title: Preliminary estimation of the basic reproduction number of novel coronavirus (2019-nCoV) in China, from 2019 to 2020: A data-driven analysis in the early phase of the outbreak

text: Backgrounds An ongoing outbreak of a novel coronavirus (2019-nCoV) pneumonia hit a major city of China, Wuhan, December 2019 and subsequently reached other provinces/regions of China and countries. We present estimates of the basic reproduction number, R0, of 2019-nCoV in the early phase of the outbreak. Methods Accounting for the impact of the variations in disease reporting rate, we modelled the epidemic curve of 2019-nCoV cases time series, in mainland China from January 10 to January 24, 2020, through the exponential growth. With the estimated intrinsic growth rate (γ), we estimated R0 by using the serial intervals (SI) of two other well-known coronavirus diseases, MERS and SARS, as approximations for the true unknown SI. Findings The early outbreak data largely follows the exponential growth. We estimated that the mean R0 ranges from 2.24 (95%CI: 1.96-2.55) to 3.58 (95%CI: 2.89-4.39) associated with 8-fold to 2-fold increase in the reporting rate. We demonstrated that changes in reporting rate substantially affect estimates of R0. Conclusion The mean estimate of R0 for the 2019-nCoV ranges from 2.24 to 3.58, and significantly larger than 1. Our findings indicate the potential of 2019-nCoV to cause outbreaks.


title: Structure-activity relationship studies of lipophilic teicoplanin pseudoaglycon derivatives as new anti-influenza virus agents

text: Six series of semisynthetic lipophilic glycopeptide antibiotic derivatives were evaluated for in vitro activity against influenza A and B viruses. The new teicoplanin pseudoaglycon-derived lipoglycopeptides were prepared by coupling one or two side chains to the N-terminus of the glycopeptide core, using various conjugation methods. Three series of derivatives bearing two lipophilic groups were synthesized by attaching bis-alkylthio maleimides directly or through linkers of different lengths to the glycopeptide. Access to the fourth and fifth series of compounds was achieved by click chemistry, introducing single alkyl/aryl chains directly or through a tetraethylene glycol linker to the same position. A sixth group of semisynthetic derivatives was obtained by sulfonylation of the N-terminus. Of the 42 lipophilic teicoplanin pseudoaglycon derivatives tested, about half showed broad activity against influenza A and B viruses, with some of them having reasonable or no cytotoxicity. Minor differences in the side chain length as well as lipophilicity appeared to have significant impact on antiviral activity and cytotoxicity. Several lipoglycopeptides were also found to be active against human coronavirus.


title: Immunogenicity and safety of virus-like particle of the porcine encephalomyocarditis virus in pig

text: BACKGROUND: In this study, porcine encephalomyocarditis virus (EMCV) virus-like particles (VLPs) were generated using a baculovirus expression system and were tested for immunogenicity and protective efficacy in vivo. RESULTS: VLPs were successfully generated from Sf9 cells infected with recombinant baculovirus and were confirmed to be approximately 30-40 nm by transmission electron microscopy (TEM). Immunization of mice with 0.5 μg crude protein containing the VLPs resulted in significant protection from EMCV infection (90%). In swine, increased neutralizing antibody titers were observed following twice immunization with 2.0 μg crude protein containing VLPs. In addition, high levels of neutralizing antibodies (from 64 to 512 fold) were maintained during a test period following the second immunization. No severe injection site reactions were observed after immunization and all swine were healthy during the immunization period CONCLUSION: Recombinant EMCV VLPs could represent a new vaccine candidate to protect against EMCV infection in pig farms.


title: The tree shrew provides a useful alternative model for the study of influenza H1N1 virus

text: BACKGROUND: The influenza pandemics have resulted in significant morbidity and mortality worldwide. Animal models are useful in the study of influenza virus pathogenesis. Because of various limitations in current laboratory animal models, it is essential to develop new alternative animal models for influenza virus research aimed at understanding the viral and host factors that contribute to virus infection in human. METHOD: We investigated the replicative efficiency of influenza H1N1 virus (classic strain (Influenza A/PR/8/34), seasonal influenza isolate (A/Guangzhou/GIRD/02/09) and swine-origin human influenza virus (A/Guangzhou/GIRD/07/09)) at Day1,2,4,6 and 9 p.i. using TCID(50) and qPCR assay in tree shrew model. Body temperature was monitored in the morning and evening for 3 days before infection and for 14 days. Seroconversion was detected by determining the neutralizing antibody titers against the challenge viruses in the pre- and exposure serum samples collected before infection and at 14 days p.i., respectively. Lungs and tracheas of tree shews were collected at day 14 post p.i. for histopathological analysis. Lectinhistochemistry analysis was conducted to identify the distribution of SAα2,3 Gal and SAα2,6 Gal receptors in the lung and trachea. RESULTS: The infected tree shrew displayed mild or moderate systemic and respiratory symptoms and pathological changes in respiratory tracts. The human H1N1 influenza virus may replicate in the upper respiratory tract of tree shrews. Analysis of the receptors distribution in the respiratory tract of tree shrews by lectinhistochemistry showed that sialic acid (SA)α2,6-Gal receptors were widely distributed in the trachea and nasal mucosa, whereas (SA)α2,3-Gal receptor was the main receptor in the lung tissue. CONCLUSIONS: Based on these findings, tree shrew seemed to mimic well influenza virus infection in humans. We propose that tree shrews could be a useful alternative mammalian model to study pathogenesis of influenza H1N1 virus.


title: How we treat patients with brain tumour during the COVID-19 pandemic

text: The COVID-19 pandemic has created major insecurities regarding whether we can and should maintain the current standards of diagnosis and treatment and access to care for patients with cancer. This is particularly true in the field of neuro-oncology, where the perceived benefit of therapeutic interventions is often low, although this notion is partially incorrect. We acknowledge that the recommendations for care of patients with cancer have become a moving target and that all recommendations are subject to modification based on national and institutional regulations. Still, some important considerations and proposals may apply broadly. First, it is important to note that old age and cardiovascular and pulmonary co-morbidities are the major risk factors for experiencing a severe course of and for dying of COVID-19, not chronic immunosuppression and cancer. Second, many of the considerations on how we should adapt clinical practice in neuro-oncology in view of COVID-19 that are now dominating discussions at local tumour boards, as well as on the institutional level and within societies of neuro-oncology, are not novel but have been valid before and only now have become a priority. More than ever, it seems to be mandatory to adhere to evidence-based medicine and not to prescribe potentially toxic, notably immunsuppresssive systemic therapy where evidence for efficacy is low. Furthermore, it is more obvious now that oncologists must not miss the right time for advance care planning, that is, supporting patients in understanding and sharing their personal values, life goals and preferences regarding future medical care. The major psychological impact of transforming oncology care to teleconferences and videoconferences and of the important strict recommendation of social distancing must not be overlooked in a patient population that is characterised by significant prevalence of cognitive decline and by the general perception that their life span may not exceed the life span of the COVID-19 pandemic


COVID-19-Risikopatienten mit Echo-Marker identifizieren


title: Use of Stem Cell Extracellular Vesicles as a “Holistic” Approach to CNS Repair

text: Neurodegeneration is a hallmark of many diseases and disorders of the central nervous system (CNS). High levels of neuroinflammation are often associated with irreparable damage to CNS cells due to the dysregulation of signaling cascades that are unable to restore a homeostatic balance. Due to the inherent complexity of the CNS, development of CNS-related therapeutics has met limited success. While stem cell therapy has been evaluated in the context of CNS repair, the mechanisms responsible for their functional properties have not been clearly defined. In recent years, there has been growing interest in the use of stem cell extracellular vesicles (EVs) for the treatment of various CNS pathologies as these vesicles are believed to mediate many of the functional effects associated with their donor stem cells. The potency of stem cell EVs is believed to be largely driven by their biological cargo which includes various types of RNAs, proteins, and cytokines. In this review, we describe the characteristic properties of stem cell EVs and summarize their reported neuroprotective and immunomodulatory functions. A special emphasis is placed on the identification of specific biological cargo, including proteins and non-coding RNA molecules, that have been found to be associated with stem cell EVs. Collectively, this review highlights the potential of stem cell EVs as an alternative to traditional stem cell therapy for the repair of cellular damage associated with diverse CNS pathologies.


title: Evaluation of Antigen-Conjugated Fluorescent Beads to Identify Antigen-Specific B Cells

text: Selection of single antigen-specific B cells to identify their expressed antibodies is of considerable interest for evaluating human immune responses. Here, we present a method to identify single antibody-expressing cells using antigen-conjugated fluorescent beads. To establish this, we selected Folate Receptor alpha (FRα) as a model antigen and a mouse B cell line, expressing both the soluble and the membrane-bound forms of a human/mouse chimeric antibody (MOv18 IgG1) specific for FRα, as test antibody-expressing cells. Beads were conjugated to FRα using streptavidin/avidin-biotin bridges and used to select single cells expressing the membrane-bound form of anti-FRα. Bead-bound cells were single cell-sorted and processed for single cell RNA retrotranscription and PCR to isolate antibody heavy and light chain variable regions. Variable regions were then cloned and expressed as human IgG1/k antibodies. Like the original clone, engineered antibodies from single cells recognized native FRα. To evaluate whether antigen-coated beads could identify specific antibody-expressing cells in mixed immune cell populations, human peripheral blood mononuclear cells (PBMCs) were spiked with test antibody-expressing cells. Antigen-specific cells could comprise up to 75% of cells selected with antigen-conjugated beads when the frequency of the antigen-positive cells was 1:100 or higher. In PBMC pools, beads conjugated to recombinant antigens FRα and HER2 bound antigen-specific anti-FRα MOv18 and anti-HER2 Trastuzumab antibody-expressing cells, respectively. From melanoma patient-derived B cells selected with melanoma cell line-derived protein-coated fluorescent beads, we generated a monoclonal antibody that recognized melanoma antigen-coated beads. This approach may be further developed to facilitate analysis of B cells and their antibody profiles at the single cell level and to help unravel humoral immune repertoires.


