title: Removal of a C-terminal serine residue proximal to the inter-chain disulfide bond of a human IgG1 lambda light chain mediates enhanced antibody stability and antibody dependent cell-mediated cytotoxicity

text: Optimization of biophysical properties is a critical success factor for the developability of monoclonal antibodies with potential therapeutic applications. The inter-domain disulfide bond between light chain (Lc) and heavy chain (Hc) in human IgG1 lends structural support for antibody scaffold stability, optimal antigen binding, and normal Fc function. Recently, human IgG1λ has been suggested to exhibit significantly greater susceptibility to reduction of the inter Lc-Hc disulfide bond relative to the same disulfide bond in human IgG1κ. To understand the molecular basis for this observed difference in stability, the sequence and structure of human IgG1λ and human IgG1κ were compared. Based on this Lc comparison, three single mutations were made in the λ Lc proximal to the cysteine residue, which forms a disulfide bond with the Hc. We determined that deletion of S214 (dS) improved resistance of the association between Lc and Hc to thermal stress. In addition, deletion of this terminal serine from the Lc of IgG1λ provided further benefit, including an increase in stability at elevated pH, increased yield from transient transfection, and improved in vitro antibody dependent cell-mediated cytotoxicity (ADCC). These observations support the conclusion that the presence of the terminal serine of the λ Lc creates a weaker inter-chain disulfide bond between the Lc and Hc, leading to slightly reduced stability and a potential compromise in IgG1λ function. Our data from a human IgG1λ provide a basis for further investigation of the effects of deleting terminal serine from λLc on the stability and function of other human IgG1λ antibodies.


title: Clinical characteristics of Coronavirus Disease 2019 patients in Beijing, China

text: The outbreak of Coronavirus Disease (COVID-19) in Wuhan have affected more than 250 countries and regions worldwide. However, most of the clinical studies have been focused on Wuhan, and little is known about the disease outside of Wuhan in China. In this retrospective cohort study, we report the early clinical features of 80 patients with COVID-19 admitted to the hospital in Beijing. The results show that 27 (33.8%) patients had severe illness. Six (7.5%) patients were admitted to the ICU, and 3 (3.8%) patients died. Forty-eight percent (39/80) of the patients had a history of living/traveling in Wuhan. Patients with severe- illness were significantly older (average age, 71 years old vs 44 years old) and had a high incidence of expectoration (59.3% vs 34.0%), shortness of breath (92.6% vs 9.4%), anorexia (51.9% vs 18.9%) and confusion(18.5% vs 0%) compared with nonsevere patients. The systolic blood pressure (median, 130 mmHg vs 120 mmHg) was higher and the oxygen saturation (median, 98.3% vs 92.0%) was significantly lower in severe patients than nonsevere patients. In addition, myoglobin (median, 56.0 ng/mL vs 35.0 ng/mL), troponin I (median, 0.02 pg/mL vs 0.01 pg/mL), C-reactive protein (median, 69.7 mg/L vs 12.9 mg/L) and neutrophils (median, 3.3×10(9)/L vs 2.2×10(9)/L) were significantly increased, while lymphocytes (median, 0.8×10(9)/L vs 1.2×10(9)/L), albumin (mean, 32.8 g/L vs 36.8 g/L) and the creatinine clearance rate (median, 91.2 vs 108.2 ml/min/1.73m(2)) were significantly decreased among severe patients. Our study revealed that older patients with high levels of C-reactive protein, myoglobin, troponin I, and neutrophil and high systolic blood pressure as well as low levels of lymphocytes, and albumin and a low creatinine clearance rate and oxygen saturation were more likely to have severe disease.


title: How much would you be willing to pay for preventing a new dangerous infectious disease: A willingness-to-pay study in medical personnel working in the emergency department

text: BACKGROUND: The risk of developing nosocomial infectious diseases among medical personnel in the emergency department (ED) can result in tremendous psychologic stress. The objective of this study was to estimate the median amount of money ED personnel would be willing to pay for preventing nosocomial severe acute respiratory syndrome (SARS). METHODS: A contingent valuation approach with close-ended format was used. During the study period from June 15, 2003 through June 30, 2003, a convenience sample of all medical personnel working in the ED of National Taiwan University Hospital was carried out. Participants were interviewed by a standard questionnaire and were asked to choose whether or not they would pay at a specified price to purchase a hypothetical SARS vaccine. A logistic regression model was created to evaluate the relationship between willingness-to-pay and the log of the price offered in the bid questions. The median and mean amounts of willingness-to-pay were calculated. RESULTS: A total of 115 subjects were interviewed and most were nurses (68.7%). The median and mean amount subjects reported being willing to pay for a SARS vaccine was US $1762 and US $720, respectively. Subject responses were significantly related to the price of vaccination and their type of job. CONCLUSIONS: Medical personnel in the ED reported that they would be willing to pay substantial monetary amounts for preventing nosocomial SARS.


title: Dynamical analysis and control strategies of an SIVS epidemic model with imperfect vaccination on scale-free networks

text: Vaccination is an effective method to prevent the spread of infectious diseases. In this paper, we develop an SIVS epidemic model with degree-related transmission rates and imperfect vaccination on scale-free networks. Firstly, we derive two threshold parameters and existence conditions of multiple endemic equilibria. Secondly, not only the global asymptotical stability of disease-free equilibrium and the persistence of the disease are derived, but also the global attractivity of the unique endemic equilibrium is proved using the monotone iterative technique. Thirdly, the effects of various immunization schemes including uniform immunization, targeted immunization and acquaintance immunization are studied, and the optimal vaccination strategy is analyzed by Pontryagin’s maximum principle. Finally, we perform numerical simulations to verify these theoretical results.


title: MiR-10a-5p-Mediated Syndecan 1 Suppression Restricts Porcine Hemagglutinating Encephalomyelitis Virus Replication

text: Porcine hemagglutinating encephalomyelitis virus (PHEV) is a single-stranded RNA coronavirus that causes nervous dysfunction in the infected hosts and leads to widespread alterations in the host transcriptome by modulating specific microRNA (miRNA) levels. MiRNAs contribute to RNA virus pathogenesis by promoting antiviral immune response, enhancing viral replication, or altering miRNA-mediated host gene regulation. Thus, exploration of the virus–miRNA interactions occurring in PHEV-infected host may lead to the identification of novel mechanisms combating the virus life cycle or pathogenesis. Here, we discovered that the expression of miR-10a-5p was constitutively up-regulated by PHEV in both the N2a cells in vitro and mice brain in vivo. Treatment with miR-10a-5p mimics allowed miR-10a-5p enrichment and resulted in a significant restriction in PHEV replication, suggesting widespread negative regulation of the RNA virus infection by miR-10a-5p. The outcomes were also evidenced by miR-10a-5p inhibitor over-expression. Luciferase reporter, quantitative real-time PCR (qRT-PCR), and western blotting analysis further showed that Syndecan 1 (SDC1), a cell surface proteoglycan associated with host defense mechanisms, acts as a target gene of miR-10a-5p during PHEV infection. Naturally, siRNA-mediated knockdown of SDC1 leads to a reduction in viral replication, implying that SDC1 expression is likely a favorable condition for viral replication. Together, the findings demonstrated that the abundant miR-10a-5p leads to downstream suppression of SDC1, and it functions as an antiviral mechanism in the PHEV-induced disease, providing a potential strategy for the prevention and treatment of PHEV infection in the future work.


title: Multiplex PCR methods for detection of several viruses associated with canine respiratory and enteric diseases

text: Viral respiratory and intestinal infections are the most common causes of canine viral illness. Infection with multiple pathogens occurs in many cases. Rapid diagnosis of these multiple infections is important for providing timely and effective treatment. To improve diagnosis, in this study, two new multiplex polymerase chain reactions (mPCRs) were developed for simultaneous detection of canine respiratory viruses (CRV) and canine enteric viruses (CEV) using two separate primer mixes. The viruses included canine adenovirus type 2 (CAV-2), canine distemper virus (CDV), canine influenza virus (CIV), canine parainfluenza virus (CPIV), canine circovirus (CanineCV), canine coronavirus (CCoV) and canine parvovirus (CPV). The sensitivity of the mPCR results showed that the detection limit of both mPCR methods was 1×10(4) viral copies. Twenty nasal swabs (NS) and 20 anal swabs (AS) collected from dogs with symptoms of respiratory disease or enteric disease were evaluated using the novel mPCR methods as a clinical test. The mPCR protocols, when applied to these respiratory specimens and intestinal samples, could detect 7 viruses simultaneously, allowing rapid investigation of CRV (CAV-2, CDV, CIV and CPIV) and CEV (CAV-2, CanineCV, CCoV and CPV) status and prompt evaluation of coinfection. Our study provides an effective and accurate tool for rapid differential diagnosis and epidemiological surveillance in dogs.


title: Pathogenic Viruses: Smart Manipulators of the Interferon System

text: Vertebrate cells are equipped with specialized receptors that sense the presence of viral nucleic acids and other conserved molecular signatures of infecting viruses. These sensing receptors are collectively called pattern recognition receptors (PRRs) and trigger the production of type I (α/β) interferons (IFNs).IFNs are secreted and establish a local and systemic antiviral state in responsive cells. Viruses, in turn, have evolved multiple strategies to escape the IFN system. They try to avoid PRR activation, inhibit IFN synthesis, bind and inactivate secreted IFN molecules, block IFN-activated signaling, or disturb the action of IFN-induced antiviral proteins. Here, we summarize current knowledge in light of most recent findings on the intricate interactions of viruses with the IFN system.


title: Preliminary investigation on feline coronavirus presence in the reproductive tract of the tom cat as a potential route of viral transmission

text: OBJECTIVES: Feline infectious peritonitis (FIP) is an immune-mediated disease initiated by feline coronavirus (FCoV) infection. To date, the only proven route of transmission is the faecal–oral route, but a possible localisation of FCoV in the reproductive tract of tom cats is of concern, owing to the involvement of the male reproductive tract during FIP and to the presence of reproduction disorders in FCoV-endemic feline catteries. The aim of the study was to investigate the presence and localisation of FCoV in semen and/or in the reproductive tract of tom cats, and its possible association with seroconversion and viraemic phase. METHODS: Blood, serum, semen and/or testicle samples were obtained from 46 tom cats. Serology was performed on 38 serum samples, nested reverse transcriptase PCR (nRT-PCR) and reverse transcriptase quantitative PCR (RT-qPCR) were performed on 39 blood samples and on 17 semen samples, and histology, immunohistochemistry and nRT-PCR were performed on 39 testicles. RESULTS: Twenty-four of 38 serum samples were positive on serology. Semen samples were negative on RT-PCR and RT-qPCR for FCoV, while all blood samples were negative at both molecular methods, except for one sample positive at RT-qPCR with a very low viral load. All testicles were negative at immunohistochemistry, while six were positive at nRT-PCR for FCoV. Serology and blood PCR results suggest that the virus was present in the environment, stimulating transient seroconversion. FCoV seems not to localise in the semen of tom cats, making the venereal route as a way of transmission unlikely. Although viral RNA was found in some testicles, it could not be correlated with the viraemic phase. CONCLUSIONS AND RELEVANCE: In the light of these preliminary results, artificial insemination appears safer than natural mating as it eliminates the direct contact between animals, thus diminishing the probability of faecal–oral FCoV transmission.


