title: Absence of CCR5 increases neutrophil recruitment in severe herpetic encephalitis

text: BACKGROUND: The neuroinflammatory response aimed at clearance of herpes simplex virus-1 (HSV-1) plays a key role in the pathogenesis of neuroaxonal damage in herpetic encephalitis. Leukocytes activated in an adaptive immune response access brain tissue by passing through the blood–brain barrier. The chemokine CCL5/RANTES is involved in recruitment of these cells to the brain acting via the receptors CCR1, CCR3 and mainly CCR5. Here, we evaluated the role of CCR5 on traffic of leukocytes in the brain microvasculature, cellular and cytokines profile in a severe form of herpetic encephalitis. RESULTS: Wild type and mice lacking CCR5 (CCR5(-/-)) were inoculated intracerebrally with 10(4) PFU of neurotropic HSV-1. We evaluated the traffic of leukocytes in the brain microvasculature using intravital microscopy and the profile of cytokines by Enzyme-Linked Immunosorbent Assay at 1 day post infection. Flow cytometry and histopathological analyses were also carried out in brain tissue. Absence of CCR5 leads to lower viral load and an increased leukocyte adhesion in brain microvasculature, predominantly of neutrophils (CD11(+) Ly6G(+) cells). Moreover, there was a significant increase in the levels of MIP-1/CCL2, RANTES/CCL5, KC/CXCL1 and MIG/CXCL9 in the brain of infected CCR5(-/-) mice. CONCLUSIONS: These results suggest that the absence of CCR5 may boost the immune response with a high neutrophil recruitment which most likely helps in viral clearance. Nonetheless, the elevated immune response may be detrimental to the host.


title: Efficient disinfection of Escherichia coli in water by silver loaded alumina

text: Abstract The catalytic inactivation of Escherichia coli (E. coli) in water by silver loaded alumina as catalyst was investigated. Ag/Al2O3 and AgCl/Al2O3 catalysts exhibited high bactericidal activity at room temperature in water with no need for any light or electrical power input. Dissolved oxygen which can be catalyzed to reactive oxygen species (ROS) was found to be essential for the strong bactericidal activities of the catalysts. Decomposition of the cell wall leading to leakage of the intracellular component and the complete lysis of the whole cell were directly observed by transmission electron microscopy (TEM). The resultant change in cell permeability was confirmed by potassium ion leakage. The different morphological changes between E. coli cells treated with the catalysts and Ag+ were also observed. The formation of ROS involved in the bactericidal process by AgCl/Al2O3 was confirmed by addition of catalase and OH scavenger. Higher temperature and pH value were found to have positive effect on the bactericidal activity of AgCl/Al2O3. All these results indicated that the bactericidal effect of the catalyst was a synergic action of ROS and Ag+, not an additive one. A possible mechanism is proposed.


title: ICU management of severe acute respiratory syndrome

text: BACKGROUND: Severe acute respiratory syndrome (SARS) is a contagious viral illness first recognized in late 2002. It has now been documented in 26 countries worldwide, with significant outbreaks in China, Hong Kong, Singapore, and Toronto. Research into identifying the etiological agent, evaluating modes of disease transmission, and treatment options is currently ongoing. DISCUSSION: The disease can produce a severe bilateral pneumonia, with progressive hypoxemia. Up to 20% of patients require mechanical ventilatory support, with a fatal outcome occurring in about 5% of cases. CONCLUSIONS: We review the current knowledge about this disease, with particular emphasis on ICU management and infection control precautions to prevent disease transmission. ELECTRONIC SUPPLEMENTARY MATERIAL: Supplementary material is available if you access this article at http://dx.doi.org/10.1007/s00134-003-1821-0. On that page (frame on the left side) a link takes you directly to the supplementary material.


title: Favorable COVID‐19 course despite significant comorbidities in a ruxolitinib‐treated patient with primary myelofibrosis

text: COVID‐19 carries a high risk of severe disease course, particularly in patients with comorbidities. Therapy of severe COVID‐19 infection has relied on supportive intensive care measures. More specific approaches including drugs that limit the detrimental “cytokine storm”, such as Janus‐activated kinase (JAK) inhibitors, are being discussed. Here, we report a compelling case of a 55‐yo patient with proven COVID‐19 pneumonia, who was taking the JAK1/2 inhibitor ruxolitinib in‐label for co‐existing primary myelofibrosis for 15 months prior to coronavirus infection. The patient had significant comorbidities, including chronic kidney disease, arterial hypertension, and obesity, and our previous cohort suggested that he was thus at high risk for acute respiratory distress syndrome (ARDS) and death from COVID‐19. Since abrupt discontinuation of ruxolitinib may cause fatal cytokine storm and ARDS, ruxolitinib treatment was continued and was well tolerated, and the patient´s condition remained stable, without the need for mechanical ventilation or vasopressors. The patient became negative for SARS‐CoV‐2 and was discharged home after 15 days. In conclusion, our report provides clinical evidence that ruxolitinib treatment is feasible and can be beneficial in patients with COVID‐19 pneumonia, preventing cytokine storm and ARDS.


title: Determination of the infectious titer and virulence of an original US porcine epidemic diarrhea virus PC22A strain

text: The infectious dose of a virus pool of original US PEDV strain PC22A was determined in 4-day-old, cesarean-derived, colostrum-deprived (CDCD) piglets. The median pig diarrhea dose (PDD(50)) of the virus pool was determined as 7.35 log(10) PDD(50)/mL, similar to the cell culture infectious titer, 7.75 log(10) plaque-forming units (PFU)/mL. 100 PDD(50) caused watery diarrhea in all conventional suckling piglets (n = 12) derived from a PEDV-naive sow, whereas 1000 and 10 000 PDD(50) did not cause diarrhea in piglets derived from two PEDV-field exposed-recovered sows. This information is important for future PEDV challenge studies and validation of PEDV vaccines.


title: Influenza A Viruses Target Type II Pneumocytes in the Human Lung

text: Background. Highly pathogenic avian H5N1 influenza viruses preferentially infect alveolar type II pneumocytes in human lung. However, it is unknown whether this cellular tropism contributes to high viral virulence because the primary target cells of other influenza viruses have not been systematically studied. Methods. We provide the first comparison of the replication, tropism, and cytokine induction of human, highly pathogenic avian influenza A virus subtype H5N1 and other animal influenza A viruses in primary human lung organ cultures. Results. Subytpe H5N1 and human-adapted subtype H1N1 and H3N2 viruses replicated efficiently in the lung tissue, whereas classic swine and low-pathogenicity avian viruses propagated only poorly. Nevertheless, all viruses examined were detected almost exclusively in type II pneumocytes, with a minor involvement of alveolar macrophages. Infection with avian viruses that have a low and high pathogenicity provoked a pronounced induction of cytokines and chemokines, while human and pandemic H1N1-2009 viruses triggered only weak responses. Conclusions. These findings show that differences in the pathogenic potential of influenza A viruses in the human lung cannot be attributed to a distinct cellular tropism. Rather, high or low viral pathogenicity is associated with a strain-specific capacity to productively replicate in type II pneumocytes and to cope with the induced cytokine response.


