for clustering expected in testing practices at the individual clinics and shelters. RESULTS: In the multivariable random intercept model, the odds of FIV compared to FeLV positive ELISA results were greater for adults (OR = 2.09, CI: 1.50-2.92), intact males (OR = 3.14, CI: 1.85-3.76), neutered males (OR = 2.68, CI: 1.44- 3.14), cats with outdoor access (OR = 2.58, CI: 1.85-3.76) and lower for cats with clinical illness (OR = 0.60, 95% CI: 0.52-0.90). The variance components obtained from the model indicated clustering at the testing facility level. CONCLUSIONS: Risk factors that have a greater effect on FIV seropositivity include adulthood, being male (neutered or not) and having access to outdoors, while clinical illness was a stronger predictor for FeLV seropositivity. Further studies are warranted to assess the implications of these results for the management and control of these infections.


Dissecting Virus Infectious Cycles by Cryo-Electron Microscopy


Hemostasis profile in COVID-19 infection


title: Decline in temperature and humidity increases the occurrence of influenza in cold climate

text: BACKGROUND: Both temperature and humidity may independently or jointly contribute to the risk of influenza infections. We examined the relations between the level and decrease of temperature, humidity and the risk of influenza A and B virus infections in a subarctic climate. METHODS: We conducted a case-crossover study among military conscripts (n = 892) seeking medical attention due to respiratory symptoms during their military training period and identified 66 influenza A and B cases by PCR or serology. Meteorological data such as measures of average and decline in ambient temperature and absolute humidity (AH) during the three preceding days of the onset (hazard period) and two reference periods, prior and after the onset were obtained. RESULTS: The average temperature preceding the influenza onset was −6.8 ± 5.6°C and AH 3.1 ± 1.3 g/m(3). A decrease in both temperature and AH during the hazard period increased the occurrence of influenza so that a 1°C decrease in temperature and 0.5 g decrease per m(3) in AH increased the estimated risk by 11% [OR 1.11 (1.03 to 1.20)] and 58% [OR 1.58 (1.28 to 1.96)], respectively. The occurrence of influenza infections was positively associated with both the average temperature [OR 1.10 per 1°C (95% confidence interval 1.02 to 1.19)] and AH [OR 1.25 per g/m(3) (1.05 to 1.49)] during the hazard period prior to onset. CONCLUSION: Our results demonstrate that a decrease rather than low temperature and humidity per se during the preceding three days increase the risk of influenza episodes in a cold climate.


title: HIV Vaccine Mystery and Viral Shell Disorder

text: Hundreds of billions of dollars have been spent for over three decades in the search for an effective human immunodeficiency virus (HIV) vaccine with no success. There are also at least two other sexually transmitted viruses, for which no vaccine is available, the herpes simplex virus (HSV) and the hepatitis C virus (HCV). Traditional textbook explanatory paradigm of rapid mutation of retroviruses cannot adequately address the unavailability of vaccine for many sexually transmissible viruses, since HSV and HCV are DNA and non-retroviral RNA viruses, respectively, whereas effective vaccine for the horsefly-transmitted retroviral cousin of HIV, equine infectious anemia virus (EIAV), was found in 1973. We reported earlier the highly disordered nature of proteins in outer shells of the HIV, HCV, and HSV. Such levels of disorder are completely absent among the classical viruses, such as smallpox, rabies, yellow fever, and polio viruses, for which efficient vaccines were discovered. This review analyzes the physiology and shell disorder of the various related and non-related viruses to argue that EIAV and the classical viruses need harder shells to survive during harsher conditions of non-sexual transmissions, thus making them vulnerable to antibody detection and neutralization. In contrast, the outer shell of the HIV-1 (with its preferential sexual transmission) is highly disordered, thereby allowing large scale motions of its surface glycoproteins and making it difficult for antibodies to bind to them. The theoretical underpinning of this concept is retrospectively traced to a classical 1920s experiment by the legendary scientist, Oswald Avery. This concept of viral shapeshifting has implications for improved treatment of cancer and infections via immune evasion.


title: Gaseous nitric oxide reduces influenza infectivity in vitro

text: Abstract Gaseous nitric oxide (gNO) is an approved vasodilator drug for inhalation up to a maximum dose of 80ppm. While gNO has been shown, in vitro, to be an effective antibacterial agent (at 160ppm), NO-donor compounds have been shown to inhibit a variety of viruses at varying stages of replication. This research was done in order to determine whether gNO at 80 or 160ppm possesses an antiviral effect on influenza viruses. Three strains of influenza (A and B) were exposed to gNO for up to 180min, before and after infection of MDCK cells. In search for possible mechanism of antiviral action, Neuraminidase (NA) inhibition assay of H1N1 that was exposed to gNO was performed. Results show that when virions were exposed to gNO prior to infection a complete inhibition of infectivity was achieved for all three strains. Post infection exposure of influenza with gNO resulted in about 30% inhibition of infectivity. Further testing showed that when eliminating the pH effect by exposing a dried virus to gNO, 90% inhibition was found after 2h exposure. NA activity, of whole dried H1N1 virus, was found to be inhibited by gNO (80%). These results suggest that 80 and 160ppm gNO have a time dependent antiviral effect on influenza strains of viruses during various stages of cellular infection, which are not due to concomitant changes in pH in the surrounding milieu. Viral NA inhibition by gNO was shown and may be responsible for this antiviral effect.


title: Semiquantitative lung ultrasound scores in the evaluation and follow-up of critically ill patients with COVID-19: a single-center study

text: RATIONALE AND OBJECTIVES: Chest CT is not suitable for critically ill patients with COVID-19 and lung ultrasound (LUS) may play an important role for these patients. In this study, we summarized the findings of LUS and explore the value of semiquantitative LUS scores in evaluation and follow-up of COVID-19 pneumonia. MATERIALS AND METHODS: Retrospectively studied the LUS and chest CT imaging of 128 critically ill patients with COVID-19. The imaging data were reviewed to acquire the LUS and CT scores. The correlation between LUS scores and CT scores were made to evaluate the accuracy of LUS. A cut-off point of LUS score was calculated to distinguish critical-type patients from severe-type patients. LUS follow-up of 72 patients were compared with the gold standard chest CT. RESULTS: The most common LUS features of COVID-19 pneumonia were crowded or coalescent B-lines with multifocal small consolidations in multi-zone. The mean LUS score was 8.1 points in severe-type patients and 15.7 points in critical-type patients (P<0.05). The correlation between LUS scores and CT scores was high (r=0.891, p<0.01) and it was higher in critical-type patients than that in severe-type patients. The LUS score higher than 10.5 points had a 97.4% sensitivity and 75.0% specificity to distinguish critical-type patients. The consistency of LUS and chest CT in follow-up was 0.596, with higher consistency in diagnosis of lesion progression (Kappa values was 0.774). CONCLUSION: Our scoring system provides a more quantitative use of LUS findings and accurate evaluation of lung damage for critically ill patients with COVID-19.


title: Coronavirus advice for associates: what we know so far

text: The NHS has said that it will continue to pay NHS contract payments to NHS practices in England and Wales, and to NHS dentists in Scotland and Northern Ireland There are a number of conditions that apply to the continued contract payments Those conditions include: •That practices do not seek other assistance which would be considered duplicate •All available staff may be required to be redeployed


title: An online solution focused brief therapy for adolescent anxiety during the novel coronavirus disease (COVID-19) pandemic: a structured summary of a study protocol for a randomised controlled trial

text: OBJECTIVES: This study aims to assess the effectiveness of delivering Solution Focused Brief Therapy (SFBT) through telecommunication with a group of adolescents who present anxiety symptoms during the COVID-19 outbreak. We hypothesize that participants who are randomly assigned to receive 2–4 sessions of Solution Focused Brief Therapy would have better clinical outcomes than participants who are in the waitlist group. We additionally hypothesized that using SFBT can also change participants’ depression levels and their coping strategies in dealing with distress during the COVID-19 pandemic. TRIAL DESIGN: This study employs a randomized delayed crossover open label controlled trial in adolescents who are presenting anxiety symptoms during the COVID-19 outbreak. Participants who meet the enrollment criteria stated below will be invited to participate in this study through telecommunication. Those accepting will be randomly allocated to the intervention group or waitlist group.