title: Time Course and Cellular Localization of SARS-CoV Nucleoprotein and RNA in Lungs from Fatal Cases of SARS

text: BACKGROUND: Cellular localization of severe acute respiratory syndrome coronavirus (SARS-CoV) in the lungs of patients with SARS is important in confirming the etiological association of the virus with disease as well as in understanding the pathogenesis of the disease. To our knowledge, there have been no comprehensive studies investigating viral infection at the cellular level in humans. METHODS AND FINDINGS: We collected the largest series of fatal cases of SARS with autopsy material to date by merging the pathological material from two regions involved in the 2003 worldwide SARS outbreak in Hong Kong, China, and Toronto, Canada. We developed a monoclonal antibody against the SARS-CoV nucleoprotein and used it together with in situ hybridization (ISH) to analyze the autopsy lung tissues of 32 patients with SARS from Hong Kong and Toronto. We compared the results of these assays with the pulmonary pathologies and the clinical course of illness for each patient. SARS-CoV nucleoprotein and RNA were detected by immunohistochemistry and ISH, respectively, primarily in alveolar pneumocytes and, less frequently, in macrophages. Such localization was detected in four of the seven patients who died within two weeks of illness onset, and in none of the 25 patients who died later than two weeks after symptom onset. CONCLUSIONS: The pulmonary alveolar epithelium is the chief target of SARS-CoV, with macrophages infected subsequently. Viral replication appears to be limited to the first two weeks after symptom onset, with little evidence of continued widespread replication after this period. If antiviral therapy is considered for future treatment, it should be focused on this two-week period of acute clinical disease.


title: Phosphorylation of the arginine/serine dipeptide‐rich motif of the severe acute respiratory syndrome coronavirus nucleocapsid protein modulates its multimerization, translation inhibitory activity and cellular localization

text: Coronavirus nucleocapsid protein is abundant in infected cells and participates in viral RNA replication and transcription. The central domain of the nucleocapsid protein contains several arginine/serine (RS) dipeptides, the biological significance of which has not been well investigated. In the present study, we demonstrate that the severe acute respiratory syndrome coronavirus nucleocapsid protein is phosphorylated primarily within the RS‐rich region in cells and by SR protein kinase 1 in vitro. The nucleocapsid protein could suppress translation and its RS motif is essential for such an activity. Moreover, phosphorylation of the RS motif could modulate the translation inhibitory activity of the nucleocapsid protein. We further found that RS motif phosphorylation did not significantly affect RNA binding of the nucleocapsid protein but impaired its multimerization ability. We observed that the nucleocapsid protein could translocate to cytoplasmic stress granules in response to cellular stress. Deletion or mutations of the RS motif enhanced stress granule localization of the nucleocapsid protein, whereas overexpression of SR protein kinase 1 inhibited nucleocapsid protein localization to stress granules. The nucleocapsid protein lacking the RS motif formed high‐order RNP complexes, which may also account for its enhanced stress granule localization. Taken together, phosphorylation of the severe acute respiratory syndrome‐CoV nucleocapsid protein modulates its activity in translation control and also interferes with its oligomerization and aggregation in stress granules.


title: Lung Ultrasound in Children with COVID-19: Preliminary Findings

text: Abstract— Recent evidence indicates the usefulness of lung ultrasound (LUS) in detecting coronavirus disease 19 (COVID-19) pneumonia. However, no data are available on the use of LUS in children with COVID-19 pneumonia. In this report, we describe LUS features of 10 consecutively admitted children with COVID-19 in two tertiary-level pediatric hospitals in Rome. LUS revealed signs of lung involvement during COVID-19 infection. In particular, vertical artifacts (70%), pleural irregularities (60%), areas of white lung (10%) and subpleural consolidations (10%) were the main findings in patients with COVID-19. No cases of pleural effusions were found. According to our experience, the routine use of LUS in the evaluation of children with suspected or confirmed COVID-19, when performed by clinicians with documented experience in LUS, was useful in diagnosing and monitoring pediatric COVID-19 pneumonia, reducing unnecessary radiation/sedation in children and exposure of health care workers to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).


title: National Early Warning Score 2 (NEWS2) on admission predicts severe disease and in-hospital mortality from Covid-19 – a prospective cohort study

text: BACKGROUND: There is a need for validated clinical risk scores to identify patients at risk of severe disease and to guide decision-making during the covid-19 pandemic. The National Early Warning Score 2 (NEWS2) is widely used in emergency medicine, but so far, no studies have evaluated its use in patients with covid-19. We aimed to study the performance of NEWS2 and compare commonly used clinical risk stratification tools at admission to predict risk of severe disease and in-hospital mortality in patients with covid-19. METHODS: This was a prospective cohort study in a public non-university general hospital in the Oslo area, Norway, including a cohort of all 66 patients hospitalised with confirmed SARS-CoV-2 infection from the start of the pandemic; 13 who died during hospital stay and 53 who were discharged alive. Data were collected consecutively from March 9th to April 27th 2020. The main outcome was the ability of the NEWS2 score and other clinical risk scores at emergency department admission to predict severe disease and in-hospital mortality in covid-19 patients. We calculated sensitivity and specificity with 95% confidence intervals (CIs) for NEWS2 scores ≥5 and ≥ 6, quick Sequential Organ Failure Assessment (qSOFA) score ≥ 2, ≥2 Systemic Inflammatory Response Syndrome (SIRS) criteria, and CRB-65 score ≥ 2. Areas under the curve (AUCs) for the clinical risk scores were compared using DeLong’s test. RESULTS: In total, 66 patients (mean age 67.9 years) were included. Of these, 23% developed severe disease. In-hospital mortality was 20%. Tachypnoea, hypoxemia and confusion at admission were more common in patients developing severe disease. A NEWS2 score ≥ 6 at admission predicted severe disease with 80.0% sensitivity and 84.3% specificity (Area Under the Curve (AUC) 0.822, 95% CI 0.690–0.953). NEWS2 was superior to qSOFA score ≥ 2 (AUC 0.624, 95% CI 0.446–0.810, p < 0.05) and other clinical risk scores for this purpose. CONCLUSION: NEWS2 score at hospital admission predicted severe disease and in-hospital mortality, and was superior to other widely used clinical risk scores in patients with covid-19.


title: Linking disease epidemiology and livestock productivity: The case of bovine respiratory disease in France

text: Concerns are growing over the impact of livestock farming on environment and public health. The livestock industry is faced with the double constraint of limiting its use of natural resources and antimicrobials while ensuring its economic sustainability. In this context, reliable methods are needed to evaluate the effect of the prevention of endemic animal diseases on the productivity of livestock production systems. In this study, an epidemiological and productivity model was used to link changes in Bovine Respiratory Disease (BRD) incidence with the productivity of the beef and dairy cattle sectors in France. Cattle production parameters significantly affected by BRD were selected through literature review. Previous field study results and national cattle performance estimates were used to infer growth performances, mortality rates and carcass quality in the cattle affected and not affected by BRD. A steady-state deterministic herd production model was used to predict the productivity of the dairy and beef sector and their defined compartments (breeding-fattening, feedlot young bulls, and feedlot veal) in case of BRD incidence reduction by 20%, 50% or 100%. Results suggested that BRD should be controlled at a priority in beef breeding farms as eradication of BRD in beef calves would increase the whole beef sector’s productivity by 4.7–5.5% while eradication in other production stages would result in lower productivity gain in their respective sectors. However, the analysis performed at compartment level showed that, in both the beef and dairy sector, young bull and veal feedlot enterprises derive more economic benefits from BRD eradication for their own compartment (increase in productivity of 8.7–12.8% for beef young bulls) than the breeding farms (increase in productivity of 5.1–6% for beef calves), which may limit the investments in BRD control.


title: Severe Acute Respiratory Syndrome (SARS) and the GDP. Part I: Epidemiology, virology, pathology and general health issues

text: The health profession faces a new challenge with the emergence of a novel viral disease Severe Acute Respiratory Syndrome (SARS), a form of atypical pneumonia caused by a coronavirus termed SARS-CoV. This highly infectious disease has spread through 32 countries, infecting more than 8,400 patients with over 790 deaths in just over 6 months. Over one quarter of those infected were unsuspecting healthcare workers. The major transmission mode of SARS-coronavirus appears to be through droplet spread with other minor subsidiary modes of transmission such as close contact and fomites although air borne transmission has not been ruled out. There is as yet no definitive treatment protocol. Although the peak period of the outbreak is likely to have passed and the risk of SARS in the UK is therefore assessed to be low, the World Health Organisation has asked all countries to remain vigilant lest SARS re-emerges. Recent laboratory acquired cases of SARS reported from Taiwan and Beijing, China are a testimony to this risk. Until reliable diagnostic tests, vaccine and medications are available, control of SARS outbreaks depends on close surveillance, early identification of index cases, quick isolation of carriers and effective infection control and public health measures.