title: Unsung Heroes: Gay Physicians’ Lived Journeys During the HIV/AIDS Pandemic

text: The HIV/AIDS pandemic was a major crisis at the end of the 20th and beginning of the 21st century. Such a defining moment in the history of health-related infections led to transformations in its proponents, as well as their medical practice. This research article, using a study consisting of semi-structured interviews with six Canadian gay physicians from different Canadian HIV/AIDS treatment centers, aims to offer insights into their lived journeys, from 1981 to 2009, while they attempted to treat, care for, and cure/heal their gay HIV/AIDS patients. The results of the study, deduced from a qualitative and interpretative data analysis, suggest that through reflection on their experiences during the HIV/AIDS pandemic, they transformed their personal and professional identities, and rethought their relationship with their patients, as well as their professional, pharmaceutical, and community networks. These results are testimonies from Canadian gay physicians who fought against the HIV/AIDS pandemic and who advocated for their gay HIV/AIDS patients. In fact, these results are evidence of an untold and valuable period in medical history. For some, it will serve as a reminder. For others, it will be foreign. It was a time marked by a major crisis that mobilized gay militant physicians who were personally and professionally affected, and who were forever transformed by their response to the HIV/AIDS pandemic. This is their hereto untold lived journeys.


title: Pathogen inactivation and removal methods for plasma‐derived clotting factor concentrates

text: Pathogen safety is crucial for plasma‐derived clotting factor concentrates used in the treatment of bleeding disorders. Plasma, the starting material for these products, is collected by plasmapheresis (source plasma) or derived from whole blood donations (recovered plasma). The primary measures regarding pathogen safety are selection of healthy donors donating in centers with appropriate epidemiologic data for the main blood‐transmissible viruses, screening donations for the absence of relevant infectious blood‐borne viruses, and release of plasma pools for further processing only if they are nonreactive for serologic markers and nucleic acids for these viruses. Despite this testing, pathogen inactivation and/or removal during the manufacturing process of plasma‐derived clotting factor concentrates is required to ensure prevention of transmission of infectious agents. Historically, hepatitis viruses and human immunodeficiency virus have posed the greatest threat to patients receiving plasma‐derived therapy for treatment of hemophilia or von Willebrand disease. Over the past 30 years, dedicated virus inactivation and removal steps have been integrated into factor concentrate production processes, essentially eliminating transmission of these viruses. Manufacturing steps used in the purification of factor concentrates have also proved to be successful in reducing potential prion infectivity. In this review, current techniques for inactivation and removal of pathogens from factor concentrates are discussed. Ideally, production processes should involve a combination of complementary steps for pathogen inactivation and/or removal to ensure product safety. Finally, potential batch‐to‐batch contamination is avoided by stringent cleaning and sanitization methods as part of the manufacturing process.


title: Design and production of a multiepitope construct derived from hepatitis E virus capsid protein

text: The aim of this study was to design a high density multiepitope protein, which can be a promising multiepitope vaccine candidate against Hepatitis E virus (HEV). Initially, conserved and antigenic helper T‐lymphocyte (HTL) epitopes in the HEV capsid protein were predicted by in silico analysis. Subsequently, a multiepitope comprising four HTL epitopes with high‐affinity binding to the HLA molecules was designed, and repeated four times as high density multiepitope construct. This construct was synthesized and cloned into pET‐30a (+) vector. Then, it was transformed and expressed in Escherichia coli BL21 cells. The high density multiepitope protein was purified by Ni‐NTA agarose and concentrated using Amicon filters. Finally, the immunological properties of this high density multiepitope protein were evaluated in vitro. The results showed that the high density multiepitope construct was successfully expressed and purified. SDS‐PAGE and Western blot analyses showed the presence of a high density multiepitope protein band of approximately 33 kDa. Approximately 1 mg of the purified protein was obtained from each liter of the culture media. Moreover, the purified multiepitope protein was capable of induction of proliferation responses, IFN‐γ ELISPOT responses and IFN‐γ and IL‐12 cytokines production in a significant level in peripheral blood mononuclear cells (PBMCs) isolated from HEV‐recovered individuals compared to the control group. In conclusion, the newly produced multiepitope protein can induce significant T helper type 1 responses in vitro, and can be considered as a novel strategy for the development of HEV vaccines in the future. J. Med. Virol. 87:1225–1234, 2015. © 2015 Wiley Periodicals, Inc.


title: The impact of government failure on tourism in the Philippines

text: Abstract While the Philippines aspires to be one of the top tourist destinations in Southeast Asia, self-inflicted wounds like the failure of the government to comply with international aviation safety standards may derail the country from achieving its goals. This article estimates the short- and long-term impact of the US FAA downgrade of the Philippine civil aviation system in 2008 and the EU ban of Philippine carriers in 2010 on tourist expenditures, arrivals, and length of stay using monthly time series data. The econometric model, consisting of three equations due to the endogeneity of the tourist arrivals and length of stay variables in the tourist expenditures equation, is estimated simultaneously using the generalized method of moments. The results indicate that the US FAA downgrade and the EU ban impact monthly tourist receipts negatively in the short term while the downgrade also impacts tourist expenditures in the long term. Moreover, the ban impacts length of stay negatively in the short and long term while the downgrade impacts length of stay negatively only in the long term. The substantial decline in tourism receipts from 2008 to 2010 despite an increasing trend in tourist arrivals is due to the shorter stay of tourists, indicating that high-spending tourists have not returned following the downgrade and ban.


title: Two Sides of the Coin: Ezrin/Radixin/Moesin and Merlin Control Membrane Structure and Contact Inhibition

text: The merlin-ERM (ezrin, radixin, moesin) family of proteins plays a central role in linking the cellular membranes to the cortical actin cytoskeleton. Merlin regulates contact inhibition and is an integral part of cell–cell junctions, while ERM proteins, ezrin, radixin and moesin, assist in the formation and maintenance of specialized plasma membrane structures and membrane vesicle structures. These two protein families share a common evolutionary history, having arisen and separated via gene duplication near the origin of metazoa. During approximately 0.5 billion years of evolution, the merlin and ERM family proteins have maintained both sequence and structural conservation to an extraordinary level. Comparing crystal structures of merlin-ERM proteins and their complexes, a picture emerges of the merlin-ERM proteins acting as switchable interaction hubs, assembling protein complexes on cellular membranes and linking them to the actin cytoskeleton. Given the high level of structural conservation between the merlin and ERM family proteins we speculate that they may function together.


title: Comparative efficacy of diclazuril (Vecoxan(®)) and toltrazuril (Baycox bovis(®)) against natural infections of Eimeria bovis and Eimeria zuernii in French calves

text: A blinded, randomized, controlled, multi-centric field study was conducted on French dairy farms (n = 9) to evaluate the long term efficacy of metaphylactic, single oral treatments with either 1 mg/kg body weight (BW) of diclazuril (Vecoxan(®)), or 15 mg/kg BW of toltrazuril (Baycox(®)) against natural infections with Eimeria zuernii and/or Eimeria bovis, compared to untreated control animals. A total of 199 calves from nine commercial farms aged between 21 and 55 days old at the start of study were included and randomly allocated to one of three groups. Calves on all farms were observed for a period of 78 days post treatment, using both parasitological (oocyst excretion), and clinical parameters (faecal score and body weight). The assessment of efficacy was based on both control of oocyst excretion, and on the average daily weight gains throughout the study. During the whole study period, the mean number of days with diarrhoea (≥2) was similar (0.7 days) between treated groups. Excretion in the untreated group peaked at 21 days after treatment. In both the diclazuril and toltrazuril-treated groups, mean oocyst excretion decreased dramatically in the five days following treatment. Thereafter, particularly towards the end of the study period, oocyst counts and percentage levels of E. zuernii were highest in the toltrazuril-treated group. In pooled data from all trial sites, the average daily weight gain was significantly (p = 0.01) higher (+0.057 kg/day) in the diclazuril group when compared to the toltrazuril group, and the average body weight gain of the diclazuril treated group was 4.4 kg higher than the toltrazuril group. On eight of the nine trial sites, the average daily gain was greater in the diclazuril group than in the toltrazuril group. This study demonstrates that, over an extended observation period of 78 days, metaphylactic treatment with both diclazuril and toltrazuril reduces the impact of coccidiosis, but greater performance benefits based on average daily weight gains, were achieved following the use of diclazuril.