title: Protein‐Templated Fragment Ligations—From Molecular Recognition to Drug Discovery

text: Protein‐templated fragment ligation is a novel concept to support drug discovery and can help to improve the efficacy of protein ligands. Protein‐templated fragment ligations are chemical reactions between small molecules (“fragments”) utilizing a protein's surface as a reaction vessel to catalyze the formation of a protein ligand with increased binding affinity. The approach exploits the molecular recognition of reactive small‐molecule fragments by proteins both for ligand assembly and for the identification of bioactive fragment combinations. In this way, chemical synthesis and bioassay are integrated in one single step. This Review discusses the biophysical basis of reversible and irreversible fragment ligations and gives an overview of the available methods to detect protein‐templated ligation products. The chemical scope and recent applications as well as future potential of the concept in drug discovery are reviewed.


Store‐and‐forward Teledermatology in the era of COVID‐19: A Pilot Study


title: The potential of recurrent epidemics and pandemics in a highly mobile global society

text: The aim of this study was to demonstrate how latent epidemics can potentially evolve into a pandemic instantaneously due to globally mobile human population in recent times, as can be seen in the ongoing Ebola epidemic in West Africa. Selected cases of current epidemics are used in this study to identify emergent patterns. These cases exemplify the need for a comprehensive analysis of infectious diseases and serve as an initial stage when developing appropriate strategies in improving epidemic management. This study can help better understand the complexities of infectious diseases and assist in developing a specific set of preventative processes from the individual to international levels when developing strategies to reducing the effects of an epidemic outbreak.


title: A porcine enterovirus G associated with enteric disease contains a novel papain-like cysteine protease

text: Identification of unknown pathogens in pigs displaying enteric illness is difficult due to the large diversity of bacterial and viral species found within faecal samples. Current methods often require bacterial or viral isolation, or testing only a limited number of known species using quantitative PCR analysis. Herein, faeces from two 25-day-old piglets with diarrhoea from Texas, USA, were analysed by metagenomic next-generation sequencing to rapidly identify possible pathogens. Our analysis included a bioinformatics pipeline of rapid short-read classification and de novo genome assembly which resulted in the identification of a porcine enterovirus G (EV-G), a complete genome with substantial nucleotide differences (>30 %) among current sequences, and a novel non-structural protein similar in sequence to the Torovirus papain-like cysteine protease (PL(pro)). This discovery led to the identification and circulation of an EV-G with a novel PL(pro) in the USA that has not been previously reported.


title: US university response to H1N1: A study of access to online preparedness and response information

text: BACKGROUND: The recent outbreaks of severe acute respiratory syndrome, H5N1 (avian influenza), and, most recently, the novel H1N1 influenza pandemic of 2009 have raised awareness of the danger of new and emerging infections. Preparedness and response plans for such outbreaks are crucial, and given the centrality of the Internet as a source of information on university and college campuses, such plans should be made available at pandemic-dedicated university Web sites. The information on these sites must be comprehensive, accessible, and tailored to the specific circumstances of individual schools. METHODS: An Internet-based search was conducted in September 2009 to evaluate university Web sites for influenza-specific information in a sample of 51 universities. Web sites were assessed by applying a set of key words and a list of 10 indicators used as measures of accessibility and comprehensiveness. RESULTS: Of the 51 universities evaluated, only 9 (17.6%) either had no influenza Web site or had a university influenza preparedness plan with no dedicated Web site. Only 6 (14.3%) of the schools with influenza specific Web sites had information for parents, with 23 (54.8%) providing information specifically for faculty and staff, and 24 (57.1%) providing information specifically to students. CONCLUSION: We found no guidelines for maximizing the access to and effectiveness of online pandemic communications at institutions of higher learning. Until such time as appropriate guidelines are developed, university authorities must carefully assess their needs, taking into account local, national, and international public health circumstances and resources; ease of access; comprehensiveness; and appropriately tailored strategies in their online communications.


title: Infectious Diseases Physicians: Improving and Protecting the Public’s Health: Why Equitable Compensation Is Critical

text: Infectious diseases (ID) physicians play a crucial role in public health in a variety of settings. Unfortunately, much of this work is undercompensated despite the proven efficacy of public health interventions such as hospital acquired infection prevention, antimicrobial stewardship, disease surveillance, and outbreak response. The lack of compensation makes it difficult to attract the best and the brightest to the field of ID, threatening the future of the ID workforce. Here, we examine compensation data for ID physicians compared to their value in population and public health settings and suggest policy recommendations to address the pay disparities that exist between cognitive and procedural specialties that prevent more medical students and residents from entering the field. All ID physicians should take an active role in promoting the value of the subspecialty to policymakers and influencers as well as trainees.


title: C-Type Lectin Receptors in Antiviral Immunity and Viral Escape

text: C-type lectin receptors (CLRs) are important pattern recognition receptors involved in recognition and induction of adaptive immunity to pathogens. Certain CLRs play an important role in viral infections as they efficiently interact with viruses. However, it has become clear that deadly viruses subvert the function of CLRs to escape antiviral immunity and promote infection. In particular, viruses target CLRs to suppress or modulate type I interferons that play a central role in the innate and adaptive defense against viruses. In this review, we discuss the function of CLRs in binding to enveloped viruses like HIV-1 and Dengue virus, and how uptake and signaling cascades have decisive effects on the outcome of infection.


title: Ribose 2′-O-methylation provides a molecular signature for the distinction of self and non-self mRNA dependent on the RNA sensor Mda5

text: The 5′ cap structures of higher eukaryote mRNAs have ribose 2′-O-methylation. Likewise, many viruses that replicate in the cytoplasm of eukaryotes have evolved 2′-O-methyltransferases to autonomously modify their mRNAs. However, a defined biological role for 2′-O-methylation of mRNA remains elusive. Here we show that 2′-O-methylation of viral mRNA was critically involved in subverting the induction of type I interferon. We demonstrate that human and mouse coronavirus mutants lacking 2′-O-methyltransferase activity induced higher expression of type I interferon and were highly sensitive to type I interferon. Notably, the induction of type I interferon by viruses deficient in 2′-O-methyltransferase was dependent on the cytoplasmic RNA sensor Mda5. This link between Mda5-mediated sensing of viral RNA and 2′-O-methylation of mRNA suggests that RNA modifications such as 2′-O-methylation provide a molecular signature for the discrimination of self and non-self mRNA.


docid: fxrbzfht

title: Exploring the Presence of Animal Origin in the Causation of Corona Virus Disease 2019 Outbreak and Strategies to Prevent Acquisition of the Infection


title: Functional genomics as a tool in virus research

text: Genomics is the study of an organism’s entire genome. It started out as a great scientific endeavor in the 1990s which aimed to sequence the complete genomes of certain biological species. However viruses are not new to this field as complete viral genomes have routinely been sequenced since the past thirty years. The ‘genomic era’ has been said to have revolutionized biology. This knowledge of full genomes has created the field of functional genomics in today’s post-genomic era, which, is in most part concerned with the studies on the expression of the organism’s genome under different conditions. This article is an attempt to introduce its readers to the application of functional genomics to address and answer several complex biological issues in virus research.