Yersinia Species Isolated from Bats, Germany


title: 26 Bronchiectasis and Chronic Suppurative Lung Disease

text: Abstract Bronchiectasis, chronic suppurative lung disease, and protracted bacterial bronchitis (PBB) are increasingly recognized conditions. Bronchiectasis is now again increasingly diagnosed, and its renewed interest has resulted in further in-depth studies in children and adults. However, diagnostic labeling of childhood bronchiectasis by radiology using adult-derived criteria has substantial limitations. Thus, pediatric-derived criteria are advocated. A paradigm presenting a spectrum related to airway bacteria, with associated degradation and inflammation products causing airway damage if untreated, entails PBB (at the mild end) to irreversible airway dilatation with cystic formation as determined by chest computed tomography (CT) scan (at the severe end of the spectrum). Increasing evidence suggest that progression of airway damage can be limited by intensive treatment, even in those predestined to have bronchiectasis (e.g., immune deficiency). Treatment is aimed at achieving a cure in those at the milder end of the spectrum to limiting further deterioration in those with severe “irreversible” radiological bronchiectasis. Anne Chang is supported by Australian National Health and Medical Research Council practitioner fellowship (1058213), Centre for Research Excellence grant (1040830) and project grants (1098443 and 1019834). Greg Redding is supported in part by Maternal Child Health Grant T72MC00007.


title: Epidemiology and seasonality of respiratory viral infections in hospitalized children in Kuala Lumpur, Malaysia: a retrospective study of 27 years

text: BACKGROUND: Viral respiratory tract infections (RTI) are relatively understudied in Southeast Asian tropical countries. In temperate countries, seasonal activity of respiratory viruses has been reported, particularly in association with temperature, while inconsistent correlation of respiratory viral activity with humidity and rain is found in tropical countries. A retrospective study was performed from 1982-2008 to investigate the viral etiology of children (≤ 5 years old) admitted with RTI in a tertiary hospital in Kuala Lumpur, Malaysia. METHODS: A total of 10269 respiratory samples from all children ≤ 5 years old received at the hospital's diagnostic virology laboratory between 1982-2008 were included in the study. Immunofluorescence staining (for respiratory syncytial virus (RSV), influenza A and B, parainfluenza types 1-3, and adenovirus) and virus isolation were performed. The yearly hospitalization rates and annual patterns of laboratory-confirmed viral RTIs were determined. Univariate ANOVA was used to analyse the demographic parameters of cases. Multiple regression and Spearman's rank correlation were used to analyse the correlation between RSV cases and meteorological parameters. RESULTS: A total of 2708 cases were laboratory-confirmed using immunofluorescence assays and viral cultures, with the most commonly detected being RSV (1913, 70.6%), parainfluenza viruses (357, 13.2%), influenza viruses (297, 11.0%), and adenovirus (141, 5.2%). Children infected with RSV were significantly younger, and children infected with influenza viruses were significantly older. The four main viruses caused disease throughout the year, with a seasonal peak observed for RSV in September-December. Monthly RSV cases were directly correlated with rain days, and inversely correlated with relative humidity and temperature. CONCLUSION: Viral RTIs, particularly due to RSV, are commonly detected in respiratory samples from hospitalized children in Kuala Lumpur, Malaysia. As in temperate countries, RSV infection in tropical Malaysia also caused seasonal yearly epidemics, and this has implications for prophylaxis and vaccination programmes.


title: Characteristics of Ocular Findings of Patients With Coronavirus Disease 2019 (COVID-19) in Hubei Province, China

text: IMPORTANCE: While the outbreak of coronavirus disease 2019 (COVID-19) has resulted in more than 100 000 infected individuals in China and worldwide, there are few reports on the association of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with ocular abnormalities. Understanding ocular manifestations of patients with COVID-19 by ophthalmologists and others may facilitate the diagnosis and prevention of transmission of the disease. OBJECTIVE: To investigate ocular manifestations and viral prevalence in the conjunctiva of patients with COVID-19. DESIGN, SETTING, AND PARTICIPANTS: In this case series, patients with COVID-19 treated from February 9 to 15, 2020, at a hospital center in Hubei province, China, were retrospectively reviewed for ocular manifestations. During the period of treatment, the ocular signs and symptoms as well as results of blood tests and reverse transcriptase–polymerase chain reaction (RT-PCR) from nasopharyngeal and conjunctival swabs for SARS-CoV-2 were noted and analyzed. MAIN OUTCOMES AND MEASURES: Ocular signs and symptoms as well as results of blood tests and RT-PCR for SARS-CoV-2. RESULTS: Of the 38 included patients with clinically confirmed COVID-19, 25 (65.8%) were male, and the mean (SD) age was 65.8 (16.6) years. Among them, 28 patients (73.7%) had positive findings for COVID-19 on RT-PCR from nasopharyngeal swabs, and of these, 2 patients (5.2%) yielded positive findings for SARS-CoV-2 in their conjunctival as well as nasopharyngeal specimens. A total of 12 of 38 patients (31.6%; 95% CI, 17.5-48.7) had ocular manifestations consistent with conjunctivitis, including conjunctival hyperemia, chemosis, epiphora, or increased secretions. By univariate analysis, patients with ocular symptoms were more likely to have higher white blood cell and neutrophil counts and higher levels of procalcitonin, C-reactive protein, and lactate dehydrogenase than patients without ocular symptoms. In addition, 11 of 12 patients with ocular abnormalities (91.7%; 95% CI, 61.5-99.8) had positive results for SARS-CoV-2 on RT-PCR from nasopharyngeal swabs. Of these, 2 (16.7%) had positive results for SARS-CoV-2 on RT-PCR from both conjunctival and nasopharyngeal swabs. CONCLUSIONS AND RELEVANCE: In this study, one-third of patients with COVID-19 had ocular abnormalities, which frequently occurred in patients with more severe COVID-19. Although there is a low prevalence of SARS-CoV-2 in tears, it is possible to transmit via the eyes.


title: Leveraging Wettability Engineering to Develop Three-Layer DIY Face Masks From Low-Cost Materials

text: With the rapid spread of COVID-19 worldwide, the demand for appropriate face masks in the market has also skyrocketed. To ease strain on the supply of masks to the essential healthcare sector, it has become imperative that ordinary people rely more on home-made masks that can be easily put together using commonly available materials, while at the same time performing reasonably at arresting the ingress or egress of airborne droplets. Here, we propose a simple do-it-yourself (DIY) method for preparing a three-layered face mask that deploys two hydrophobic polypropylene nonwoven layers interspaced with a hydrophilic cellulosic cloth. The first hydrophobic layer, facing the user, allows high-momentum droplets (e.g., expelled by a sneeze or cough) to pass through and get absorbed in the next hydrophilic layer, thereby keeping the skin in contact with the mask dry and comfortable. The third (outermost) hydrophobic layer prevents penetration of the liquids from the middle layer to the outside, and also arrests any airborne droplets on its exterior. Simple tests show that our masks perform better in arresting the droplet transmission as compared to surgical masks available in the market. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s41403-020-00115-9) contains supplementary material, which is available to authorized users.


title: Sequential Emergence and Wide Spread of Neutralization Escape Middle East Respiratory Syndrome Coronavirus Mutants, South Korea, 2015

text: The unexpectedly large outbreak of Middle East respiratory syndrome in South Korea in 2015 was initiated by an infected traveler and amplified by several “superspreading” events. Previously, we reported the emergence and spread of mutant Middle East respiratory syndrome coronavirus bearing spike mutations (I529T or D510G) with reduced affinity to human receptor CD26 during the outbreak. To assess the potential association of spike mutations with superspreading events, we collected virus genetic information reported during the outbreak and systemically analyzed the relationship of spike sequences and epidemiology. We found sequential emergence of the spike mutations in 2 superspreaders. In vivo virulence of the mutant viruses seems to decline in human patients, as assessed by fever duration in affected persons. In addition, neutralizing activity against these 2 mutant viruses in serum samples from mice immunized with wild-type spike antigen were gradually reduced, suggesting emergence and wide spread of neutralization escapers during the outbreak.


title: Serum phosphorylated neurofilament heavy-chain levels reflect phenotypic heterogeneity and are an independent predictor of survival in motor neuron disease

text: To investigate the prognostic role and the major determinants of serum phosphorylated neurofilament heavy -chain (pNfH) concentration across a large cohort of motor neuron disease (MND) phenotypes. Enzyme-linked immunosorbent assay (ELISA) was used to measure serum pNfH concentration in 219 MND patients consecutively enrolled in our tertiary MND clinic. A multifactorial analysis was carried out to investigate the major clinical determinants of serum pNfH. Kaplan–Meier survival curves and Cox regression analysis were performed to explore the prognostic value of serum pNfH. Serum pNfH levels were not homogenous among MND phenotypes; higher concentrations in pyramidal, bulbar, and classic phenotypes were observed. C9orf72-MND exhibited higher pNfH concentrations compared to non-C9orf72 MND. Multiple linear regression analysis revealed mean MEP/cMAP and disease progression rate as the two major predictors of serum pNfH levels (R(2) = 0.188; p ≤ 0.001). Kaplan–Meier curves showed a significant difference of survival among MND subgroups when divided into quartiles based on pNfH concentrations, log-rank X(2) = 53.0, p ≤ 0.0001. Our study evidenced that higher serum pNfH concentration is a negative independent prognostic factor for survival. In Cox multivariate model, pNfH concentration showed the highest hazard ratio compared to the other factors influencing survival included in the analysis. pNfH differs among the MND phenotypes and is an independent prognostic factor for survival. This study provides supporting evidence of the role of pNfH as useful prognostic biomarker for MND patients. Neurofilament measurements should be considered in the future prognostic models and in clinical trials for biomarker-based stratification, and to evaluate treatment response. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00415-020-09838-9) contains supplementary material, which is available to authorized users.


title: pH-dependent Conformational Flexibility of the SARS-CoV Main Proteinase (Mpro) Dimer: Molecular Dynamics Simulations and Multiple X-ray Structure Analyses

text: The SARS coronavirus main proteinase (Mpro) is a key enzyme in the processing of the viral polyproteins and thus an attractive target for the discovery of drugs directed against SARS. The enzyme has been shown by X-ray crystallography to undergo significant pH-dependent conformational changes. Here, we assess the conformational flexibility of the Mpro by analysis of multiple crystal structures (including two new crystal forms) and by molecular dynamics (MD) calculations. The MD simulations take into account the different protonation states of two histidine residues in the substrate-binding site and explain the pH-activity profile of the enzyme. The low enzymatic activity of the Mpro monomer and the need for dimerization are also discussed.


title: SARS‐CoV‐2 infection in two patients following recent lung transplantation

text: Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) that causes Coronavirus disease 2019 (COVID‐19) has become a world spreading health problem with pandemic character. Lung transplant recipients may be particularly at risk due to the high degree of immunosupression and the lung being the organ primarily affected by COVID‐19. We describe a 16‐year old male and a 64‐year old female recently lung transplanted patients with COVID‐19 during inpatient rehabilitation. Both patients were on triple immunosuppressive therapy and had no signs of allograft dysfunction. Both patients had close contact to a person who developed COVID‐19 and were tested positive for SARS‐CoV‐2. Subsequently, both patients underwent systematic screening and SARS‐CoV‐2 was detected ultimately. While the 16‐year old boy was completely asymptomatic, the 64‐year old woman developed only mild COVID‐19. Immunosuppressive therapy was unchanged and no experimental treatment was initiated. No signs of graft involvement or dysfunction were noticed. In conclusion, our report of patients with asymptomatic SARS‐CoV‐2 infection and mild COVID‐19 respectively, may indicate that lung transplant recipients are not per se at risk for severe COVID‐19. Further observations and controlled trials are urgently needed to study SARS‐CoV‐2 infection in lung transplant recipients.