title: Studies with an unclassified virus isolated from diarrheic calves

text: Abstract A transmissible agent (Breda agent) was isolated from a calf with diarrhea and shown to be infectious by inoculation orally into gnotobiotic and conventionally reared calves. The “Breda” agent had the morphology of a virus and possessed a hemagglutinin. Antigenic studies showed the virus to be antigenically different from bovine coronavirus, parainfluenza 3 virus, bovine rotavirus, bovine parvovirus and bovine pestivirus (BVD). Attempts to culture the virus in cell or organ cultures or in embryonated eggs, were unsuccessful. The virus was either spherical or kidney shaped, with 7–9 nm peplomers on the surface. A few particles possessed coronavirus processes of 17–20 nm, but these were arranged irregularly and were thought to be tissue debris. Three out of eight experimental calves developed severe diarrhea and the lesions in the small and large intestines were similar to those reported for coronavirus. The virus replicated in the jejunal and ileal regions of the small intestine and in the spiral colon, as judged by immunofluorescence. The virus multiplied in all experimental calves and was excreted in the feces; excretion correlating with the onset of diarrhea or a change in the appearance of the feces. There was little or no malabsorption measured by the uptake of D-xylose and the fact that infection of both the crypt and villus epithelial cells was observed, suggests that the pathogenesis may be different from rotavirus and coronavirus. Fourteen of fortyseven calves in the outbreak were infected with the virus, virus was not identified in other farm outbreaks of the disease.


title: Nocturnal oxygen therapy as an option for early COVID-19

text: Abstract Currently, there is no effective antiviral therapy or immune-based treatments for coronavirus disease (COVID-19), and the urgent challenge is to prevent the transition of COVID-19 from mild to severe. In this paper, we provide nocturnal oxygen therapy as a new option for the patients with COVID-19 under home quarantine, and suggest that nocturnal oxygen therapy at the early stage may be helpful to prevent the disease from mild to worse by inhibiting the rapid replication of the virus and improving the body's antiviral ability.


title: Management of a patient presenting with anterior STEMI with concomitant COVID‐19 infection early in the course of the U.S. pandemic

text: The coronavirus disease‐2019 (COVID‐19) is a viral illness with heterogenous clinical manifestations, ranging from mild symptoms to severe acute respiratory distress syndrome and shock caused by the severe acute respiratory syndrome coronavirus‐2. The global healthcare community is rapidly learning more about the effects of COVID‐19 on the cardiovascular system, as well as the strategies for management of infected patients with cardiovascular disease. There is minimal literature available surrounding the relationship between COVID‐19 infection and acute coronary syndrome. We describe the case of a woman who presented with an acute anterior ST‐elevation myocardial infarction managed by primary percutaneous coronary intervention, who subsequently developed severe COVID‐19 infection and ultimately succumbed to multisystem organ failure.


Hidradenitis suppurativa: the importance of virtual outpatient care during COVID-19 pandemic


title: Demographic and Health Indicators in Correlation to Interstate Variability of Incidence, Confirmation, Hospitalization, and Lethality in Mexico: Preliminary Analysis from Imported and Community Acquired Cases during COVID-19 Outbreak

text: This study’s objective is to analyze the incidence, lethality, hospitalization, and confirmation of COVID-19 cases in Mexico. Sentinel surveillance for COVID-19 cases in Mexico began after the confirmation of the first patient with community transmission. Methods: This epidemiologic, cross-sectional study includes all clinically suspected, and laboratory-confirmed cases nationwide from the beginning of the outbreak to 21 April 2020. State-cluster demographic data and health indicators were analyzed in reference to epidemiologic measures, with logistic regressions for the dependent variables of incidence, confirmation, and lethality. Results: The national incidence was 13.89/100,000 inhabitants with a 6.52% overall lethality and a confirmed-case mortality of 11.1%. The incidence variation significantly correlated with migration, but not urbanization. Pediatric patients were less prone to be tested (OR = −3.92), while geriatric individuals were a priority. State lethality positively correlated with the proportion of the population assisted at public hospitals and correlated inversely to the number of hospitals and clinics in the state. Conclusions: Migration strongly correlated with incidence; elderly patients had lower odds of being hospitalized but were likely to die. Patients aged <15 were less prone to be laboratory-confirmed. Case confirmation was not performed in all hospitalized patients, but 72.15% of hospitalized patients had favorable outcomes to date.


title: Modeling the spread of bird flu and predicting outbreak diversity

text: Abstract Avian influenza, commonly known as bird flu, is an epidemic caused by H5N1 virus that primarily affects birds like chickens, wild water birds, etc. On rare occasions, these can infect other species including pigs and humans. In the span of less than a year, the lethal strain of bird flu is spreading very fast across the globe mainly in South East Asia, parts of Central Asia, Africa and Europe. In order to study the patterns of spread of epidemic, we made an investigation of outbreaks of the epidemic in one week, that is from February 13–18, 2006, when the deadly virus surfaced in India. We have designed a statistical transmission model of bird flu taking into account the factors that affect the epidemic transmission such as source of infection, social and natural factors and various control measures are suggested. For modeling the general intensity coefficient f ( r ) , we have implemented the recent ideas given in the article Fitting the Bill, Nature [R. Howlett, Fitting the bill, Nature 439 (2006) 402], which describes the geographical spread of epidemics due to transportation of poultry products. Our aim is to study the spread of avian influenza, both in time and space, to gain a better understanding of transmission mechanism. Our model yields satisfactory results as evidenced by the simulations and may be used for the prediction of future situations of epidemic for longer periods. We utilize real data at these various scales and our model allows one to generalize our predictions and make better suggestions for the control of this epidemic.


title: High-Risk Airway Management in the Emergency Department: Diseases and Approaches Part I

text: Abstract Background Successful airway management is critical to the practice of emergency medicine. Thus, emergency physicians must be ready to optimize and prepare for airway management in critically ill patients with a wide range of physiologic challenges. Challenges in airway management commonly encountered in the emergency department are discussed using a pearl and pitfall discussion in this first part of a two-part series. Objective This narrative review presents an evidence-based approach to airway and patient management during endotracheal intubation in challenging cases commonly encountered in the emergency department. Discussion Adverse events during emergent airway management are common with post-intubation cardiac arrest reported in as many as 1 in 25 intubations. Many of these adverse events can be avoided by proper identification and understanding the underlying physiology, preparation, and post intubation management. Those with high risk features including severe metabolic acidosis; shock and hypotension; obstructive lung disease; pulmonary hypertension, right ventricle failure, and pulmonary embolism; and severe hypoxemia must be managed with airway expertise. Conclusions This narrative review discusses the pearls and pitfalls of commonly encountered physiologic high-risk intubations with a focus on the emergency clinician.


title: A generalized approach to predicting protein-protein interactions between virus and host

text: BACKGROUND: Viral infection involves a large number of protein-protein interactions (PPIs) between virus and its host. These interactions range from the initial binding of viral coat proteins to host membrane receptor to the hijacking the host transcription machinery by viral proteins. Therefore, identifying PPIs between virus and its host helps understand the mechanism of viral infections and design antiviral drugs. Many computational methods have been developed to predict PPIs, but most of them are intended for PPIs within a species rather than PPIs across different species such as PPIs between virus and host. RESULTS: In this study, we developed a prediction model of virus-host PPIs, which is applicable to new viruses and hosts. We tested the prediction model on independent datasets of virus-host PPIs, which were not used in training the model. Despite a low sequence similarity between proteins in training datasets and target proteins in test datasets, the prediction model showed a high performance comparable to the best performance of other methods for single virus-host PPIs. CONCLUSIONS: Our method will be particularly useful to find PPIs between host and new viruses for which little information is available. The program and support data are available at http://bclab.inha.ac.kr/VirusHostPPI.


title: COVID 19 in INDIA: Strategies to combat from combination threat of life and livelihood

text: Abstract INDIA- As for reported in 360 COVID-19 cases (till March 22, 2020), seven people were died, and 23 people were treated successfully.1 This virus can easily affect who having respiratory problem and especially who all have been aged older than sixty. Most of the affected peoples had reached India from different part of the world, as like of carrier. Owing to this, India made several precautionary measures to mitigate/neglect the disease in beginning stage, however, the denser population of country will not be simple to control the same for long time (community spread), if government will not incorporate the visionary strategies. Since attacked several nations have been worried mostly for their people life (health), despite that developing country like India with huge population should consider about the livelihood (for Below Poverty Line (BPL) people), equally with the life. This article will give insights to make effective strategy to culminate the world threat COVID-19 in India.


title: Unveiling the druggable RNA targets and small molecule therapeutics

text: Abstract The increasing appreciation for the crucial roles of RNAs in infectious and non-infectious human diseases makes them attractive therapeutic targets. Coding and non-coding RNAs frequently fold into complex conformations which, if effectively targeted, offer opportunities to therapeutically modulate numerous cellular processes, including those linked to undruggable protein targets. Despite the considerable skepticism as to whether RNAs can be targeted with small molecule therapeutics, overwhelming evidence suggests the challenges we are currently facing are not outside the realm of possibility. In this review, we highlight the most recent advances in molecular techniques that have sparked a revolution in understanding the RNA structure-to-function relationship. We bring attention to the application of these modern techniques to identify druggable RNA targets and to assess small molecule binding specificity. Finally, we discuss novel screening methodologies that support RNA drug discovery and present examples of therapeutically valuable RNA targets.


title: Implementation of Artifact Detection in Critical Care: A Methodological Review

text: Artifact Detection (AD) techniques minimize the impact of artifacts on physiologic data acquired in Critical Care Units (CCU) by assessing quality of data prior to Clinical Event Detection (CED) and Parameter Derivation (PD). This methodological review introduces unique taxonomies to synthesize over 80 AD algorithms based on these six themes: (1) CCU; (2) Physiologic Data Source; (3) Harvested data; (4) Data Analysis; (5) Clinical Evaluation; and (6) Clinical Implementation. Review results show that most published algorithms: (a) are designed for one specific type of CCU; (b) are validated on data harvested only from one Original Equipment Manufacturer (OEM) monitor; (c) generate Signal Quality Indicators (SQI) that are not yet formalised for useful integration in clinical workflows; (d) operate either in standalone mode or coupled with CED or PD applications; (e) are rarely evaluated in real-time; and (f) are not implemented in clinical practice. In conclusion, it is recommended that AD algorithms conform to generic input and output interfaces with commonly defined data: (1) type; (2) frequency; (3) length; and (4) SQIs. This shall promote (a) reusability of algorithms across different CCU domains; (b) evaluation on different OEM monitor data; (c) fair comparison through formalised SQIs; (d) meaningful integration with other AD, CED and PD algorithms; and (e) real-time implementation in clinical workflows.


