title: Trends in US approvals: new biopharmaceuticals and vaccines

text: The efficient development and approval of new therapeutics and vaccines is vital to the health and welfare of patients. Tufts Center for the Study of Drug Development has collected and analyzed data for new protein therapeutics and vaccines approved in the USA during the past decade. Our results suggest trends toward longer clinical and approval phases for the therapeutics, particularly for oncology products. In this Opinion article, we discuss various legislative acts and FDA initiatives that might improve the efficiency of drug development and approval. Furthermore, few new vaccines have been approved in the past 10 years owing, at least in part, to the lack of incentives for the development of the products. We predict that this might change in the future as government and industry respond to the twin threats of the global spread of infectious diseases and potential bioterrorism.


title: Inflammasomes and their roles in the pathogenesis of viral hepatitis and their related complications: An updated systematic review

text: Abstract Inflammasomes are a set of innate receptors which are the responsible molecules for activation of pro-interleukin (IL)-1β and IL-18 and induction of inflammation. Due to the key roles of the inflammasomes in the induction of inflammation, it has been hypothesized that the molecules may be the main parts of immune responses against viral infections and the tissue damage. Because some cases of viral hepatitis infections, including hepatitis B and C, are diagnosed as chronic and may be associated with various complications such as liver cirrhosis and hepatocellular carcinoma (HCC), several studies focused on the roles played by the inflammation on the pathogenesis of viral hepatitis. Based on the roles played by inflammasomes in induction of inflammation, it has been hypothesized that inflammasomes may be the main parts of the puzzle of the viral hepatitis complications. This article reviews the roles of the inflammasomes in the pathogenesis of hepatitis B and C viral infections and their complications, liver cirrhosis, and HCC.


title: A core extended naphtalene diimide G-quadruplex ligand potently inhibits herpes simplex virus 1 replication

text: G-quadruplexes (G4s) are nucleic acids secondary structures, epigenetic regulators in cells and viruses. In herpes simplex virus 1 (HSV-1)-infected cells, G4s are massively present during viral replication. We here aimed at investigating the possibility to target the HSV-1 G4s by a core extended naphtalene diimide (c-exNDI) G4 ligand. Biophysical and biomolecular analysis proved that c-exNDI stabilized the HSV-1 G4s in a concentration dependent manner. In MS competition assays, c-exNDI preferentially recognized HSV-1 G4s over cellular telomeric G4s, the most represented G4s within cells; other less abundant cellular G4s were also recognized. Treatment of HSV-1 infected cells with c-exNDI at low nanomolar concentrations induced significant virus inhibition with no cytotoxicity. The mechanism of action was ascribed to G4-mediated inhibition of viral DNA replication, with consequent impairment of viral genes transcription. Our data suggest that the observed potent antiviral activity and low cytotoxicity mainly depend on a combination of c-exNDI affinity for HSV-1 G4s and their massive presence during infection. HSV-1 G4s may thus represent new effective antiviral targets: the fact that no current antiherpetic drug exploits them and their presence at the viral genome, responsible for both active and latent HSV infections, makes them particularly attracting.


title: A step towards gender equity to strengthen the pharmaceutical workforce during COVID-19

text: There is plenty of evidence to support that women leaders are needed in the health and pharmaceutical sectors, although most of the leadership positions in global health are predominantly occupied by men. This is a major challenge to global health policy. Gender diversity and inclusion within the pharmaceutical workforce is integral to optimal patient care. Women continue to be underrepresented in senior and leadership positions within pharmacy, despite outnumbering the men in the global pharmacy workforce. This commentary highlights the need towards gender equity and discusses the several key initiatives that are building momentum and making substantial progress towards this agenda in the pharmaceutical workforce.


title: The coronavirus spread: the Italian case

text: A model based on population growth, chaotic maps, and turbulent flows is applied to the spread of Coronavirus for each Italian region in order to obtain useful information and help to contrast it. We divide the regions into different risk categories and discuss anomalies. The worst cases are confined between the Appenine and the Alps mountain ranges but the situation seem to improve closer to the sea. The Veneto region gave the most efficient response so far and some of their resources could be diverted to other regions, in particular, more tests to the Lombardia, Liguria, Piemonte, Marche and V. Aosta regions, which seem to be worst affected. We noticed worrying anomalies in the Lazio, Campania and Sicilia regions to be monitored. We stress that the number of fatalities we predicted on March 12 has been confirmed daily by the bulletins. This suggests a change of strategy in order to reduce such number maybe moving the weaker population (and negative to the virus test) to beach resorts, which should be empty presently. The ratio deceased/positives on April 4, 2020 is 5.4% worldwide, 12.3% in Italy, 1.4% in Germany, 2.7% in the USA, 10.3% in the UK and 4.1% in China. These large fluctuations should be investigated starting from the Italian regions, which show similar large fluctuations.


title: Mass gathering and globalization of respiratory pathogens during the 2013 Hajj

text: Every year, more than 10 million pilgrims arrive in the Kingdom of Saudi Arabia for the Hajj or Umrah. Crowding conditions lead to high rates of respiratory infections among the pilgrims, representing a significant cause of morbidity and a major cause of hospitalization. Pre- and post-Hajj nasal specimens were prospectively obtained from a paired cohort (692 pilgrims) and from nonpaired cohorts (514 arriving and 470 departing pilgrims) from 13 countries. The countries of residence included Africa (44.2%), Asia (40.2%), the United States (8.4%) and Europe (7.2%). Nasal specimens were tested for 34 respiratory pathogens using RT-PCR. A total of 80 512 PCRs were performed. The prevalence of viruses and bacteria increased, from 7.4% and 15.4% before the Hajj to 45.4% and 31.0% after the Hajj, respectively, due to the acquisition of rhinovirus, coronaviruses (229E, HKU1, OC43), influenza A H1N1, Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus. We did not identify Middle East respiratory coronavirus carriage. At arrival, the prevalence of several viruses was clearly dependent on the pilgrim's country of origin. After Hajj participation, these viruses were isolated among pilgrims from all countries, with few exceptions. No significant differences were observed between paired and nonpaired cohort results. Our results strongly suggest that, given the particularly crowded conditions during the rituals, an international mass gathering such as the Hajj may contribute to the globalization of respiratory pathogens after the cross-contamination of pilgrims harbouring pathogens that easily spread among participants. Influenza and pneumococcal vaccination, face mask use and hand hygiene should be considered in the context of the Hajj.


title: Occupation-Related Respiratory Infections Revisited

text: Occupational pulmonary infectious diseases include tuberculosis (TB) and many viral pathogens, including influenza, coronavirus (severe acute respiratory syndrome or SARS), varicella, respiratory syncytial virus, and hantavirus. This review focuses on TB, influenza, and SARS, because the published literature is extensive for these 3 infections. The lessons from these 3 are relevant for all nosocomial pulmonary infectious diseases.


title: Detection of respiratory viruses in adult patients with perennial allergic rhinitis

text: Abstract Background The symptoms of allergic rhinitis may be worsened by a viral respiratory infection. However, there are few data on the presence of respiratory virus in patients with allergic rhinitis. Objective To evaluate whether patients with allergic rhinitis have an increased frequency of respiratory virus detection in a prospective case–control study. Methods Fifty-eight adult patients diagnosed with perennial allergic rhinitis were evaluated from September 2011 through June 2012. A control group of 61 adult patients without allergy was included. Multiplex polymerase chain reaction was used to detect respiratory viruses in nasal lavage samples. Results Respiratory viruses were detected in 25 of 58 patients (43.1%) with perennial allergic rhinitis, but in only 15 of 61 control patients (24.6%). In virus-positive samples, multiple viruses were detected in 9 of 25 patients (36.0%) with perennial allergic rhinitis but in only 2 of 15 control patients (12.5%). Rhinovirus was the most common virus in patients without allergy and those with allergic rhinitis. There were significant differences in the detection rates of overall and multiple respiratory viruses and rhinovirus between the 2 groups (P < .05). However, in patients with allergic rhinitis, there was no statistically significant association between the detection of respiratory viruses and symptom scores. Conclusion This study shows that there is a high prevalence of respiratory viruses, especially rhinovirus, in patients with allergic rhinitis. Subsequent studies are needed to determine the clinical significance of highly prevalent respiratory viruses in patients with allergic rhinitis.


title: Assembly of pseudorabies virus genome-based transfer vehicle carrying major antigen sites of S gene of transmissible gastroenteritis virus: Potential perspective for developing live vector vaccines

text: Abstract Two severe porcine infectious diseases, pseudorabies (PR) and transmissible gastroenteritis (TGE) caused by pseudorabies virus (PRV) and transmissible gastroenteritis virus (TGEV) respectively often result in serious economic loss in animal husbandry worldwide. Vaccination is the important prevention means against both infections. To achieve a PRV genome-based virus live vector, aiming at further TGEV/PRV bivalent vaccine development, a recombinant plasmid pUG was constructed via inserting partial PK and full-length gG genes of PRV strain Bartha K-61 amplified into pUC119 vector. In parallel, another recombinant pHS was generated by introducing a fragment designated S1 encoding the major antigen sites of S gene from TGEV strain TH-98 into a prokaryotic expression vector pPROEX HTc. The SV40 polyA sequence was then inserted into the downstream of S1 fragment of pHS. The continuous region containing S1fragment, SV40 polyA and four single restriction enzyme sites digested from pHS was subcloned into the downstream of gG promoter of pUG. In addition, a LacZ reporter gene was introduced into the universal transfer vector named pUGS-LacZ. Subsequently, a PRV genome-based virus live vector was generated via homologous recombination. The functionally effective vector was purified and partially characterized. Moreover, the potential advantages of this system are discussed.


title: Prevalence of comorbidities and their association with mortality in patients with COVID‐19: A Systematic Review and Meta‐analysis

text: AIMS: COVID‐19 is a global pandemic that as of the 4th May has registered over 3 585 711 confirmed cases and 248 780 deaths. This review aims to estimate the prevalence of both cardiometabolic and other co‐morbidities in patients with COVID‐19 infection, and to estimate the increased risk of severity and mortality in people with co‐morbidities. MATERIALS AND METHODS: Medline, Scopus and the World Health Organisation (WHO) website for Global research on COVID‐19 were searched from January 2019 up to April 23, 2020. Study inclusion was restricted to English language publications, original articles that reported prevalence of co‐morbidities in individuals with COVID‐19 disease, and case‐series >10 patients. 18 studies were selected for inclusion. Data were analysed using random effects meta‐analysis models. RESULTS: Eighteen studies with a total of 14 558 individuals were identified. The pooled prevalence for co‐morbidities in patients with COVID‐19 disease was 22.9% (95% CI: 15.8 to 29.9) for hypertension; 11.5% (9.7 to 13.4) for diabetes; and 9.7% (6.8 to 12.6) for cardiovascular disease (CVD). For chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), cerebrovascular disease, and cancer, the pooled prevalences were all less than 4%. With the exception of cerebrovascular disease, all other co‐morbidities had a significantly increased risk for having severe COVID‐19. In addition, the risk of mortality was significantly increased in individuals with CVD, COPD, CKD, cerebrovascular disease, and cancer. CONCLUSIONS: In individuals with COVID‐19, the presence of co‐morbidities (both cardiometabolic and other) is associated with a higher risk of severe COVID‐19 and mortality. These findings have important implications for the public health with regards to risk stratification and future planning. This article is protected by copyright. All rights reserved.