title: The Potential of Social Media and Internet-Based Data in Preventing and Fighting Infectious Diseases: From Internet to Twitter

text: Health threats due to infectious diseases used to be a major public health concerns around the globe till mid of twentieth century when effective public health interventions helped in eradicating a number of infectious diseases around the world. Over the past 15 years, there has been a rise in the number of emerging and reemerging infectious diseases being reported such as the Acute Respiratory Syndrome (SARS) in 2002, HINI in 2009, Middle East Respiratory Syndrome (MERS) in 2012, Ebola in 2014, and Zika in 2016. These emerging viral infectious diseases have led to serious public health concerns leading to death and causing fear and anxiety among the public. More importantly, at the moment, the prevention and control of viral infectious diseases is difficult due to a lack of effective vaccines. Thus having real-time reporting tools are paramount to alert relevant public health surveillance systems and authorities about taking the right and necessary actions to control and minimize the potential harmful effects of viral infectious diseases. Social media and Internet-based data can play a major role in real-time reporting to empower active public health surveillance systems for controlling and fighting infectious diseases.


title: Measles Vaccines Designed for Enhanced CD8(+) T Cell Activation

text: Priming and activation of CD8(+) T cell responses is crucial to achieve anti-viral and anti-tumor immunity. Live attenuated measles vaccine strains have been used successfully for immunization for decades and are currently investigated in trials of oncolytic virotherapy. The available reverse genetics systems allow for insertion of additional genes, including heterologous antigens. Here, we designed recombinant measles vaccine vectors for priming and activation of antigen-specific CD8(+) T cells. For proof-of-concept, we used cytotoxic T lymphocyte (CTL) lines specific for the melanoma-associated differentiation antigen tyrosinase-related protein-2 (TRP-2), or the model antigen chicken ovalbumin (OVA), respectively. We generated recombinant measles vaccine vectors with TRP-2 and OVA epitope cassette variants for expression of the full-length antigen or the respective immunodominant CD8(+) epitope, with additional variants mediating secretion or proteasomal degradation of the epitope. We show that these recombinant measles virus vectors mediate varying levels of MHC class I (MHC-I)-restricted epitope presentation, leading to activation of cognate CTLs, as indicated by secretion of interferon-gamma (IFNγ) in vitro. Importantly, the recombinant OVA vaccines also mediate priming of naïve OT-I CD8(+) T cells by dendritic cells. While all vaccine variants can prime and activate cognate T cells, IFNγ release was enhanced using a secreted epitope variant and a variant with epitope strings targeted to the proteasome. The principles presented in this study will facilitate the design of recombinant vaccines to elicit CD8(+) responses against pathogens and tumor antigens.


Consumer Policy in the Age of Covid-19


docid: udwomjop

title: Coronavirus Nsp10, a Critical Co-factor for Activation of Multiple Replicative Enzymes

text: The RNA-synthesizing machinery of the severe acute respiratory syndrome Coronavirus (SARS-CoV) is composed of 16 non-structural proteins (nsp1–16) encoded by ORF1a/1b. The 148-amino acid nsp10 subunit contains two zinc fingers and is known to interact with both nsp14 and nsp16, stimulating their respective 3′-5′ exoribonuclease and 2′-O-methyltransferase activities. Using alanine-scanning mutagenesis, in cellulo bioluminescence resonance energy transfer experiments, and in vitro pulldown assays, we have now identified the key residues on the nsp10 surface that interact with nsp14. The functional consequences of mutations introduced at these positions were first evaluated biochemically by monitoring nsp14 exoribonuclease activity. Disruption of the nsp10-nsp14 interaction abrogated the nsp10-driven activation of the nsp14 exoribonuclease. We further showed that the nsp10 surface interacting with nsp14 overlaps with the surface involved in the nsp10-mediated activation of nsp16 2′-O-methyltransferase activity, suggesting that nsp10 is a major regulator of SARS-CoV replicase function. In line with this notion, reverse genetics experiments supported an essential role of the nsp10 surface that interacts with nsp14 in SARS-CoV replication, as several mutations that abolished the interaction in vitro yielded a replication-negative viral phenotype. In contrast, mutants in which the nsp10-nsp16 interaction was disturbed proved to be crippled but viable. These experiments imply that the nsp10 surface that interacts with nsp14 and nsp16 and possibly other subunits of the viral replication complex may be a target for the development of antiviral compounds against pathogenic coronaviruses.


Plasmacytoid lymphocytes in SARS‐CoV‐2 infection (Covid‐19)


title: Development and application of an integrated indoor air quality audit to an international hotel building in Taiwan

text: Indoor air quality (IAQ) has begun to surface as an important issue that affects the comfort and health of people; however, there is little research concerned about the IAQ monitoring of hotels up to now. Hotels are designed to provide comfortable spaces for guests. However, most complaints related to uncomfortable thermal environment and inadequate indoor air quality appear. In addition, microbial pollution can affect the health of tourists such as the Legionnaire’s disease and SARS problems. This study is aimed to establish the comprehensive IAQ audit approach for hotel buildings with portable equipments, and one five-star international hotel in Taiwan was selected to exam this integrated approach. Finally, four major problems are identified after the comprehensive IAQ audit. They are: (1) low room temperature (21.8°C), (2) insufficient air exchange rate (<1.5 h(−1)), (3) formaldehyde contamination (>0.02 ppm), and (4) the microbial pollution (total bacteria: 2,624–3,799 CFU/m(3)). The high level of formaldehyde may be due to the emission from the detergent and cleaning agents used for housekeeping.


title: Mechanisms of viral mutation

text: The remarkable capacity of some viruses to adapt to new hosts and environments is highly dependent on their ability to generate de novo diversity in a short period of time. Rates of spontaneous mutation vary amply among viruses. RNA viruses mutate faster than DNA viruses, single-stranded viruses mutate faster than double-strand virus, and genome size appears to correlate negatively with mutation rate. Viral mutation rates are modulated at different levels, including polymerase fidelity, sequence context, template secondary structure, cellular microenvironment, replication mechanisms, proofreading, and access to post-replicative repair. Additionally, massive numbers of mutations can be introduced by some virus-encoded diversity-generating elements, as well as by host-encoded cytidine/adenine deaminases. Our current knowledge of viral mutation rates indicates that viral genetic diversity is determined by multiple virus- and host-dependent processes, and that viral mutation rates can evolve in response to specific selective pressures.


title: COVID‐19: A great disruptor?

text: By the end of January, the World Health Organization had declared COVID‐19 a “global health emergency.”


title: Brief validation of the novel GeneXpert Xpress SARS-CoV-2 PCR assay

text: The clinical and epidemiologic management of the SARS-CoV-2 pandemic is critically dependent on molecular assays with short turn-around time. We validated the novel Xpert Xpress SARS-CoV-2 assay using a commercial nucleic acid testing (Roche Cobas 6800). We found an excellent concordance over a range of SARS-CoV-2 loads and across established human coronaviruses.