title: Circulating Markers of Angiogenesis and Endotheliopathy in COVID-19

text: Despite over 9.3 million infected and 479,000 deaths, the pathophysiological factors that determine the wide spectrum of clinical outcomes in COVID-19 remain inadequately defined. Importantly, patients with underlying cardiovascular disease have been found to have worse clinical outcomes,1 and autopsy findings of endotheliopathy as well as angiogenesis in COVID-19 have accumulated.2,3 Nonetheless, circulating vascular markers associated with disease severity and mortality have not been reliably established. To address this limitation and better understand COVID-19 pathogenesis, we report plasma profiling of factors related to the vascular system from a series of patients admitted to Yale-New Haven Hospital with confirmed diagnosis of COVID-19 via PCR, which demonstrate significant increase in markers of angiogenesis and endotheliopathy in patients hospitalized with COVID-19.


title: Venous Thromboembolism in COVID-19: Towards an Ideal Approach to Thromboprophylaxis, Screening, and Treatment

text: PURPOSE OF REVIEW: Novel coronavirus disease 2019 (COVID-19) has been associated with an increased risk of arterial and venous thromboembolic (VTE) diseases. However, there is a limited amount of data regarding the prevention and management of VTE in severe hospitalized COVID-19 patients. RECENT FINDINGS: In this article, we review currently available clinical data, and mechanisms for COVID-associated coagulopathy, and propose algorithms for screening, prevention (including extended-duration prophylaxis), and treatment of these patients. SUMMARY: Although these recommendations are subject to change given rapidly evolving data, we provide a framework that can guide clinicians in managing thrombotic complications in this challenging condition.


title: Visualization of a substrate-induced productive conformation of the catalytic triad of the Neisseria meningitidis peptidoglycan O-acetylesterase reveals mechanistic conservation in SGNH esterase family members

text: Peptidoglycan O-acetylesterase (Ape1), which is required for host survival in Neisseria sp., belongs to the diverse SGNH hydrolase superfamily, which includes important viral and bacterial virulence factors. Here, multi-domain crystal structures of Ape1 with an SGNH catalytic domain and a newly identified putative peptidoglycan-detection module are reported. Enzyme catalysis was performed in Ape1 crystals and key catalytic intermediates along the SGNH esterase hydrolysis reaction pathway were visualized, revealing a substrate-induced productive conformation of the catalytic triad, a mechanistic detail that has not previously been observed. This substrate-induced productive conformation of the catalytic triad shifts the established dogma on these enzymes, generating valuable insight into the structure-based design of drugs targeting the SGNH esterase superfamily.


title: Rheumatologists’ perspective on coronavirus disease 19 (COVID-19) and potential therapeutic targets

text: The ongoing pandemic coronavirus disease 19 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a matter of global concern. Environmental factors such as air pollution and smoking and comorbid conditions (hypertension, diabetes mellitus and underlying cardio-respiratory illness) likely increase the severity of COVID-19. Rheumatic manifestations such as arthralgias and arthritis may be prevalent in about a seventh of individuals. COVID-19 can result in acute interstitial pneumonia, myocarditis, leucopenia (with lymphopenia) and thrombocytopenia, also seen in rheumatic diseases like lupus and Sjogren’s syndrome. Severe disease in a subset of patients may be driven by cytokine storm, possibly due to secondary hemophagocytic lymphohistiocytosis (HLH), akin to that in systemic onset juvenile idiopathic arthritis or adult-onset Still’s disease. In the absence of high-quality evidence in this emerging disease, understanding of pathogenesis may help postulate potential therapies. Angiotensin converting enzyme 2 (ACE2) appears important for viral entry into pneumocytes; dysbalance in ACE2 as caused by ACE inhibitors or ibuprofen may predispose to severe disease. Preliminary evidence suggests potential benefit with chloroquine or hydroxychloroquine. Antiviral drugs like lopinavir/ritonavir, favipiravir and remdesivir are also being explored. Cytokine storm and secondary HLH might require heightened immunosuppressive regimens. Current international society recommendations suggest that patients with rheumatic diseases on immunosuppressive therapy should not stop glucocorticoids during COVID-19 infection, although minimum possible doses may be used. Disease-modifying drugs should be continued; cessation may be considered during infection episodes as per standard practices. Development of a vaccine may be the only effective long-term protection against this disease.


title: Laboratory Investigation and Phylogenetic Analysis of an Imported Middle East Respiratory Syndrome Coronavirus Case in Greece

text: Rapid and reliable laboratory diagnosis of persons suspected of Middle East respiratory syndrome coronavirus (MERS-CoV) infection is important for timely implementation of infection control practices and disease management. In addition, monitoring molecular changes in the virus can help elucidate chains of transmission and identify mutations that might influence virus transmission efficiency. This was illustrated by a recent laboratory investigation we conducted on an imported MERS-CoV case in Greece. Two oropharyngeal swab specimens were collected on the 1(st) and 2(nd) day of patient hospitalization and tested using two real-time RT-PCR (rRT-PCR) assays targeting the UpE and Orf-1a regions of the MERS-CoV genome and RT-PCR and partial sequencing of RNA-dependent RNA polymerase and nucleocapsid genes. Serum specimens were also collected and serological test were performed. Results from the first swab sample were inconclusive while the second swab was strongly positive for MERS-CoV RNA by rRT-PCR and confirmed positive by RT-PCR and partial gene sequencing. Positive serologic test results further confirmed MERS-CoV infection. Full-length nucleocapsid and spike gene coding sequences were later obtained from the positive swab sample. Phylogenetic analysis revealed that the virus was closely related to recent human-derived MERS-CoV strains obtained in Jeddah and Makkah, Saudi Arabia, in April 2014 and dromedary camels in Saudi Arabia and Qatar. These findings were consistent with the patient’s history. We also identified a unique amino acid substitution in the spike receptor binding domain that may have implications for receptor binding efficiency. Our initial inconclusive rRT-PCR results highlight the importance of collecting multiple specimens from suspect MERS-CoV cases and particularly specimens from the lower respiratory tract.


title: Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (COVID-19)

text: BACKGROUND: Estimation of the fraction and contagiousness of undocumented novel coronavirus (COVID-19) infections is critical for understanding the overall prevalence and pandemic potential of this disease. Many mild infections are typically not reported and, depending on their contagiousness, may support stealth transmission and the spread of documented infection. METHODS: Here we use observations of reported infection and spread within China in conjunction with mobility data, a networked dynamic metapopulation model and Bayesian inference, to infer critical epidemiological characteristics associated with the emerging coronavirus, including the fraction of undocumented infections and their contagiousness. RESULTS: We estimate 86% of all infections were undocumented (95% CI: [82%−90%]) prior to the Wuhan travel shutdown (January 23, 2020). Per person, these undocumented infections were 52% as contagious as documented infections ([44%−69%]) and were the source of infection for two-thirds of documented cases. Our estimate of the reproductive number (2.23; [1.77–3.00]) aligns with earlier findings; however, after travel restrictions and control measures were imposed this number falls considerably. CONCLUSIONS: A majority of COVID-19 infections were undocumented prior to implementation of control measures on January 23, and these undocumented infections substantially contributed to virus transmission. These findings explain the rapid geographic spread of COVID-19 and indicate containment of this virus will be particularly challenging. Our findings also indicate that heightened awareness of the outbreak, increased use of personal protective measures, and travel restriction have been associated with reductions of the overall force of infection; however, it is unclear whether this reduction will be sufficient to stem the virus spread.


title: Clinicopathologic Features and Magnetic Resonance Imaging Findings in 24 Cats With Histopathologically Confirmed Neurologic Feline Infectious Peritonitis

text: BACKGROUND: Feline infectious peritonitis (FIP) is the most common infectious central nervous system (CNS) disease in the cat and is invariably fatal. Improved means of antemortem diagnosis is required to facilitate clinical decision making. Information regarding the magnetic resonance imaging (MRI) findings of neurologic FIP currently is limited, resulting in the need for better descriptions to optimize its use as a diagnostic tool. OBJECTIVE: To describe the clinicopathologic features and MRI findings in cases of confirmed neurologic FIP. ANIMALS: Twenty‐four client‐owned cats with histopathologic confirmation of neurologic FIP. METHODS: Archived records from 5 institutions were retrospectively reviewed to identify cases with confirmed neurologic FIP that had undergone antemortem MRI of the CNS. Signalment, clinicopathologic, MRI, and histopathologic findings were evaluated. RESULTS: Three distinct clinical syndromes were identified: T3‐L3 myelopathy (3), central vestibular syndrome (7), and multifocal CNS disease (14). Magnetic resonance imaging abnormalities were detected in all cases, including meningeal contrast enhancement (22), ependymal contrast enhancement (20), ventriculomegaly (20), syringomyelia (17), and foramen magnum herniation (14). Cerebrospinal fluid was analysed in 11 cases; all demonstrated a marked increase in total protein concentration and total nucleated cell count. All 24 cats were euthanized with a median survival time of 14 days (range, 2–115) from onset of clinical signs. Histopathologic analysis identified perivascular pyogranulomatous infiltrates, lymphoplasmacytic infiltrates, or both affecting the leptomeninges (16), choroid plexuses (16), and periventricular parenchyma (13). CONCLUSIONS AND CLINICAL IMPORTANCE: Magnetic resonance imaging is a sensitive means of detecting neurologic FIP, particularly in combination with a compatible signalment, clinical presentation, and CSF analysis.