title: Viral infections of the CNS with special emphasis on herpes simplex infections

text: Within the past decade the management of acute HSV I encephalitis has been improved dramatically by the advent of the polymerase chain reaction (PCR), a method which has become the gold standard of diagnosis of HSV I encephalitis, replacing diagnostic uncertainties and, avoiding, in particular, invasive brain biopsy. Early detection of HSV II in the neonate is mandatory; however, prevention by Caesarean section and/or prenatal therapy of the mother are for this the best option. Very recently the causative agent of Mollaret's meningitis has proved to be, at least in part, HSV I or II. So far prospective randomized therapeutic trials are awaited for the treatment of Mollaret's meningitis using intravenous acyclovir or the more modern oral forms of virostatics (famciclovir, valaciclovir). For decades the causative agent of facial palsy (Bell's palsy) has been sought; only with the advent of PCR has this question been answered. Although one single study indicates the superiority of a combination of acyclovir plus prednisone, this finding has to be confirmed by a large scale prospective randomised double blind study. Nevertheless, if other causes for the clinical/neurological syndrome of peripheral facial palsy have been excluded, a combination therapy with acyclovir plus prednisone seems to be indicated in a patient with Bell's palsy.


title: Identification of viral agents causing diarrhea among children in the Eastern Center of Tunisia

text: Viral diarrhea remains a major cause of childhood morbidity and mortality worldwide. In Tunisia, no comprehensive studies of all viral agents related to diarrhea in children have yet been conducted. The present study was performed to investigate the role of enteric viruses in acute diarrhea in the country. Six hundred thirty‐eight stool samples were collected from children under 5 years of age seeking medical care for acute diarrhea between October 2003 and September 2005 in hospitals from the Eastern‐Center Tunisia. All samples were tested for rotavirus, astrovirus, and adenovirus using commercial antigen enzyme immunoassays (EIAs). Positive samples for rotavirus and astrovirus were confirmed by an “in‐house” reverse transcriptase‐polymerase chain reaction (RT‐PCR). Samples positive for adenovirus antigen were subjected to further EIA screening for species F enteric adenovirus types 40 and 41. At least one viral agent was found in 30% of the specimens. The frequency of rotavirus, astrovirus, and adenovirus was 20%, 7%, and 6%, respectively. Of the stool samples containing adenovirus, 57% (20/35) were found to be positive for species F adenovirus types 40/41. Dual infections were found in 9% (17/191) of the positive samples. Enteric viruses appear to play an important role in pediatric diarrhea in Tunisia. The introduction of affordable viral diagnosis in pediatric hospitals will improve patient care by reducing the unnecessary use of antibiotics. J. Med. Virol. 78:1198–1203, 2006. © 2006 Wiley‐Liss, Inc.


title: Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients

text: Abstract Background The dynamic changes of lymphocyte subsets and cytokines profiles of patients with novel coronavirus disease (COVID-19) and their correlation with the disease severity remain unclear. Methods Peripheral blood samples were longitudinally collected from 40 confirmed COVID-19 patients and examined for lymphocyte subsets by flow cytometry and cytokine profiles by specific immunoassays. Findings Of the 40 COVID-19 patients enrolled, 13 severe cases showed significant and sustained decreases in lymphocyte counts [0•6 (0•6-0•8)] but increases in neutrophil counts [4•7 (3•6-5•8)] than 27 mild cases [1.1 (0•8-1•4); 2•0 (1•5-2•9)]. Further analysis demonstrated significant decreases in the counts of T cells, especially CD8+ T cells, as well as increases in IL-6, IL-10, IL-2 and IFN-γ levels in the peripheral blood in the severe cases compared to those in the mild cases. T cell counts and cytokine levels in severe COVID-19 patients who survived the disease gradually recovered at later time points to levels that were comparable to those of the mild cases. Moreover, the neutrophil-to-lymphocyte ratio (NLR) (AUC=0•93) and neutrophil-to-CD8+ T cell ratio (N8R) (AUC =0•94) were identified as powerful prognostic factors affecting the prognosis for severe COVID-19. Interpretation The degree of lymphopenia and a proinflammatory cytokine storm is higher in severe COVID-19 patients than in mild cases, and is associated with the disease severity. N8R and NLR may serve as a useful prognostic factor for early identification of severe COVID-19 cases. Funding The National Natural Science Foundation of China, the National Science and Technology Major Project, the Health Commission of Hubei Province, Huazhong University of Science and Technology, and the Medical Faculty of the University Hospital Essen, Germany.


Letter To the Editor: [Our Response to COVID-19 as Endocrinologists and Diabetologists]


title: Small G Rac1 is involved in replication cycle of dengue serotype 2 virus in EAhy926 cells via the regulation of actin cytoskeleton

text: Bleeding is a clinical characteristic of severe dengue and may be due to increased vascular permeability. However, the pathogenesis of severe dengue remains unclear. In this study, we showed that the Rac1-microfilament signal pathway was involved in the process of DENV serotype 2 (DENV2) infection in EAhy926 cells. DENV2 infection induced dynamic changes in actin organization, and treatment with Cytochalasin D or Jasplakinolide disrupted microfilament dynamics, reduced DENV2 entry, and inhibited DENV2 assembly and maturation. Rac1 activities decreased during the early phase and gradually increased by the late phase of infection. Expression of the dominant-negative form of Rac1 promoted DENV2 entry but inhibited viral assembly, maturation and release. Our findings demonstrated that Rac1 plays an important role in the DENV2 life cycle by regulating actin reorganization in EAhy926 cells. This finding provides further insight into the pathogenesis of severe dengue.


title: Can Users Search Trends Predict People Scares or Disease Breakout? An Examination of Infectious Skin Diseases in the United States

text: BACKGROUND: In health and medicine, people heavily use the Internet to search for information about symptoms, diseases, and treatments. As such, the Internet information can simulate expert medical doctors, pharmacists, and other health care providers. AIM: This article aims to evaluate a dataset of search terms to determine whether search queries and terms can be used to reliably predict skin disease breakouts. Furthermore, the authors propose and evaluate a model to decide when to declare a particular month as Epidemic at the US national level. METHODS: A Model was designed to distinguish a breakout in skin diseases based on the number of monthly discovered cases. To apply this model, the authors correlated Google Trends of popular search terms with monthly reported Rubella and Measles cases from Centers for Disease Control and Prevention (CDC). Regressions and decision trees were used to determine the impact of different terms to trigger the occurrence of epidemic classes. RESULTS: Results showed that the volume of search keywords for Rubella and Measles rises when the volume of those reported diseases rises. Results also implied that the overall process was successful and should be repeated with other diseases. Such process can trigger different actions or activities to be taken when a certain month is declared as “Epidemic.” Furthermore, this research has shown great interest for vaccination against Measles and Rubella. CONCLUSIONS: The findings suggest that the search queries and keyword trends can be truly reliable to be used for the prediction of disease outbreaks and some other related knowledge extraction applications. Also search-term surveillance can provide an additional tool for infectious disease surveillance. Future research needs to re-apply the model used in this article, and researchers need to question whether characterizing the epidemiology of Coronavirus Disease 2019 (COVID-19) pandemic waves in United States can be done through search queries and keyword trends.


Influenza Research in the Soviet Union—1974


title: Human respiratory syncytial virus in children with lower respiratory tract infections or influenza-like illness and its co-infection characteristics with viruses and atypical bacteria in Hangzhou, China

text: Abstract Background Human respiratory syncytial virus (RSV) is the most important viral pathogen in children. However, its epidemic patterns and co-infection characteristics are not fully understood. Objectives We attempted to determine the level of genetic variation of RSV, and describe the prevalence and co-infection characteristics of RSV in Hangzhou during two epidemic seasons. Study design Single respiratory samples from 1820 pediatric patients were screened for RSV and genotyped by RT-PCR and sequencing. In all RSV positive specimens, we screened for viruses and atypical bacteria. Demographic and clinical information was recorded and analyzed. Results A total of 34.5% and 3.8% of samples from acute lower respiratory tract infections (ALRI) and influenza-like illness (ILI) were positive for RSV, respectively. Phylogenetic analysis revealed that 61.1% of the selected 167 RSV strains were NA1, 31.1% were BA, 3.6% were ON1, 2.4% were CB1, and 1.8% were NA3. A new genotype, BA11 was identified, which comprised 98.1% of BA strains in this study, while the rest were BA10. A total of 36.4% and 9.1% of RSV-positive children with ALRI and ILI respectively were found to be co-infected. Rhinovirus was the most common additional respiratory virus, followed by human metapneumovirus. Except for fever, no significant differences in other clinical presentation between the RSV mono-infection and co-infection groups were observed. Conclusions The circulating RSV strains had high genetic variability with RSV-B showing a more local pattern. In ALRI cases, co-infection of RSV with other viruses or atypical bacteria has no significant effect on the clinical presentation except fever.


title: Viral metagenomics reveals the presence of highly divergent quaranjavirus in Rhipicephalus ticks from Mozambique

text: Background: Ticks are primary vectors for many well-known disease-causing agents that affect human and animal populations globally such as tick-borne encephalitis, Crimean-Congo hemorrhagic fever and African swine fever. In this study, viral metagenomics was used to identify what viruses are present in Rhipicephalus spp. ticks collected in the Zambezi Valley of Mozambique. Methods: The RNA was amplified with sequence-independent single primer amplification (SISPA) and high-throughput sequencing was performed on the Ion Torrent platform. The generated sequences were subjected to quality check and classfied by BLAST. CodonCode aligner and SeqMan were used to assemble the sequences. Results: The majority of viral sequences showed closest sequence identity to the Orthomyxoviridae family, although viruses similar to the Parvoviridae and Coronaviridae were also identified. Nearly complete sequences of five orthomyxoviral segments (HA, NP, PB1, PB2, and PA) were obtained and these showed an amino acid identity of 32–52% to known quaranjaviruses. The sequences were most closely related to the Wellfleet Bay virus, detected and isolated from common eider during a mortality event in the USA. Conclusions: In summary, this study has identified a highly divergent virus with in the Orthomyxoviridae family associated with Rhipicephalus ticks from Mozambique. Further genetic and biological studies are needed in order to investigate potential pathogenesis of the identified orthomyxovirus.


title: Comparison of commercial RT-PCR diagnostic kits for COVID-19

text: Abstract The final months of 2019 witnessed the emergence of a novel coronavirus in the human population. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has since spread across the globe and is posing a major burden on society. Measures taken to reduce its spread critically depend on timely and accurate identification of virus-infected individuals by the most sensitive and specific method available, i.e. real-time reverse transcriptase PCR (RT-PCR). Many commercial kits have recently become available, but their performance has not yet been independently assessed. The aim of this study was to compare basic analytical and clinical performance of selected RT-PCR kits from seven different manufacturers (Altona Diagnostics, BGI, CerTest Biotec, KH Medical, PrimerDesign, R-Biopharm AG, and Seegene). We used serial dilutions of viral RNA to establish PCR efficiency and estimate the 95% limit of detection (LOD95%). Furthermore, we ran a panel of SARS-CoV-2-positive clinical samples (n = 13) for a preliminary evaluation of clinical sensitivity. Finally, we used clinical samples positive for non-coronavirus respiratory viral infections (n = 6) and a panel of RNA from related human coronaviruses to evaluate assay specificity. PCR efficiency was ≥96% for all assays and the estimated LOD95% varied within a 6-fold range. Using clinical samples, we observed some variations in detection rate between kits. Importantly, none of the assays showed cross-reactivity with other respiratory (corona)viruses, except as expected for the SARS-CoV-1 E-gene. We conclude that all RT-PCR kits assessed in this study may be used for routine diagnostics of COVID-19 in patients by experienced molecular diagnostic laboratories.