title: A controlled trial on the effect of feeding dietary chestnut extract and glycerol monolaurate on liver function in newborn calves

text: Beginning in the fall of 2010, an increasing and alarming number of cases of calves suffering from liver dystrophy were reported in the south of Germany. An epidemiological investigation was carried out by the authors between November 2010 and July 2011, leading to the implication of a commercial dietary supplement as the potential cause for this outbreak. The components of this product were first tested in a cell culture model and two of them (dietary chestnut extract and glycerol monolaurate) showed a cytotoxic effect. The objective of this study was therefore to evaluate the effect of supplemental feeding of both components alone or in combination on liver function in newborn calves on a commercial dairy farm. Ten calves were enrolled in each of the three treatment groups and the control group (group O) following a blocked design. Treatment consisted of supplementation with chestnut extract at 0.02% of birth body mass (BM) (group C), supplementation with glycerol monolaurate at 0.006% of BM (group G) or a combined treatment (group CG) for five consecutive days. The effect of treatments on liver function was evaluated clinically and by measurement of glutamate dehydrogenase (GLDH) and aspartate aminotransferase (AST) activities as well as the determination of the concentrations of glucose, L‐lactate and total bilirubin in serum. There was a significant increase in GLDH and AST activities and a significant decrease in glucose concentration in treatment groups C and CG compared with the control group (p ≤ 0.035), whereas no difference was shown for group G. Survival was significantly decreased in groups C (p = 0.029) and CG (p = 0.001) compared with both group G and the control group. These results suggest that dietary chestnut extract in an amount of 0.02% of BM alone or in combination has a toxic effect on liver function in newborn calves.


title: Review of safety and minimum pricing of nitazoxanide for potential treatment of COVID-19

text: BACKGROUND: Many treatments are being assessed for repurposing to treat coronavirus disease 2019 (COVID-19). One drug that has shown promising results in vitro is nitazoxanide. Unlike other postulated drugs, nitazoxanide shows a high ratio of maximum plasma concentration (C(max)), after 1 day of 500 mg twice daily (BD), to the concentration required to inhibit 50% replication (EC(50)) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (C(max): EC(50)roughly equal to 14:1). As such, it is important to investigate the safety of nitazoxanide for further trials. Furthermore, treatments for COVID-19 should be cheap to promote global access, but prices of many drugs are far higher than the costs of production. We aimed to conduct a review of the safety of nitazoxanide for any prior indication and calculate its minimum costs of production. METHODS: A review of nitazoxanide clinical research was conducted using EMBASE and MEDLINE databases, supplemented by ClinicalTrials.gov. We searched for phase 2 or 3 randomised controlled trials (RCTs) comparing nitazoxanide with placebo or active control for 5–14 days in participants experiencing acute infections of any kind. Data extracted were grade 1–4 and serious adverse events (AEs). Data were also extracted on gastrointestinal (GI) AEs, as well as hepatorenal and cardiovascular effects. Active pharmaceutical ingredient cost data from 2016 to 2019 were extracted from the Panjiva database and adjusted for 5% loss during production, costs of excipients, formulation, a 10% profit margin and tax. Two dosages, at 500 mg BD and a higher dose of 1100 mg three times daily (TDS), were considered. Our estimated costs were compared with publicly available list prices from a selection of countries. RESULTS: Nine RCTs of nitazoxanide were identified for inclusion. These RCTs accounted for 1514 participants and an estimated 95.3 person-years-of-follow-up. No significant differences were found in any of the AE endpoints assessed, across all trials or on subgroup analyses of active- or placebo-controlled trials. Mild GI AEs increased with dose. No hepatorenal or cardiovascular concerns were raised, but few appropriate metrics were reported. There were no teratogenic concerns, but the evidence base was very limited. Based on a weighted-mean cost of US $61/kg, a 14-day course of treatment with nitazoxanide 500 mg BD would cost $1.41. The daily cost would therefore be $0.10. The same 14-day course could cost $3944 in US commercial pharmacies, and $3 per course in Pakistan, India and Bangladesh. At a higher dose of 1100 mg TDS, our estimated cost was $4.08 per 14-day course, equivalent to $0.29 per day. CONCLUSION: Nitazoxanide demonstrates a good safety profile at approved doses. However, further evidence is required regarding hepatorenal and cardiovascular effects, as well as teratogenicity. We estimate that it would be possible to manufacture nitazoxanide as generic for $1.41 for a 14-day treatment course at 500 mg BD, up to $4.08 at 1100 mg TDS. Further trials in COVID-19 patients should be initiated. If efficacy against SARS-CoV-2 is demonstrated in clinical studies, nitazoxanide may represent a safe and affordable treatment in the ongoing pandemic.


title: A New Modelling of the COVID 19 Pandemic

text: А model of coronavirus incidence is proposed. Process of disease development is represented as analogue of first- and second order phase transition in physical systems. The model is very simple in terms of the data necessary for the calculations. To verify the proposed model, only data on the current incidence rate are required. However, the determination coefficient of model R2 is very high and exceeds 0.95 for most countries. The model permits the accurate prediction of the pandemics dynamics at intervals of up to 10 days. The ADL(autoregressive distributed lag)-model was introduced in addition to the phase transition model to describe the development of the disease at the exponential phase.The ADL-model allows describing nonmonotonic changes in relative infection over the time, and providing to governments and health care decision makers the possibility to predict the outcomes of their decisions on public health.


title: Characterization of epidemic diarrhea outbreaks associated with bovine torovirus in adult cows

text: Bovine torovirus (BToV) is recognized as an enteric pathogen of calves, but its etiological role in diarrhea and epidemiological characterization in adult cows remain unclear. In 2007-2008, three outbreaks of epidemic diarrhea occurred in adult cows at three dairy farms in Niigata Prefecture, Japan. BToV was the only enteric pathogen detected in these outbreaks, as determined by electron microscopy, reverse transcription-PCR, bacteria and parasite tests of fecal samples, and antibody tests with paired sera. The epidemiological features of the three outbreaks were similar to those of bovine coronavirus infection, except for the absence of bloody diarrhea, with diarrhea spreading among most adult cows, but not in calves, within several days and diarrhea lasting for 3-5 days with anorexia. Decreased milk production and mild respiratory symptoms were also observed in two of the outbreaks. Nucleotide sequence analysis of the BToV nucleocapsid, spike, and hemagglutinin-esterase (HE) genes revealed a close relatedness among the detected BToV strains from each outbreak and those of Japanese BToV strain Aichi/2004. Furthermore, we isolated a BToV strain, designated Niigata (TC), from a fecal sample using a human rectal tumor cell line. Sequence analysis of this isolate and Aichi/2004 indicated that both strains have truncated HE genes with deletions in the 3′ region that occurred through cell culture-adaptation. The short projections that are believed to be formed by the HE protein on virus particles were not observed in these cultured strains by electron microscopy. Taken together, these results suggest that BToV causes epidemic diarrhea in adult cows and should be included in the differential diagnosis of diarrhea in adult cows. In addition, our findings indicate that the HE protein of BToV may not be necessary for viral replication.


title: Human bocavirus isolated from children with acute respiratory tract infections in Korea, 2010–2011

text: Human bocavirus (HBoV) was first recognized in respiratory samples in 2005. The clinical importance of HBoV infection remains unclear. This report describes the clinical features and molecular phylogeny of HBoV isolates in children with acute respiratory infections. Nasopharyngeal aspirates were obtained from 1,528 children with acute respiratory infections between 2010 and 2011. Respiratory samples were screened for HBoV by multiplex PCR. A phylogenetic analysis of the HBoV VP1/VP2 gene was also undertaken. HBoV was detected in 187 (12.2%) of the 1,528 patients with a peak incidence of infection observed in patients aged 12–24 months. Coinfection with other respiratory viruses was observed in 107 (57.2%) of the HBoV‐positive children. The peak of HBoV activity occurred during the month of June in both 2010 and 2011. A higher previous history of wheezing (P = 0.016), a higher frequency of chest retraction (P < 0.001) and wheezing (P = 0.022), a higher respiratory symptom score (P = 0.002), and a longer duration of hospital stay (P = 0.021) were observed in HBoV‐positive children compared with the HBoV‐negative group. Phylogenetic analysis showed all 187 HBoV‐positive isolates were identified as HBoV 1, indicating minimal sequence variations among the isolates. A single lineage of HBoV 1 was found to have circulated in children with acute respiratory infections between 2010 and 2011 and was associated with several clinical characteristics including age, seasonality, and clinical severity with retraction, wheezing, and longer hospitalization. The clinical relevance of the minimal sequence variations of HBoV remains to be determined. J. Med. Virol. 86:2011–2018, 2014. © 2014 The Authors. Journal of Medical Virology published by Wiley Periodicals, Inc.