Preliminary therapeutic drug monitoring data of β-lactams in critically ill patients with SARS-CoV-2 infection


title: Current perspectives on Kawasaki disease

text: The etiology of Kawasaki disease (KD) remains unknown despite several years of dedicated research in this direction. Recently coronavirus infection and genetic polymorphisms have been implicated. Since first description of the disease there have been few changes in the diagnostic criteria except for newer recommendations of fever of at least 4 instead of 5 days duration. Recently, Echocardiography Criteria and Laboratory Criteria have been added to aid in the diagnosis of incomplete KD where all the historical diagnostic criteria are not present; this is now called the “incomplete form of KD” as opposed to “atypical form of KD”. The word “atypical” is reserved for unusual presentations of KD such as those with hemophagocytic syndrome or nerve palsy. The treatment of KD includes infusion of high dose immunoglobulin. Patients nonresponsive to immunoglobulin therapy are labeled as having “immunoglobulin resistant KD”. The treatment of immunoglobulin resistant KD can be challenging and new therapies that have tried with some success. Late outcomes after 4 decades of treating these patients have recently been published. There has been some concern about increased risk for premature atherosclerosis in patients with childhood KD who had coronary artery abnormalities.


title: Genetic epidemiology of porcine epidemic diarrhoea virus circulating in China in 2012–2017 based on spike gene

text: A porcine epidemic diarrhoea outbreak first occurred in southern China at the end of 2010 and afterwards the disease spread throughout the country. Spike gene is divergent and important for understanding the genetic relations of porcine epidemic diarrhoea virus field strains, the epidemiological status of the virus and vaccine development. In this study, S1 regions of spike gene of 1,235 selected strains collected from 2012 to 2017 in China were clustered along with 25 references of spike sequences mainly from China. The phylogenetic analysis demonstrates that these sequences of S1 regions were genetically more diverse with time. In all strains, G1a, G1b, G2a and G2b clusters accounted for 1.9%, 9.6%, 32.2% and 56.3%, respectively, namely G2a and G2b were the two most prevalent clusters in China. Furthermore, we made a more detailed classification for G2 group based on phylogenetic tree, in which G2a was divided into two subgroups, and G2b was separated into four subgroups.


title: Clinical Features and Radiological Findings of Adenovirus Pneumonia Associated with Progression to Acute Respiratory Distress Syndrome: A Single Center Study in 19 Adult Patients

text: OBJECTIVE: To describe radiologic findings of adenovirus pneumonia and to understand clinico-radiological features associated with progression to acute respiratory distress syndrome (ARDS) in patients with adenovirus pneumonia. MATERIALS AND METHODS: This study included 19 patients diagnosed with adenovirus pneumonia at a tertiary referral center, in the period between March 2003 and April 2015. Clinical findings were reviewed, and two radiologists assessed imaging findings by consensus. Chi-square, Fisher's exact, and Student's t tests were used for comparing patients with and without subsequent development of ARDS. RESULTS: Of 19 patients, nine were immunocompromised, and 10 were immunocompetent. Twelve patients (63%) progressed to ARDS, six of whom (32%) eventually died from the disease. The average time for progression to ARDS from symptom onset was 9.6 days. Initial chest radiographic findings were normal (n = 2), focal opacity (n = 9), or multifocal or diffuse opacity (n = 8). Computed tomography (CT) findings included bilateral (n = 17) or unilateral (n = 2) ground-glass opacity with consolidation (n = 14) or pleural effusion (n = 11). Patients having subsequent ARDS had a higher probability of pleural effusion and a higher total CT extent compared with the non-ARDS group (p = 0.010 and 0.007, respectively). However, there were no significant differences in clinical variables such as patient age and premorbid condition. CONCLUSION: Adenovirus pneumonia demonstrates high rates of ARDS and mortality, regardless of patient age and premorbid conditions, in the tertiary care setting. Large disease extent and presence of pleural effusion on CT are factors suggestive of progression to ARDS.


title: Rapid health transition in China, 1990–2010: findings from the Global Burden of Disease Study 2010

text: BACKGROUND: China has undergone rapid demographic and epidemiological changes in the past few decades, including striking declines in fertility and child mortality and increases in life expectancy at birth. Popular discontent with the health system has led to major reforms. To help inform these reforms, we did a comprehensive assessment of disease burden in China, how it changed between 1990 and 2010, and how China's health burden compares with other nations. METHODS: We used results of the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010) for 1990 and 2010 for China and 18 other countries in the G20 to assess rates and trends in mortality, causes of death, years of life lost (YLLs), years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE). We present results for 231 diseases and injuries and for 67 risk factors or clusters of risk factors relevant to China. We assessed relative performance of China against G20 countries (significantly better, worse, or indistinguishable from the G20 mean) with age-standardised rates and 95% uncertainty intervals. FINDINGS: The leading causes of death in China in 2010 were stroke (1·7 million deaths, 95% UI 1·5–1·8 million), ischaemic heart disease (948 700 deaths, 774 500–1 024 600), and chronic obstructive pulmonary disease (934 000 deaths, 846 600–1 032 300). Age-standardised YLLs in China were lower in 2010 than all emerging economies in the G20, and only slightly higher than noted in the USA. China had the lowest age-standardised YLD rate in the G20 in 2010. China also ranked tenth (95% UI eighth to tenth) for HALE and 12th (11th to 13th) for life expectancy. YLLs from neonatal causes, infectious diseases, and injuries in children declined substantially between 1990 and 2010. Mental and behavioural disorders, substance use disorders, and musculoskeletal disorders were responsible for almost half of all YLDs. The fraction of DALYs from YLDs rose from 28·1% (95% UI 24·2–32·5) in 1990 to 39·4% (34·9–43·8) in 2010. Leading causes of DALYs in 2010 were cardiovascular diseases (stroke and ischaemic heart disease), cancers (lung and liver cancer), low back pain, and depression. Dietary risk factors, high blood pressure, and tobacco exposure are the risk factors that constituted the largest number of attributable DALYs in China. Ambient air pollution ranked fourth (third to fifth; the second highest in the G20) and household air pollution ranked fifth (fourth to sixth; the third highest in the G20) in terms of the age-standardised DALY rate in 2010. INTERPRETATION: The rapid rise of non-communicable diseases driven by urbanisation, rising incomes, and ageing poses major challenges for China's health system, as does a shift to chronic disability. Reduction of population exposures from poor diet, high blood pressure, tobacco use, cholesterol, and fasting blood glucose are public policy priorities for China, as are the control of ambient and household air pollution. These changes will require an integrated government response to improve primary care and undertake required multisectoral action to tackle key risks. Analyses of disease burden provide a useful framework to guide policy responses to the changing disease spectrum in China. FUNDING: Bill & Melinda Gates Foundation.


title: Global Climate Changes and International Trade and Travel: Effects on Human Health Outcomes

text: There is now near-unanimous scientific agreement that greenhouse gas emissions generated by human activities have increased global temperatures and changed the earth's climate. There is, however, no universal agreement on how rapidly, regionally, or asymmetrically the earth will warm; or on the true impact of global warming on infectious disease outbreaks and natural disasters and their inevitable public health outcomes. In addition, many other factors influence the emergence and reemergence of infectious diseases in a changing environment including international trade and travel, exotic eating habits, lifestyle and residential choices, host susceptibility, and microbial adaptation. The ultimate effects of climate changes and the increased distribution of pathogens by international trade and travel will not be limited to infectious disease outbreaks in immunologically naïve populations but will also impact world food production and quality, air quality, drinking water availability and quality, immigration, urban relocation, and civil unrest. Despite the uncertainties in outcomes and their magnitudes, the active responses to climate changes in a global economy must include combinations of environmental, political, regulatory, socioeconomic, and public health measures.


title: The use of google trends to investigate the loss of smell related searches during COVID‐19 outbreak

text: BACKGROUND: Initial reports describing COVID‐19 were dominated by the presence of cough, breathlessness, and fever, anecdotal reports suggested anosmia may also be a manifestation. We sought to use Google Trends (GT) to investigate whether there was a surge in individuals searching for information related to smell loss during the COVID‐19 epidemic in the Italy, Spain, UK, USA, Germany, France, Iran and Netherlands. METHODS: GT was used to explore Internet activity related to loss of smell in Italy, Spain, UK, USA, Germany, France, Iran and Netherlands. Spearman rank analysis was performed to correlate loss of smell relative search volumes (RSV) with the increases of daily confirmed cases of COVID‐19 and deaths attributed to disease. As a control event, we also performed analysis of smell‐related searches during the last UK Influenza epidemic of 2009. RESULTS: In all three countries, we observed strong correlations between daily RSVs related to loss of smell, increases of daily COVID‐19+ cases and deaths ranging from 0.633 to 0.952. All correlations were statistically significant (p<0.05). CONCLUSION: There is a strong correlation between the frequency of searches for smell‐related information and the onset of COVID‐19 infection in Italy, Spain, UK, USA, Germany, France, Iran and Netherlands. We would hypothesise this may relate to a previously under‐recognised symptom. This article is protected by copyright. All rights reserved


title: Beating the odds with systematic individualized care Nationwide prospective follow‐up of all patients with COVID‐19 in Iceland

text: The current pandemic of a novel coronavirus disease 2019 (COVID‐19) began in December 2019 in Wuhan, China, and has since spread worldwide. Pandemic preparedness has been an ongoing project in Iceland since the Severe Acute Respiratory Syndrome (SARS) epidemic in 2003‐2004. In mid‐January 2020, The Directorate of Health (DOH) and The Department of Civil Protection and Emergency Management (DCPEM) revised the current pandemic preparedness response plan. The DOH and DCPEM, in close collaboration with the Department of Clinical Microbiology and Internal Medicine Services at Landspitali–The National University Hospital (LUH) and deCODE genetics, initiated a nationwide surveillance program for COVID‐19, including diagnostic testing which began on 31 January. A report on the extensive screening efforts in Iceland has recently been published.


title: The impact of US–EU “Open Skies” agreement on airline market structures and airline networks

text: Abstract The gradual liberalization of international air transport has largely benefited the traveling public. Progress since the development of concepts such as “Open Skies” in the late 1970s as an alternative to the restrictive bilateral air service agreements that had effectively controlled most international air transport since the mid-1940s has been uneven and spasmodic. The recent move to open the North Atlantic more fully to competition has proved a particularly challenging task, and the agreement between the US and the European Union is still both partial and conditional. This paper offers an overview of the economics of the situation and provides insights into the reasons why it has developed in the way it has, the outcomes that we may expect from it, and some consideration of the wider, non-commercial, impacts that it may have.