Recently published papers: small pieces of the puzzle and the long-term view


How the Irish Competition and Consumer Protection Commission is responding to the COVID-19 challenge


Shelter hospital mode: How do we prevent COVID-19 hospital-acquired infection?


title: Mental health among otolaryngology resident and attending physicians during the COVID‐19 pandemic: National study

text: BACKGROUND: Otolaryngologists are among the highest risk for COVID‐19 exposure. METHODS: This is a cross‐sectional, survey‐based, national study evaluating academic otolaryngologists. Burnout, anxiety, distress, and depression were assessed by the single‐item Mini‐Z Burnout Assessment, 7‐item Generalized Anxiety Disorder Scale, 15‐item Impact of Event Scale, and 2‐item Patient Health Questionnaire, respectively. RESULTS: A total of 349 physicians completed the survey. Of them, 165 (47.3%) were residents and 212 (60.7%) were males. Anxiety, distress, burnout, and depression were reported in 167 (47.9%), 210 (60.2%), 76 (21.8%), and 37 (10.6%) physicians, respectively. Attendings had decreased burnout relative to residents (odds ratio [OR] 0.28, confidence interval [CI] [0.11‐0.68]; P = .005). Females had increased burnout (OR 1.93, CI [1.12.‐3.32]; P = .018), anxiety (OR 2.53, CI [1.59‐4.02]; P < .005), and distress (OR 2.68, CI [1.64‐4.37]; P < .005). Physicians in states with greater than 20 000 positive cases had increased distress (OR 2.01, CI [1.22‐3.31]; P = .006). CONCLUSION: During the COVID‐19 pandemic, the prevalence of burnout, anxiety, and distress is high among academic otolaryngologists.


title: Unfolding SARS-CoV-2 viral genome to understand its gene expression regulation

text: SARS-CoV-2 is a new virus responsible for an outbreak of respiratory illness known as COVID-19, which has spread to several countries around the world and a global effort is being undertaken to characterize the molecular features and evolutionary origins of this virus. In silico analysis of the transcription start sites, promoter regions, transcription factors and their binding sites, gene ontology, CpG islands for SARS-CoV-2 viral genome are a first step to understand the regulation mechanisms of gene expression and association with genetic variations in the genomes. For this purpose, we first computationally surveyed all SARS-CoV-2 virus genes with the open reading frames from NCBI database and found eleven sequences to accomplish the mentioned features by using bioinformatics tools. Our analysis revealed that all (100%) of the SARS-CoV-2 virus genes have more than one TSS. By taking all TSSs with the highest predictive score we determined promoter regions and identified five common candidate motifs (MVI, MVII, MVIII, MVIV and MVV) of which MVI was found to be shared by all promoter regions of SARS-CoV-2 virus genes with the least E-value (3.8e-056, statistically highly significant). In our further analysis of MVI we showed MVI serve as binding sites for a single transcription factor (TF) family, EXPREG, involved in the regulatory mode of these genes. From EXPREG family four TFs that belongs to Cyclic AMP (cAMP) receptor protein (CRP) and Catabolite control protein A (CcpA) group mostly serve as transcriptional activator whereas two TFs that belong to LexA group always serve as transcriptional repressor in different kinds of cellular processes and molecular functions. Therefore, we unfolded SARS-CoV-2 viral genome to shed light on its gene expression regulation that could help to design and evaluate diagnostic tests, to track and trace the ongoing outbreak and to identify potential intervention options.


title: The propagation of “coronaviruses” in tissue-culture

text: The conditions for the cultivation of the 229-E respiratory virus in tissue culture are described. The virus multiplies only in human tissue culture systems, but a variety of cell types are sensitive to it. The virus has been isolated in three continuous cell lines and a plaque assay has been developed in one of these. This cell line (L 132) derived from human embryo lung, was also used to isolate three other viruses of similar morphology which had previously been cultivated only in organ cultures of human respiratory epithelium. High rates of isolation of these viruses were made in L 132 cells using nasal washings from experimentally inoculated volunteers. It is concluded that this cell line is a valuable tool in the study of viruses of this group.


title: Quercetin Feeding in Newborn Dairy Calves Cannot Compensate Colostrum Deprivation: Study on Metabolic, Antioxidative and Inflammatory Traits

text: Immaturity of the neonatal immune system is causative for high morbidity in calves and colostrum intake is crucial for acquiring passive immunity. Pathogenesis is promoted by reactive oxygen species accumulating at birth if counter-regulation is inadequate. The flavonol quercetin exerts antioxidative and anti-inflammatory effects that may enhance neonatal health. The aim of this work was to study effects of quercetin feeding on metabolic, antioxidative and inflammatory parameters in neonatal calves to investigate whether quercetin could compensate for insufficient colostrum supply. Twenty-eight newborn calves were assigned to two dietary groups fed colostrum or milk-based formula on day 1 and 2 and milk replacer thereafter. From day 2 onwards, 7 calves per diet group were additionally fed quercetin aglycone (50 mg/(kg body weight × day)). Blood samples were taken repeatedly to measure plasma concentrations of flavonols, glucose, lactate, total protein, albumin, urea, non-esterified fatty acids, triglycerides, cholesterol, insulin, glucagon, cortisol, immunoglobulins, fibrinogen, haptoglobin and serum amyloid A. Trolox equivalent antioxidative capacity, ferric reducing ability of plasma, thiobarbituric acid reactive species and F2-isoprostanes were analyzed to evaluate plasma antioxidative status. Expression of tumor necrosis factor, interleukin-1α, interleukin-1β, serum amyloid A, haptoglobin, fibrinogen, C-reactive protein, catalase, glutathione peroxidase and superoxide dismutase mRNA were measured in liver tissue on day 8. Plasma flavonol concentrations were detectable only after quercetin-feeding without differences between colostrum and formula feeding. Plasma glucose, lactate, total protein, immunoglobulins, triglycerides, cholesterol, trolox equivalent antioxidative capacity and thiobarbituric acid reactive species were higher after colostrum feeding. Body temperature, fecal fluidity and plasma concentrations of cortisol and haptoglobin were higher in formula- than in colostrum-fed groups. Hepatic mRNA expression of tumor necrosis factor was higher after quercetin feeding and expression of C-reactive protein was higher after formula feeding. Data confirm that colostrum improves neonatal health and indicate that quercetin feeding cannot compensate for insufficient colostrum supply.


title: The regulation mechanism of lncRNAs and mRNAs in sea cucumbers under global climate changes: Defense against thermal and hypoxic stresses

text: Abstract The aquatic environment can be greatly impacted by thermal and hypoxic stresses, particularly caused by intensified global warming. Hence, there is an urgency to understand the response mechanisms of marine organisms to adverse environment. Although long non-coding RNAs (lncRNAs) are involved in many biological processes, their roles in stress responses still remain unclear. Here, differentially expressed (DE) lncRNAs and mRNAs were identified as responses to environmental stresses in the economically important sea cucumber, Apostichopus japonicus, and their potential roles were explored. Based on a total of 159, 355 and 495 significantly upregulated genes and 230, 518 and 647 significantly downregulated genes identified in the thermal, hypoxic and combination thermal + hypoxic stress treatments, respectively, we constructed DE-lncRNA-mRNA coexpression networks. Among the networks, eight shared pairs were identified from the three treatments, and based on the connectivity degree, MSTRG.27265, MSTRG.19729 and MSTRG.95524 were shown to be crucial lncRNAs. Among all the significantly changed lncRNAs identified by RT-qPCR and sequencing data, binding sites were found in four other lncRNAs (MSTRG.34610, MSTRG.10941, MSTRG.81281 and MSTRG.93731) with Aja-miR-2013-3p, a key miRNA that responds to hypoxia in sea cucumbers. The hypoxia-inducible factor (HIF-1α) was also shown as the possible targeted mRNA of Aja-miR-2013-3p. As indicated by a dual-luciferase reporter assay system, “HIF-1α gene/Aja-miR-2013-3p/MSTRG.34610” network and the “HIF-1α gene/Aja-miR-2013-3p/MSTRG.10941” network may play important roles in sea cucumbers under environmental stresses. Moreover, environmental stress altered the expression of multiple lncRNAs and mRNAs, thus affecting various biological processes in A. japonicus, including immunity, energy metabolism and the cell cycle. At the molecular level, more comprehensive responses were elicited by the combined thermal/hypoxic stress treatment than by individual stresses alone in sea cucumbers. This study lays the groundwork for future research on molecular mechanisms of echinoderm responses to thermal and hypoxic stress in the context of global climate changes.