title: Use of influenza antivirals in patients hospitalized in Hong Kong, 2000-2015

text: OBJECTIVES: We aimed to describe patterns in the usage of antivirals to treat influenza virus infection in hospitals in Hong Kong from 2000 through 2015. METHODS: We analyzed centralized electronic health records that included dispensation information and diagnosis codes. Information collected on admissions included patient age, sex, admission year and month, and medications dispensed, and were matched with the first 15 discharge diagnosis codes. We divided monthly admission episodes by relevant population denominators to obtain admission rates, and stratified analyses by drug type, age group, and diagnosis codes. RESULTS: Amantadine was used for influenza treatment in the early 2000s but changed with recommendations to avoid its use in 2006, and is now mainly used to treat Parkinson’s disease. Oseltamivir usage increased substantially in 2009 and is now commonly used, with almost 40,000 hospitalizations treated with oseltamivir in the years 2012 through 2015, 66% of which was in persons ≥65 years of age. During the entire study period, of the 98,253 admission episodes in which oseltamivir was dispensed, 40,698 (41%) included a diagnosis code for influenza, and 80,283 (82%) included any diagnosis code for respiratory illness. CONCLUSIONS: The amount of oseltamivir used from 2012–15 was comparable to a separate ecological estimate of around 13,000 influenza-associated hospitalizations per year on average. We did not have access to individual patient laboratory testing data.


SARS-CoV2 induced respiratory distress: Can Cannabinoids be added to anti-viral therapies to reduce lung inflammation?


title: Nosocomial outbreak of influenza A H3N2 in an inpatient oncology unit related to health care workers presenting to work while ill

text: OBJECTIVE: To describe an outbreak of influenza A in an oncology unit, highlighting infection control methods implemented, and examining reasons health care workers (HCWs) present to work with influenza-like illness (ILI). METHODS: Confirmed cases were defined by the presence of ILI and a positive nasopharyngeal polymerase chain reaction swab for influenza A H3. Probable cases were defined as exposed HCWs with ILI who were unavailable for polymerase chain reaction testing. Infection prevention measures included closing the ward for new admissions, oseltamivir prophylaxis for all exposed groups, and dismissal from work of HCWs with ILI until resolution of symptoms. An anonymous survey of the cases in our HCWs was conducted to better elucidate reasons behind presenteeism. RESULTS: Over the course of 8 days (November 16, 2017, to November 22, 2017), influenza was diagnosed in 7 of 10 inpatients on the oncology ward, 16 HCWs (14 confirmed, 2 probable), and 2 visitors. The suspected index case was an HCW. Of the surveyed HCWs, 64% presented to work despite feeling ill (ie, presenteeism). The most common reason was “sense of duty as a health care worker.” CONCLUSIONS: This nosocomial outbreak of influenza highlights the challenges of protecting inpatients from viral respiratory tract infections. HCWs and patient visitors with ILI should avoid work or visiting until resolution of peak respiratory symptoms and adhere to strict respiratory etiquette.


title: Influenza Viral RNA Detection in Blood as a Marker to Predict Disease Severity in Hematopoietic Cell Transplant Recipients

text: Influenza RNA in blood (viremia) was detected in 9 of 79 (11.4%) hematopoietic cell transplant recipients with influenza, and was less frequently observed in patients with upper respiratory tract disease only and more frequently in patients infected with 2009 pandemic influenza A/H1N1 strain (versus seasonal strains). Viremia increased the risk of progression to lower respiratory tract disease (LRD), hypoxemia, respiratory failure, and overall and influenza-related death. Among patients with LRD, viremia was associated with increased hazards of overall and influenza-associated death (hazard ratio 3.5, 1.1–12). Thus, influenza viremia may serve as marker for overall poor outcome.


title: The role of extracorporeal life support for patients with COVID‐19: Preliminary results from a statewide experience

text: OBJECTIVE: There is a paucity of clinical data on critically ill patients with COVID‐19 requiring extracorporeal life support. METHODS: A statewide multi‐institutional collaborative for COVID‐19 patients was utilized to obtain clinical data on the first 10 critically ill COVID‐19 patients who required extracorporeal membrane oxygenation (ECMO). RESULTS: Of the first 10 patients that required ECMO for COVID‐19, the age ranged from 31 to 62 years with the majority (70%) being men. Seven (70%) had comorbidities. The majority (80%) of patients had known sick contact and exposure to COVID‐19 positive patients or traveled to pandemic areas inside the United States within the 2 weeks before symptom onset. None of the patients were healthcare workers. The most common symptoms leading to the presentation were high fever ≥103°F (90%), cough (80%) and dyspnea (70%), followed by fatigue and gastrointestinal symptoms (both 30%), myalgia, loss of taste, pleuritic chest pain, and confusion (all 10%). All patients had bilateral infiltrates on chest X‐rays suggestive of interstitial viral pneumonia. All patients were cannulated in the venovenous configuration. Two (20%) patients were successfully liberated from ECMO support after 7 and 10 days, respectively, and one (10%) patient is currently on a weaning course. One patient (10%) died after 9 days on ECMO from multiorgan dysfunction. CONCLUSIONS: These preliminary multi‐institutional data from a statewide collaborative offer insight into the clinical characteristics of the first 10 patients requiring ECMO for COVID‐19 and their initial clinical course. Greater morbidity and mortality is likely to be seen in these critically ill patients with longer follow‐up.


title: Epidemiological and Clinical Characteristics of Cases During the Early Phase of COVID-19 Pandemic: A Systematic Review and Meta-Analysis

text: Background: On 29th December 2019, a cluster of cases displaying the symptoms of a “pneumonia of unknown cause” was identified in Wuhan, Hubei province of China. This systematic review and meta-analysis aims to review the epidemiological and clinical characteristics of COVID-19 cases in the early phase of the COVID-19 pandemic. Methods: The search strategy involved peer-reviewed studies published between 1st January and 11th February 2020 in Pubmed, Google scholar and China Knowledge Resource Integrated database. Publications identified were screened for their title and abstracts according to the eligibility criteria, and further shortlisted by full-text screening. Three independent reviewers extracted data from these studies, and studies were assessed for potential risk of bias. Studies comprising non-overlapping patient populations, were included for qualitative and quantitative synthesis of results. Pooled prevalence with 95% confidence intervals were calculated for patient characteristics. Results: A total of 29 publications were selected after full-text review. This comprised of 18 case reports, three case series and eight cross-sectional studies on patients admitted from mid-December of 2019 to early February of 2020. A total of 533 adult patients with pooled median age of 56 (95% CI: 49–57) and a pooled prevalence of male of 60% (95% CI: 52–68%) were admitted to hospital at a pooled median of 7 days (95% CI: 7–7) post-onset of symptoms. The most common symptoms at admission were fever, cough and fatigue, with a pooled prevalence of 90% (95% CI: 81–97%), 58% (95% CI: 47–68%), and 50% (95% CI: 29–71%), respectively. Myalgia, shortness of breath, headache, diarrhea and sore throat were less common with pooled prevalence of 27% (95% CI: 20–36%), 25% (95% CI: 15–35%), 10% (95% CI: 7–13%), 8% (95% CI: 5–13%), and 7% (95% CI: 1–15%), respectively. ICU patients had a higher proportion of shortness of breath at presentation, as well as pre-existing hypertension, cardiovascular disease and COPD, compared to non-ICU patients in 2 studies (n = 179). Conclusion: This study highlights the key epidemiological and clinical features of COVID-19 cases during the early phase of the COVID-19 pandemic.


title: Avian influenza – A review for doctors in travel medicine

text: Summary First identified in humans in Hong Kong, influenza A/H5N1, known commonly as avian influenza, has caused human disease in 15 countries around the world. Although the current number of confirmed patients is tiny compared to seasonal and the recently emerged H1N1 ‘swine’ influenza, H5N1 remains a candidate for the next highly pathogenic influenza pandemic. Currently, H5N1 has very limited ability to spread from person-to-person but this may change because of mutation or reassortment with other influenza viruses leading to an influenza pandemic with high mortality. If this occurs travellers are likely to be affected and travel medicine doctors will need to consider avian influenza in returning febrile travellers. The early clinical features may be dismissed easily as ‘the flu’ resulting in delayed treatment. Treatment options are limited. Oral oseltamivir alone has been the most commonly used drug but mortality remains substantial, up to 80% in Indonesia. Intravenous peramivir has been filed for registration and IV zanamivir is being developed. This review will focus on the epidemiological and clinical features of influenza A/H5N1 avian influenza and will highlight aspects relevant to travel medicine doctors.