Global Health Education


title: Can COVID 2019 disease induces a specific cardiovascular damage or it exacerbates pre-existing cardiovascular diseases?

text: A novel coronavirus SARS-CoV-2 causes acute respiratory distress syndrome (ARDS) with cardiovascular and multiple organ failure till death. The main mechanisms of virus internalization and interaction with the host are down-regulation or upregulation of the ACE2 receptor, the surface glycoprotein competition mechanism for the binding of porphyrin to iron in heme formation as well as interference with the immune system. The interference on renin–angiotensin–aldosterone system (RAAS) activation, heme formation, and the immune response is responsible for infection diffusion, endothelial dysfunction, vasoconstriction, oxidative damage and releasing of inflammatory mediators. The main pathological findings are bilateral interstitial pneumonia with diffuse alveolar damage (DAD). Because ACE receptor is also present in the endothelium of other districts as well as in different cell types, and as porphyrins are transporters in the blood and other biological liquids of iron forming heme, which is important in the assembly of the hemoglobin, myoglobin and the cytochromes, multiorgan damage occurs both primitive and secondary to lung damage. More relevantly, myocarditis, acute myocardial infarction, thromboembolism, and disseminated intravasal coagulation (DIC) are described as complications in patients with poor outcome. Here, we investigated the role of SARSCoV-2 on the cardiovascular system and in patients with cardiovascular comorbidities, and possible drug interference on the heart.


title: COVID-19 and inflammatory bowel disease: Questions arising from patient care and follow-up during the initial phase of the pandemic (February–April 2020)

text: Abstract COVID-19 is a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which was described in China in late 2019. There are currently more than three million diagnosed cases, constituting a pandemic which has caused a worldwide crisis. The devastating effects of this infection are due to its highly contagious nature and although mild forms predominate, in absolute values, the rates for severe forms and mortality are very high. The information on the characteristics of the infection in inflammatory bowel disease is of special interest, as these patients have higher attendance at health centres, which may increase their risk of infection. Furthermore, the treatments used to control the inflammatory activity may modify the disease course of COVID-19. The Spanish Working Group on Crohn’s Disease and Ulcerative Colitis and the Spanish Nurses Working Group on Inflammatory Bowel Disease have prepared this document as a practical response to some common questions about the treatment of these patients.


title: Community-acquired pneumonia during the first post-pandemic influenza season: A prospective, multicentre cohort study

text: Summary Objectives To determine the aetiology, clinical features and prognosis of CAP during the first post-pandemic influenza season. We also assessed the factors associated with severe disease and tested the ability of a scoring system for identifying influenza A (H1N1)pdm09-related pneumonia. Methods Prospective cohort study carried out at 10 tertiary hospitals of Spain. All adults hospitalised with CAP from December 01, 2010 to March 31, 2011 were analysed. Results A total of 747 adults with CAP required hospitalisation. The aetiology was determined in 315 (42.2%) patients, in whom 154 (21.9%) were due to bacteria, 125 (16.7%) were due to viruses and 36 (4.8%) were mixed (due to viruses and bacteria). The most frequently isolated bacteria were Streptococccus pneumoniae. Among patients with viral pneumonia, the most common organism identified were influenza A (H1N1)pdm09. Independent factors associated with severe disease were impaired consciousness, septic shock, tachypnea, hyponatremia, hypoxemia, influenza B, and influenza A (H1N1)pdm09. The scoring system evaluated did not differentiate reliably between patients with influenza A (H1N1)pdm09-related pneumonia and those with other aetiologies. Conclusions The frequency of bacterial and viral pneumonia during the first post-pandemic influenza season was similar. The main identified virus was influenza A (H1N1)pdm09, which was associated with severe disease. Although certain presenting clinical features may allow recognition of influenza A (H1N1)pdm09-related pneumonia, it is difficult to express them in a reliable scoring system.


Ventilation-perfusion Scans During the Coronavirus (COVID 19) Outbreak


title: Efficient diastereoselective synthesis of a new class of azanucleosides: 2′-homoazanucleosides

text: Abstract Azanucleosides, sugar-modified nucleoside analogues containing a 4′ nitrogen atom, have shown a lot of therapeutic potential, e.g. as anti-cancer and antiviral agents. We report the synthesis of a series of 2’-homoazanucleosides, in which the nucleobase is attached to the 2’-position of the pyrrolidine ring via a methylene linker. A suitable orthogonally protected iminosugar was synthesized by ring closing metathesis and dihydroxylation as key steps and further converted to a series of 8 nucleoside analogues through Mitsunobu reaction with suitably protected nucleobases. The 5′ position of the adenine analogue was then further derivatized with thiols to afford 2 additional compounds. The final compounds were evaluated for biological activity.


title: Metalloprotease ADAM17 regulates porcine epidemic diarrhea virus infection by modifying aminopeptidase N

text: Abstract Porcine epidemic diarrhea virus (PEDV) is a causative agent of porcine epidemic diarrhea (PED). PED, characterized by acute diarrhea, vomiting, dehydration, has caused serious economic losses in pig industry worldwide. Here, we demonstrate that activation of a disintergrin and metalloprotease 17 (ADAM17) induced the decrease of PEDV infection in HEK293 and IPEC-J2 cells and the downregulation of cell surface aminopeptidase N (APN) expression, an important entry factor for PEDV infection. Furthermore, overexpression of ADAM17 suppressed PEDV infection in HEK293 and IPEC-J2 cells, whereas ablation of ADAM17 expression using ADAM17 specific siRNA resulted in a corresponding increase of PEDV infection and an upregulation of cell surface APN expression. Taken together, these data demonstrate that modulation of APN expression by metalloprotease ADAM17 regulates PEDV infection. Hence, the reduction in APN expression represents another component of the anti-PEDV infection response initiated by ADAM17.


title: Understanding the Spatial Clustering of Severe Acute Respiratory Syndrome (SARS) in Hong Kong

text: We applied cartographic and geostatistical methods in analyzing the patterns of disease spread during the 2003 severe acute respiratory syndrome (SARS) outbreak in Hong Kong using geographic information system (GIS) technology. We analyzed an integrated database that contained clinical and personal details on all 1,755 patients confirmed to have SARS from 15 February to 22 June 2003. Elementary mapping of disease occurrences in space and time simultaneously revealed the geographic extent of spread throughout the territory. Statistical surfaces created by the kernel method confirmed that SARS cases were highly clustered and identified distinct disease “hot spots.” Contextual analysis of mean and standard deviation of different density classes indicated that the period from day 1 (18 February) through day 16 (6 March) was the prodrome of the epidemic, whereas days 86 (15 May) to 106 (4 June) marked the declining phase of the outbreak. Origin-and-destination plots showed the directional bias and radius of spread of superspreading events. Integration of GIS technology into routine field epidemiologic surveillance can offer a real-time quantitative method for identifying and tracking the geospatial spread of infectious diseases, as our experience with SARS has demonstrated.


title: Prevalence of Wēnzhōu virus in small mammals in Yunnan Province, China

text: BACKGROUND: Mammarenaviruses are associated with human hemorrhagic fever diseases in Africa and America. Recently, a rodent mammarenavirus, Wēnzhōu virus (WENV) and related viruses, have been reported in China, Cambodia, and Thailand. Moreover, in Cambodia, these viruses were suspected to be associated with human disease. In China, Yunnan Province is famous for its abundant animal and plant diversity and is adjacent to several South-eastern Asia countries. Therefore, it is necessary to know whether WENV-related viruses, or other mammarenaviruses, are prevalent in this province. METHODOLOGY/PRINCIPAL FINDINGS: Small mammals were trapped, euthanized, and sampled. Mammarenavirus RNA was detected using a nested reverse transcription polymerase chain reaction (RT-PCR) and quantified by real-time RT-PCR. A total of 1040 small mammals belonging to 13 genera and 26 species were trapped in Yunnan Province. WENV-related mammarenaviruses were detected in 41 rodent liver samples, mainly in brown rats (Rattus norvegicus) and oriental house rats (R. tanezumi).Viral nucleocapsid protein was detected in liver sections by indirect immunofluorescence assay. Full-length-genomes were amplified by RT-PCR and used for phylogenetic analysis with the MEGA package. Recombination analysis was performed using the SimPlot and Recombination Detection Program. CONCLUSIONS/SIGNIFICANCE: WENV related viruses circulated in small mammals in Yunnan Province. Whole genome sequence analysis of five selected viral strains showed that these viruses are closely related to WENVs discovered in Asia and form an independent branch in the phylogenetic tree in the WENV clade. Paying attention to investigate the influence of these viruses to public health is essential in the epidemic regions.


title: Diagnosis and treatment recommendations for pediatric respiratory infection caused by the 2019 novel coronavirus

text: Since December 2019, an epidemic caused by novel coronavirus (2019-nCoV) infection has occurred unexpectedly in China. As of 8 pm, 31 January 2020, more than 20 pediatric cases have been reported in China. Of these cases, ten patients were identified in Zhejiang Province, with an age of onset ranging from 112 days to 17 years. Following the latest National recommendations for diagnosis and treatment of pneumonia caused by 2019-nCoV (the 4th edition) and current status of clinical practice in Zhejiang Province, recommendations for the diagnosis and treatment of respiratory infection caused by 2019-nCoV for children were drafted by the National Clinical Research Center for Child Health, the National Children’s Regional Medical Center, Children’s Hospital, Zhejiang University School of Medicine to further standardize the protocol for diagnosis and treatment of respiratory infection in children caused by 2019-nCoV.


title: Metagenomic Analysis of the Jinding Duck Fecal Virome

text: Ducks play an important role in transmitting and maintaining mammalian viruses in nature, and are a reservoir host of many animal viruses. We analyzed the fecal virome of four strains (A, B, C, and D) of ducks living in isolation by using metagenomic analysis. The feces of the ducks tested contained 18 animal virus families. The percentage values of RNA virus reads, compared to the total animal virus reads in each of the four strains were 96.96% (A), 97.30% (B), 98.01 (C), and 67.49% (D), and were mainly from Orthomyxoviridae, Mimiviridae, Bunyaviridae, Picobirnaviridae, and Reoviridae. Meanwhile, the minority of DNA virus reads were related to Herpesviridae, Adenoviridae, Iridoviridae, and other, low abundance viral families. The percentage values of Orthomyxoviridae, Mimiviridae, Bunyaviridae, Picobirnaviridae, and Herpesviridae reads were not significantly different among strains A, B, and C; however, there were marked differences in the abundance of these reads in strain D. In summary, this study provides an unbiased examination of the viral diversity in the feces of four strains of ducks in specific-pathogen-free periods, and highlights the variation in the percentage of viral families present. These results can be used as a reference for detecting duck viral pathogens and predicting zoonotic potential.