One Health-based control strategies for MERS-CoV


title: Efficacy of a Carrageenan nasal spray in patients with common cold: a randomized controlled trial

text: BACKGROUND: The common cold is the most widespread viral infection in humans. Iota-carrageenan has previously shown antiviral effectiveness against cold viruses in clinical trials. This study investigated the efficacy of a carrageenan-containing nasal spray on the duration of the common cold and nasal fluid viral load in adult patients. METHODS: In a randomized, double-blind, placebo-controlled trial, 211 patients suffering from early symptoms of the common cold were treated for seven days. Application was performed three times daily with either a carrageenan-supplemented nasal spray or saline solution as placebo with an overall observation period of 21 days. The primary endpoint was the duration of disease defined as the time until the last day with symptoms followed by all other days in the study period without symptoms. During the study, but prior unblinding, the definition of disease duration was adapted from the original protocol that defines disease duration as the time period of symptoms followed by 48 hours without symptoms. RESULTS: In patients showing a laboratory-confirmed cold virus infection and adherence to the protocol, alleviation of symptoms was 2.1 days faster in the carrageenan group in comparison to placebo (p = 0.037). The primary endpoint that had been prespecified but was changed before unblinding was not met. Viral titers in nasal fluids showed a significantly greater decrease in carrageenan patients in the intention-to-treat population (p = 0.024) and in the per protocol population (p = 0.018) between days 1 and 3/4. CONCLUSIONS: In adults with common cold virus infections, direct local administration of carrageenan with nasal sprays reduced the duration of cold symptoms. A significant reduction of viral load in the nasal wash fluids of patients confirmed similar findings from earlier trials in children and adults. TRIAL REGISTRATION: Current Controlled Trials ISRCTN80148028


title: A brief history of risk

text: Despite increasing life expectancy and high levels of welfare, health care, and public safety in most post-industrial countries, the public discourse often revolves around perceived threats. Terrorism, global pandemics, and environmental catastrophes are just a few of the risks that dominate media coverage. Is this public discourse on risk disconnected from reality? To examine this issue, we analyzed the dynamics of the risk discourse in two natural language text corpora. Specifically, we tracked latent semantic patterns over a period of 150 years to address four questions: First, we examined how the frequency of the word risk has changed over historical time. Is the construct of risk playing an ever-increasing role in the public discourse, as the sociological notion of a ‘risk society’ suggests? Second, we investigated how the sentiments for the words co-occurring with risk have changed. Are the connotations of risk becoming increasingly ominous? Third, how has the meaning of risk changed relative to close associates such as danger and hazard? Is risk more subject to semantic change? Finally, we decompose the construct of risk into the specific topics with which it has been associated and track those topics over historical time. This brief history of the semantics of risk reveals new and surprising insights—a fourfold increase in frequency, increasingly negative sentiment, a semantic drift toward forecasting and prevention, and a shift away from war toward chronic disease—reflecting the conceptual evolution of risk in the archeological records of public discourse.


title: Projecting social contact matrices in 152 countries using contact surveys and demographic data

text: Heterogeneities in contact networks have a major effect in determining whether a pathogen can become epidemic or persist at endemic levels. Epidemic models that determine which interventions can successfully prevent an outbreak need to account for social structure and mixing patterns. Contact patterns vary across age and locations (e.g. home, work, and school), and including them as predictors in transmission dynamic models of pathogens that spread socially will improve the models’ realism. Data from population-based contact diaries in eight European countries from the POLYMOD study were projected to 144 other countries using a Bayesian hierarchical model that estimated the proclivity of age-and-location-specific contact patterns for the countries, using Markov chain Monte Carlo simulation. Household level data from the Demographic and Health Surveys for nine lower-income countries and socio-demographic factors from several on-line databases for 152 countries were used to quantify similarity of countries to estimate contact patterns in the home, work, school and other locations for countries for which no contact data are available, accounting for demographic structure, household structure where known, and a variety of metrics including workforce participation and school enrolment. Contacts are highly assortative with age across all countries considered, but pronounced regional differences in the age-specific contacts at home were noticeable, with more inter-generational contacts in Asian countries than in other settings. Moreover, there were variations in contact patterns by location, with work-place contacts being least assortative. These variations led to differences in the effect of social distancing measures in an age structured epidemic model. Contacts have an important role in transmission dynamic models that use contact rates to characterize the spread of contact-transmissible diseases. This study provides estimates of mixing patterns for societies for which contact data such as POLYMOD are not yet available.


title: The airborne transmission of infection between flats in high-rise residential buildings: Particle simulation

text: Abstract Several case clusters occurred in high-rise residential buildings in Hong Kong in the 2003 SARS (the severe acute respiratory syndrome) epidemic, which motivated a series of engineering investigations into the possible airborne transport routes. It is suspected that, driven by buoyancy force, the polluted air that exits the window of the lower floor may re-enter the immediate upper floor through the window on the same side. This cascade effect has been quantified and reported in a previous paper, and it is found that, by tracer gas concentration analysis, the room in the adjacent upstairs may contain up to 7% of the air directly from the downstairs room. In this study, after validation against the experimental data from literatures, Eulerian and Lagrangian approaches are both adopted to numerically investigate the dispersion of expiratory aerosols between two vertically adjacent flats. It is found that the particle concentration in the upper floor is two to three orders of magnitude lower than in the source floor. 1.0μm particles disperse like gaseous pollutants. For coarse particles larger than 20.0μm, strong deposition on solid surfaces and gravitational settling effect greatly limit their upward transport.


title: Antiviral activity of berberine

text: Plants are a rich source of new antiviral, pharmacologically active agents. The naturally occurring plant alkaloid berberine (BBR) is one of the phytochemicals with a broad range of biological activity, including anticancer, anti-inflammatory and antiviral activity. BBR targets different steps in the viral life cycle and is thus a good candidate for use in novel antiviral drugs and therapies. It has been shown that BBR reduces virus replication and targets specific interactions between the virus and its host. BBR intercalates into DNA and inhibits DNA synthesis and reverse transcriptase activity. It inhibits replication of herpes simplex virus (HSV), human cytomegalovirus (HCMV), human papillomavirus (HPV), and human immunodeficiency virus (HIV). This isoquinoline alkaloid has the ability to regulate the MEK-ERK, AMPK/mTOR, and NF-κB signaling pathways, which are necessary for viral replication. Furthermore, it has been reported that BBR supports the host immune response, thus leading to viral clearance. In this short review, we focus on the most recent studies on the antiviral properties of berberine and its derivatives, which might be promising agents to be considered in future studies in the fight against the current pandemic SARS-CoV-2, the virus that causes COVID-19.


Not so soft soap


Impact of targeted vaccination on HBV genotypes in Amsterdam


title: Effects of AntagomiRs on Different Lung Diseases in Human, Cellular, and Animal Models

text: Introduction: MiRNAs have been shown to play a crucial role among lung cancer, pulmonary fibrosis, tuberculosis (TBC) infection, and bronchial hypersensitivity, thus including chronic obstructive pulmonary disease (COPD) and asthma. The oncogenic effect of several miRNAs has been recently ruled out. In order to act on miRNAs turnover, antagomiRs have been developed. Materials and methods: The systematic review was conducted under the PRISMA guidelines (registration number is: CRD42019134173). The PubMed database was searched between 1 January 2000 and 30 April 2019 under the following search strategy: (((antagomiR) OR (mirna antagonists) OR (mirna antagonist)) AND ((lung[MeSH Terms]) OR (“lung diseases”[MeSH Terms]))). We included original articles, published in English, whereas exclusion criteria included reviews, meta-analyses, single case reports, and studies published in a language other than English. Results and Conclusions: A total of 68 articles matching the inclusion criteria were retrieved. Overall, the use of antagomiR was seen to be efficient in downregulating the specific miRNA they are conceived for. The usefulness of antagomiRs was demonstrated in humans, animal models, and cell lines. To our best knowledge, this is the first article to encompass evidence regarding miRNAs and their respective antagomiRs in the lung, in order to provide readers a comprehensive review upon major lung disorders.


title: Monitoring and Characterization of Oseltamivir-Resistant Pandemic (H1N1) 2009 Virus, Japan, 2009–2010

text: To monitor and characterize oseltamivir-resistant (OR) pandemic (H1N1) 2009 virus with the H275Y mutation, we analyzed 4,307 clinical specimens from Japan by neuraminidase (NA) sequencing or inhibition assay; 61 OR pandemic (H1N1) 2009 viruses were detected. NA inhibition assay and M2 sequencing indicated that OR pandemic (H1N1) 2009 virus was resistant to M2 inhibitors, but sensitive to zanamivir. Full-genome sequencing showed OR and oseltamivir-sensitive (OS) viruses had high sequence similarity, indicating that domestic OR virus was derived from OS pandemic (H1N1) 2009 virus. Hemagglutination inhibition test demonstrated that OR and OS pandemic (H1N1) 2009 viruses were antigenically similar to the A/California/7/2009 vaccine strain. Of 61 case-patients with OR viruses, 45 received oseltamivir as treatment, and 10 received it as prophylaxis, which suggests that most cases emerged sporadically from OS pandemic (H1N1) 2009, due to selective pressure. No evidence of sustained spread of OR pandemic (H1N1) 2009 was found in Japan; however, 2 suspected incidents of human-to-human transmission were reported.


title: The first detection and full-length genome sequence of porcine deltacoronavirus isolated in Lao PDR

text: Porcine deltacoronavirus (PDCoV) has been reported in many countries, including Hong Kong, the United States, South Korea, China and Thailand. In January 2016, clinical diarrhea similar to that of porcine epidemic diarrhea virus (PEDV) with a lower mortality rate was reported on a swine farm in Lao PDR. Intestine samples were collected from 3-day-old pigs with clinical diarrhea and assayed for the presence of swine enteric coronaviruses. The PCR results were positive for PDCoV but negative for PEDV and TGEV. A phylogenetic tree demonstrated that PDCoV from Lao PDR was grouped separately from PDCoV isolates from China and the USA, but was more closely related to the Chinese isolates than to the US isolates. The full-length genome sequence of the novel PDCoV isolate P1_16_BTL_0116 was determined. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00705-016-2983-8) contains supplementary material, which is available to authorized users.