title: Genomic characterization of canine circovirus associated with fatal disease in dogs in South America

text: Canine circovirus (CanineCV) was detected, together with canine parvovirus (CPV), in samples from an outbreak of fatal gastroenteritis in dogs in Argentina. We obtained the full-length genome of this recently discovered virus by overlapping PCR, designated strain UBA-Baires. Sequence analysis revealed a highly conserved genome but also showed several unique mutations in amino acids from the capsid protein that have not been previously reported. Phylogenetic analysis shows that this strain is more closely related to European strains than to viruses detected in North America or Asia. Although the pathogenic role of CanineCV in dogs is still unclear, this study highlights the importance of CanineCV as a coinfecting virus in disease development. To our knowledge, this is the first report of the involvement of CanineCV in severe clinical disease in dogs in South America. Our results expand our information on the geographical extent of this virus and contribute to the understanding of its role in disease.


title: Complex Epidemiology of a Zoonotic Disease in a Culturally Diverse Region: Phylogeography of Rabies Virus in the Middle East

text: The Middle East is a culturally and politically diverse region at the gateway between Europe, Africa and Asia. Spatial dynamics of the fatal zoonotic disease rabies among countries of the Middle East and surrounding regions is poorly understood. An improved understanding of virus distribution is necessary to direct control methods. Previous studies have suggested regular trans-boundary movement, but have been unable to infer direction. Here we address these issues, by investigating the evolution of 183 rabies virus isolates collected from over 20 countries between 1972 and 2014. We have undertaken a discrete phylogeographic analysis on a subset of 139 samples to infer where and when movements of rabies have occurred. We provide evidence for four genetically distinct clades with separate origins currently circulating in the Middle East and surrounding countries. Introductions of these viruses have been followed by regular and multidirectional trans-boundary movements in some parts of the region, but relative isolation in others. There is evidence for minimal regular incursion of rabies from Central and Eastern Asia. These data support current initiatives for regional collaboration that are essential for rabies elimination.


docid: axvonzvq

title: ACE inhibitors and COVID‐19: We don't know yet


title: Platelets to surrogate lung inflammation in COVID-19 Patients

text: The neoteric severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been jeopardizing the world with the symptoms of seasonal flu. The virus contagion predicted to have been originated from Wuhan, China has by far trapped 4,198,418 cases from 212 countries in the world with two international conveyances with 284,102 deaths as of 11 May 2020 (10:18 GMT). Researchers around the globe have indulged in deciphering viral mode in the body for devising a cure. Affirmations from autopsies and preliminary findings on SARS-CoV-2 hypothesized on viral pathogenesis within the host, for instance, source of inflammation in lungs and pneumonia. This hypothesis assigns the platelets as agents of infection after viral entry. Presently, curbing infection to stall the spread of SARS-CoV-2 is the prima facie intervention employed, worldwide. However, public health authorities must monitor the state of affairs scrupulously, as the deeper our understanding of this novel virus and its associated outbreak, the better we can deal with it. Knowing this idea might be far-fetched, yet this postulate would serve as the groundwork for the present situation.


title: Respiratory viral infections and the risk of rheumatoid arthritis

text: BACKGROUND: We aimed to investigate the effects of ambient respiratory viral infections in the general population on rheumatoid arthritis (RA) development. METHODS: Data of weekly incident RA (2012–2013) were obtained from the Korean National Health Insurance claims database, and those of weekly observations on eight respiratory viral infections were obtained from the Korea Centers for Disease Control and Prevention database. We estimated the percentage change in incident RA associated with ambient mean respiratory viral infections using a generalized linear model, after adjusting for time trend, air pollution, and meteorological data. RESULTS: A total of 24,117 cases of incident RA (mean age 54.7 years, 18,688 [77.5%] women) were analyzed. Ambient respiratory viral infections in the population were associated with a higher number of incident RA over time, and its effect peaked 6 or 7 weeks after exposure. Among the 8 viruses, parainfluenza virus (4.8% for 1% respiratory viral infection increase, 95% CI 1.6 to 8.1, P = .003), coronavirus (9.2%, 3.9 to 14.8, P < .001), and metapneumovirus (44%, 2.0 to 103.4, P = .038) were associated with increased number of incident RA. The impact of these respiratory viral infections remained significant in women (3.8%, 12.1%, and 67.4%, respectively, P < .05) and in older patients (10.7%, 14.6%, and 118.2%, respectively, P < .05). CONCLUSIONS: Ambient respiratory viral infections in the population were associated with an increased number of incident RA, especially in women and older patients, suggesting that respiratory viral infections can be a novel environmental risk factor for the development of RA. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13075-019-1977-9) contains supplementary material, which is available to authorized users.


title: Human Coronaviruses: General Features

text: Abstract Human coronaviruses (HCoVs), including HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1, are traditionally known to cause symptoms of common cold with only moderate clinical impact. Severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), on the other hand, have strike humans in the past two decades as highly fatal human pathogens leading to considerable mortality and economic loss. This article summaries the updates on the structure, genome organization, replication and clinical features of human coronaviruses. Recent studies also shed light upon the zoonotic origin of emerging human pathogens including SARS-CoV and MERS-CoV, providing insight for future surveillance and intervention.


title: Autophagy and antiviral immunity

text: Autophagy is an ancient pathway designed to maintain cellular homeostasis by degrading long-lived proteins and organelles in the cytosol. Recent studies demonstrate that autophagy is utilized by the cells of the innate and adaptive immune systems to combat viral infections. Autophagy plays a key role in recognizing signatures of viral infection, and represents a critical effector mechanism to restrict viral replication. On the other hand, autophagosomes have been exploited by certain viruses as a niche for viral replication. Furthermore, autophagy can be used to deliver endogenous viral antigens to the MHC class II loading compartment, allowing activation of CD4 T cells. In this review, we describe recent advances in the field of autophagy as it relates to innate and adaptive antiviral immune responses.


title: The Impact of Healthcare Provider Relationships and Communication Dynamics on Urinary Tract Infection Management and Antibiotic Utilization for Long-Term Care Facility Residents Treated in the Emergency Department: A Qualitative Study

text: BACKGROUND: : For older adults, over diagnosis of urinary tract infections (UTI) is a primary driver of inappropriate antibiotic use. This risk is increased for patients in long term care facilities (LTCF), especially as they transition back and forth to emergency departments (ED). In this study, we aimed to understand how healthcare provider communication and relationship dynamics affect LTCF residents treated in the ED to identify barriers to antibiotic stewardship for UTIs. METHODS: : We conducted semi-structured interviews with nurses and physicians from LTCFs and EDs, guided by the Systems Engineering Initiative for Patient Safety framework. Data were systematically coded and underwent iterative, conventional content analysis. RESULTS: : We interviewed 16 LTCF and 16 ED providers across Wisconsin. ED and LTCF nurses have a critical role in both intrafacility and interfacility communication. Fragmented communication and interprofessional power dynamics were identified barriers to optimal antibiotic prescribing for UTIs. Identified strategies to overcome these issues included using objective diagnostic criteria, development of communication scripts and nurse-to-nurse education. CONCLUSIONS: : Our qualitative approach revealed important insights about how communication and relationship dynamics influence UTI diagnosis and optimal antibiotic stewardship for LTCF residents evaluated in the ED. Future interventions should strengthen communications between settings and across provider types, and address standardization of diagnostic and treatment communication pathways for LTCF residents with suspected infections transitioning between EDs and LTCFs.