title: Exosomal vaccines containing the S protein of the SARS coronavirus induce high levels of neutralizing antibodies

text: Abstract Infection with the SARS-associated coronavirus (SARS-CoV) induces an atypical pulmonary disease with a high lethality rate. Although the initial SARS epidemic was contained, sporadic outbreaks of the disease still occur, suggesting a continuous need for a vaccine against this virus. We therefore explored exosome-based vaccines containing the spike S proteins of SARS-CoV. S-containing exosomes were obtained by replacing the transmembrane and cytoplasmic domains of the S protein by those of VSV-G. The immunogenicity and efficacy of the S-containing exosomes were tested in mice and compared to an adenoviral vector vaccine expressing the S protein. Both, S-containing exosomes and the adenoviral vector vaccine induced neutralizing antibody titers. After priming with the SARS-S exosomal vaccine and boosting with the adenoviral vector the neutralizing antibody titers exceeded those observed in the convalescent serum of a SARS patient. Both approaches were effective in a SARS-S-expressing tumor challenge model and thus warrant further investigation.


title: Guidance for Resumption of Routine Electrodiagnostic Testing during the COVID‐19 Pandemic

text: As the world accommodates to the COVID‐19 pandemic, routine in‐person medical services are resuming. The resumption of non‐urgent electrodiagnostic (EDX) testing faces unique challenges due to the long duration of the procedure and direct close contact with patients, including studies with risk of exposure to oropharyngeal secretions. We provide consensus guidance for resumption of EDX testing, addressing scheduling, patient arrival and registration, use of personal protective equipment, COVID‐19 screening and testing, the performance of EDX in outpatient and inpatient settings, cleaning and maintenance of the EDX equipment and laboratory, balancing trainee safety and training requirements, and patient care issues. These are broad recommendations which need to be adapted to local COVID‐19 risks, institutional guidelines and policies, and changing federal, state and local regulations, and to changes in the pandemic over time. This article is protected by copyright. All rights reserved.


title: Chemokine expression and viral infection of the central nervous system: Regulation of host defense and neuropathology

text: An effective host response against viral infection of the central nervous system (CNS) is the principal factor dictating the outcome of infection. It is the responsibility of the immune response to contain and control viral replication. Paradoxically, it is the immune response that may also contribute to the development of neuropathology. We have used mouse hepatitis virus (MHV), a positive-strand RNA virus, infection of the CNS to understand the dynamic interaction between viral replication, protection, and pathology with an emphasis on understanding how chemokines participate in these interrelated processes. Herein, we demonstrate the complexity of the chemokine response to MHV infection of the CNS and the delicate balance that exists between host defense and development of disease.


title: Degradation of thymic humoral factor 2 in human, rat and mouse blood: An experimental and theoretical study

text: The degradation of the immunomodulatory octapeptide, thymic humoral factor γ2 (THF-γ2, thymoctonan) has been studied in whole blood samples from human, rat and mouse. The peptide, Leu-Glu-Asp-Gly-Pro-Lys-Phe-Leu, was shown to be rapidly degraded by peptidases. The half-life of the intact peptide was less than 6 min at 37 °C in blood from the three species tested. The main fragments formed from THF-γ2 were found to be Glu-Asp-Gly-Pro-Lys-Phe-Leu (2–8), Asp-Gly-Pro-Lys-Phe-Leu (3–8) and Glu-Asp-Gly-Pro-Lys (2–6) in human and in rat blood and 2–8 and 2–6 in mouse blood. Analysis of the time course of degradation revealed a sequential removal of single amino acids from the N-terminus (aminopeptidase activities) in a process that was apparently unable to cleave the Gly-Pro bond (positions 4–5 in the peptide) together with an independent cleavage of the Lys-Phe bond (positions 6–7 in the peptide) to release the dipeptide Phe-Leu. This behaviour and the effects of inhibitors showed the involvement of metallo-exopeptidases in the N-terminal digestion and a phosphoramidon-sensitive metallo-endopeptidase in the cleavage of the Lys-Phe bond. The degradation patterns in human blood were modelled in terms of the competing pathways involved approximating to first-order kinetics, and an analytical solution obtained via the method of Laplace Transforms. The half-life of THF degradation in whole rat blood sample was found to be significantly lower than in human or mouse.


title: Post‐Acute Care Preparedness in a COVID‐19 World

text: Coronavirus disease 2019 (COVID‐19) has led to a surge of patients requiring post‐acute care. In order to support federal, state and corporate planning, we offer a four‐stage regionally oriented approach to achieving optimal systemwide resource allocation across a region's post‐acute service settings and providers over time. In the first stage, the post‐acute care system must, to the extent possible, help relieve acute hospitals of non‐COVID‐19 patients to create as much inpatient capacity as possible over the surge period. In the second stage after the initial surge as subsided, post‐acute providers must protect vulnerable populations from COVID‐19, prepare treat‐in‐place protocols for non‐COVID‐19 admissions, and create and formalize COVID‐19 specific settings. In the third stage after a vaccine has been developed or an effective prophylactic option is available, post‐acute care providers must assist with distribution and administration of vaccinations and prophylaxis, develop strategies to deliver non‐COVID‐19 related medical care, and begin to transition to the post‐COVID‐19 landscape. In the final stage, we must create health advisory bodies to review post‐acute sector's response, identify opportunities to improve performance going forward, and develop a pandemic response plan for post‐acute care providers.


title: Counting the cost of COVID-19

text: Coronavirus disease 2019 (COVID-19) is the name given by the World Health Organization (WHO) to the highly contagious and infectious disease caused by the Novel Corona Virus or SARS-CoV-2, which was first reported on 31 December 2019 in Wuhan city of the capital of China's Hubei province. Due to the rapid increase in the number of infections worldwide, the WHO in March 2020, declared COVID-19 as a pandemic. Historically, first coronavirus had surfaced in 1965 with symptoms of common cold. Since then five different strands of this virus have emerged, most lethal of them was the Severe Acute Respiratory Syndrome (SARS), which infected about eight thousand people, killing ten percent of them. The COVID-19 is not the most deadly pandemic world has ever witnessed as the Spanish influenza pandemic, during 1918–19, killed more than fifty million people. Indeed COVID-19 has turned out to be the most lethal of all coronaviruses as it has infected at least three million people killing more than two hundred thousands of them in the first 4 months of its spread. Many politicians and social scientists have dubbed the depression, being caused by COVID-19, worse than that caused by the Second World War. In this article, we shall analyze economic, social, cultural, educational and political impact of the COVID-19.


title: Viral and Bacterial Etiologies of Acute Respiratory Infections Among Children Under 5 Years in Senegal

text: Acute respiratory infections (ARIs) are the leading cause of infectious disease–related morbidity, hospitalization, and morbidity among children worldwide. This study aimed to assess the viral and bacterial causes of ARI morbidity and mortality in children under 5 years in Senegal. Nasopharyngeal samples were collected from children under 5 years who had ARI. Viruses and bacteria were identified using multiplex real-time reverse transcription-polymerase chain reaction and conventional biochemical techniques, respectively. Adenovirus was the most prevalent virus (50%; n = 81), followed by influenza virus (45.68%, n = 74), rhinovirus (40.12%; n = 65), enterovirus (25.31%; n = 41), and respiratory syncytial virus (16.05%; n = 26), whereas Streptococcus pneumoniae (17%; n = 29), Moraxella catarrhalis (15.43%; n = 25), and Haemophilus influenzae (8.02%; n = 13) were the most commonly isolated bacteria. Virus pathogens seem more likely to be more prevalent in our settings and were often associated with bacteria and S. pneumoniae (6%; 16) coinfection.


title: Induction of protective immunity against severe acute respiratory syndrome coronavirus (SARS-CoV) infection using highly attenuated recombinant vaccinia virus DIs

text: Abstract SARS-coronavirus (SARS-CoV) has recently been identified as the causative agent of SARS. We constructed a series of recombinant DIs (rDIs), a highly attenuated vaccinia strain, expressing a gene encoding four structural proteins (E, M, N and S) of SARS-CoV individually or simultaneously. These rDIs elicited SARS-CoV-specific serum IgG antibody and T-cell responses in vaccinated mice following intranasal or subcutaneous administration. Mice that were subcutaneously vaccinated with rDIs expressing S protein with or without other structural proteins induced a high level of serum neutralizing IgG antibodies and demonstrated marked protective immunity against SARS-CoV challenge in the absence of a mucosal IgA response. These results indicate that the potent immune response elicited by subcutaneous injection of rDIs containing S is able to control mucosal infection by SARS-CoV. Thus, replication-deficient DIs constructs hold promise for the development of a safe and potent SARS vaccine.