Antibodies to Nipah or Nipah-like Viruses in Bats, China


title: Comparison of Epidemiological Variations in COVID-19 Patients Inside and Outside of China—A Meta-Analysis

text: The objective of this study is to compare the epidemiological variations in COVID-19 patients reported in studies from inside and outside of China. We selected COVID-19 observational studies from eight countries, including, China, Italy, Australia, Canada, Korea, Taiwan, Singapore, and the USA, comprising a total of 13 studies and performed a meta-analysis for age, gender, fatality rate, and clinical symptoms of fever, cough, shortness of breath, and diarrhea. The meta-analysis shows that there are differences in symptoms and other characteristics reported by the patients of COVID-19 inside and outside China. Patients in China have a higher proportion of fever, cough, and shortness of breath as compared to patients outside of China. However, we found the opposite results for the gastrointestinal symptoms such as Diarrhea. Patients outside of China have a significantly higher proportion of Diarrhea as compared to patients within China. We also observed gender disparity among our studies, with the male population being more susceptible than the female population. Moreover, the analysis suggests that the fatality rate in China is relatively lower as compared to the fatality rate in other countries. These findings also suggest that the clinical symptoms of COVID-19 should not be generalized to fever, shortness of breath, and cough only but other symptoms such as diarrhea are also prevalent in patients with COVID-19.


title: The role of infections and coinfections with newly identified and emerging respiratory viruses in children

text: Acute respiratory infections are a major cause of morbidity in children both in developed and developing countries. A wide range of respiratory viruses, including respiratory syncytial virus (RSV), influenza A and B viruses, parainfluenza viruses (PIVs), adenovirus, rhinovirus (HRV), have repeatedly been detected in acute lower respiratory tract infections (LRTI) in children in the past decades. However, in the last ten years thanks to progress in molecular technologies, newly discovered viruses have been identified including human Metapneumovirus (hMPV), coronaviruses NL63 (HcoV-NL63) and HKU1 (HcoV-HKU1), human Bocavirus (HBoV), new enterovirus (HEV), parechovirus (HpeV) and rhinovirus (HRV) strains, polyomaviruses WU (WUPyV) and KI (KIPyV) and the pandemic H1N1v influenza A virus. These discoveries have heavily modified previous knowledge on respiratory infections mainly highlighting that pediatric population is exposed to a variety of viruses with similar seasonal patterns. In this context establishing a causal link between a newly identified virus and the disease as well as an association between mixed infections and an increase in disease severity can be challenging. This review will present an overview of newly recognized as well as the main emerging respiratory viruses and seek to focus on the their contribution to infection and co-infection in LRTIs in childhood.


title: In response to the letter of Montagud‐Marrahi et al.

text: We read with interest the correspondence from Montagud‐Marrahi et al. putting forward that solid organ transplant (SOT) recipients are not at higher risk of severe COVID‐19 infection despite their immunosuppression and the mild or atypical nature of their symptoms in their Spanish cohort. In the recent literature, this population achieves a mortality rate between 20% and 52% when they become critically ill. Moreover, as innate immunity is altered by the infection, decreased doses of immunosuppressive drugs should be considered.


title: Living With COVID-19: A Systemic and Multi-Criteria Approach to Enact Evidence-Based Health Policy

text: The lifting of COVID-19 (coronavirus disease 2019) lockdown requires, in the short and medium terms, a holistic and evidence-based approach to population health management based on combining risk factors and bio-economic outcomes, including actors' behaviors. This dynamic and global approach to health control is necessary to deal with the new paradigm of living with an infectious disease, which disrupts our individual freedom and behaviors. The challenge for policymakers consists of defining methods of lockdown-lifting and follow-up (middle-term rules) that best meet the needs for resumption of economic activity, societal wellbeing, and containment of the outbreak. There is no simple and ready-to-use way to do this since it means considering several competing objectives at the same time and continuously adapting the strategy and rules, ideally at local scale. We propose a framework for creating a precision evidence-based health policy that simultaneously considers public health, economic, and societal dimensions while accounting for constraints and uncertainty. It is based on the four following principles: integrating multiple and heterogeneous information, accepting navigation with uncertainty, adjusting the strategy dynamically with feedback mechanisms, and managing clusters through a multi-scalar conception. The evidence-based policy intervention for COVID-19 obtained includes scientific background via epidemiological modeling and bio-economic modeling. A set of quantitative and qualitative indicators are used as feedback to precisely monitor the societal-economic-epidemiological dynamics, allowing tightening or loosening of measures before epidemic damage (re-)occurs. Altogether, this allows an evidence-based policy that steers the strategy with precision and avoids any political shock.


title: Myeloid Cells during Viral Infections and Inflammation

text: Myeloid cells represent a diverse range of innate leukocytes that are crucial for mounting successful immune responses against viruses. These cells are responsible for detecting pathogen-associated molecular patterns, thereby initiating a signaling cascade that results in the production of cytokines such as interferons to mitigate infections. The aim of this review is to outline recent advances in our knowledge of the roles that neutrophils and inflammatory monocytes play in initiating and coordinating host responses against viral infections. A focus is placed on myeloid cell development, trafficking and antiviral mechanisms. Although known for promoting inflammation, there is a growing body of literature which demonstrates that myeloid cells can also play critical regulatory or immunosuppressive roles, especially following the elimination of viruses. Additionally, the ability of myeloid cells to control other innate and adaptive leukocytes during viral infections situates these cells as key, yet under-appreciated mediators of pathogenic inflammation that can sometimes trigger cytokine storms. The information presented here should assist researchers in integrating myeloid cell biology into the design of novel and more effective virus-targeted therapies.