Letter to the Editor in response to the article: “Increase in the risk of type 2 diabetes during lockdown for the COVID19 pandemic in India: A cohort analysis” (Ghoshal et al.)


title: Copper Transport and Trafficking at the Host–Bacterial Pathogen Interface

text: [Image: see text] The human innate immune system has evolved the means to reduce the bioavailability of first-row late d-block transition metal ions to invading microbial pathogens in a process termed “nutritional immunity”. Transition metals from Mn(II) to Zn(II) function as metalloenzyme cofactors in all living cells, and the successful pathogen is capable of mounting an adaptive response to mitigate the effects of host control of transition metal bioavailability. Emerging evidence suggests that Mn, Fe, and Zn are withheld from the pathogen in classically defined nutritional immunity, while Cu is used to kill invading microorganisms. This Account summarizes new molecular-level insights into copper trafficking across cell membranes from studies of a number of important bacterial pathogens and model organisms, including Escherichia coli, Salmonella species, Mycobacterium tuberculosis, and Streptococcus pneumoniae, to illustrate general principles of cellular copper resistance. Recent highlights of copper chemistry at the host–microbial pathogen interface include the first high resolution structures and functional characterization of a Cu(I)-effluxing P(1B)-ATPase, a new class of bacterial copper chaperone, a fungal Cu-only superoxide dismutase SOD5, and the discovery of a small molecule Cu-bound SOD mimetic. Successful harnessing by the pathogen of host-derived bactericidal Cu to reduce the bacterial load of reactive oxygen species (ROS) is an emerging theme; in addition, recent studies continue to emphasize the importance of short lifetime protein–protein interactions that orchestrate the channeling of Cu(I) from donor to target without dissociation into bulk solution; this, in turn, mitigates the off-pathway effects of Cu(I) toxicity in both the periplasm in Gram negative organisms and in the bacterial cytoplasm. It is unclear as yet, outside of the photosynthetic bacteria, whether Cu(I) is trafficked to other cellular destinations, for example, to cuproenzymes or other intracellular storage sites, or the general degree to which copper chaperones vs copper efflux transporters are essential for bacterial pathogenesis in the vertebrate host. Future studies will be directed toward the identification and structural characterization of other cellular targets of Cu(I) trafficking and resistance, the physical and mechanistic characterization of Cu(I)-transfer intermediates, and elucidation of the mutual dependence of Cu(I) trafficking and cellular redox status on thiol chemistry in the cytoplasm. Crippling bacterial control of Cu(I) sensing, trafficking, and efflux may represent a viable strategy for the development of new antibiotics.


docid: dxbvfwqu

title: Non-animal replacement methods for human vaccine potency testing: state of the science and future directions

text: Abstract NICEATM and ICCVAM convened an international workshop to review the state of the science of human and veterinary vaccine potency and safety testing methods, and to identify opportunities to advance new and improved methods that can further reduce, refine, and replace animal use. This report addresses methods and strategies identified by workshop participants for replacement of animals used for potency testing of human vaccines. Vaccines considered to have the highest priority for future efforts were (1) vaccines for which antigen quantification methods are already developed but not validated, (2) vaccines/components that require the largest number of animals, (3) vaccines that require an in vivo challenge test, and (4) vaccines with in vivo tests that are highly variable and cause a significant number of invalid tests. Vaccine potency tests identified as the highest priorities for replacement were those for diphtheria and tetanus, pertussis (whole cell and acellular), rabies, anthrax, polio vaccine (inactivated) and complex combination vaccines based on DT or DTwP/aP. Research into understanding the precise mechanism of protection afforded by vaccines and the identification of clinically relevant immunological markers are needed to facilitate the successful implementation of in vitro testing alternatives. This report also identifies several priority human vaccines and associated research objectives that are necessary to successfully implement in vitro vaccine potency testing alternatives.


title: A nucleobase-binding pocket in a viral RNA-dependent RNA polymerase contributes to elongation complex stability

text: The enterovirus 71 (EV71) 3D(pol) is an RNA-dependent RNA polymerase (RdRP) that plays the central role in the viral genome replication, and is an important target in antiviral studies. Here, we report a crystal structure of EV71 3D(pol) elongation complex (EC) at 1.8 Å resolution. The structure reveals that the 5′-end guanosine of the downstream RNA template interacts with a fingers domain pocket, with the base sandwiched by H44 and R277 side chains through hydrophobic stacking interactions, and these interactions are still maintained after one in-crystal translocation event induced by nucleotide incorporation, implying that the pocket could regulate the functional properties of the polymerase by interacting with RNA. When mutated, residue R277 showed an impact on virus proliferation in virological studies with residue H44 having a synergistic effect. In vitro biochemical data further suggest that mutations at these two sites affect RNA binding, EC stability, but not polymerase catalytic rate (k(cat)) and apparent NTP affinity (K(M,NTP)). We propose that, although rarely captured by crystallography, similar surface pocket interaction with nucleobase may commonly exist in nucleic acid motor enzymes to facilitate their processivity. Potential applications in antiviral drug and vaccine development are also discussed.


title: Clinical respiratory infections and pneumonia during the Hajj pilgrimage: A systematic review

text: Abstract Background The Islamic Hajj pilgrimage to Mecca is one of the world's largest annual mass gatherings. Inevitable overcrowding during the pilgrims' stay greatly increases the risk of acquiring and spreading infectious diseases, especially respiratory diseases. Method The MEDLINE/PubMed and Scopus databases were searched for all relevant papers published prior to February 2018 that evaluated the prevalence of clinical symptoms of respiratory infections, including pneumonia, among Hajj pilgrims, as well as their influenza and pneumococcal vaccination status. Results A total of 61 papers were included in the review. Both cohort- and hospital-based studies provide complementary data, and both are therefore necessary to provide a complete picture of the total burden of respiratory diseases during the Hajj. Respiratory symptoms have been common among Hajj pilgrims over the last 15 years. In cohorts of pilgrims, cough ranged from 1.9% to 91.5%. However, the prevalence rates of the most common symptoms (cough, sore throat, and subjective fever) of influenza-like illness (ILI) varied widely across the included studies. These studies have shown variable results, with overall rates of ILI ranging from 8% to 78.2%. These differences might result from differences in study design, study period, and rates of vaccination against seasonal influenza that ranged from 1.1% to 100% among study participants. Moreover, the definition of ILI was inconsistent across studies. In hospitalized Hajj pilgrims, the prevalence of pneumonia, that remains a major concern in critically ill patients, ranged from 0.2% to 54.8%. Conclusions Large multinational follow-up studies are recommended for clinic-based syndromic surveillance, in conjunction with microbiological surveillance. Matched cohorts ensure better comparability across studies. However, study design and data collection procedures should be standardized to facilitate reporting and to achieve comparability between studies. Furthermore, the definition of ILI, and of most common symptoms used to define respiratory infections (e.g., upper respiratory tract infection), need to be precisely defined and consistently used. Future studies need to address potential effect of influenza and pneumococcal vaccine in the context of the Hajj pilgrimage.