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title: Japan ECMOnet for COVID-19: telephone consultations for cases with severe respiratory failure caused by COVID-19

text: Recently, the novel coronavirus disease 2019 (COVID-19) started spreading in Japan. Therefore, the number of patients with severe COVID-19 requiring extracorporeal membranous oxygenation (ECMO) is expected to increase. A working group has been formed to provide telephone consultation services for cases with severe respiratory failure caused by COVID-19 in Japan. During the first 13 days of the service, there were 12 consultations. For each consultation, we advised the patient on the initiation of ECMO and arranged transportation for patients with ECMO. Based on experience from the H1N1 influenza pandemic, transporting patients to experienced facilities is essential to obtain better outcomes.


title: Organelle dynamics and viral infections: at cross roads

text: Abstract Viruses are obligate intracellular parasites of the host cells. A commonly accepted view is the requirement of internal membranous structures for various aspects of viral life cycle. Organelles enable favourable intracellular environment for several viruses. However, studies reporting organelle dynamics upon viral infections are scant. In this review, we aim to summarize and highlight modulations caused to various organelles upon viral infection or expression of its proteins.


title: miR‐223: infection, inflammation and cancer

text: Expression of the microRNA miR‐223 is deregulated during influenza or hepatitis B infection and in inflammatory bowel disease, type 2 diabetes, leukaemia and lymphoma. Although this may also be the result of the disease per se, increasing evidence suggests a role for miR‐223 in limiting inflammation to prevent collateral damage during infection and in preventing oncogenic myeloid transformation. Validated targets for miR‐223 that have effects on inflammation and infection include granzyme B, IKKα, Roquin and STAT3. With regard to cancer, validated targets include C/EBPβ, E2F1, FOXO1 and NFI‐A. The effect of miR‐223 on these targets has been documented individually; however, it is more likely that miR‐223 affects multiple targets simultaneously for key processes where the microRNA is important. Such processes include haematopoietic cell differentiation, particularly towards the granulocyte lineage (where miR‐223 is abundant) and as cells progress down the myeloid lineage (where miR‐223 expression decreases). NF‐κB and the NLRP3 inflammasome are important inflammatory mechanisms that are dampened by miR‐223 in these cell types. The miRNA can also directly target viruses such as HIV, leading to synergistic effects during infection. Here we review the recent studies of miR‐223 function to show how it modulates inflammation, infection and cancer development.


title: Virus Taxonomy

text: Abstract Virus taxonomy is the classification of viruses into categories called taxa and the development and implementation of a standardized nomenclature for taxa. Whereas virus taxonomy has been a niche subspecialty over many decades, the field has recently gained importance due to the exponentially increasing number of new viruses discovered by next-generation sequencing methods. The expanded known global virome and associated viral genome sequence space gradually morph virus taxonomy from a phenotype-based and inherently subjective process, focussing on shared or distinct, often arbitrarily chosen biophysical characteristics of virions to a significant subspecialty of systematic evolutionary biology. Indeed, current virus classification is increasingly performed using ever more complex phylogenetic approaches that move researchers closer to a rudimentary understanding of the origin, evolution, relatedness, and diversification of viruses over eons.


title: A Conserved Histidine in the RNA Sensor RIG-I Controls Immune Tolerance to N(1)-2′O-Methylated Self RNA

text: The cytosolic helicase retinoic acid-inducible gene-I (RIG-I) initiates immune responses to most RNA viruses by detecting viral 5′-triphosphorylated RNA (pppRNA). Although endogenous mRNA is also 5′-triphosphorylated, backbone modifications and the 5′-ppp-linked methylguanosine ((m7)G) cap prevent immunorecognition. Here we show that the methylation status of endogenous capped mRNA at the 5′-terminal nucleotide (N(1)) was crucial to prevent RIG-I activation. Moreover, we identified a single conserved amino acid (H830) in the RIG-I RNA binding pocket as the mediator of steric exclusion of N(1)-2′O-methylated RNA. H830A alteration (RIG-I(H830A)) restored binding of N(1)-2′O-methylated pppRNA. Consequently, endogenous mRNA activated the RIG-I(H830A) mutant but not wild-type RIG-I. Similarly, knockdown of the endogenous N(1)-2′O-methyltransferase led to considerable RIG-I stimulation in the absence of exogenous stimuli. Studies involving yellow-fever-virus-encoded 2′O-methyltransferase and RIG-I(H830A) revealed that viruses exploit this mechanism to escape RIG-I. Our data reveal a new role for cap N(1)-2′O-methylation in RIG-I tolerance of self-RNA.


title: B cell homeostasis and follicle confines are governed by fibroblastic reticular cells

text: Fibroblastic reticular cells (FRCs) are known to inhabit T cell-rich areas of lymphoid organs where they function to coordinate T cell and dendritic cell interactions. However, in vivo manipulation of FRCs has been limited by a dearth of genetic tools targeting this lineage. Here, using a mouse model to conditionally ablate FRCs, we demonstrate their indispensable role in anti-viral T cell responses. Unexpectedly, FRC loss also attenuated humoral immunity due to impaired B cell viability and follicular organization. Follicle-resident FRCs established a favorable niche for B lymphocytes via production of the cytokine BAFF. Thus, our study indicates that adaptive immunity requires an intact FRC network and illuminates a subset of FRCs that controls B cell homeostasis and follicle identity.


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title: Mutational and inhibitive analysis of SARS coronavirus 3C-like protease by fluorescence resonance energy transfer-based assays

text: Abstract The 3C-like protease (3CLpro) of severe acute respiratory syndrome coronavirus (SARS-CoV) plays key roles in viral replication and is an attractive target for anti-SARS drug discovery. In this report, a fluorescence resonance energy transfer (FRET)-based method was developed to assess the proteolytic activity of SARS-CoV 3CLpro. Two internally quenched fluorogenic peptides, 1NC and 2NC, corresponding to the N-terminal and the C-terminal autocleavage sites of SARS-CoV 3CLpro, respectively, were used as substrates. SARS-CoV 3CLpro seemed to work more efficiently on 1NC than on 2NC in trans-cleavage assay. Mutational analysis demonstrated that the His41 residue, the N-terminal 7 amino acids, and the domain III of SARS-CoV 3CLpro were important for the enzymatic activity. Antibodies recognizing domain III could significantly inhibit the enzymatic activity of SARS-CoV 3CLpro. The effects of class-specific protease inhibitors on the trans-cleavage activity revealed that this enzyme worked more like a serine protease rather than the papain protease.


title: Risk Factors for MERS-CoV Seropositivity among Animal Market and Slaughterhouse Workers, Abu Dhabi, United Arab Emirates, 2014–2017

text: Camel contact is a recognized risk factor for Middle East respiratory syndrome coronavirus (MERS-CoV) infection. Because specific camel exposures associated with MERS-CoV seropositivity are not fully understood, we investigated worker–camel interactions and MERS-CoV seroprevalence. We assessed worker seroprevalence in 2 slaughterhouses and 1 live-animal market in Abu Dhabi, United Arab Emirates, during 2014–2017 and administered an epidemiologic survey in 2016 and 2017. Across 3 sampling rounds during 2014–2017, we sampled 100–235 workers, and 6%–19% were seropositive for MERS-CoV at each sampling round. One (1.4%) of 70 seronegative workers tested at multiple rounds seroconverted. On multivariable analyses, working as a camel salesman, handling live camels or their waste, and having diabetes were associated with seropositivity among all workers, whereas handling live camels and either administering medications or cleaning equipment was associated with seropositivity among market workers. Characterization of high-risk exposures is critical for implementation of preventive measures.


title: Novel Betacoronavirus in Dromedaries of the Middle East, 2013

text: In 2013, a novel betacoronavirus was identified in fecal samples from dromedaries in Dubai, United Arab Emirates. Antibodies against the recombinant nucleocapsid protein of the virus, which we named dromedary camel coronavirus (DcCoV) UAE-HKU23, were detected in 52% of 59 dromedary serum samples tested. In an analysis of 3 complete DcCoV UAE-HKU23 genomes, we identified the virus as a betacoronavirus in lineage A1. The DcCoV UAE-HKU23 genome has G+C contents; a general preference for G/C in the third position of codons; a cleavage site for spike protein; and a membrane protein of similar length to that of other betacoronavirus A1 members, to which DcCoV UAE-HKU23 is phylogenetically closely related. Along with this coronavirus, viruses of at least 8 other families have been found to infect camels. Because camels have a close association with humans, continuous surveillance should be conducted to understand the potential for virus emergence in camels and for virus transmission to humans.


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title: Development and evaluation of an antigen-capture ELISA for detection of the UL24 antigen of the duck enteritis virus, based on a polyclonal antibody against the UL24 expression protein

text: Abstract An antigen-capture enzyme-linked immunosorbent assay (AC-ELISA) method was developed for the efficient detection of the UL24 antigen of the duck enteritis virus (DEV) using polyclonal antibodies. Ducks and rabbits were immunized, respectively, with expressed UL24 recombinant protein. The IgG antibodies against UL24 from ducks and rabbits were purified and used as the capture antibodies. The specificity of the optimized AC-ELISA was evaluated by use of DEV, duck hepatitis virus (DHV), duck hepatitis B virus (DHBV), gosling plague virus (GPV), Riemerella anatipestifer (R.A.), Escherichia coli (E. coli), Pasteurella multocida (P.M.) and Salmonella Enteritidis (S.E.). Only DEV specimens yielded a specific and strong signal. The limit of the sensitivity of this method for the detection of DEV was 46ng/100μl. Compared with PCR and virus isolation, the rate of agreement for the detection of experimentally infected sera was 100%. A comparative test used on clinical specimens between the neutralization test and the AC-ELISA showed that the proportions of true positives and true negatives by the AC-ELISA were 0.90 and 0.67 respectively. These results indicated that the AC-ELISA approach is rapid, sensitive, and reliable for specific detection of DEV antigen.


title: Temporal variation of human encounters and the number of locations in which they occur: a longitudinal study of Hong Kong residents

text: Patterns of social contact between individuals are important for the transmission of many pathogens and shaping patterns of immunity at the population scale. To refine our understanding of how human social behaviour may change over time, we conducted a longitudinal study of Hong Kong residents. We recorded the social contact patterns for 1450 individuals, up to four times each between May 2012 and September 2013. We found individuals made contact with an average of 12.5 people within 2.9 geographical locations, and spent an average estimated total duration of 9.1 h in contact with others during a day. Distributions of the number of contacts and locations in which contacts were made were not significantly different between study waves. Encounters were assortative by age, and the age mixing pattern was broadly consistent across study waves. Fitting regression models, we examined the association of contact rates (number of contacts, total duration of contact, number of locations) with covariates and calculated the inter- and intra-participant variation in contact rates. Participant age was significantly associated with the number of contacts made, the total duration of contact and the number of locations in which contact occurred, with children and parental-age adults having the highest rates of contact. The number of contacts and contact duration increased with the number of contact locations. Intra-individual variation in contact rate was consistently greater than inter-individual variation. Despite substantial individual-level variation, remarkable consistency was observed in contact mixing at the population scale. This suggests that aggregate measures of mixing behaviour derived from cross-sectional information may be appropriate for population-scale modelling purposes, and that if more detailed models of social interactions are required for improved public health modelling, further studies are needed to understand the social processes driving intra-individual variation.


title: Lack of Protection Against Ebola Virus from Chloroquine in Mice and Hamsters

text: The antimalarial drug chloroquine has been suggested as a treatment for Ebola virus infection. Chloroquine inhibited virus replication in vitro, but only at cytotoxic concentrations. In mouse and hamster models, treatment did not improve survival. Chloroquine is not a promising treatment for Ebola. Efforts should be directed toward other drug classes.