title: Alterations in sialic-acid O-acetylation glycoforms during murine erythrocyte development

text: 9-O-acetylation of sialic acid is a common modification that plays important roles in host-pathogen interactions. CASD1 has been described as a sialate-O-acetyltransferase and has been shown to be essential for 9-O-acetylation of sialic acid in some cell lines in vitro. In this study, we used knockout mice to confirm that CASD1 is indeed responsible for 9-O-acetylation of sialic acids in vivo. We observed a complete loss of 9-O-acetylation of sialic acids on the surface of myeloid, erythroid and CD4+ T cells in Casd1-deficient mice. Although 9-O-acetylation of sialic acids on multiple hematopoietic lineages was lost, there were no obvious defects in hematopoiesis. Interestingly, red blood cells from Casd1-deficient mice also lost reactivity to TER-119, a rat monoclonal antibody that is widely used to mark the murine erythroid lineage. The sialic acid glyco-epitope recognized by TER-119 on red blood cells was sensitive to the sialic acid O-acetyl esterase activity of the hemagglutinin esterase from bovine coronavirus but not to the corresponding enzyme from the influenza C virus. During erythrocyte development TER-119+ Ery-A and Ery-B cells could be stained by catalytically inactive bovine coronavirus hemaggutinin-esterase but not by the inactive influenza C hemagglutinin esterase, while TER-119+ Ery-C stage cells and mature erythrocytes were recognized by both virolectins. These results suggest that throughout murine erythrocyte development, cells of the erythroid lineage express a glycoconjugate bearing a modified 7,9-di-O-acetyl form of sialic acid, that is recognized specifically by the bovine coronavirus lectin and not by the influenza C hemagglutinin, and this modified sialic acid moiety is a component of the TER-119 epitope. As erythrocytes mature, the surface of Ery-C cells and mature erythrocytes also acquires a distinct CASD1-dependent 9-O-acetyl sialic acid moiety that can be recognized by virolectins from both influenza C and bovine coronavirus that are specific for 9-O-acetyl sialic acid.


title: Antiviral action of interferon-alpha against porcine transmissible gastroenteritis virus

text: Abstract Swine testis (ST) cell cultures were treated with various doses of recombinant human interferon-alpha 2a (IFN), and assayed for 2′,5′ oligoadenylate synthetase (2–5 A synthetase) activity. Treatment with 100 or 1000 units/ml of IFN resulted in increased 2–5 A synthetase activity, but there was no significant response to 1 unit/ml of IFN. Titres of porcine transmissible gastroenteritis virus (TGEV) were reduced between 6 and 15 hours post-infection in ST cells treated with 1000 or 2500 units/ml of IFN. Polyacrylamide gel electrophoresis of lysates of TGEV-infected ST cells, and of lysates immunoprecipitated with anti-TGEV antibodies, revealed that the synthesis of the N and S proteins of TGEV was reduced in cells treated with 100 or 1000 units/ml of IFN. Viral RNA production, as determined with a probe which hybridized to the S gene of TGEV, was found to be reduced in ST cells treated with 1000 units/ml of IFN, but not in cells treated with 100 units/ml. It was concluded that, in IFN-treated ST cells, TGEV protein production may be decreased in the absence of reduced viral RNA production, and that 2–5 A synthetase may not be a significant factor in the antiviral activity of IFN against TGEV.


title: Coronavirus disease 2019: The harms of exaggerated information and non‐evidence‐based measures

text: The evolving coronavirus disease 2019 (COVID-19) epidemic1 is certainly cause for concern. Proper communication and optimal decision-making is an ongoing challenge, as data evolve. The challenge is compounded, however, by exaggerated information. This can lead to inappropriate actions. It is important to differentiate promptly the true epidemic from an epidemic of false claims and potentially harmful actions.


title: FilmArray Respiratory Panel Integrated in a field Point Of Care dispositive for the diagnosis of respiratory tract infections in rural areas in Senegal

text: The development of molecular syndrome-based kits for the diagnosis of respiratory infections offers rapid and sensitive detection of common respiratory pathogens and will have a significant impact on the care of patients. In this study, we present the results obtained after the introduction of the FilmArray respiratory panel in a field Point of care (POC) for the diagnosis of virus and bacteria responsible of respiratory tract infections in Senegal rural area. From February to August 2017, we collected nasal swabs from febrile patients that presented symptoms of respiratory tract infections in three health posts located in Niakhar. Specimens were tested on site by multiplex Polymerase Chain Reaction (PCR), using the FilmArray respiratory panel® that targets 20 pathogens, including 17 virus and 3 bacteria (bioMérieux). Nasal swabs were collected from 113 patients. The median age was 4 years (ranging from 4 months to 60 years) and 51 (45%) were males. The prevalence of respiratory pathogens was 37.5% (12/32) during the dry season and 54.3% (44/81) in the rainy season (p=0.16). The prevalence of respiratory pathogen carriage was higher in children under 5 years of age (38/55, 69.1%). The most prevalent micro-organisms detected were influenza B virus (16/113, 14%), human rhinovirus/enterovirus (10/113, 9%), parainfluenzae virus (9/113, 8%), respiratory syncytial virus (8/113, 7%), adenovirus (5/113, 4%), human metapneumovirus (3/113, 3%), Chlamydia pneumoniae (2/113, 2%) and Coronavirus (2/113, 2%). The study has demonstrated that the integration of the FilmArray respiratory panel into a field POC could significantly improve the management of respiratory tract infections in rural areas. Author summary Respiratory tract infections are one of the leading causes of death worldwide. Populations in underdeveloped countries are the most affected, especially children under 5 years of age. Among the pathogens responsible for these infections, bacteria and viruses are the most identified. In poor countries, laboratory diagnosis can only be done in urban areas. They are generally based on bacteriological, immunological or molecular biology techniques. The concept of POC is not developed in underdeveloped countries. Its existence would have made it possible to carry out RDTs to confirm the clinician’s diagnosis and allow rapid management of the patient. In the current situation, the time required to achieve results is often very long for patients. In this study, we sought to demonstrate the significant contribution of the FilmArray respiratory panel in the management of respiratory tract infections in rural areas. We also wanted to reduce the time it takes to deliver results in order to improve patient care. This dispositif was integrated in a field POC which was implemented in Niakhar since 2015, in order to improve the management of emerging diseases. The FilmArray respiratory panel gave us the opportunity to investigate the causes of respiratory tract infections in this area. For each patient, we systematically target 20 pathogens, including 17 viruses and 3 bacteria, with a single multiplex PCR. One of the main results of this study is that children under 5 years of age are the most affected by respiratory tract infections. Then we noted a lack of consultation among adults that could be explained by the banalization of respiratory problems or a preference for traditional care. The fact that children under 5 years of age are the most affected could also serve as a basis for implementing vaccination programmes directly targeting the most vulnerable age groups. It should be noted that for 51% of patients, the result of the diagnosis was negative. It would appear that some pathogens responsible for respiratory tract infections are not targeted by the multiplex PCR. Thus, it would be necessary to screen these pathogens in order to integrate them into a panel that would cover the most pathogens in circulation in this area.


LUNG CANCER SURGICAL MANAGEMENT DURING THE OUTBREAK OF COVID-19


A Dermatologic Manifestation of COVID-19: Transient Livedo Reticularis


title: A Mouse Model for Betacoronavirus Subgroup 2c Using a Bat Coronavirus Strain HKU5 Variant

text: Cross-species transmission of zoonotic coronaviruses (CoVs) can result in pandemic disease outbreaks. Middle East respiratory syndrome CoV (MERS-CoV), identified in 2012, has caused 182 cases to date, with ~43% mortality, and no small animal model has been reported. MERS-CoV and Pipistrellus bat coronavirus (BtCoV) strain HKU5 of Betacoronavirus (β-CoV) subgroup 2c share >65% identity at the amino acid level in several regions, including nonstructural protein 5 (nsp5) and the nucleocapsid (N) protein, which are significant drug and vaccine targets. BtCoV HKU5 has been described in silico but has not been shown to replicate in culture, thus hampering drug and vaccine studies against subgroup 2c β-CoVs. We report the synthetic reconstruction and testing of BtCoV HKU5 containing the severe acute respiratory syndrome (SARS)-CoV spike (S) glycoprotein ectodomain (BtCoV HKU5-SE). This virus replicates efficiently in cell culture and in young and aged mice, where the virus targets airway and alveolar epithelial cells. Unlike some subgroup 2b SARS-CoV vaccines that elicit a strong eosinophilia following challenge, we demonstrate that BtCoV HKU5 and MERS-CoV N-expressing Venezuelan equine encephalitis virus replicon particle (VRP) vaccines do not cause extensive eosinophilia following BtCoV HKU5-SE challenge. Passage of BtCoV HKU5-SE in young mice resulted in enhanced virulence, causing 20% weight loss, diffuse alveolar damage, and hyaline membrane formation in aged mice. Passaged virus was characterized by mutations in the nsp13, nsp14, open reading frame 5 (ORF5) and M genes. Finally, we identified an inhibitor active against the nsp5 proteases of subgroup 2c β-CoVs. Synthetic-genome platforms capable of reconstituting emerging zoonotic viral pathogens or their phylogenetic relatives provide new strategies for identifying broad-based therapeutics, evaluating vaccine outcomes, and studying viral pathogenesis.


title: Estimating risks of importation and local transmission of Zika virus infection

text: Background. An international spread of Zika virus (ZIKV) infection has attracted global attention. ZIKV is conveyed by a mosquito vector, Aedes species, which also acts as the vector species of dengue and chikungunya viruses. Methods. Arrival time of ZIKV importation (i.e., the time at which the first imported case was diagnosed) in each imported country was collected from publicly available data sources. Employing a survival analysis model in which the hazard is an inverse function of the effective distance as informed by the airline transportation network data, and using dengue and chikungunya virus transmission data, risks of importation and local transmission were estimated. Results. A total of 78 countries with imported case(s) have been identified, with the arrival time ranging from 1 to 44 weeks since the first ZIKV was identified in Brazil, 2015. Whereas the risk of importation was well explained by the airline transportation network data, the risk of local transmission appeared to be best captured by additionally accounting for the presence of dengue and chikungunya viruses. Discussion. The risk of importation may be high given continued global travel of mildly infected travelers but, considering that the public health concerns over ZIKV infection stems from microcephaly, it is more important to focus on the risk of local and widespread transmission that could involve pregnant women. The predicted risk of local transmission was frequently seen in tropical and subtropical countries with dengue or chikungunya epidemic experience.