title: Transmissible gastroenteritis virus infection induces NF-κB activation through RLR-mediated signaling

text: Abstract Transmissible gastroenteritis virus (TGEV) is a porcine enteric coronavirus which causes lethal severe watery diarrhea in piglets. The pathogenesis of TGEV is strongly associated with inflammation. In this study, we found that TGEV infection activates transcription factors NF-κB, IRF3 and AP-1 in a time- and dose-dependent manner in porcine kidney cells. Treatment with the NF-κB-specific inhibitor BAY11-7082 significantly decreased TGEV-induced proinflammatory cytokine production, but did not affect virus replication. Phosphorylation of NF-κB subunit p65 and proinflammatory cytokine production were greatly decreased after knockdown of retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) or its adaptors MAVS and STING, while only slight reduction was observed in cells following silencing of Toll-like receptor adaptors, MyD88 and TRIF. Furthermore, TGEV infection significantly upregulated mRNA expression of RIG-I and MDA5. Taken together, our results indicate that the RLR signaling pathway is involved in TGEV-induced inflammatory responses.


title: C-terminal domain of SARS-CoV main protease can form a 3D domain-swapped dimer

text: SARS coronavirus main protease (M(pro)) plays an essential role in the extensive proteolytic processing of the viral polyproteins (pp1a and pp1ab), and it is an important target for anti-SARS drug development. We have reported that both the M(pro) C-terminal domain alone (M(pro)-C) and the N-finger deletion mutant of M(pro) (M(pro)-Δ7) exist as a stable dimer and a stable monomer (Zhong et al., J Virol 2008; 82:4227-4234). Here, we report structures of both M(pro)-C monomer and dimer. The structure of the M(pro)-C monomer is almost identical to that of the C-terminal domain in the crystal structure of M(pro). Interestingly, the M(pro)-C dimer structure is characterized by 3D domain-swapping, in which the first helices of the two protomers are interchanged and each is enwrapped by four other helices from the other protomer. Each folding subunit of the M(pro)-C domain-swapped dimer still has the same general fold as that of the M(pro)-C monomer. This special dimerization elucidates the structural basis for the observation that there is no exchange between monomeric and dimeric forms of M(pro)-C and M(pro)-Δ7.


title: The impact of ambient fine particles on influenza transmission and the modification effects of temperature in China: A multi-city study

text: Abstract Background There is good evidence that air pollution is a risk factor for adverse respiratory and vascular health outcomes. However, data are limited as to whether ambient fine particles contribute to the transmission of influenza and if so, how the association is modified by weather conditions. Objectives We examined the relationship between ambient PM2.5 and influenza incidence at the national level in China and explored the associations at different temperatures. Methods Daily data on concentrations of particulate matter with aerodynamic diameter<2.5μm (PM2.5) and influenza incidence counts were collected in 47 Chinese cities. A Poisson regression model was used to estimate the city-specific PM2.5-influenza association, after controlling for potential confounders. Then, a random-effect meta-analysis was used to pool the effects at national level. In addition, stratified analyses were performed to examine modification effects of ambient temperature. Results For single lag models, the highest effect of ambient PM2.5 on influenza incidence appeared at lag day 2, with relative risk (RR) of 1.015 (95% confidence interval (CI): 1.004, 1.025) associated with a 10μg/m3 increase in PM2.5. For moving average lag models, the significant association was found at lag 2–3days, with RR of 1.020 (95% CI: 1.006, 1.034). The RR of influenza transmission associated with PM2.5 was higher for cold compared with hot days. Overall, 10.7% of incident influenza cases may result from exposure to ambient PM2.5. Conclusions Ambient PM2.5 may increase the risk of exposure to influenza in China especially on cooler days. Control measures to reduce PM2.5 concentrations could potentially also be of benefit in lowering the risk of exposure and subsequent transmission of influenza in China.


title: Chapter 2 Metagenomics revealing new virus species in farm and pet animals and aquaculture

text: Abstract Viral metagenomics is slowly taking over the traditional and widely used molecular techniques for the investigation of pathogenic viruses responsible for illness and inflicting great economic burden on the farm animal industry. Owing to the continued improvements in sequencing technologies and the dramatic reduction of per base costs of sequencing the use of next generation sequencing have been key factors in this progress. Discoveries linked to viral metagenomics are expected to be beneficial to the field of veterinary medicine starting from the development of better diagnostic assays to the design of new subunit vaccines with minimal investments. With these achievements the research has taken a giant leap even toward the better healthcare of animals and, as a result, the animal sector could be growing at an unprecedented pace.


title: Factors Associated with Depression, Anxiety, and PTSD Symptomatology During the COVID-19 Pandemic: Clinical Implications for U.S. Young Adult Mental Health

text: This study sought to identify factors associated with depression, anxiety, and PTSD symptomatology in U.S. young adults (18-30 years) during the COVID-19 pandemic. This cross-sectional online study assessed 898 participants from April 13, 2020 to May 19, 2020, approximately one month after the U.S. declared a state of emergency due to COVID-19 and prior to the initial lifting of restrictions across 50 U.S. states. Respondents reported high levels of depression (43.3%, PHQ-8 scores ≥ 10), high anxiety scores (45.4%, GAD-7 scores ≥ 10), and high levels of PTSD symptoms (31.8%, PCL-C scores ≥ 45). High levels of loneliness, high levels of COVID-19-specific worries, and low distress tolerance were significantly associated with clinical levels of depression, anxiety, and PTSD symptoms. Resilience was associated with low levels of depression and anxiety symptoms but not PTSD. Most respondents had high levels of social support; social support from family, but not from partner or peers, was associated with low levels of depression and PTSD. Compared to Whites, Asian Americans were less likely to report high levels across mental health symptoms, and Hispanic/Latinos were less likely to report high levels of anxiety. These factors provide initial guidance regarding clinical management for COVID-19-related mental health problems.


title: Defining infections in international travellers through the GeoSentinel surveillance network

text: International travellers are often exposed to a wide range of infections, most of which are a reflection of common diseases in the destination country. The consequences of acquiring such infections are serious and can be associated with substantial morbidity and mortality. Attempting to define the range of infections and the risk factors that are associated with acquiring them during travel to different regions worldwide will provide an evidence base for the development and implementation of effective preventative interventions. This Science and Society article focuses on the valuable function served by the GeoSentinel surveillance network in defining the range of infections in travellers.


title: Design and Evaluation of a Portable Negative Pressure Hood with HEPA Filtration to Protect Health Care Workers Treating Patients with Transmissible Respiratory Infections

text: BACKGROUND: To mitigate potential exposure of healthcare workers (HCWs) to SARS-CoV-2 via aerosol routes, we have developed a portable hood which not only creates a barrier between HCW and patient, but also utilizes negative pressure with filtration of aerosols by a HEPA filter. MATERIAL AND METHODS: The hood has iris-port openings for access to the patient, and an opening large enough for a patient's head and upper torso. The top of the hood is a HEPA filter connected to a blower to apply negative pressure. We determined the aerosol penetration from outside to inside in laboratory experiments. RESULTS: The penetration of particles from within the hood to the breathing zones of HCWs outside the hood was near 10(-4) (0.01%) in the 200-400 nm size range, and near 10(-3) (0.1%) for smaller particles. Penetration values for particles in the 500 nm – 5 μm range were below 10(-2) (1%). Fluorometric analysis of deposited fluorescein particles on the personal protective equipment of a HCW revealed that negative pressure reduces particle deposition both outside and inside the hood. CONCLUSIONS: We find that negative pressure hoods can be effective controls to mitigate aerosol exposure to HCWs, while simultaneously allowing access to patients.