title: Animal Health Equipment Management

text: Proper health equipment management requires significant attention to detail. Establishing and following protocols during processing (eg, cleaning and disinfecting equipment at the end of the work day) is required to ensure a safe product that is free of defects and residues. Overall cleanliness of equipment and facilities is important not only from a food safety standpoint but many view these as an overall indicator of attention to detail in the entire production system. Ensuring that needles are changed, implant guns are managed properly, vaccine is handled in an acceptable manner, and that proper chute operation occurs is essential.


docid: vfagxsdz

title: Seasonality of respiratory viruses causing hospitalizations for acute respiratory infections in children in Nha Trang, Vietnam

text: Abstract Background Acute respiratory infections (ARIs) are the most common causes of death in children under 5 years of age. While the etiology of most pneumonia and ARI episodes is undiagnosed, a broad range of ARI-causing viruses circulate widely in South East Asia. However, the patterns and drivers of the seasonal transmission dynamics are largely unknown. Here we identify the seasonal patterns of multiple circulating viruses associated with hospitalizations for ARIs in Nha Trang, Vietnam. Methods Hospital based enhanced surveillance of childhood ARI is ongoing at Khanh Hoa General Hospital in Nha Trang. RT-PCR was performed to detect 13 respiratory viruses in nasopharyngeal samples from enrolled patients. Seasonal patterns of childhood ARI hospital admissions of various viruses were assessed, as well as their association with rainfall, temperature, and dew point. Results Respiratory syncytial virus peaks in the late summer months, and influenza A in April to June. We find significant associations between detection of human parainfluenza 3 and human rhinovirus with the month's mean dew point. Using a cross-wavelet transform we find a significant out-of-phase relationship between human parainfluenza 3 and temperature and dew point. Conclusions Our results are important for understanding the temporal risk associated with circulating pathogens in Southern Central Vietnam. Specifically, our results can inform timing of routing seasonal influenza vaccination and for when observed respiratory illness is likely viral, leading to judicious use of antibiotics in the region.


title: Studies in a Murine Model Confirm the Safety of Griffithsin and Advocate Its Further Development as a Microbicide Targeting HIV-1 and Other Enveloped Viruses

text: Griffithsin (GRFT), a lectin from Griffithsia species, inhibits human immunodeficiency virus-1 (HIV-1) replication at sub-nanomolar concentrations, with limited cellular toxicity. However, in vivo safety of GRFT is not fully understood, especially following parenteral administration. We first assessed GRFT’s effects in vitro, on mouse peripheral blood mononuclear cell (mPBMC) viability, mitogenicity, and activation using flow-cytometry, as well as cytokine secretion through enzyme-linked immunosorbent assay (ELISA). Toxicological properties of GRFT were determined after a single subcutaneous administration of 50 mg/kg or 14 daily doses of 10 mg/kg in BALB/c mice. In the context of microbicide development, toxicity of GRFT at 2 mg/kg was determined after subcutaneous, intravaginal, and intraperitoneal administrations, respectively. Interestingly, GRFT caused no significant cell death, mitogenicity, activation, or cytokine release in mPBMCs, validating the usefulness of a mouse model. An excellent safety profile for GRFT was obtained in vivo: no overt changes were observed in animal fitness, blood chemistry or CBC parameters. Following GRFT treatment, reversible splenomegaly was observed with activation of certain spleen B and T cells. However, spleen tissues were not pathologically altered by GRFT (either with a single high dose or chronic doses). Finally, no detectable toxicity was found after mucosal or systemic treatment with 2 mg/kg GRFT, which should be further developed as a microbicide for HIV prevention.


title: A unique water optional health care personnel handwash provides antimicrobial persistence and residual effects while decreasing the need for additional products

text: BACKGROUND: The Centers for Disease Control and Prevention (CDC) has published guidelines for hand hygiene practices, recommending a handwash regimen that alternates between waterless alcohol products and antimicrobial or nonantimicrobial soap and water. The advent of an alcohol-based product that can be used with or without water (ie, water optional) to decontaminate the hands while providing immediacy of kill and antimicrobial persistence could reduce the confusion associated with handwash guidelines. Such a product has been developed, is alcohol-based (61%), and zinc pyrithione (ZPT) preserved (61% alcohol-ZPT) and has proven to be fully compliant with the Food and Drug Administration (FDA) and CDC guidelines. METHODS: FDA-required testing of the 61% alcohol-ZPT product for the health care personnel handwash indication was performed as outlined in the Tentative Final Monograph (TFM) for Health-Care Antiseptic Drug Products, employing waterless and water-aided product applications. It was next assessed for antimicrobial persistence and residual effects by comparing it, in separate waterless and water-aided applications, with commonly available handwashes containing various antimicrobials in a 5-day study employing 49 subjects, in which samples were collected immediately and at 4 hours and 8 hours postapplication. The skin conditioning properties of this formulation were investigated via appropriate methods. RESULTS: The 61% alcohol-ZPT product easily produced >3.0 log(10) reduction in the indicator strain (Serratia marcescens) following the first wash, exceeding the 2.0 log(10) FDA requirement. This level of performance was maintained through the tenth wash, surpassing the 3.0 log(10) FDA requirement for the handwash indication. For the assessment of persistence and residual effect in the waterless mode, the water-optional, 61% alcohol-ZPT product consistently produced log(10) reductions of nearly 3.5 or greater at every point over the entire study period. In the water-aided configuration, similar results were obtained as log(10) reductions of 2.5 were observed. The formulation is nonirritating, actually contributing to hand skin condition. CONCLUSIONS: The 61% alcohol-ZPT product exceeds all FDA criteria for the health care personnel handwash indication and is a significant advancement in the concept of skin antisepsis. It represents a single product suitable for use in all hand hygiene settings, demonstrating improved antimicrobial persistence and residual effects. The 61% alcohol-ZPT formulation contributes positively to overall hand conditioning, and a previously reported study has documented it to be virucidal for several DNA and RNA viruses.


title: Immunogenicity and protective efficacy in monkeys of purified inactivated Vero-cell SARS vaccine

text: BACKGROUND: In 2003, severe acute respiratory syndrome (SARS) resulted in hundreds of infections and deaths globally. We aim to assess immunogenicity and protective efficacy of purified inactivated Vero-cell SARS vaccine in monkeys. METHODS: The cultures of SARS coronavirus (SARS-CoV) BJ-01 strain infected Vero cells were inactivated with β-propiolactone. Sequential procedures, including ultrafiltration, gel filtration and ion exchange chromatography, were performed to obtain purified inactivated SARS vaccine. The purified SARS vaccine was analyzed with electron microscope, HPLC and Western blotting. We immunized three groups of cynomolgus macaques fascicularis with adjuvant-containing purified vaccine, purified vaccine and unpurified vaccine, respectively, and a fourth group served as a control. Antibody titers were measured by plaque reduction neutralization test. The vaccinated monkeys were challenged with SARS-CoV BJ-01 strain to observe protective efficacy. Additionally, three groups of rhesus monkeys were immunized with different doses of the purified inactivated SARS vaccine (0.5, 1 and 2 μg/time/monkey) on days 0 and 7, and the monkeys were challenged with SARS-CoV GZ-01 strain. We assessed the safety of the SARS vaccine and observed whether the antibody dependent enhancement (ADE) occurred under low levels of neutralizing antibody in rhesus. FINDINGS: The purity of SARS vaccine was 97.6% by HPLC identification and reacted with convalescent sera of SARS patients. The purified SARS vaccine induced high levels of neutralizing antibodies and prevented the replication of SARS-CoV in monkeys. Under low levels of neutralizing antibody, no exacerbation of clinical symptoms was observed when the immunized monkeys were challenged with SARS-CoV. In this preliminary animal trial, no side effects were detected when monkeys were immunized with purified SARS vaccine either at normal or large doses. INTERPRETATION: The purified inactivated SARS vaccine could induce high levels of neutralizing antibody, and protect the monkeys from the challenge of SARS-CoV. The SARS vaccine prepared in the study appeared to be safe in monkeys.


title: Dynamic profile for the detection of anti-SARS-CoV-2 antibodies using four immunochromatographic assays

text: Abstract In order to fight the SARS-CoV-2 pandemic infection, there is a growing need and demand for diagnostic tools that are complementary and different from the RT-PCR currently in use. Multiple serological tests are or will be very soon available but need to be evaluated and validated. We have thus tested 4 immunochromatographic tests for the detection of antibodies to SARS-CoV-2. In addition, we assessed the kinetics of antibody appearance using these assays in 22 patients after they were tested positive by RT-PCR. We observed great heterogeneity in antiboy detection post-symptom onset. The median antibody detection time was between 8 and 10 days according to the manufacturers. All the tests showed a sensitivity of 60 to 80% on day 10 and 100% on day 15. In addition, a single cross-reaction was observed with other human coronavirus infections. Thus, immunochromatographic tests for the detection of anti-SARS-CoV-2 antibodies may have their place for the diagnostic panel of COVID-19.


title: Observing and quantifying airflows in the infection control of aerosol- and airborne-transmitted diseases: an overview of approaches

text: Summary With concerns about the potential for the aerosol and airborne transmission of infectious agents, particularly influenza, more attention is being focused on the effectiveness of infection control procedures to prevent hospital-acquired infections by this route. More recently a number of different techniques have been applied to examine the temporal–spatial information about the airflow patterns and the movement of related, suspended material within this air in a hospital setting. Closer collaboration with engineers has allowed clinical microbiologists, virologists and infection control teams to assess the effectiveness of hospital isolation and ventilation facilities. The characteristics of human respiratory activities have also been investigated using some familiar engineering techniques. Such studies aim to enhance the effectiveness of such preventive measures and have included experiments with human-like mannequins using various tracer gas/particle techniques, real human volunteers with real-time non-invasive Schlieren imaging, numerical modelling using computational fluid dynamics, and small scale physical analogues with water. This article outlines each of these techniques in a non-technical manner, suitable for a clinical readership without specialist airflow or engineering knowledge.