title: Support vector machine (SVM) based multiclass prediction with basic statistical analysis of plasminogen activators

text: BACKGROUND: Plasminogen (Pg), the precursor of the proteolytic and fibrinolytic enzyme of blood, is converted to the active enzyme plasmin (Pm) by different plasminogen activators (tissue plasminogen activators and urokinase), including the bacterial activators streptokinase and staphylokinase, which activate Pg to Pm and thus are used clinically for thrombolysis. The identification of Pg-activators is therefore an important step in understanding their functional mechanism and derives new therapies. METHODS: In this study, different computational methods for predicting plasminogen activator peptide sequences with high accuracy were investigated, including support vector machines (SVM) based on amino acid (AC), dipeptide composition (DC), PSSM profile and Hybrid methods used to predict different Pg-activators from both prokaryotic and eukaryotic origins. RESULTS: Overall maximum accuracy, evaluated using the five-fold cross validation technique, was 88.37%, 84.32%, 87.61%, 85.63% in 0.87, 0.83,0.86 and 0.85 MCC with amino (AC) or dipeptide composition (DC), PSSM profile and Hybrid methods respectively. Through this study, we have found that the different subfamilies of Pg-activators are quite closely correlated in terms of amino, dipeptide, PSSM and Hybrid compositions. Therefore, our prediction results show that plasminogen activators are predictable with a high accuracy from their primary sequence. Prediction performance was also cross-checked by confusion matrix and ROC (Receiver operating characteristics) analysis. A web server to facilitate the prediction of Pg-activators from primary sequence data was implemented. CONCLUSION: The results show that dipeptide, PSSM profile, and Hybrid based methods perform better than single amino acid composition (AC). Furthermore, we also have developed a web server, which predicts the Pg-activators and their classification (available online at http://mamsap.it.deakin.edu.au/plas_pred/home.html). Our experimental results show that our approaches are faster and achieve generally a good prediction performance.


title: Evaluation of the English Version of the Fear of COVID-19 Scale and Its Relationship with Behavior Change and Political Beliefs

text: The COVID-19 pandemic has many individuals around the world fearing for their lives. The constant news coverage, rapid transmission, and relatively high mortality rate, make fearfulness a natural response. To assess the fear of COVID-19, the Fear of COVID-19 Scale (FCV-19S) was developed. The primary aim of the present study was to conduct the first psychometric assessment and validation of the English version of the FCV-19S. Two samples were collected in New Zealand. Sample 1 comprised 1624 participants of which 1397 completed all questions and were used in the analyses. Sample 2 comprised 1111 participants of which 1023 completed all questions and were used in the analyses. Several psychometric tests were conducted to ascertain the scale’s reliability and validity. Across both samples, the FCV-19S had high internal consistency. Consistent with the earlier validation studies, the FCV-19S displayed a moderately strong relationship with the perceived infectability and germ aversion subscales of the perceived vulnerability to disease scale (PVDS). Furthermore, FCV-19S scores were negatively correlated with the Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS) scores. With respect to the motivating role of fear, there was a significant relationship between FCV-19S scores and adherence to the lockdown rules that were implemented in New Zealand. Finally, consistent with recent reports on the politicization of the COVID-19 pandemic, an exploratory question found that participants who rated themselves as more conservative tended to report lower FCV-19S scores. The English version of the COVID-19S is a sound unidimensional scale with robust psychometric properties and can be used with confidence among English-speaking populations. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11469-020-00342-9) contains supplementary material, which is available to authorized users.


title: Discovery of a Novel Bat Gammaherpesvirus

text: Zoonosis is the leading cause of emerging infectious diseases. In a recent article, R. S. Shabman et al. (mSphere 1[1]:e00070-15, 2016, http://dx.doi.org/10.1128/mSphere.00070-15) report the identification of a novel gammaherpesvirus in a cell line derived from the microbat Myotis velifer incautus. This is the first report on a replicating, infectious gammaherpesvirus from bats. The new virus is named bat gammaherpesvirus 8 (BGHV8), also known as Myotis gammaherpesvirus 8, and is able to infect multiple cell lines, including those of human origin. Using next-generation sequencing technology, the authors constructed a full-length annotated genomic map of BGHV8. Phylogenetic analysis of several genes from BGHV8 revealed similarity to several mammalian gammaherpesviruses, including Kaposi’s sarcoma-associated herpesvirus (KSHV).


title: Salt bridge-forming residues positioned over viral peptides presented by MHC class I impacts T-cell recognition in a binding-dependent manner

text: Abstract The viral peptides presentation by major histocompatibility complex class I (MHC I) molecules play a pivotal role in T-cell recognition and the subsequent virus clearance. This process is delicately adjusted by the variant residues of MHC I, especially the residues in the peptide binding groove (PBG). In a series of MHC I molecules, a salt bridge is formed above the N-terminus of the peptides. However, the potential impact of the salt bridge on peptide binding and T-cell receptor (TCR) recognition of MHC I, as well as the corresponding molecular basis, are still largely unknown. Herein, we determined the structures of HLA-B*4001 and H-2Kd in which two different types of salt bridges (Arg62-Glu163 or Arg66-Glu163) across the PBG were observed. Although the two salt bridges led to different conformation shifts of both the MHC I α helix and the peptides, binding of the peptides with the salt bridge residues was relatively conserved. Furthermore, through a series of in vitro and in vivo investigations, we found that MHC I mutations that disrupt the salt bridge alleviate peptide binding and can weaken the TCR recognition of MHC I-peptide complexes. Our study may provide key references for understanding MHC I-restricted peptide recognition by T-cells.


title: Chloroquine and Its Derivatives Exacerbate B19V-Associated Anemia by Promoting Viral Replication

text: BACKGROUND: An unexpectedly high seroprevalence and pathogenic potential of human parvovirus B19 (B19V) have been observed in certain malaria-endemic countries in parallel with local use of chloroquine (CQ) as first-line treatment for malaria. The aims of this study were to assess the effect of CQ and other common antimalarial drugs on B19V infection in vitro and the possible epidemiological consequences for children from Papua New Guinea (PNG). METHODOLOGY/PRINCIPAL FINDINGS: Viral RNA, DNA and proteins were analyzed in different cell types following infection with B19V in the presence of a range of antimalarial drugs. Relationships between B19V infection status, prior 4-aminoquinoline use and anemia were assessed in 200 PNG children <10 years of age participating in a case-control study of severe infections. In CQ-treated cells, the synthesis of viral RNA, DNA and proteins was significantly higher and occurred earlier than in control cells. CQ facilitates B19V infection by minimizing intracellular degradation of incoming particles. Only amodiaquine amongst other antimalarial drugs had a similar effect. B19V IgM seropositivity was more frequent in 111 children with severe anemia (hemoglobin <50 g/L) than in 89 healthy controls (15.3% vs 3.4%; P = 0.008). In children who were either B19V IgM or PCR positive, 4-aminoquinoline use was associated with a significantly lower admission hemoglobin concentration. CONCLUSIONS/SIGNIFICANCE: Our data strongly suggest that 4-aminoquinoline drugs and their metabolites exacerbate B19V-associated anemia by promoting B19V replication. Consideration should be given for choosing a non-4-aminoquinoline drug to partner artemisinin compounds in combination antimalarial therapy.


title: Subcutaneous meloxicam suspension pharmacokinetics in mice and dose considerations for postoperative analgesia

text: Meloxicam is a cyclooxygenase (COX) inhibitor with a higher selectivity for cyclooxygenase‐2 (COX‐2) than for cyclooxygenase‐1 (COX‐1). In the laboratory setting, this nonsteroidal anti‐inflammatory drug (NSAID) is commonly selected for analgesia in mice and administered every 24 h. This study characterizes the plasma concentration achieved from a dose of 1.6 mg/kg of meloxicam administered once every 24 h subcutaneously for 72 h in male and female C57BL/6 mice. These values were compared, over time, to reference COX‐2 inhibition constants for meloxicam. No significant differences in trough plasma concentrations were noted between genders. The plasma concentrations were below the COX‐2 IC (50) after 12 h. To maintain a plasma concentration at or above the COX‐2 whole blood IC (50,) the study results suggest an administration frequency of every 12 h when using a dose of 1.6 mg/kg in C57BL/6 mice.


title: Extraction of Glycyrrhizic Acid and Glabridin from Licorice

text: The extraction and separation conditions of glycyrrhizic acid and glabridin from licorice were investigated. By changing the different extraction solvents, procedures, times and temperature, the optimum extraction condition was established: the used of ethanol/water (30:70, v/v) as an extraction solvent, and 60 min dipping time under 50°C. The extracts of licorice were separated and determined by reversed-phase high performance liquid chromatography with a methanol/water (70:30, v/v, containing 1% acetic acid) as the mobile phase. Under the optimum extraction condition, 2.39 mg/g of glycyrrhizic acid and 0.92 mg/g of glabridin were extracted from Chinese licorice and the recoveries were 89.7% and 72.5% respectively.