title: Yeasts in the gastrointestinal tract of preweaned calves and possible involvement of Candida glabrata in neonatal calf diarrhea

text: To examine the possibility of a mycotic involvement in neonatal calf diarrhea (NCD) the presence of fungi was assessed in (a) the intestinal contents of dead calves and fecal samples submitted for routine laboratory examination, (b) fecal specimens, sampled once in winter and once in summer, of calves raised on 2 farms with different management systems, and (c) mucosal scrapings of various segments of the digestive tract of a diarrheic calf, massively shedding Candida glabrata. C. glabrata was the most prevalent fungal species isolated from the routine samples. It was the only fungus which was shed by the calves on the 2 farms, for continuous, more or less prolonged periods, but exclusively in the winter months. Diarrhea and C. glabrata shedding seemed to be associated. C. glabrata colonized the abomasum (the functional equivalent of the monogastric stomach) but not the other segments of the digestive tract of the euthanized calf Based on the findings of this study it seems that while some yeast species may be considered as commensals of the digestive tract of calves, and consequently their isolation from intestinal contents or fecal samples has no clinical significance, others, such as C. glabrata may be involved in enteric pathogenic processes. Moreover, characteristics of the culture, previous chemotherapeutic treatments, the animal's age and possibly climatic conditions should be taken into account before deciding on the fungal isolate's clinical relevance. Determination of mycotic involvement in NCD by routine mycological examination of intestinal contents and fecal samples of diarrheic calves may be useful to avoid unnecessary and potentially harmful antibacterial therapy.


title: Micafungin (FK463), alone or in combination with other systemic antifungal agents, for the treatment of acute invasive aspergillosis

text: Summary Background Micafungin (FK463) is a new lipopeptide compound (echinocandin) with activity against Aspergillus and Candida species. This study evaluated the safety and efficacy of micafungin in patients with proven or probable invasive aspergillosis (IA). Methods A multinational, non-comparative study was conducted to examine proven or probable (pulmonary only) Aspergillus species infection in a wide variety of patient populations. The study employed an open-label design utilizing micafungin alone or in combination with another systemic antifungal agent. Criteria for IA and therapeutic responses were judged by an independent panel. Results Of the 331 patients enrolled, only 225 met diagnostic criteria for IA as determined by the independent panel and received at least one dose of micafungin. Patients included 98/225 who had undergone hematopoietic stem cell transplantation (HSCT) (88/98 allogeneic), 48 with graft versus host disease (GVHD), and 83/225 who had received chemotherapy for hematologic malignancy. A favorable response rate at the end of therapy was seen in 35.6% (80/225) of patients. Of those only treated with micafungin, favorable responses were seen in 6/12 (50%) of the primary and 9/22 (40.9%) of the salvage therapy group, with corresponding numbers in the combination treatment groups of 5/17 (29.4%) and 60/174 (34.5%) of the primary and salvage treatment groups, respectively. Of the 326 micafungin-treated patients, 183 (56.1%) died during therapy or in the 6-week follow-up phase; 107 (58.5%) deaths were attributable to IA. Conclusions Micafungin as primary or salvage therapy proved efficacious and safe in high-risk patients with IA, although patient numbers are small in the micafungin-only groups.


Epidemiological surveillance and comparative analysis of patients with influenza like illness and other respiratory viruses


title: Independent inhibition of the polymerase and deubiquitinase activities of the Crimean-Congo Hemorrhagic Fever Virus full-length L-protein

text: BACKGROUND: The Crimean-Congo hemorrhagic fever virus (CCHFV) is a segmented negative-sense RNA virus that can cause severe human disease. The World Health Organization (WHO) has listed CCHFVas a priority pathogen with an urgent need for enhanced research activities to develop effective countermeasures. Here we adopted a biochemical approach that targets the viral RNA-dependent RNA polymerase (RdRp). The CCHFV RdRp activity is part of a multifunctional L protein that is unusually large with a molecular weight of ~450 kDa. The CCHFV L-protein also contains an ovarian tumor (OTU) domain that exhibits deubiquitinating (DUB) activity, which was shown to interfere with innate immune responses and viral replication. We report on the expression, characterization and inhibition of the CCHFV full-length L-protein and studied both RNA synthesis and DUB activity. METHODOLOGY/PRINCIPLE FINDINGS: Recombinant full-length CCHFV L protein was expressed in insect cells and purified to near homogeneity using affinity chromatography. RdRp activity was monitored with model primer/templates during elongation in the presence of divalent metal ions. We observed a 14-mer full length RNA product as well as the expected shorter products when omitting certain nucleotides from the reaction mixture. The D2517N mutation of the putative active site rendered the enzyme inactive. Inhibition of RNA synthesis was studies with the broad-spectrum antivirals ribavirin and favipiravir that mimic nucleotide substrates. The triphosphate form of these compounds act like ATP or GTP; however, incorporation of ATP or GTP is markedly favored over the inhibitors. We also studied the effects of bona fide nucleotide analogues 2’-deoxy-2’-fluoro-CTP (FdC) and 2’-deoxy-2’-amino-CTP and demonstrate increased inhibitory effects due to higher rates of incorporation. We further show that the CCHFV L full-length protein and the isolated OTU domain cleave Lys48- and Lys63-linked polyubiqutin chains. Moreover, the ubiquitin analogue CC.4 inhibits the CCHFV-associated DUB activity of the full-length L protein and the isolated DUB domain to a similar extent. Inhibition of DUB activity does not affect elongation of RNA synthesis, and inhibition of RNA synthesis does not affect DUB activity. Both domains are functionally independent under these conditions. CONCLUSIONS/SIGNIFICANCE: The requirements for high biosafety measures hamper drug discovery and development efforts with infectious CCHFV. The availability of full-length CCHFV L-protein provides an important tool in this regard. High-throughput screening (HTS) campaigns are now feasible. The same enzyme preparations can be employed to identify novel polymerase and DUB inhibitors.


title: Levels of complexity in pathogen recognition by C-type lectins

text: In pathogen recognition by C-type lectins, several levels of complexity can be distinguished; these might modulate the immune response in different ways. Firstly, the pathogen-associated molecular pattern repertoire expressed at the microbial surface determines the interactions with specific receptors. Secondly, each immune cell type possesses a specific set of pathogen-recognition receptors. Thirdly, changes in the cell-surface distribution of C-type lectins regulate carbohydrate binding by modulating receptor affinity for different ligands. Crosstalk between these receptors results in a network of multimolecular complexes, adding a further level of complexity in pathogen recognition.


title: Targeting of Renin-Angiotensin System In COVID-19 Patients Affected by Stroke: Emerging Concerns About Detrimental vs. Benefit Effect

text: OBJECTIVE: The present short report summarizes some clinical characteristics of six patients affected by stroke while being on angiotensin-converting enzyme (ACE)2 inhibitors and angiotensin II receptor blockers (ARBs) before and during COVID-19. METHODS: Medical charts and images of six patients affected by stroke while being on ACE-Is and ARBs therapy before and during COVID-19 outbreak in Lombardy region, Italy, were reviewed. RESULTS: Three patients had a dural sinus thrombosis, whereas the remaining suffered by an arterial ischemia, which was a middle cerebral artery occlusion in one case, and a posterior-inferior cerebellar artery occlusion in the remaining two. All patients showed clinical features typical of SARS-CoV-2 infection and positive chest CT scan, and were treated with ACE-Is as needed. Hypercoagulability panel was negative in any case. A recovery was achieved in all cases, although in a variable manner. CONCLUSIONS: Whether or not and in which manner the pharmacomodulation of the renin-angiotensin system may had affect the clinical course of the reported six COVID-19 patients affected by stroke has to be still clarified. An urgent need of randomized clinical trials aimed to assess the safety profile and neuroprotective properties of ACE-Is and ARBs in COVID-19 patients diagnosed with stroke does exists.