title: Cardiac involvement in recovered COVID-19 patients identified by magnetic resonance imaging

text: Abstract Objective To evaluate cardiac involvement in recovered COVID-19 patients using cardiac MRI. Background Myocardial injury caused by COVID-19 was previously reported in hospitalized patients. It is unknown if there is sustained cardiac involvement after patients’ recovery from COVID-19. Methods Twenty-six recovered COVID-19 patients that reported cardiac symptoms and underwent MRI exams were retrospectively included. MRI protocols consisted of conventional sequences (cine, T2WI, LGE), and quantitative mapping sequences (T1, T2, and ECV mapping). Edema ratio and LGE were assessed in post-COVID-19 patients. Cardiac function, native T1/T2, and ECV were quantitatively evaluated and compared with controls. Results Fifteen patients (58%) had abnormal MRI findings on conventional MRI sequences: myocardial edema was found in 14 (54%) patients and LGE was found in 8 (31%) patients. Decreased RV functional parameters including EF, CI, and SV/ BSA were found in patients with positive conventional MRI findings. Using quantitative mapping, global native T1, T2, and ECV were all found to be significantly elevated in patients with positive conventional MRI findings, compared to patients without positive findings and controls (median [IQR], native T1 1271ms [1243-1298] vs 1237ms [1216-1262] vs 1224ms [1217-1245]; mean [SD], T2 42.7ms [3.1] vs 38.1ms [2.4] vs 39.1ms [3.1]; median [IQR], 28.2% [24.8-36.2] vs 24.8% [23.1-25.4] vs 23.7% [22.2-25.2]; p=0.002, p <0.001, and p =0.002, respectively). Conclusions Cardiac involvement was found in a proportion of the recovered COVID-19 patients. MRI manifestation included myocardial edema, fibrosis, and impaired RV function. Attention should be paid to the possible myocardial involvement in recovered COVID-19 patients with cardiac symptoms.


title: Prevalence and correlates of PTSD and depressive symptoms one month after the outbreak of the COVID-19 epidemic in a sample of home-quarantined Chinese university students

text: BACKGROUND: : When COVID-19 emerged in China in late 2019, most citizens were home-quarantined to prevent the spread of the virus. This study explored the prevalence of post-traumatic stress disorder (PTSD) and depression in a sample of home-quarantined college students to identify the psychological distress risk factors. METHOD: : The PTSD and depressive symptoms in the 2485 participants from 6 universities were investigated using online survey versions of the PTSD Checklist Civilian Version and the 9-question Patient Health Questionnaires (PHQ-9), and data on sleep durations, exposure, home-quarantine time and socio-demographic variables were also collected. RESULTS: : The PTSD and depression prevalence were found to be 2.7% and 9.0%. Subjectively, feeling extreme fear was the most significant risk factor for psychological distress, followed by short sleep durations, being in their graduating year (4(th) year) and living in severely afflicted areas. Sleep durations was a mediator between exposures and mental health problems. CONCLUSIONS: : The results suggested that the psychological consequences of the COVID-19 could be serious. Psychological interventions that reduce fear and improve sleep durations need to be made available to the home-quarantined university students, and graduating students and those in the worst-hit areas should be given priority focus.


title: Advice regarding COVID‐19 and use of immunomodulators, in patients with severe dermatological diseases

text: Coronavirus disease 2019 (COVID-19) is the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as named by the International Committee on Taxonomy of Viruses (ICTV). There is very limited evidence base to formulate specific advice for dermatology patients on immunomodulators with regards to COVID-19. The following is based on expert opinion, taking into account known risks of influenza (a negative sense single-stranded RNA virus) and other, positive-sense single-stranded, RNA virus infections (such as SARS, MERS, and the common cold). An Australia/New Zealand consensus document is in development.


title: Effect of Feline Interferon‐Omega on the Survival Time and Quality of Life of Cats with Feline Infectious Peritonitis

text: Background: There is no therapy with proven efficacy to treat cats with feline infectious peritonitis (FIP). Hypothesis: Feline interferon‐omega (FeIFN‐ω) prolongs survival time and increases quality of life in cats with FIP. Animals: Thirty‐seven privately owned cats were subjects of this study. Methods: The study was performed as a placebo‐controlled double‐blind trial. Feline infectious peritonitis was confirmed by histology or immunostaining of feline coronavirus (FCoV) antigen in effusion or tissue macrophages or both. The cats were randomly selected for treatment with either FeIFN‐to or a placebo. All cats received adjunctive treatment with glucocorticoids and antibiotics and passive immunization with Feliserin. Results: There was no statistically significant difference in the survival time of cats treated with FeIFN‐ω versus placebo or in any other variable evaluated (with the exception of the lymphocyte count). The cats survived between 3 and 200 days (median, 9 days). There was only 1 long‐term survivor (>3 months), and the cat was in the FeIFN‐ω group. Conclusion and Clinical Relevance: No effect of FeIFN‐ω on survival time or quality of life could be demonstrated in this study.


Reflections and new developments within the COVID‐19 pandemic


title: Effective factors in expansion of medical tourism in Iran

text: Background: Medical tourism (MT) refers to circumstances in which people travel for medical treatments. The present study focuses on determining factors affecting MT in Iran. Methods: The study uses a mixed method approach. Initially, through a qualitative study, 12 experts were interviewed deeply; then, 22 participants in three equal focus groups expressed their ideas about growth and development of MT in Iran. Based on the expressed ideas, 120 factors were identified and accordingly a structured questionnaire was developed. Some members from the focus groups confirmed the questionnaire’s face and content validity. The reliability of pertinent items was confirmed using Cronbach’s alpha=0.8. Afterwards, 61 eligible subjects filled out this questionnaire. Results: The findings showed that "healthcare quality" and "high level of expertise" are two most attractive factors in MT. However, other factors such as "healthcare costs", and "visa facilities" are among key factors as well. Also, the role of "the healthcare providers" was found to be more prominent than the roles of "the government" and "the general tourist services". Conclusion: Although some attractive MT factors are present currently, MT expansion to a desirable level in Iran requires a comprehensive plan of which its factors were discussed in this paper.


Chapter 88 Middle Ear and Eustachian Tube


title: Out Patient Department practices in orthopaedics amidst COVID-19: The evolving model

text: Severe Acute Respiratory Syndrome COVID-19 was declared as a pandemic on 11(th) March 2020 by the World Health Organization and consequent lockdown imposed in several areas resulted in a marked reduction in orthopaedic practice. Although some guidelines for patient care in orthopaedic practice have been published, overall, publications focusing exclusively on guidelines on starting orthopaedic outpatient departments (OPD) after the COVID-19 lockdown amidst the on-going pandemic are lacking. We hereby propose the evolving knowledge in changes in OPD management practices for orthopaedic surgeons in the COVID- 19 era. The emphasis on online registration (e-registration) should be given impetus and become the new norm supplemented by telephonic and spot registration for the uneducated patients. The review highlights the safety of patient and orthopaedic surgeons in OPD by screening and maintaining hygiene at various levels. The article also mentions the duties of the help desk, OPD hall supervisor and the new norms of Air Conditioning, ventilation, safe use of elevators, sanitization of OPD premises and biomedical waste disposal. The optimum and safe utilization of human & material resources, DO's and DON'Ts for patients & health staff have also been proposed. The reorganization of plaster room, the precaution during plastering, fracture clinic, dressing and injection room services are discussed as per evolving guidelines. This article will give deep insight into the OPD plan &telemedicine graphically also. The authors suggest updating and downward permeation of existing e-infrastructure of government health services that is up-gradation of existing tertiary level online registration services, a paperless model of OPD Consultation & dispensation. The future updating of Aarogya Setu App (https://mygov.in/aarogya-setu-app/). for convenient online OPD registration and dispensation has been discussed and proposed. This review will help in containing the spread of COVID 19 and build upon the health gains achieved after lockdown. The easy concept of CCCATTT has been introduced, and the OPD Plan has also been suggested. We have endeavoured to holistically detail an orthopaedic OPD setup and its upkeep in COVID-19 pandemic, but since the knowledge of COVID 19 is ever-evolving it needs replenishment by regular education for health staff.


Covid‐19 and exacerbation of psoriasis


title: Comparative genomic signature representations of the emerging COVID-19 coronavirus and other coronaviruses: High identity and possible recombination between Bat and Pangolin coronaviruses

text: Abstract Coronaviruses are responsible on respiratory diseases in animal and human. The combination of numerical encoding techniques and digital signal processing methods are becoming increasingly important in handling large genomic data. In this paper, we propose to analyze the SARS-CoV-2 genomic signature using the combination of different nucleotide representations and signal processing tools in the aim to identify its genetic origin. The sequence of SARS-CoV-2 was compared with 21 relevant sequences including bat, yak and pangolin coronavirus sequences. In addition, we developed a new algorithm to locate the nucleotide modifications. The results show that the Bat and Pangolin coronaviruses were the most related to SARS-CoV-2 with 96% and 86% of identity all along the genome. Within the S gene sequence, the Pangolin sequence presents local highest nucleotide identity. Those findings suggest genesis of SARS-Cov-2 through evolution from bat and pangolin strains. This study offers new ways to automatically characterize viruses.


title: Promoting Better Clinical Trials and Drug Information as Public Health Interventions for the COVID-19 Emergency in Italy

text: According to these authors from the Italian Medicines Agency, “evidence-informed prescribing and clinical trials were beaten off the mark by social media, rumors, and panic in the early phase of the COVID-19 pandemic.” In this article, they describe lessons learned to counteract misleading information and nudge the research community to do high-quality, informative multigroup trials.


title: Non-operative management of acute appendicitis in a pediatric patient with concomitant COVID-19 infection

text: INTRODUCTION: In late December 2019, reports emerged from Wuhan, China of a novel corovonavirus SARS-CoV-2, which caused severe acute respiratory distress syndrome referred to as COVID-19. As the virus spread, reports of severe perioperative complications, including fatalities, began to emerge in the literature. We present a case of a previously healthy patient who developed classic symptoms of appendicitis. The patient was also found to be positive for COVID-19. Given the risks to both the patient and surgical team, we elected to pursue a non-operative management strategy for this patient with appendicitis. MATERIALS AND METHODS: A 13 year old female with COVID-19 presented with a day of right lower quadrant abdominal pain. A computerized tomography (CT) scan diagnosed uncomplicated appendicitis. The patient was successfully treated non-operatively with antibiotics and discharged home. CONCLUSION: To our knowledge, this case illustrates the first report of a pediatric patient with concomitant appendicitis and COVID-19 infection. We have been able to utilize a non-operative management strategy to effectively treat the patient's acute appendicitis, while protecting her from the risks of undergoing a general anesthetic as well as the operative team. We hope this report can provide others with a potential management strategy for similar patients.