title: A novel method for the capture-based purification of whole viral native RNA genomes

text: Current technologies for targeted characterization and manipulation of viral RNA primarily involve amplification or ultracentrifugation with isopycnic gradients of viral particles to decrease host RNA background. The former strategy is non-compatible for characterizing properties innate to RNA strands such as secondary structure, RNA–RNA interactions, and also for nanopore direct RNA sequencing involving the sequencing of native RNA strands. The latter strategy, ultracentrifugation, causes loss in genomic information due to its inability to retrieve unassembled viral RNA. To address this, we developed a novel application of current nucleic acid hybridization technologies for direct characterization of RNA. In particular, we modified a current enrichment protocol to capture whole viral native RNA genomes for downstream RNA assays to circumvent the abovementioned problems. This technique involves hybridization of biotinylated baits at 500 nucleotides (nt) intervals, stringent washes and release of free native RNA strands using DNase I treatment, with a turnaround time of about 6 h 15 min. RT-qPCR was used as the primary proof of concept that capture-based purification indeed removes host background. Subsequently, capture-based purification was applied to direct RNA sequencing as proof of concept that capture-based purification can be coupled with downstream RNA assays. We report that this protocol was able to successfully purify viral RNA by 561- to 791-fold. We also report that application of this protocol to direct RNA sequencing yielded a reduction in human host RNA background by 1580-fold, a 99.91% recovery of viral genome with at least 15× coverage, and a mean coverage across the genome of 120×. This report is, to the best of our knowledge, the first description of a capture-based purification method for assays that involve direct manipulation or characterisation of native RNA. This report also describes a successful application of capture-based purification as a direct RNA sequencing strategy that addresses certain limitations of current strategies in sequencing RNA viral genomes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13568-019-0772-y) contains supplementary material, which is available to authorized users.


title: Secondary myopathy due to systemic diseases

text: BACKGROUND: Some systemic diseases also affect the skeletal muscle to various degrees and with different manifestations. This review aimed at summarizing and discussing recent advances concerning the management of muscle disease in systemic diseases. METHOD: Literature review by search of MEDLINE, and Current Contents with appropriate search terms. RESULTS: Secondary muscle disease occurs in infectious disease, endocrine disorders, metabolic disorders, immunological disease, vascular diseases, hematological disorders, and malignancies. Muscle manifestations in these categories include pathogen‐caused myositis, muscle infarction, rhabdomyolysis, myasthenia, immune‐mediated myositis, necrotising myopathy, or vasculitis‐associated myopathy. Muscle affection may concern only a single muscle, a group of muscles, or the entire musculature. Severity of muscle affection may be transient or permanent, may be a minor part of or may dominate the clinical picture, or may be mild or severe, requiring invasive measures including artificial ventilation if the respiratory muscles are additionally involved. Diagnostic work‐up is similar to that of primary myopathies by application of non‐invasive and invasive techniques. Treatment of muscle involvement in systemic diseases is based on elimination of the underlying cause and supportive measures. The prognosis is usually fair if the causative disorder is effectively treatable but can be fatal in single cases if the entire musculature including the respiratory muscles is involved, in case of infection, or in case of severe rhabdomyolysis. CONCLUSION: Secondary muscle manifestations of systemic diseases must be addressed and appropriately managed. Prognosis of secondary muscle disease in systemic diseases is usually fair if the underlying condition is accessible to treatment.


Moyens opérationnels du service de santé des armées déployés dans le cadre de la pandémie COVID


title: COVID-19 in Newborns and Infants—Low Risk of Severe Disease: Silver Lining or Dark Cloud?

text: One hundred years after the 1918 influenza pandemic, we now face another pandemic with the severe acute respiratory syndrome–novel coronavirus-2 (SARS-CoV-2). There is considerable variability in the incidence of infection and severe disease following exposure to SARS-CoV-2. Data from China and the United States suggest a low prevalence of neonates, infants, and children, with those affected not suffering from severe disease. In this article, we speculate different theories why this novel agent is sparing neonates, infants, and young children. The low severity of SARS-CoV-2 infection in this population is associated with a high incidence of asymptomatic or mildly symptomatic infection making them efficient carriers. Key Points: There is a low prevalence of novel coronavirus disease in neonates, infants, and children. The fetal hemoglobin may play a protective role against coronavirus in neonates. Immature angiotensin converting enzyme (ACE2) interferes with coronavirus entry into the cells.


title: History of the World Allergy Organization: 1989 to 2006, the XVIII World Allergy Congress, Journal Development, Reorganization, and New Programs

text: History of the World Allergy Organization: In 1951, the leaders in allergy from all over the world came together to form the International Association of Allergology and Clinical Immunology (IAACI). For the next 60 years, the allergy world converged at the IAACI triennial meetings, which became biennial in 2003. The international meetings, originally named the International Congress of Allergology and Clinical Immunology (ICACI), are now the World Allergy Congress (WAC) hosted by the World Allergy Organization (WAO). Everyone who has aspired to have worldwide recognition has played a part in IAACI-WAO. The History of the WAO traces the global arc of the allergy field over the past 60 years. The current officers of WAO elected to focus on this rich history, inviting prominent leaders who are interested in being part of this history project to write about their time with IAACI-WAO. This series will be presented in Cancún, México, as part of the XXII World Allergy Congress (December 4-8, 2011). Leading up to the Congress in Cancún, the WAO Journal is presenting segments of the History as part of the "Notes of Allergy Watchers Series." Please enjoy. --Michael A. Kaliner, MD Historian, and Past-President (2006-2007), World Allergy Organization


title: Diagnóstico microbiológico de las infecciones virales respiratorias en el paciente adulto

text: Resumen Las técnicas tradicionales para el diagnóstico de los virus respiratorios siguen estando todavía vigentes, aunque los métodos moleculares aplicados al diagnóstico de la infección viral respiratoria han supuesto una auténtica revolución. Las técnicas moleculares tienen como principales ventajas una excelente sensibilidad, especificidad, capacidad de adaptación a virus emergentes, capacidad para detectar múltiples dianas en un mismo ensayo y posibilidad de automatización. Adicionalmente, estas técnicas han permitido profundizar en el papel de los virus en la infección respiratoria aguda a la vez que han descrito la existencia de nuevos virus no conocidos previamente. Los métodos moleculares y no moleculares de diagnóstico rápido para 1 o más virus respiratorios han permitido la toma de decisiones de forma inmediata en el manejo del paciente mejorando su pronóstico y evitando la transmisión nosocomial. Sin embargo, también hay inconvenientes, la mayor sensibilidad de las técnicas moleculares ha supuesto un incremento significativo de la tasa de codetecciones múltiples de virus respiratorios, cuya implicación clínica resulta difícil de interpretar. Finalmente queda por demostrar todavía si la utilización de las nuevas técnicas, de elevado coste, en el diagnóstico microbiológico de rutina de las infecciones respiratorias agudas de etiología viral, en el paciente hospitalizado, es coste-efectiva. Abstract Conventional techniques for the diagnosis of respiratory viruses are still being used, although molecular methods are now considered as a gold standard in this field. Molecular techniques have a great number of advantages such as an excellent sensitivity, specificity, adaptability to emerging viruses, capability for multiplex and for automation. With all the available repertoire of techniques for microbiological diagnosis, the knowledge relative to respiratory viruses is growing up not only for new aetiological agents but also for its epidemiology. The advances in molecular and non-molecular fast diagnostic methods for one or more respiratory viruses allow quick decisions in the management of the patient. However, there are also disadvantages. The great sensitivity of molecular techniques has meant a significant increase in the rate of multiple detections of respiratory viruses, whose clinical involvement is difficult to interpret. Finally, it remains to show whether the use of new techniques, of high cost, in the microbiological routine diagnosis of acute respiratory viral infections in the hospitalized patient, is cost effective.


title: Wie stark trifft die Corona-Pandemie die Kliniken für Orthopädie und Unfallchirurgie?: Eine Analyse der ersten 5 Wochen

text: BACKGROUND: The corona pandemic poses enormous financial challenges for hospitals. Using the example of a clinic for orthopaedics and trauma surgery, the performance development of the first 5 weeks in comparison to last year and an evaluation of the compensation measures laid down by law will be evaluated. METHODOLOGY: Based on the performance figures, a comparison is made between the period 16.03 to 17.04.2019 and the same period in 2020. Changes in the number of cases, case mix, case-mix index and day-mix index, as well as the occupancy days are recorded. The monetary measures from the COVID-19 Hospital Relief Act are applied to these changes, and the adequacy is evaluated. RESULTS: Compared to last year, there was a decrease in inpatient admissions of n = 307 patients in the observation period. As a result, there was a decrease of 595 points in case mix and 2320 days of occupancy. This results in a decrease in revenue of approximately EUR 1.9 million. The flat rate for empty beds represents the largest monetary compensation for the loss of revenue. It amounts to approximately EUR 1.3 million. Taking into account further support and an adjustment for variable costs, a deficit of EUR 382,069 remains for 5 weeks. DISCUSSION: The measures taken by the Government are an important pillar for the economic security of German hospitals. The lack of differentiation of measures by specialty leads to insufficient compensation for orthopaedics and trauma surgery.


title: Intracellular localization of Crimean-Congo Hemorrhagic Fever (CCHF) virus glycoproteins

text: BACKGROUND: Crimean-Congo Hemorrhagic Fever virus (CCHFV), a member of the genus Nairovirus, family Bunyaviridae, is a tick-borne pathogen causing severe disease in humans. To better understand the CCHFV life cycle and explore potential intervention strategies, we studied the biosynthesis and intracellular targeting of the glycoproteins, which are encoded by the M genome segment. RESULTS: Following determination of the complete genome sequence of the CCHFV reference strain IbAr10200, we generated expression plasmids for the individual expression of the glycoproteins G(N )and G(C), using CMV- and chicken β-actin-driven promoters. The cellular localization of recombinantly expressed CCHFV glycoproteins was compared to authentic glycoproteins expressed during virus infection using indirect immunofluorescence assays, subcellular fractionation/western blot assays and confocal microscopy. To further elucidate potential intracellular targeting/retention signals of the two glycoproteins, GFP-fusion proteins containing different parts of the CCHFV glycoprotein were analyzed for their intracellular targeting. The N-terminal glycoprotein G(N )localized to the Golgi complex, a process mediated by retention/targeting signal(s) in the cytoplasmic domain and ectodomain of this protein. In contrast, the C-terminal glycoprotein G(C )remained in the endoplasmic reticulum but could be rescued into the Golgi complex by co-expression of G(N). CONCLUSION: The data are consistent with the intracellular targeting of most bunyavirus glycoproteins and support the general model for assembly and budding of bunyavirus particles in the Golgi compartment.


Psychiatry hospital management facing COVID-19: from medical staff to patients