Burnout: A risk factor amongst mental health professionals during COVID-19: With the on-going pandemic, a crisis is headed for India’s mental healthcare system


title: Upper respiratory virus detection without parent-reported illness in children is virus-specific

text: Abstract Background Viral upper respiratory tract infection (vURI) may or may not present with a cold/flu-like illness (CFLI). Objectives For common upper respiratory viruses that cause vURIs, to determine the relative frequencies of virus detection by PCR in subjects with and without CFLIs. Study design Prospective follow-up of 170 children aged 1–8.6 years through the CFLI season by daily parental diary for CFLI episodes and nasal secretion sampling using PCR assays for adenovirus, coronavirus (types 229E and OC43), influenza virus (types A and B), parainfluenza (types 1–3) virus, rhinovirus, and respiratory syncytial virus (RSV). Results Virus was detected in 415 of 956 independent assays: 425 CFLI episodes and 531 non-CFLI periods were sampled; samples from 270 (64%) CFLI episodes and 145 (27%) non-CFLI periods contained virus detected by PCR. Rhinovirus was most frequently detected at 64%, followed by mixed viruses at 12%, RSV at 7%, and the other viruses at 3–5% of all detections. About 85% of RSV, influenza A and adenovirus detections were associated with a CFLI, whereas less than 62% of other virus detections were associated with CFLI. Conclusions The frequency of PCR virus detection without CFLI was different among viruses. This introduces virus-specific biases to estimating the frequencies of specific complications attributable to a vURI when ascertained by CFLI identification.


title: Safety and Immunogenicity of DNA Vaccines Encoding Ebolavirus and Marburgvirus Wild-Type Glycoproteins in a Phase I Clinical Trial

text: BACKGROUND: Ebolavirus and Marburgvirus cause severe hemorrhagic fever with high mortality and are potential bioterrorism agents. There are no available vaccines or therapeutic agents. Previous clinical trials evaluated transmembrane-deleted and point-mutation Ebolavirus glycoproteins (GPs) in candidate vaccines. Constructs evaluated in this trial encode wild-type (WT) GP from Ebolavirus Zaire and Sudan species and the Marburgvirus Angola strain expressed in a DNA vaccine. METHODS: The VRC 206 study evaluated the safety and immunogenicity of these DNA vaccines (4 mg administered intramuscularly by Biojector) at weeks 0, 4, and 8, with a homologous boost at or after week 32. Safety evaluations included solicited reactogenicity and coagulation parameters. Primary immune assessment was done by means of GP-specific enzyme-linked immunosorbent assay. RESULTS: The vaccines were well tolerated, with no serious adverse events; 80% of subjects had positive enzyme-linked immunosorbent assay results (≥30) at week 12. The fourth DNA vaccination boosted the immune responses. CONCLUSIONS: The investigational Ebolavirus and Marburgvirus WT GP DNA vaccines were safe, well tolerated, and immunogenic in this phase I study. These results will further inform filovirus vaccine research toward a goal of inducing protective immunity by using WT GP antigens in candidate vaccine regimens. CLINICAL TRIALS REGISTRATION: NCT00605514.


title: Epidemiological analysis and follow‐up of human rhinovirus infection in children with asthma exacerbation

text: To determine the prevalence of human rhinovirus (HRV) infection in children with acute asthma exacerbations, investigation of HRV viral load and severity of asthma exacerbations is also required. Nasopharyngeal aspirates and swabs were collected and assessed for respiratory viruses. HRV‐positive samples were sequenced to identify types and determine viral load. Outpatients with asthma exacerbations underwent follow‐up evaluations, their swabs were collected and clinical outcomes were recorded at their next clinic visit 4 weeks later. One hundred forty‐three inpatients and 131 outpatients, including 88 patients with asthma exacerbations and 43 controls with stable asthma were recruited. HRV‐A was mainly detected in September and February (45.5% and 33.3%, respectively), while HRV‐C was mainly detected in November and April (70.0% and 55.6%, respectively). HRV‐C was the primary type and was primarily found in inpatients with severe asthma exacerbations. HRV‐A viral load in the group of inpatients with severe exacerbations was higher than in the mild and moderate groups (P < 0.001 and P = 0.022). The HRV‐A viral load of both inpatients and outpatients was higher than that of HRV‐C (P < 0.001 and P = 0.036). The main genotypes were HRV‐C53 and HRV‐A20 among inpatients, and this genotype caused more severe clinical manifestations. HRV persisted for no more than 4 weeks, and their symptoms or signs of disease were well‐controlled well. HRV‐C was most frequently detected in asthma exacerbations. HRV‐A with high viral load led to severe asthma exacerbations.


title: Multivariate Analysis of Black Race and Environmental Temperature on COVID-19 In the US

text: BACKGROUND: There has been much interest in environmental temperature and race as modulators of Coronavirus disease-19 (COVID-19) infection and mortality. However, in the United States race and temperature correlate with various other social determinants of health, comorbidities, and environmental influences that could be responsible for noted effects. This study investigates the independent effects of race and environmental temperature on COVID-19 incidence and mortality in United States counties. METHODS: Data on COVID-19 and risk factors in all United States counties was collected. 661 counties with at least 50 COVID-19 cases and 217 with at least 10 deaths were included in analyses. Upper and lower quartiles for cases/100,000 people and halves for deaths/100,000 people were compared with t-tests. Adjusted linear and logistic regression analyses were performed to evaluate the independent effects of race and environmental temperature. RESULTS: Multivariate regression analyses demonstrated Black race is a risk factor for increased COVID-19 cases (OR=1.22, 95% CI: 1.09-1.40, P=0.001) and deaths independent of comorbidities, poverty, access to health care, and other risk factors. Higher environmental temperature independently reduced caseload (OR=0.81, 95% CI: 0.71-0.91, P=0.0009), but not deaths. CONCLUSIONS: Higher environmental temperatures correlated with reduced COVID-19 cases, but this benefit does not yet appear in mortality models. Black race was an independent risk factor for increased COVID-19 cases and deaths. Thus, many proposed mechanisms through which Black race might increase risk for COVID-19, such as socioeconomic and healthcare-related predispositions, are inadequate in explaining the full magnitude of this health disparity.