title: Dynamic network measures reveal the impact of cattle markets and alpine summering on the risk of epidemic outbreaks in the Swiss cattle population

text: BACKGROUND: Livestock herds are interconnected with each other via an intricate network of transports of animals which represents a potential substrate for the spread of epidemic diseases. We analysed four years (2012–2015) of daily bovine transports to assess the risk of disease transmission and identify times and locations where monitoring would be most effective. Specifically, we investigated how the seasonal dynamics of transport networks, driven by the alpine summering and traditional cattle markets, affect the risk of epidemic outbreaks. RESULTS: We found strong and consistent seasonal variation in several structural network measures as well as in measures for outbreak risk. Analysis of the consequences of excluding markets, dealers and alpine pastures from the network shows that markets contribute much more to the overall outbreak risk than alpine summering. Static descriptors of monthly transport networks were poor predictors of outbreak risk emanating from individual holdings; a dynamic measure, which takes the temporal structure of the network into account, gave better risk estimates. A stochastic simulation suggests that targeted surveillance based on this dynamic network allows a higher detection rate and smaller outbreak size at detection than compared to other sampling schemes. CONCLUSIONS: Dynamic measures based on time-stamped data—the outgoing contact chain—can give better risk estimates and could help to improve surveillance schemes. Using this measure we find evidence that even in a country with intense summering practice, markets continue being the prime risk factor for the spread of contagious diseases.


title: Fibrinolytic abnormalities in acute respiratory distress syndrome (ARDS) and versatility of thrombolytic drugs to treat COVID‐19

text: The global pandemic of coronavirus disease 2019 (COVID‐19) is associated with the development of acute respiratory distress syndrome (ARDS), which requires ventilation in critically ill patients. The pathophysiology of ARDS results from acute inflammation within the alveolar space and prevention of normal gas exchange. The increase in proinflammatory cytokines within the lung leads to recruitment of leukocytes, further propagating the local inflammatory response. A consistent finding in ARDS is the deposition of fibrin in the air spaces and lung parenchyma. COVID‐19 patients show elevated D‐Dimers and fibrinogen. Fibrin deposits are found in the lungs of patients due to the dysregulation of the coagulation and fibrinolytic systems. Tissue factor (TF) is exposed on damaged alveolar endothelial cells and on the surface of leukocytes promoting fibrin deposition, while significantly elevated levels of plasminogen activator inhibitor 1 (PAI‐1) from lung epithelium and endothelial cells create a hypofibrinolytic state. Prophylaxis treatment of COVID‐19 patients with low molecular weight heparin (LMWH) is important to limit coagulopathy. However, to degrade pre‐existing fibrin in the lung it is essential to promote local fibrinolysis. In this review, we discuss the repurposing of fibrinolytic drugs, namely tissue‐type plasminogen activator (tPA), to treat COVID‐19 associated ARDS. tPA is an approved intravenous thrombolytic treatment, and the nebulizer form has been shown to be effective in plastic bronchitis and is currently in Phase II clinical trial. Nebulizer plasminogen activators may provide a targeted approach in COVID‐19 patients to degrade fibrin and improving oxygenation in critically ill patients.


title: Pathogenic characteristics of a QX-like infectious bronchitis virus strain SD in chickens exposed at different ages and protective efficacy of combining live homologous and heterologous vaccination

text: Continued reports of infections with infectious bronchitis virus (IBV) variants have occurred since its first isolation in the 1930s. Currently, QX-like IBVs are the predominant circulating genotype around the world. Here, the pathogenicity of QX-like IBV strain SD was characterized in chickens at different ages of exposure to the virus, and the protection efficacy of available vaccine combinations against IBV was evaluated. The results revealed that QX-like IBV strain SD was severely pathogenic in chickens, causing respiratory, urinary and reproductive infections, irrespective of age, based on clinical observations, viral distribution in tissues and a ciliostasis study. Severe respiratory signs, tracheal cilia injury, nephritis and abnormal development of the oviduct and ovarian follicles were evident throughout the experiment. A challenge experiment demonstrated that the homologous QX vaccine showed superior protection efficacy compared with other available vaccines, confirming the importance of IBV vaccine seed homology against the circulating IBV strains. Our findings aid an understanding of the pathogenicity of QX-like IBVs that may help to further control the infection.


title: A Small Region of Porcine Hemagglutinating Encephalomyelitis Virus Spike Protein Interacts with the Neural Cell Adhesion Molecule

text: OBJECTIVE: The spike (S) protein of porcine hemagglutinating encephalomyelitis virus (PHEV) may mediate infection by binding to a cellular neural cell adhesion molecule (NCAM). This study aimed to identify the crucial domain of the S1 subunit of the S protein that interacts with NCAM. METHODS: Three truncated segments (S(1-291), S(277-794) and S(548-868)) of the S gene of PHEV and the NCAM gene were cloned individually into the Escherichia coli expression vectors and yeast two-hybrid expression vectors. The interaction between S(1-291), S(277-794), S(548-868) and NCAM were detected by a GST pull-down experiment and yeast two-hybrid assay. RESULTS: Three fusion proteins (S(1-291), S(277-794) and S(548-868)) were screened for their interactions with NCAM by protein-protein interaction assays. The results of these assays clarified that S(277-794) interacted with NCAM, while S(1-291) and S(548-868) did not. CONCLUSIONS: A small fragment (258-amino-acid fragment, residues 291-548) on the PHEV S protein was posited to be the minimum number of amino acids necessary to interact with NCAM. This fragment may be the receptor-binding domain that mediates PHEV binding to NCAM.


The potential benefits of Chinese integrative medicine for pregnancy women during the COVID-19 pandemic


title: When science goes viral: The research response during three months of the COVID-19 outbreak

text: Here we present the results of a bibliometric survey of peer-reviewed and pre-print papers published in the English language on issues related to COVID-19 within the first three months since a cluster of a severe acute respiratory disease of unknown etiology was officially confirmed by the Chinese Center for Disease Control and Prevention on 31 December 2019. A systematic search using PubMed/Medline and Scopus databases and preprint servers was performed. The articles were classified according to their type, subject and country of origin. Up to 31 March 2020, a total of 2062 papers published in 578 peer-reviewed journals and 1425 preprints posted mostly on medRxiv (55.4%), were identified. The mean number of published journal papers and preprints per day in the considered period was 27 and 12, respectively, and reached a maximum of 51 and 46 per day in March, respectively. The identified articles, journal papers and preprints, mostly covered the epidemiology of COVID-19 (35.7%), clinical aspects of infection (21.0%), preventative measures (12.8%), treatment options (12.5%), diagnostics (12.2%), mathematical modeling of disease transmission and mitigation (9.6%), and molecular biology and pathogenesis of SARS-CoV-2 (8.7%). The majority of the journal papers were commentaries (38.5%), reviews (33.6%) and original research (21.3%), while preprints predominantly presented original results (89.8%). Chinese scientists contributed the highest share of original research and were responsible for 32.9% journal papers and 43.9% preprints published in the considered period. A high number of contributions was also seen from the United States, the United Kingdom, and Italy. The benefits and potential risks of such a massive publication output are discussed. The scientific response seen during the first 3 months of the COVID-19 outbreak is a demonstration of the capabilities of modern science to react rapidly to emerging global health threats by providing and discussing the essential information for understanding the etiological factor, its spread, preventative measures, and mitigation strategies.


title: Sub-basin prioritization for assessment of soil erosion susceptibility in Kangsabati, a plateau basin: A comparison between MCDM and SWAT models

text: Abstract Kangsabati basin located in tropical plateau region faces multiple problems of soil erosion susceptibility (SES), soil fertility deterioration, and sedimentation in reservoirs. Hence, identification of SES zones in thirty-eight sub-basins (SB) for basin prioritization is necessary. The present research addressed the issue by using four multi-criteria decision-making (MCDM) models: VlseKriterijumska optimizacija I Kompromisno Resenje (VIKOR), technique for order preference by similarity to ideal solution (TOPSIS), simple additive weighing (SAW), compound factor (CF). To determine the best fitted method from MCDM for erosion susceptibility (ES), a comparison has been made with Soil and Water Assessment Tool (SWAT), where fifteen morphometric parameters were considered for MCDM, and meteorological data, soil, slope and land use land cover (LULC) were considered for SWAT model. Two validation indices of percentage change and intensity change were used for evaluation and comparison of MCDM results. With SWAT model performance, SWAT calibration and uncertainty analysis programs (CUP) was used for sensitive analysis of SWAT parameters on flow discharge and sediment load simulation. The results showed that 23, 16, 18 SB have high ES; therefore they were given 1 to 3 ranks, whereas 31, 37, 21SB have low ES, hence given 38 to 36 rank as predicted by MCDM methods and SWAT. MCDM validation results depict that VIKOR and CF methods are more acceptable than TOPSIS and SAW. Calibration (flow discharge R2 0.86, NSE 0.75; sediment load R2 0.87, NSE 0.69) and validation (flow discharge R2 0.79, NSE 0.55; sediment load R2 0.79, NSE 0.76) of SWAT model indicated that simulated results are well fitted with observed data. Therefore, VIKOR reflects the significant role of morphometric parameters on ES, whereas SWAT reflects the significant role of LULC, slope, and soil on ES. However, it could be concluded that VIKOR is more effective MCDM method in comparison to SWAT prediction.


title: Other viruses causing gastroenteritis

text: Publisher Summary Besides the viruses producing the majority of human viral gastroenteritis, other viruses infect more rarely but are sometimes able to cause epidemics. In particular, they cause chronic infection in the immunocompromised. Some of these viruses discussed in this chapter are toroviruses, picobirnaviruses, enteroviruses, human immunodeficiency virus (HIV), herpesviruses, and coronaviruses. Toroviruses make up a genus of the Coronaviridae family. They are a well-described cause of diarrhea in calves and horses but may also infect sheep, goats, and pigs. Picobirnaviruses are related to members of the Birnaviridae family. They are found in the feces of HIV-infected patients with diarrhea more frequently than in HIV-infected patients without diarrhea, but a virus-specific immune response was not measurable. The genus Enterovirus is of the Picornaviridae family. All enteroviruses infect man via the gastrointestinal tract where they have their first site of replication, probably in lymphoid tissues of the pharynx and gut. HIV, the causative agent of the acquired immunodeficiency syndrome (AIDS), is a member of the Lentivirus genus of the Retroviridae family. Cytomegalovirus (CMV) and herpes simplex viruses, members of the Herpesviridae family, are found as the cause of colitis and esophagitis, mainly in HIV-infected patients. Coronavirus is another genus of the Coronaviridae family. Coronaviruses infect the respiratory and gastrointestinal tracts. They are a recognized cause of the common cold in man.