Violencia doméstica entre los ancianos durante la pandemia COVID-19


title: Impact of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on COVID-19 in a western population. CARDIOVID registry

text: ABSTRACT Introduction and objectives: Coronavirus disease (COVID-19) has been designated a global pandemic by the World Health Organization. It is unclear whether previous treatment with angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) affects the prognosis of COVID-19 patients. The aim of this study was to evaluate the clinical implications of previous treatment with ACEI/ARB on the prognosis of patients with COVID-19 infection. Methods: Single-center, retrospective, observational cohort study based on all the inhabitants of our health area. Analyses of main outcomes (mortality, heart failure, hospitalization, intensive care unit [ICU] admission, and major acute cardiovascular events [a composite of mortality and heart failure]) were adjusted by multivariate logistic regression and propensity score matching models. Results: Of the total population, 447 979 inhabitants, 965 patients (0.22%) were diagnosed with COVID-19 infection, and 210 (21.8%) were under ACEI or ARB treatment at the time of diagnosis. Treatment with ACEI/ARB (combined and individually) had no effect on mortality (OR, 0.62; 95%CI, 0.17-2.26; P = .486), heart failure (OR, 1.37; 95%CI, 0.39-4.77; P = .622), hospitalization rate (OR, 0.85; 95%CI, 0.45-1.64; P = .638), ICU admission (OR, 0.87; 95%CI, 0.30-2.50; P = .798), or major acute cardiovascular events (OR, 1.06; 95%CI, 0.39-2.83; P = .915). This neutral effect remained in a subgroup analysis of patients requiring hospitalization. Conclusions: Previous treatment with ACEI/ARB in patients with COVID-19 had no effect on mortality, heart failure, requirement for hospitalization, or ICU admission. Withdrawal of ACEI/ARB in patients testing positive for COVID-19 would not be justified, in line with current recommendations of scientific societies and government agencies.


title: COVID-19 zugzwang: potential public health moves towards population (herd) immunity

text: Summary COVID-19 is pandemic, and likely to become endemic, possibly returning with greater virulence. Outlining potential public health actions, including hygiene measures, social distancing and face masks, and realistic future advances, this paper focuses on the consequences of taking no public health action; the role of natural changes such as weather; the adverse public health consequences of lockdowns; testing for surveillance and research purposes; testing to identify cases and contacts, including the role of antibody tests; the public health value of treatments; mobilising people who have recovered; population (a synonym for herd) immunity through vaccination and through natural infection; involving the entire population; and the need for public debate. Until there is a vaccine, population immunity is going to occur only from infection. Allowing infection in those at very low risk while making it safer for them and wider society needs consideration but is currently taboo. About 40-50% population immunity is sufficient to suppress an infection with a reproduction number of about 1 or slightly more. Importantly, in children and young people COVID-19 is currently rarely fatal, roughly comparable with influenza. The balance between the damage caused by COVID-19 and that caused by lockdowns needs quantifying. Public debate, including on population immunity, informed by epidemiological data, is now urgent.


title: Activation of the SARS-CoV-2 receptor Ace2 by cytokines through pan JAK-STAT enhancers

text: ACE2, in concert with the protease TMPRSS2, binds the novel coronavirus SARS-CoV-2 and facilitates its cellular entry. The ACE2 gene is expressed in SARS-CoV-2 target cells, including Type II Pneumocytes (Ziegler, 2020), and is activated by interferons. Viral RNA was also detected in breast milk (Wu et al., 2020), raising the possibility that ACE2 expression is under the control of cytokines through the JAK-STAT pathway. Here we show that Ace2 expression in mammary tissue is induced during pregnancy and lactation, which coincides with the establishment of a candidate enhancer. The prolactin-activated transcription factor STAT5 binds to tandem sites that coincide with activating histone enhancer marks and additional transcription components. The presence of pan JAK-STAT components in mammary alveolar cells and in Type II Pneumocytes combined with the autoregulation of both STAT1 and STAT5 suggests a prominent role of cytokine signaling pathways in cells targeted by SARS-CoV-2.


title: Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia

text: BACKGROUND: In the recent outbreak of novel coronavirus infection in Wuhan, China, significantly abnormal coagulation parameters in severe novel coronavirus pneumonia (NCP) cases were a concern. OBJECTIVES: To describe the coagulation feature of patients with NCP. METHODS: Conventional coagulation results and outcomes of 183 consecutive patients with confirmed NCP in Tongji hospital were retrospectively analyzed. RESULTS: The overall mortality was 11.5%, the non‐survivors revealed significantly higher D‐dimer and fibrin degradation product (FDP) levels, longer prothrombin time and activated partial thromboplastin time compared to survivors on admission (P < .05); 71.4% of non‐survivors and 0.6% survivors met the criteria of disseminated intravascular coagulation during their hospital stay. CONCLUSIONS: The present study shows that abnormal coagulation results, especially markedly elevated D‐dimer and FDP are common in deaths with NCP.


title: Características epidemiológicas, clínicas y terapéuticas de lactantes hospitalizados por bronquiolitis

text: Resumen Objetivos Describir los datos epidemiológicos, clínicos y actitud terapéutica empleada en los lactantes hospitalizados por bronquiolitis en nuestro medio. Material y métodos Estudio observacional, descriptivo y prospectivo de lactantes menores de 18 meses ingresados en Hospital Virgen de la Arrixaca (Murcia) con el diagnóstico de bronquiolitis, durante el periodo de máxima incidencia (diciembre 2008-abril 2009). Resultados Ingresaron 235 lactantes, de los que el 78,7% tenía una edad menor o igual a 5 meses de vida. Había una correlación positiva entre el número de cigarrillos consumidos por la madre en la gestación y el número de días de oxigenoterapia y los días de estancia. Los niños cuya madre era fumadora en el momento de su ingreso fueron tratados con oxígeno un mayor número de días. Los lactantes que no habían recibido lactancia materna precisaron oxígeno durante más tiempo. El 23,8% tenía patología de base, siendo la prematuridad la más frecuente, la cual fue un factor de riesgo para la prolongación del tratamiento con oxígeno y de la estancia hospitalaria. La utilización de exploraciones complementarias y el uso de broncodilatadores, corticoides y antibióticos fueron elevados. La aparición de fiebre se asoció a un mayor uso de antibióticos en el medio extra e intrahospitalario y lo mismo sucedía si la radiografía de tórax era patológica o existía una elevación de la proteína C reactiva (PCR). El VRS fue el principal agente etiológico, seguido por rinovirus, bocavirus, adenovirus y metapneumovirus. Conclusiones La mayoría de los ingresos por bronquiolitis ocurrieron en los primeros meses de la vida. La exposición al tabaco durante la gestación se asoció a una peor evolución clínica. A pesar de las indicaciones de las guías de práctica clínica, en nuestro medio, el uso de exploraciones complementarias y de tratamientos farmacológicos fue elevado. Abstract Objectives To describe the epidemiology, clinical characteristics and treatments prescribed in children with bronchiolitis admitted to our hospital. Material and methods Observational, descriptive and prospective study of children younger than 18 months, admitted to Hospital Virgen de la Arrixaca of Murcia (Spain), with the diagnosis of bronchiolitis, during the season of maximum incidence (December 2008-April 2009). Results A total of 235 infants were admitted, of whom 78.7% of them were aged 5 months or less. We found a positive correlation between the number of cigarettes smoked by their mothers during pregnancy and the number of hospitalization and oxygen therapy days. Children whose mothers were smokers at the time of their admission needed a greater number of oxygen therapy days. Also infants who were not breastfed needed oxygen therapy during more days. Just under one quarter (23.8%) of them had underlying diseases, with prematurity being the most frequent and a risk factor for the ongoing of oxygen therapy and hospital stay. The use of diagnostic tests, bronchodilators, corticosteroids and antibiotics was high. The onset of high temperature was associated with an increased use of antibiotics in outside and inside the hospital setting. An abnormal chest X-ray or a raised C-reactive protein was associated with a higher use of antibiotics. Respiratory Syncytial virus (RSV) was the main aetiological agent, followed by Rhinovirus, Bocavirus, Adenovirus and Metapneumovirus Conclusions The majority of hospital admissions due to bronchiolitis took place during the first months of life. Infants whose mothers smoked during pregnancy had a worse clinical outcome. Despite the availability of clinical practice guidelines in our area, the use of diagnostic tests and pharmacological treatment was high.


title: The route of inoculation determines the tissue tropism of modified vaccinia tiantan expressing the spike glycoprotein of SARS‐CoV in mice,

text: The live replication‐competent modified vaccinia virus Tiantan (MVTT) is an attractive vaccine vector, yet little is known about its tissue tropism and pathology in vivo. Recently, we demonstrated that a recombinant MVTT expressing the spike glycoprotein of SARS‐CoV (namely MVTT‐S) is superior to the non‐replicating modified vaccinia Ankara (MVA‐S) for inducing high level of neutralizing antibodies through mucosal vaccination. In this study, we further determined the tissue tropism and safety of MVTT‐S after the vaccine was administrated through various routes including: intramuscular (i.m.), intranasal (i.n.), and intravaginal (i.vag.) inoculations, respectively. Using real‐time PCR, nested PCR, immunohistochemistry and in situ hybridization assays, we found that MVTT‐S was able to produce a transient infection in all cases within 48 hr post‐inoculation, yet the major site of viral replication in various tissues or organs was dependent on the route of viral administration. We demonstrated that i.m. injection of MVTT‐S primarily targeted draining inguinal lymph nodes, whereas mucosal inoculation had broader range of tissue infections. i.n. inoculation involved infections in lungs, kidneys, spleens and cervix lymph nodes while i.vag. administration targeted uteruses, ovaries, kidneys and spleens. Critically, the infection did not cause severe pathogenic consequences in infected tissues, which was consistent to the attenuated phenotype of MVTT‐S. Our findings have implications for the optimization of vaccination route and for studies on the correlation between the magnitude of immune responses and the extent of tissue involvement in vivo. J. Med. Virol. 82: 727–734, 2010. © 2010 Wiley‐Liss, Inc.


title: Recommendations and guidance for providing pharmaceutical care services during COVID-19 pandemic: A China perspective

text: Abstract Background The novel coronavirus pneumonia (COVID-19), which was first detected in Wuhan City, has now became a pandemic that affecting patients around the world. Particularly, the community patient population are at high risk of infection and are facing potential failure of proper medication use during the pandemic. Objective To discuss community pharmacists’ role and the content of pharmaceutical care (PC) during the novel coronavirus pandemic to promote effective prevention and control and safe drug use of the community patient population. Method Collect and summarize the experience Chinese community pharmacies gained from providing pharmacy services during the COVID-19 outbreak, and taking patients' PC needs into consideration, analyze and discuss the methods and strategies that community pharmacies and pharmacists shall use to provide PC during the pandemic. Results Community pharmacy management teams shall support PC services by providing adequate supply of COVID-19 related medications and preventative products, following environment regulations, and providing sufficient staff trainings. Pharmacists shall use various approaches to provide PC services in drug dispensing, consulting and referrals, chronic disease management, safe use of infusions, patient education, home care guidance and psychological support to promote the COVID-19 pandemic control and ensure safe medication use of community patients during the pandemic. Conclusion PC services in communities during the COVID-19 shall possess different properties due to disease characteristics and related change in patients' need. Community pharmacies shall work as a strong supporter of patient's medication and protective equipment supply. Community pharmacists shall be prepared to provide skilled and effective PC services for community patient population to ensure medication safety and promote the overall COVID-19 pandemic control.