title: Targeting zoonotic viruses: structure-based inhibition of the 3C-like protease from bat coronavirus HKU4 – the likely reservoir host to the human coronavirus that causes Middle East Respiratory Syndrome (MERS)

text: The bat coronavirus HKU4 belongs to the same 2c lineage as that of the deadly Middle East Respiratory Syndrome coronavirus (MERS-CoV) and shows high sequence similarity, therefore potentiating a threat to the human population through a zoonotic shift or “spill over” event. To date, there are no effective vaccines or antiviral treatments available that are capable of limiting the pathogenesis of any human coronaviral infection. An attractive target for the development of anti-coronaviral therapeutics is the 3C-like protease (3CL(pro)), which is essential for the progression of the coronaviral life cycle. Herein, we report the screening results of a small, 230-member peptidomimetic library against HKU4-CoV 3CL(pro) and the identification of 43 peptidomimetic compounds showing good to excellent inhibitory potency of HKU4-CoV 3CL(pro) with IC(50) values ranging from low micromolar to sub-micromolar. We established structure-activity relationships (SARs) describing the important ligand-based features required for potent HKU4-CoV 3CL(pro) inhibition and identified a seemingly favored peptidic backbone for HKU4-CoV 3CL(pro) inhibition. To investigate this, a molecular sub-structural analysis of the most potent HKU4-CoV 3CL(pro) inhibitor was accomplished by the synthesis and testing of the lead peptidomimetic inhibitor's sub-structural components, confirming the activity of the favored backbone (22A) identified via SAR analysis. In order to elucidate the structural reasons for such potent HKU4-CoV 3CL(pro) inhibition by the peptidomimetics having the 22A backbone, we determined the X-ray structures of HKU4-CoV 3CL(pro) in complex with three peptidomimetic inhibitors. Sequence alignment of HKU4-CoV 3CL(pro), and two other lineage C Betacoronaviruses 3CL(pro)'s, HKU5-CoV and MERS-CoV 3CL(pro), show that the active site residues of HKU4-CoV 3CL(pro) that participate in inhibitor binding are conserved in HKU5-CoV and MERS-CoV 3CL(pro). Furthermore, we assayed our most potent HKU4-CoV 3CL(pro) inhibitor for inhibition of HKU5-CoV 3CL(pro) and found it to have sub-micromolar inhibitory activity (IC(50) = 0.54 ± 0.03 μM). The X-ray structures and SAR analysis reveal critical insights into the structure and inhibition of HKU4-CoV 3CL(pro), providing fundamental knowledge that may be exploited in the development of anti-coronaviral therapeutics for coronaviruses emerging from zoonotic reservoirs.


title: Controlling avian flu at the source

text: Global agricultural authorities should harmonize with the public-health sector to ensure the exchange of flu virus samples, and establish a single international standard for vaccines, say Robert Webster and Diane Hulse.


title: Comprehensive investigation of an in-hospital transmission cluster of a symptomatic SARS-CoV-2–positive physician among patients and healthcare workers in Germany

text: We investigated potential transmissions of a symptomatic SARS-CoV-2–positive physician in a tertiary-care hospital who worked for 15 cumulative hours without wearing a face mask. No in-hospital transmissions occurred, despite 254 contacts among patients and healthcare workers. In conclusion, exposed hospital staff continued work, accompanied by close clinical and virologic monitoring.


title: RSNA Expert Consensus Statement on Reporting Chest CT Findings Related to COVID-19: Interobserver Agreement Between Chest Radiologists

text: PURPOSE: To assess the interobserver variability between chest radiologists in the interpretation of the Radiological Society of North America (RSNA) expert consensus statement reporting guidelines in patients with suspected coronavirus disease 2019 (COVID-19) pneumonia in a setting with limited reverse transcription polymerase chain reaction testing availability. METHODS: Chest computed tomography (CT) studies in 303 consecutive patients with suspected COVID-19 were reviewed by 3 fellowship-trained chest radiologists. Cases were assigned an impression of typical, indeterminate, atypical, or negative for COVID-19 pneumonia according to the RSNA expert consensus statement reporting guidelines, and interobserver analysis was performed. Objective CT features associated with COVID-19 pneumonia and distribution of findings were recorded. RESULTS: The Fleiss kappa for all observers was almost perfect for typical (0.815), atypical (0.806), and negative (0.962) COVID-19 appearances (P < .0001) and substantial (0.636) for indeterminate COVID-19 appearance (P < .0001). Using Cramer V analysis, there were very strong correlations between all radiologists’ interpretations, statistically significant for all (typical, indeterminate, atypical, and negative) COVID-19 appearances (P < .001). Objective CT imaging findings were recorded in similar percentages of typical cases by all observers. CONCLUSION: The RSNA expert consensus statement on reporting chest CT findings related to COVID-19 demonstrates substantial to almost perfect interobserver agreement among chest radiologists in a relatively large cohort of patients with clinically suspected COVID-19. It therefore serves as a reliable reference framework for radiologists to accurately communicate their level of suspicion based on the presence of evidence-based objective findings.


title: Expression profile of genes involved in pathogenesis of pediatric Crohn's disease

text: Background and Aim: Expression profiling of genes specific to pediatric Crohn's Disease (CD) patients was performed to elucidate the molecular mechanisms underlying disease cause and pathogenesis at disease onset. Methods: We used suppressive subtractive hybridization (SSH) and differential screening analysis to profile the mRNA expression patterns of children with CD and age‐ and sex‐matched controls without inflammatory bowel disease (IBD). Results: Sequence analysis of 1000 clones enriched by SSH identified 75 functionally annotated human genes, represented by 430 clones. The 75 genes have potential involvement in gene networks, such as antigen presentation, inflammation, infection mechanism, connective tissue development, cell cycle and cancer. Twenty‐eight genes were previously described in association with CD, while 47 were new genes not previously reported in the context of IBD. Additionally, 29 of the 75 genes have been previously implicated in bacterial and viral infections. Quantitative real‐time reverse transcription polymerase chain reaction performed on ileal‐derived RNA from 13 CD and nine non‐IBD patients confirmed the upregulation of extracellular matrix gene MMP2 (P = 0.001), and cell proliferation gene REG1A (P = 0.063) in our pediatric CD cohort. Conclusion: The retrieval of 28 genes previously reported in association with adult CD emphasizes the importance of these genes in the pediatric setting. The observed upregulation of REG1A and MMP2, and their known impact on cell proliferation and extracellular matrix remodeling, agrees with the clinical behavior of the disease. Moreover, the expressions of bacterial‐ and virus‐related genes in our CD‐patient tissues support the concept that microbial agents are important in the etiopathogenesis of CD.


title: COVID-19 pneumonia: CD8(+) T and NK cells are decreased in number but compensatory increased in cytotoxic potential

text: BACKGROUND: Coronavirus disease 2019 (COVID-19) is posing a huge threat to human health worldwide. We aim to investigate the immune status of CD8(+) T and NK cells in COVID-19 patients. METHODS: The count and immune status of lymphocytes were detected by flow cytometry in 32 COVID-19 patients and 18 healthy individuals. RESULTS: As the disease progression in COVID-19 patients, CD8(+) T and NK cells were significantly decreased in absolute number but highly activated. After patients' condition improved, the count and immune status of CD8(+) T and NK cells restored to some extent. GrA(+)CD8(+) T and perforin(+) NK cells had good sensitivity and specificity for assisting diagnosis of COVID-19. CONCLUSIONS: As the disease progression, the declined lymphocytes in COVID-19 patients might lead to compensatory activation of CD8(+) T and NK cells. GrA(+)CD8(+) T and perforin(+) NK cells might be used as meaningful indicators for assisting diagnosis of COVID-19.


title: Dupilumab and COVID‐19: What should we expect?

text: Coronavirus disease 2019 (COVID‐19) is a pandemic disease caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) with high morbidity and mortality. There are very limited data on the interference of immunomodulating drugs on the risk of infection and on the course of the disease. In particular, there are no current clinical data about the interference exerted by dupilumab, a biologic drugs blocking IL‐4 and IL‐13, used for adult atopic dermatitis. The pathogenesis of COVID‐19 is complex, characterized by an immune response mainly Th1/Th17. The hyper‐activation of these cells may cause the release of pro‐inflammatory cytokines that may result in lung impairment. IL‐4 and IL‐13 are Th2 cytokines, thus being part of a pathway not considered implicated in host defense mechanism against viral infections. Indeed, viral infections, including respiratory infections, have not been reported as a significant adverse event in clinical trials. Furthermore, dupilumab has been proved to be efficacious also in exacerbations of asthma, and it is known that viral infections can worsen asthma. Therefore, the current data seem to suggest that treatment with dupilumab should not be stopped during COVID‐19 pandemic. Obviously, a careful assessment is mandatory for each individual patient and further studies are necessary to characterize the immunologic responses in COVID‐19.