title: Association between clinical manifestations and prognosis in patients with COVID-19

text: Abstract Purpose The purpose of this study was to find out risk factors associated with pneumonia, acute respiratory distress syndrome (ARDS) and clinical outcome among patients with 2019 novel coronavirus disease (COVID-19). Methods This was a cross-sectional multicenter clinical study. A total of 95 patients infected with COVID-19 were enrolled. The COVID-19 diagnostic standard was PCR detection of target genes of 2019 novel coronavirus(2019-nCoV). Clinical, laboratory, and radiological results as well as treatment outcome data were obtained. ARDS was defined as oxygenation index (PaO2/FiO2) ≤ 300mmHg. Findings Multivariate analysis showed that older age (OR=1.078, P=0.008) and high BMI (OR=1.327, P=0.024) were independent risk factor associated with patients with pneumonia. For patients with ARDS, multivariate analysis showed that only high systolic blood pressure (SBP) level (OR=1.046, P=0.025) and high lactate dehydrogenase (LDH) level (OR=1.010, P=0.021) were independent risk factors associated with ARDS. A total of 70 patients were conducted CT scan repeatedly after treatment. Patients were divided in disease exacerbation group (n=19) and disease relieve group (n=51). High BMI (OR=1.285, P=0.017) and tobacco smoking (OR=16.13, P=0.032) were independent risk factors associated with disease exacerbation after treatment. Implications Our results help to risk stratification in patients with 2019-nCoV infection. Patients with risk factors should be given timely intervention to avoid disease progression.


title: Sars-CoV-2 infection in cancer patients undergoing active treatment. Analysis of clinical features and predictive factors for severe respiratory failure and death

text: AIM: Previous studies have suggested a more frequent and severe course of novel coronavirus Sars-coV-2 infection in cancer patients undergoing active oncologic treatment. Our aim was to describe the characteristics of the disease in this population and to determine predictive factors for poor outcome in terms of severe respiratory distress (ARDS) or death. PATIENTS AND METHODS: Patients consecutively admitted for SARS-CoV-2 infection were prospectively collected and retrospective statistical analysis was performed. Univariate and multivariate analyses were performed to assess potential factors for poor outcomes defined as ARDS or death. RESULTS: 63 patients were analyzed, 34 of them developed respiratory failure (70% as ARDS). Lymphocytes/mm3 (412 vs. 686; p=0.001), serum albumin (2.84 vs. 3.1); LDH (670vs. 359; p<0.001) and C-Reactive Protein (CRP) levels (25.8 vs. 9.9; p<0.001) discriminate those that developed respiratory failure. Mortality Rate was 25%, significantly higher among ARDS, neutropenic patients (p=0.01) and in those with bilateral infiltrates (44% vs. 0%; p<0.001). Multivariate logistic analyses model confirmed the predictive value of severe neutropenia (OR 16.54 CI 95% 1.43-190.9, p 0.025), bilateral infiltrates (OR 32.83, CI95% 3.51-307, p 0.002) and tumor lung involvement (OR 4.34, CI95% 1.2-14.95, p 0.02). CONCLUSION: Cancer patients under active treatment admitted for Sars-coV2 infection have worse outcomes in terms of mortality and respiratory failure rates compared with COVID-19 global population. Lymphopenia, LDH, CRP and albumin discriminate illness severity while neutropenia; bilateral infiltrates and tumor pulmonary involvement are predictive of higher mortality.


title: Anesthesia and potential aerosol generation during Magnetic Resonance Imaging in Children with COVID‐19

text: The American College of Radiology recommends minimizing Magnetic Resonance Imaging (MRI) in COVID‐19 patients, postponing non‐urgent exams, and using alternative imaging.(1)Sedation/anesthesia are aerosol generating procedures (AGP) due to requirement of bag‐mask ventilation, intubation, and extubation with consequent risk of exposure to healthcare workers. This is complicated by limitation in the use of personal protective equipment (PPE) in the magnet zone (Zone IV).We describe our experience for children requiring anesthesia for emergency MRI during the COVID‐19 outbreak in Philadelphia.


title: Hypermutation in single-stranded DNA

text: Regions of genomic DNA can become single-stranded in the course of normal replication and transcription as well as during DNA repair. Abnormal repair and replication intermediates can contain large stretches of persistent single-stranded DNA, which is extremely vulnerable to DNA damaging agents and hypermutation. Since such single-stranded DNA spans only a fraction of the genome at a given instance, hypermutation in these regions leads to tightly-spaced mutation clusters. This phenomenon of hypermutation in single-stranded DNA has been documented in several experimental models as well as in cancer genomes. Recently, hypermutated single-stranded RNA viral genomes also have been documented. Moreover, indications of hypermutation in single-stranded DNA may also be found in the human germline. This review will summarize key current knowledge and the recent developments in understanding the diverse mechanisms and sources of ssDNA hypermutation.


title: A Succesful Treatment of Avian Influenza İnfection in Turkey

text: Avian influenza is a disease characterized with severe pneumonia caused by virus influenza A. Birds and poultry are vectors for spread of this disease. It is diagnosed by clinical evidence and reverse transcription-polymerase chain reaction. Here, we discuss the treatment procedures of a child diagnosed as avian influenza.


title: Lessons learned from SARS: The experience of the Health Protection Agency, England

text: Summary The United Kingdom was assessed as a low risk country throughout the 2003 global SARS outbreaks. Despite this, 368 reports of potential SARS cases were made to the Health Protection Agency (HPA) between March and July 2003. The public health actions undertaken in response to these reports, the establishment of reporting mechanisms and the development of guidance documents were substantial. Lessons learned from mounting a UK response to SARS included: the importance of international collaboration; formation of a UK-wide, multidisciplinary Task Force; flexible case reporting mechanisms; integration of surveillance and laboratory data; generation of prompt and web-accessible guidance and advice; availability of surge capacity; and contingency planning. Lessons learned are being incorporated into the HPA's preparedness to prevent and control future newly emerging infectious disease threats.


title: A nematode-specific gene underlies bleomycin-response variation in Caenorhabditis elegans

text: Bleomycin is a powerful chemotherapeutic drug used to treat a variety of cancers. However, individual patients vary in their responses to bleomycin. The identification of genetic differences that underlie this response variation could improve treatment outcomes by tailoring bleomycin dosages to each patient. We used the model organism Caenorhabditis elegans to identify genetic determinants of bleomycin-response differences by performing linkage mapping on recombinants derived from a cross between the laboratory strain (N2) and a wild strain (CB4856). This approach identified a small genomic region on chromosome V that underlies bleomycin-response variation. Using near-isogenic lines and strains with CRISPR-Cas9 mediated deletions and allele replacements, we discovered that a novel nematode-specific gene (scb-1) is required for bleomycin resistance. Although the mechanism by which this gene causes variation in bleomycin responses is unknown, we suggest that a rare variant present in the CB4856 strain might cause differences in the potential stress-response function of scb-1 between the N2 and CB4856 strains, thereby leading to differences in bleomycin resistance.


title: Studying health-related internet and mobile device use using web logs and smartphone records

text: Many people use the internet to seek information that will help them understand their body and their health. Motivations for such behaviors are numerous. For example, users may wish to figure out a medical condition by searching for symptoms they experience. Similarly, they may seek more information on how to treat conditions they have been diagnosed with or seek resources on how to live a healthy life. With the ubiquitous availability of the internet, searching and finding relevant information is easier than ever before and a widespread phenomenon. To understand how people use the internet for health-related information, we use data from a sample of 1,959 internet users. A unique combination of data containing four months of users’ browsing histories and mobile application use on computers and mobile devices allows us to study which health websites they visited, what information they searched for and which health applications they used. Survey data inform us about users’ socio-demographic background, medical conditions and other health-related behaviors. Results show that women, young users, users with a university education and nonsmokers are most likely to use the internet and mobile applications for health-related purposes. On search engines, internet users most frequently search for pharmacies, symptoms of medical conditions and pain. Moreover, users seem most interested in information on how to live a healthy life, alternative medicine, mental health and women’s health. With this study, we extend the field’s understanding of who seeks and consumes health information online, what users look for as well as how individuals use mobile applications to monitor their health. Moreover, we contribute to methodological research by exploring new sources of data for understanding humans, their preferences and behaviors.


From herbal small RNAs to one medicine


title: “Toxic erythema” and eosinophilia associated to tocilizumab therapy in a COVID‐19 patient

text: Since the new fatal pneumonia was identified in December 2019 in Wuhan, China, the WHO declared the infection a health emergency of international concern. The novel ss‐RNA ß‐coronavirus (SARS‐CoV‐2) spreads through airborne and direct contagion; virulence is high in the elderly and in patients with diabetes, chronic pulmonary, cardiovascular and neoplastic diseases. SARS‐CoV‐2 ssRNA is recognized by intracellular Pattern Recognition Receptors (PRRs), which trigger NF‐kB – the master regulator of inflammation – and Interferon Regulatory Factors (IRFs)(1).


title: “Exercise with facemask; Are we handling a devil's sword?” – a physiological hypothesis

text: Straying away from a sedentary lifestyle is essential, especially in these troubled times of a global pandemic to reverse the ill effects associated with the health risks as mentioned earlier. In the view of anticipated effects on immune system and prevention against influenza and Covid-19, globally moderate to vigorous exercises are advocated wearing protective equipment such as facemasks. Though WHO supports facemasks only for Covid-19 patients, healthy “social exercisers” too exercise strenuously with customized facemasks or N95 which hypothesized to pose more significant health risks and tax various physiological systems especially pulmonary, circulatory and immune systems. Exercising with facemasks may reduce available Oxygen and increase air trapping preventing substantial carbon dioxide exchange. The hypercapnic hypoxia may potentially increase acidic environment, cardiac overload, anaerobic metabolism and renal overload, which may substantially aggravate the underlying pathology of established chronic diseases. Further contrary to the earlier thought, no evidence exists to claim the facemasks during exercise offer additional protection from the droplet transfer of the virus. Hence, we recommend social distancing is better than facemasks during exercise and optimal utilization rather than exploitation of facemasks during exercise.


title: Chapter 4 Replication

text: Publisher Summary This chapter begins with an overview of virus replication, and explains how studying bacteriophages has helped understand more complex viruses that are harder to work with, and then explains the processes involved in virus replication step by step. The virus replication involves three broad essential stages carried out by all types of viruses: the initiation of infection, replication and expression of the genome, and the release of mature virions from the infected cell. At a detailed level, there are many differences in the replication processes of different viruses that are imposed by the biology of the host cell and the nature of the virus genome. The other stages that have been discussed are: attachment, penetration, uncoating, genome replication, gene expression, assembly, maturation, and release. The chapter illustrates similarities in the pattern of replication of different viruses. Regardless of their hosts, all viruses must undergo each of these stages in some form to successfully complete their replication cycles.