title: SARS Risk Perceptions in Healthcare Workers, Japan

text: In coping with severe acute respiratory syndrome (SARS), infection control measures are a key aspect of protecting healthcare workers. We conducted a survey concerning perception of risk and countermeasures for SARS in 7 tertiary hospitals in Japan from July through September 2003, immediately after the SARS epidemic in neighboring countries. Based on 7,282 respondents out of 9,978 questionnaires administered, we found the perception of risk to be relatively high and the perception of countermeasures at the institutional level to be relatively low. Knowledge of preventive measures, concept of (opinions regarding) institutional measures, and perception of risk differed substantially among the 3 job categories, notably between physicians and nurses. The concept of institutional measures was the most important predictor of individual perception of risk. In view of the potential for future epidemics, planning and implementing institutional measures should be given a high priority.


title: Spread from the Sink to the Patient: In Situ Study Using Green Fluorescent Protein (GFP)-Expressing Escherichia coli To Model Bacterial Dispersion from Hand-Washing Sink-Trap Reservoirs

text: There have been an increasing number of reports implicating Gammaproteobacteria as often carrying genes of drug resistance from colonized sink traps to vulnerable hospitalized patients. However, the mechanism of transmission from the wastewater of the sink P-trap to patients remains poorly understood. Herein we report the use of a designated hand-washing sink lab gallery to model dispersion of green fluorescent protein (GFP)-expressing Escherichia coli from sink wastewater to the surrounding environment. We found no dispersion of GFP-expressing E. coli directly from the P-trap to the sink basin or surrounding countertop with coincident water flow from a faucet. However, when the GFP-expressing E. coli cells were allowed to mature in the P-trap under conditions similar to those in a hospital environment, a GFP-expressing E. coli-containing putative biofilm extended upward over 7 days to reach the strainer. This subsequently resulted in droplet dispersion to the surrounding areas (<30 in.) during faucet operation. We also demonstrated that P-trap colonization could occur by retrograde transmission along a common pipe. We postulate that the organisms mobilize up to the strainer from the P-trap, resulting in droplet dispersion rather than dispersion directly from the P-trap. This work helps to further define the mode of transmission of bacteria from a P-trap reservoir to a vulnerable hospitalized patient. IMPORTANCE Many recent reports demonstrate that sink drain pipes become colonized with highly consequential multidrug-resistant bacteria, which then results in hospital-acquired infections. However, the mechanism of dispersal of bacteria from the sink to patients has not been fully elucidated. Through establishment of a unique sink gallery, this work found that a staged mode of transmission involving biofilm growth from the lower pipe to the sink strainer and subsequent splatter to the bowl and surrounding area occurs rather than splatter directly from the water in the lower pipe. We have also demonstrated that bacterial transmission can occur via connections in wastewater plumbing to neighboring sinks. This work helps to more clearly define the mechanism and risk of transmission from a wastewater source to hospitalized patients in a world with increasingly antibiotic-resistant bacteria that can thrive in wastewater environments and cause infections in vulnerable patients.


title: COVID Curve Guides India’s Health Infrastructure Growth Needs

text: COVID-19 has led to many unprecedented situations across the world. With lockdowns and severe restrictions on movement and activities, countries have managed to slow down the COVID curve but developing countries like India are likely to face a humongous task of containing the virus spread in coming months. High population density, continuing economic activities, movement of people etc. will keep causing newer hotspots across India. We look at the compounded daily growth rates (CDGR) of USA, Spain, India and Brazil over the duration of the virus spread since January, 2020. We also analyze the correlation between the total cases and active cases across India. We estimate the projected number of beds, ICU beds, oxygen support and ventilators for different CDGRs in the coming months and also define a metric target to control the virus spread through various preventive measures.


title: Respiratory syncytial virus nonstructural proteins 1 and 2: Exceptional disrupters of innate immune responses

text: Human respiratory syncytial virus (RSV) is the most important cause of acute lower respiratory tract disease in infants worldwide. As a first line of defense against respiratory infections, innate immune responses, including the production of type I and III interferons (IFNs), play an important role. Upon infection with RSV, multiple pattern recognition receptors (PRRs) can recognize RSV-derived pathogen-associated molecular patterns (PAMPs) and mount innate immune responses. Retinoic-acid-inducible gene-I (RIG-I) and nucleotide-binding oligomerization domain-containing protein 2 (NOD2) have been identified as important innate receptors to mount type I IFNs during RSV infection. However, type I IFN levels remain surprisingly low during RSV infection despite strong viral replication. The poor induction of type I IFNs can be attributed to the cooperative activity of 2 unique, nonstructural (NS) proteins of RSV, i.e., NS1 and NS2. These viral proteins have been shown to suppress both the production and signaling of type I and III IFNs by counteracting a plethora of key host innate signaling proteins. Moreover, increasing numbers of IFN-stimulated genes (ISGs) are being identified as targets of the NS proteins in recent years, highlighting an underexplored protein family in the identification of NS target proteins. To understand the diverse effector functions of NS1 and NS2, Goswami and colleagues proposed the hypothesis of the NS degradasome (NSD) complex, a multiprotein complex made up of, at least, NS1 and NS2. Furthermore, the crystal structure of NS1 was resolved recently and, remarkably, identified NS1 as a structural paralogue of the RSV matrix protein. Unfortunately, no structural data on NS2 have been published so far. In this review, we briefly describe the PRRs that mount innate immune responses upon RSV infection and provide an overview of the various effector functions of NS1 and NS2. Furthermore, we discuss the ubiquitination effector functions of NS1 and NS2, which are in line with the hypothesis that the NSD shares features with the canonical 26S proteasome.


title: Immune‐related Factors Associated with Pneumonia in 127 Children with Coronavirus Disease 2019 in Wuhan

text: OBJECTIVE: Information regarding the association of immune‐related factors with pneumonia in children with coronavirus disease 2019 (COVID‐19) is scarce. This study aims to summarize the immune‐related factors and their association with pneumonia in children with COVID‐19. METHODS: Children with COVID‐19 at Wuhan Children's Hospital from January 28 to March 12, 2020 were enrolled. Pneumonia due to causes other than COVID‐19 were excluded. The clinical and laboratory information including routine blood tests, blood biochemistry, lymphocyte subsets, immunoglobulins, cytokines and inflammatory factors were analyzed retrospectively in 127 patients. Normal ranges and mean values of laboratory markers were applied as parameters for logistic regression analyses of their association with pneumonia. RESULTS: In non‐intensive care unit patients, 48.8% and 22.4% of patients had increased levels of procalcitonin and hypersensitive C‐reactive protein (hs‐CRP) respectively. 12.6% and 18.1% of patients had decreased levels of immunoglobulin (Ig) A and interleukin (IL)‐10 respectively. Approximately 65.8% of patients had pneumonia. These patients had decreased levels of globulin (odds ratio [OR] 3.13, 95% confidence interval [CI] 1.41‐6.93, P=0.005), IgA (OR 4.00, 95% CI 1.13‐14.18, P=0.032), and increased levels of hs‐CRP (OR 3.14, 95% CI 1.34‐7.36, P=0.008), procalcitonin (OR 3.83, 95% CI 2.03‐7.24, P<0.001), IL‐10 (OR 7.0, 95% CI 1.59‐30.80, P=0.010), and CD4+CD25+ T lymphocyte < 5.0 % (OR 1.93, 95% CI 1.04‐3.61, P=0.038). CONCLUSION: Decreased IgA and CD4+CD25+ T lymphocyte percentage, and increased hs‐CRP, procalcitonin and IL‐10 were associated with pneumonia, suggesting that the immune‐related factors may participate in the pathogenesis of pneumonia in children with COVID‐19. This article is protected by copyright. All rights reserved.


International perspectives: Impact of the COVID‐19 pandemic on cytology


Analysis of dermatology-related search engine trends during the COVID-19 pandemic: implications for patient demand for outpatient services and telehealth.


title: The GPRLQPY motif located at the carboxy-terminal of the spike protein induces antibodies that neutralize Porcine epidemic diarrhea virus

text: Abstract The spike protein of Porcine epidemic diarrhea virus is the main surface glycoprotein involved in virus attachment and entry and therefore is the target of neutralizing antibodies. Here, the immunogenicity of a novel antigenic domain found on the carboxy-terminal of the spike protein characterized by the peptide motif GPRLQPY, was evaluated. A synthetic peptide whose linear sequence is identical to the 24a.a. carboxy-terminal portion of the spike protein (S-CT24) elicited a strong antibody response in BALB/c mice that had specific reactivity against the S-CT24 and PEDV. These antibodies were shown to have a specific affinity to the GPRLQPY motif, as demonstrated by non-reactivity with a peptide that lacks this motif. In addition, antiS-CT24 antibodies exhibited neutralizing activities against KPEDV-9 in focus reduction neutralization tests suggesting that the GPRLQPY motif induces neutralizing antibodies against PEDV.


title: Spontaneous coronary artery dissection of the left anterior descending artery in a patient with COVID‐19 infection

text: A 48‐year‐old woman with a past medical history of migraines and hyperlipidemia presented due to severe retrosternal chest pain with no other associated signs or symptoms. The patient was hemodynamically stable and was found to have an elevated troponin with electrocardiogram showing no ischemic changes. Computed tomography of the coronary arteries showed a left dominant system with dissection extending from the mid‐to‐distal left anterior descending (LAD) artery. The patient was subsequently discharged on medical therapy but returned 3 days later due to worsening chest pain. Electrocardiogram revealed inferior and anteroseptal ST segment changes with peak troponin of 14.9 ng/ml (reference range <0.80 ng/ml). Coronavirus disease 2019 (COVID‐19) nasopharyngeal swab was performed prior to urgent coronary angiogram. Coronary angiogram was performed with full personal protective equipment for respiratory and droplet precautions due to pending COVID‐19 testing results. Angiogram revealed spontaneous coronary artery dissection (SCAD) extending from the ostium of the LAD to the distal vessel. COVID‐19 testing returned positive while in intensive care unit. The patient was not a percutaneous coronary intervention candidate due to the extent of the dissection and was not a surgical candidate due to a lack of graftable target and medical management was continued. To our knowledge, this case is the first in which SCAD has been reported in the LAD in a patient with COVID‐19 with no other symptoms of respiratory illness or symptoms classically associated with the novel coronavirus. SCAD should be considered on the differential as one of the various cardiac manifestations of COVID‐19 infection.