title: Will COVID‐19 be a litmus test for post‐Ebola sub‐Saharan Africa?

text: In 2014, the worst outbreak of Ebola virus disease (EVD) emerged in sub-Saharan Africa (SSA) causing fear and panic. The outbreak which started in Guinea quickly moved across to Sierra Leone and Liberia. With an average EVD case fatality rate of around 50% (range 25-90%), there were many casualties, and the number of recorded deaths exceeded 11,300 by June 2016.1 This article is protected by copyright. All rights reserved.


title: An exclusive 42 amino acid signature in pp1ab protein provides insights into the evolutive history of the 2019 novel human‐pathogenic coronavirus (SARS‐CoV‐2)

text: The city of Wuhan, Hubei province, China, was the origin of a severe pneumonia outbreak in December 2019, attributed to a novel coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS‐CoV‐2]), causing a total of 2761 deaths and 81109 cases (25 February 2020). SARS‐CoV‐2 belongs to genus Betacoronavirus, subgenus Sarbecovirus. The polyprotein 1ab (pp1ab) remains unstudied thoroughly since it is similar to other sarbecoviruses. In this short communication, we performed phylogenetic‐structural sequence analysis of pp1ab protein of SARS‐CoV‐2. The analysis showed that the viral pp1ab has not changed in most isolates throughout the outbreak time, but interestingly a deletion of 8 aa in the virulence factor nonstructural protein 1 was found in a virus isolated from a Japanese patient that did not display critical symptoms. While comparing pp1ab protein with other betacoronaviruses, we found a 42 amino acid signature that is only present in SARS‐CoV‐2 (AS‐SCoV2). Members from clade 2 of sarbecoviruses have traces of this signature. The AS‐SCoV2 located in the acidic‐domain of papain‐like protein of SARS‐CoV‐2 and bat‐SL‐CoV‐RatG13 guided us to suggest that the novel 2019 coronavirus probably emerged by genetic drift from bat‐SL‐CoV‐RaTG13. The implication of this amino acid signature in papain‐like protein structure arrangement and function is something worth to be explored.


title: Potential pathogenesis of ageusia and anosmia in COVID‐19 patients

text: From the first reports, ageusia and anosmia appear to be frequent clinical features in coronavirus disease 19 (COVID‐19) patients. We have performed a survey of the literature, analyzing the possible causes of these chemosensory alterations, which may be useful as a starting point for specific further studies. This article is protected by copyright. All rights reserved


title: Purification of melibiose‐binding lectins from two cultivars of Chinese black soybeans

text: A dimeric 50 kDa melibiose‐binding lectin was isolated from the seeds of the cultivar of soybean (Glycine max), called the small glossy black soybean. The isolation procedure comprised ion exchange chromatography on Q Sepharose, SP Sepharose and Mono Q followed by gel filtration on Superdex 75. The lectin was adsorbed on all three ion exchangers, and it exhibited an N‐terminal sequence identical to that of soybean lectin. Of all the sugars tested, melibiose most potently inhibited the hemagglutinating activity of the lectin, which was stable between pH 3‐12 and 0‐70 °C. The lectin evoked maximal mitogenic response at about the same molar concentration as Con A. However, the response was much weaker. The soybean lectin inhibited the activity of HIV‐1 reverse transcriptase as well as the proliferation of breast cancer MCF7 cells and hepatoma HepG2 cells with an IC(50) of 2.82 μM, 2.6 μM and 4.1 μM, respectively. There was no antifungal activity. Another lectin was isolated from a different cultivar of soybean called little black soybean. The lectin was essentially similar to small glossy black soybean lectin except for a larger subunit molecular mass (31 kDa), a more potent mitogenic activity and lower thermostability. The results indicate that different cultivars of soybean produce lectins that are not identical in every aspect.


title: The leukocyte-stiffening property of plasma in early acute respiratory distress syndrome (ARDS) revealed by a microfluidic single-cell study: the role of cytokines and protection with antibodies

text: BACKGROUND: Leukocyte-mediated pulmonary inflammation is a key pathophysiological mechanism involved in acute respiratory distress syndrome (ARDS). Massive sequestration of leukocytes in the pulmonary microvasculature is a major triggering event of the syndrome. We therefore investigated the potential role of leukocyte stiffness and adhesiveness in the sequestration of leukocytes in microvessels. METHODS: This study was based on in vitro microfluidic assays using patient sera. Cell stiffness was assessed by measuring the entry time (ET) of a single cell into a microchannel with a 6 × 9–μm cross-section under a constant pressure drop (ΔP = 160 Pa). Primary neutrophils and monocytes, as well as the monocytic THP-1 cell line, were used. Cellular adhesiveness to human umbilical vein endothelial cells was examined using the laminar flow chamber method. We compared the properties of cells incubated with the sera of healthy volunteers (n = 5), patients presenting with acute cardiogenic pulmonary edema (ACPE; n = 6), and patients with ARDS (n = 22), of whom 13 were classified as having moderate to severe disease and the remaining 9 as having mild disease. RESULTS: Rapid and strong stiffening of primary neutrophils and monocytes was induced within 30 minutes (mean ET >50 seconds) by sera from the ARDS group compared with both the healthy subjects and the ACPE groups (mean ET <1 second) (p < 0.05). Systematic measurements with the THP-1 cell line allowed for the establishment of a strong correlation between stiffening and the severity of respiratory status (mean ET 0.82 ± 0.08 seconds for healthy subjects, 1.6 ± 1.0 seconds for ACPE groups, 10.5 ± 6.1 seconds for mild ARDS, and 20.0 ± 8.1 seconds for moderate to severe ARDS; p < 0.05). Stiffening correlated with the cytokines interleukin IL-1β, IL-8, tumor necrosis factor TNF-α, and IL-10 but not with interferon-γ, transforming growth factor-β, IL-6, or IL-17. Strong stiffening was induced by IL-1β, IL-8, and TNF-α but not by IL-10, and incubations with sera and blocking antibodies against IL-1β, IL-8, or TNF-α significantly diminished the stiffening effect of serum. In contrast, the measurements of integrin expression (CD11b, CD11a, CD18, CD49d) and leukocyte–endothelium adhesion showed a weak and slow response after incubation with the sera of patients with ARDS (several hours), suggesting a lesser role of leukocyte adhesiveness compared with leukocyte stiffness in early ARDS. CONCLUSIONS: The leukocyte stiffening induced by cytokines in the sera of patients might play a role in the sequestration of leukocytes in the lung capillary beds during early ARDS. The inhibition of leukocyte stiffening with blocking antibodies might inspire future therapeutic strategies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13054-015-1157-5) contains supplementary material, which is available to authorized users.


title: From farm management to bacteriophage therapy: strategies to reduce antibiotic use in animal agriculture

text: To reduce the use of antibiotics in animal agriculture, a number of effective or commercially viable alternatives have been implemented by food animal producers or are under development. Perhaps the most well‐established strategies are flock and herd management practices to mitigate disease introduction and spread, and, subsequently, reduce the need for antibiotic use. While vaccines in food animal production have been used to prevent both bacterial and viral diseases, but historically, most vaccines have targeted viral diseases. Though vaccines against viral diseases can help reduce the need for antibiotic use by controlling the spread of secondary bacterial infections, more recent vaccines under development specifically target bacteria. New developments in selecting and potentially tailoring bacteriophages provide a promising avenue for controlling pathogenic bacteria without the need for traditional small‐molecule antibiotics. In this article we discuss these established and emerging strategies, which are anticipated to reduce the reliance on antibiotics in food animal production and should reduce the prevalence and transmission to humans of antimicrobial resistant bacteria from these systems.


Options thérapeutiques de prise en charge des sarcomes durant la pandémie COVID-19 : propositions du groupe sarcome français


title: Coronavirus genomic RNA packaging

text: Abstract RNA viruses carry out selective packaging of their genomes in a variety of ways, many involving a genomic packaging signal. The first coronavirus packaging signal was discovered nearly thirty years ago, but how it functions remains incompletely understood. This review addresses the current state of knowledge of coronavirus genome packaging, which has mainly been studied in two prototype species, mouse hepatitis virus and transmissible gastroenteritis virus. Despite the progress that has been made in the mapping and characterization of some packaging signals, there is conflicting evidence as to whether the viral nucleocapsid protein or the membrane protein plays the primary role in packaging signal recognition. The different models for the mechanism of genomic RNA packaging that have been prompted by these competing views are described. Also discussed is the recent exciting discovery that selective coronavirus genome packaging is critical for in vivo evasion of the host innate immune response.


title: Common Cold – an Umbrella Term for Acute Infections of Nose, Throat, Larynx and Bronchi

text: Acute respiratory tract infections, i. e. rhinitis, sinusitis, pharyngitis, laryngitis, bronchitis, belong to the most common medical conditions with a high economic burden. Nonetheless, there is little agreement concerning their differential diagnosis. This paper will discuss to what extent different anatomical sites of acute respiratory tract infections can be uniquely identified or whether the overlap and consecutive development in signs and symptoms renders these distinctions meaningless. Acute respiratory tract infections are variable but definition of diagnostic categories based on the anatomical sites of the dominant complaints shows that signs and symptoms both overlap to a great extent and/or emerge successively. Thus, in common cold distinguishing between acute symptom-based diagnoses arising from different anatomical sites of the aerodigestive system remains elusive. Therefore, preferred symptomatic treatments should foster a resolution of all possible symptoms as opposed to an isolated treatment of a single symptom (e. g. mucus hypersecretion) according to the presumed anatomical site (i. e. acute bronchitis).


title: Computational analysis of interactomes: Current and future perspectives for bioinformatics approaches to model the host–pathogen interaction space

text: Abstract Bacterial and viral pathogens affect their eukaryotic host partly by interacting with proteins of the host cell. Hence, to investigate infection from a systems’ perspective we need to construct complete and accurate host–pathogen protein–protein interaction networks. Because of the paucity of available data and the cost associated with experimental approaches, any construction and analysis of such a network in the near future has to rely on computational predictions. Specifically, this challenge consists of a number of sub-problems: First, prediction of possible pathogen interactors (e.g. effector proteins) is necessary for bacteria and protozoa. Second, the prospective host binding partners have to be determined and finally, the impact on the host cell analyzed. This review gives an overview of current bioinformatics approaches to obtain and understand host–pathogen interactions. As an application example of the methods covered, we predict host–pathogen interactions of Salmonella and discuss the value of these predictions as a prospective for further research.