title: Identification of essential residues in potyvirus proteinase HC-pro by site-directed mutagenesis

text: Abstract Two virus-encoded proteinases are responsible for proteolysis of potyvirus polyproteins. One of these, HC-Pro, is a multifunctional protein that autolytically cleaves at its carboxyl-terminus (J. C. Carrington et al., 1989, EMBO J. 8, 365–370). To identify the class of proteinase to which HC-Pro belongs, tobacco etch virus (TEV) HC-Pro mutants containing single amino acid substitutions at serine, cysteine, aspartic acid, and histidine positions were synthesized by in vitro transcription and translation and were tested for autoproteolytic activity. Combinations of these residues are constituents of the active sites of diverse groups of cellular and viral proteinases. Only those positions that were strictly conserved among four potyvirus HC-Pro proteolytic domains (for which sequences have been deduced) were mutagenized. Of the 19 mutant proteinases synthesized and tested, only those with alterations at Cys-649 and His-722 were defective for HC-Pro autolytic activity. Most of the other mutant proteinases exhibited no impairments in processing kinetics experiments. The spectrum of essential residues, as defined by this genetic analysis, supports the hypothesis that HC-Pro most closely resembles members of the cysteine-type family of proteinases.


title: Characteristics of inflammatory factors and lymphocyte subsets in patients with severe COVID‐19

text: To investigate the inflammatory factors and lymphocyte subsets which play an important role in the course of severe coronavirus disease 2019 (COVID‐19). A total of 27 patients with severe COVID‐19 who were admitted to Tongji Hospital in Wuhan from 1 to 21 February 2020 were recruited to the study. The characteristics of interleukin‐1β (IL‐1β), IL‐2 receptor (IL‐2R), IL‐6, IL‐8, IL‐10, tumor necrosis factor‐α (TNF)‐α, C‐reactive protein (CRP), serum ferritin and procalcitonin (PCT), and lymphocyte subsets of these patients were retrospectively compared before and after treatment. Before treatment, there was no significant difference in most inflammatory factors (IL‐1β, IL‐2R, IL‐6, IL‐8, IL‐10, CRP, and serum ferritin) between male and female patients. Levels of IL‐2R, IL‐6, TNF‐α, and CRP decreased significantly after treatment, followed by IL‐8, IL‐10, and PCT. Serum ferritin was increased in all patients before treatment but did not decrease significantly after treatment. IL‐1β was normal in most patients before treatment. Lymphopenia was common among these patients with severe COVID‐19. Analysis of lymphocyte subsets showed that CD4+ and particularly CD8+ T lymphocytes increased significantly after treatment. However, B lymphocytes and natural killer cells showed no significant changes after treatment. A pro‐inflammatory response and decreased level of T lymphocytes were associated with severe COVID‐19.


title: Capter 11 Filtering in Drug Discovery

text: Publisher Summary This chapter discusses the concept of filtering in drug discovery. Multiple ﬁlters may be incorporated into a deﬁnition of drug-likeness and this leads to tradeoffs among compound properties in compounds intended for screening. The optimization of compound properties may require some type of multiparameter optimization scheme in library design. Fingerprint algorithms can be used to guide diversity. Filters also need to be employed in the chemistry synthesis planning process so that good quality compounds are made. Differences in property ranges between oral and injectable drugs are summarized in the chapter. Oral drugs are lower in MWT and have fewer H-bond donors, acceptors, and rotatable bonds. A scheme for separating central nervous system (CNS)- from non-CNS-active drugs in the WDI allowed the discovery of simple parameters relating to passive blood brain barrier (BBB) permeability and the prediction of p-glycoprotein (PGP) afﬁnity. The PGP transporter is a major barrier to the entry of compounds to the CNS. Appropriately determined PGP efﬂux ratios can be used as a measure of compound afﬁnity to PGP.


title: The Evolution of Poxvirus Vaccines

text: After Edward Jenner established human vaccination over 200 years ago, attenuated poxviruses became key players to contain the deadliest virus of its own family: Variola virus (VARV), the causative agent of smallpox. Cowpox virus (CPXV) and horsepox virus (HSPV) were extensively used to this end, passaged in cattle and humans until the appearance of vaccinia virus (VACV), which was used in the final campaigns aimed to eradicate the disease, an endeavor that was accomplished by the World Health Organization (WHO) in 1980. Ever since, naturally evolved strains used for vaccination were introduced into research laboratories where VACV and other poxviruses with improved safety profiles were generated. Recombinant DNA technology along with the DNA genome features of this virus family allowed the generation of vaccines against heterologous diseases, and the specific insertion and deletion of poxvirus genes generated an even broader spectrum of modified viruses with new properties that increase their immunogenicity and safety profile as vaccine vectors. In this review, we highlight the evolution of poxvirus vaccines, from first generation to the current status, pointing out how different vaccines have emerged and approaches that are being followed up in the development of more rational vaccines against a wide range of diseases.


Stap vooruit in onderzoek naar preventie


title: Conveyance Contact Investigation for Imported Middle East Respiratory Syndrome Cases, United States, May 2014

text: In 2014, the Centers for Disease Control and Prevention conducted conveyance contact investigations for 2 Middle East respiratory syndrome cases imported into the United States, comprising all passengers and crew on 4 international and domestic flights and 1 bus. Of 655 contacts, 78% were interviewed; 33% had serologic testing. No secondary cases were identified.


title: Establishment of a Bluetongue Virus Infection Model in Mice that Are Deficient in the Alpha/Beta Interferon Receptor

text: Bluetongue (BT) is a noncontagious, insect-transmitted disease of ruminants caused by the bluetongue virus (BTV). A laboratory animal model would greatly facilitate the studies of pathogenesis, immune response and vaccination against BTV. Herein, we show that adult mice deficient in type I IFN receptor (IFNAR((−/−))) are highly susceptible to BTV-4 and BTV-8 infection when the virus is administered intravenously. Disease was characterized by ocular discharges and apathy, starting at 48 hours post-infection and quickly leading to animal death within 60 hours of inoculation. Infectious virus was recovered from the spleen, lung, thymus, and lymph nodes indicating a systemic infection. In addition, a lymphoid depletion in spleen, and severe pneumonia were observed in the infected mice. Furthermore, IFNAR((−/−)) adult mice immunized with a BTV-4 inactivated vaccine showed the induction of neutralizing antibodies against BTV-4 and complete protection against challenge with a lethal dose of this virus. The data indicate that this mouse model may facilitate the study of BTV pathogenesis, and the development of new effective vaccines for BTV.


title: Phylodynamic analysis of avian infectious bronchitis virus in South America

text: Infectious bronchitis virus (IBV) is a coronavirus of chickens that causes great economic losses to the global poultry industry. The present study focuses on South American IBVs and their genetic relationships with global strains. We obtained full-length sequences of the S1 coding region and N gene of IBV field isolates from Uruguay and Argentina, and performed Phylodynamic analysis to characterize the strains and estimate the time of the most recent common ancestor. We identified two major South American genotypes, which were here denoted South America I (SAI) and Asia/South America II (A/SAII). The SAI genotype is an exclusive South American lineage that emerged in the 1960s. The A/SAII genotype may have emerged in Asia in approximately 1995 before being introduced into South America. Both SAI and A/SAII genotype strains clearly differ from the Massachusetts strains that are included in the vaccine formulations being used in most South American countries.


title: Canine parvovirus: a predicting canine model for sepsis

text: BACKGROUND: Sepsis is a severe condition associated with high prevalence and mortality rates. Parvovirus enteritis is a predisposing factor for sepsis, as it promotes intestinal bacterial translocation and severe immunosuppression. This makes dogs infected by parvovirus a suitable study population as far as sepsis is concerned. The main objective of the present study was to evaluate the differences between two sets of SIRS (Systemic Inflammatory Response Syndrome) criteria in outcome prediction: SIRS 1991 and SIRS 2001. The possibility of stratifying and classifying septic dogs was assessed using a proposed animal adapted PIRO (Predisposition, Infection, Response and Organ dysfunction) scoring system. RESULTS: The 72 dogs enrolled in this study were scored for each of the PIRO elements, except for Infection, as all were considered to have the same infection score, and subjected to two sets of SIRS criteria, in order to measure their correlation with the outcome. Concerning SIRS criteria, it was found that the proposed alterations on SIRS 2001 (capillary refill time or mucous membrane colour alteration) were significantly associated with the outcome (OR = 4.09, p < 0.05), contrasting with the 1991 SIRS criteria (p = 0.352) that did not correlate with the outcome. No significant statistical association was found between Predisposition (p = 1), Response (p = 0.1135), Organ dysfunction (p = 0.1135), total PIRO score (p = 0.093) and outcome. To explore the possibility of using the SIRS criteria as a fast decision-making tool, a Fast-and-Frugal tree (FFT) was created with a sensitivity of 92% and a specificity of 29%. CONCLUSION: These results suggest that increasing the SIRS criteria specificity may improve their prognostic value and their clinical usefulness. In order to improve the proposed PIRO scoring system outcome prediction ability, more specific criteria should be added, mainly inflammatory and organ dysfunction biomarkers.


The Coronavirus Replicase: Insights into a Sophisticated Enzyme Machinery


title: Chapter 6 Natural Product Inhibitors of Ubiquitin Conjugation and Deconjugation

text: Abstract The ubiquitin–proteasome system has been recognized as fundamental toward protein turnover in eukaryotic cells. The system comprises the ubiquitin conjugation machinery consisting of an enzyme cascade of E1, E2, and E3 enzymes, the deubiquitinases (DUBs) and the proteasome, a multisubunit protease complex acting through an N-terminal threonine protease mechanism. A number of natural product inhibitors of the proteasome have been studied in detail and these inhibitors and their derivatives have been highly valuable in developing our understanding of this system. These efforts culminated in the successful development of bortezomib as a pharmacological agent used clinically as a cancer therapeutic in the treatment of multiple myeloma. This review is focused on natural product inhibitors of the enzymes involved in intracellular ubiquitin conjugation (ubiquitin-activating enzyme E1, ubiquitin-conjugating enzyme E2, ubiquitin ligase E3) and ubiquitin deconjugation (DUBs). Members of both of these enzyme systems have been proposed as pharmacological targets for cancer therapy and several other diseases. Furthermore compounds with activities toward enzymes from the analogous ubiquitin-like (Ubl) protein families have been identified for SUMO and NEDD8. To date natural product inhibitors have been described for members of each of these protein families and were isolated from plant, fungal, animal, and microbial sources. Insights into the mechanism of action of natural products and their derivatives will enhance our understanding of this complex system and will improve our ability to rationally design novel inhibitors. The increased availability of assays and research tools for the study of protein ubiquitination, deubiquitination, and Ubl proteins will contribute to the discovery of more potent and selective compounds. We expect that these studies will stimulate development of further potential pharmacological agents in this area.


The Application of Eight-Segment Pulmonary Rehabilitation Exercise in People With Coronavirus Disease 2019


What’s new in lung ultrasound during the COVID-19 pandemic