title: Telemedicine Evaluation and Techniques in Hand Surgery

text: Abstract The demand for telemedicine has been increasing over the past several years with the growth of technology and digital connectivity in our daily lives. With the impact of the global COVID-19 pandemic, telemedicine implementation has become a necessity for many specialties as social distancing measures have greatly impacted access to routine medical care. This article presents a detailed and systematic approach to conducting a hand physical examination during a video telemedicine encounter. While the telemedicine physical examination presents its limitations, most components of the normal physical examination can be completed remotely with a systematic approach. We enumerate modifications to maximize examination remotely and present considerations for improved delivery of telemedicine care. These methods may be beneficial to providers incorporation telemedicine into their practice.


title: High-throughput Luminex xMAP assay for simultaneous detection of antibodies against rabbit hemorrhagic disease virus, Sendai virus and rabbit rotavirus

text: Rabbits are widely used as models in biological research, and the pathogen status of rabbits used in studies can directly affect the results of experiments. Serological surveillance is the common monitoring method used in laboratory animals. A rapid, sensitive, and cost-effective high-throughput Luminex xMAP assay could be an attractive alternative to labor-intensive enzyme-linked immunosorbent assay (ELISA) methods. In this study, recombinant proteins from rabbit hemorrhagic disease virus and rabbit rotavirus and whole viral lysates of Sendai virus were used as coating antigens in an xMAP assay for the simultaneous detection of antibodies against these pathogens. The xMAP assay showed high specificity, with no cross-reaction with other pathogens. The coefficient of variation for intra-assay and inter-assay comparisons was less than 3% and 4%, respectively, indicating good repeatability and stability of the assay. The xMAP assay exhibited similar limits of detection for rabbit hemorrhagic virus and Sendai virus and was less sensitive for the detection of rabbit rotavirus when compared with commercial ELISA kits. A total of 52 clinical samples were tested simultaneously using both the xMAP assay and ELISA kits. The results obtained using these two methods were 100% coincident. In summary, the novel xMAP assay offers an alternative choice for rapid and sensitive high-throughput detection of antibodies in rabbit serum and can be used as a daily monitoring tool for laboratory animals. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00705-019-04226-9) contains supplementary material, which is available to authorized users.


title: Prospects for the creation of new antiviral drugs based on glycyrrhizic acid and its derivatives (a review)

text: The review is devoted to the problem of creating new antiviral drugs based on glycyrrhizic acid (GA), the major triterpene glycoside extracted from roots of common and Ural licorice (Glycyrrhiza glabra L. and G. uralensis Fisher, respectively). Published data on the natural GA sources, antiviral activity of GA and its derivatives, clinical applications of GA-based drugs, and the properties of GA-containing biologically active nutrient additives are summarized. Possible mechanisms of the antiviral activity of GA and its derivatives are examined. It is shown that chemical modification of GA is a promising way of designing new highly active antiviral drugs for the prophylaxis and treatment of HIV, hepatitis B and C, corona-virus, and herpes simplex virus infections.


title: T cell aging: naive but not young

text: The immune system exhibits profound age-related changes, collectively termed immunosenescence. The most visible of these is the decline in protective immunity, which results from a complex interaction of primary immune defects and compensatory homeostatic mechanisms. The sum of these changes is a dysregulation of many processes that normally ensure optimal immune function. Recent advances suggest that old mice can produce fully functional new T cells, opening both intriguing inquiry avenues and raising critical questions to be pursued.


title: Recent Advances in the Vaccine Development Against Middle East Respiratory Syndrome-Coronavirus

text: Middle East respiratory syndrome (MERS) is a deadly viral respiratory disease caused by MERS-coronavirus (MERS-CoV) infection. To date, there is no specific treatment proven effective against this viral disease. In addition, no vaccine has been licensed to prevent MERS-CoV infection thus far. Therefore, our current review focuses on the most recent studies in search of an effective MERS vaccine. Overall, vaccine candidates against MERS-CoV are mainly based upon the viral spike (S) protein, due to its vital role in the viral infectivity, although several studies focused on other viral proteins such as the nucleocapsid (N) protein, envelope (E) protein, and non-structural protein 16 (NSP16) have also been reported. In general, the potential vaccine candidates can be classified into six types: viral vector-based vaccine, DNA vaccine, subunit vaccine, nanoparticle-based vaccine, inactivated-whole virus vaccine and live-attenuated vaccine, which are discussed in detail. Besides, the immune responses and potential antibody dependent enhancement of MERS-CoV infection are extensively reviewed. In addition, animal models used to study MERS-CoV and evaluate the vaccine candidates are discussed intensively.


Evaluating the dermatology communities' public health response to COVID‐19


title: Expression profiles of immune mediators in feline Coronavirus-infected cells and clinical samples of feline Coronavirus-positive cats

text: BACKGROUND: There are two biotypes of feline coronavirus (FCoV): the self-limiting feline enteric coronavirus (FECV) and the feline infectious peritonitis virus (FIPV), which causes feline infectious peritonitis (FIP), a fatal disease associated with cats living in multi-cat environments. This study provides an insight on the various immune mediators detected in FCoV-positive cats which may be responsible for the development of FIP. RESULTS: In this study, using real-time PCR and multiplex bead-based immunoassay, the expression profiles of several immune mediators were examined in Crandell-Reese feline kidney (CRFK) cells infected with the feline coronavirus (FCoV) strain FIPV 79–1146 and in samples obtained from FCoV-positive cats. CRFK cells infected with FIPV 79–1146 showed an increase in the expression of interferon-related genes and pro-inflammatory cytokines such as MX1, viperin, CXCL10, CCL8, RANTES, KC, MCP1, and IL8. In addition, an increase in the expression of the above cytokines as well as GM-CSF and IFNγ was also detected in the PBMC, serum, and peritoneal effusions of FCoV-positive cats. Although the expression of MX1 and viperin genes was variable between cats, the expression of these two genes was relatively higher in cats having peritoneal effusion compared to cats without clinically obvious effusion. Higher viral load was also detected in the supernatant of peritoneal effusions compared to in the plasma of FCoV-positive cats. As expected, the secretion of IL1β, IL6 and TNFα was readily detected in the supernatant of peritoneal effusions of the FCoV-positive cats. CONCLUSIONS: This study has identified various pro-inflammatory cytokines and interferon-related genes such as MX1, viperin, CXCL10, CCL8, RANTES, KC, MCP1, IL8, GM-CSF and IFNγ in FCoV-positive cats. With the exception of MX1 and viperin, no distinct pattern of immune mediators was observed that distinguished between FCoV-positive cats with and without peritoneal effusion. Further studies based on definitive diagnosis of FIP need to be performed to confirm the clinical importance of this study.


More genes versus environment


Human rights and global health emergencies preparedness


title: A pandemic influenza modeling and visualization tool

text: Abstract The National Strategy for Pandemic Influenza outlines a plan for community response to a potential pandemic. In this outline, state and local communities are charged with enhancing their preparedness. In order to help public health officials better understand these charges, we have developed a visual analytics toolkit (PanViz) for analyzing the effect of decision measures implemented during a simulated pandemic influenza scenario. Spread vectors based on the point of origin and distance traveled over time are calculated and the factors of age distribution and population density are taken into effect. Healthcare officials are able to explore the effects of the pandemic on the population through a geographical spatiotemporal view, moving forward and backward through time and inserting decision points at various days to determine the impact. Linked statistical displays are also shown, providing county level summaries of data in terms of the number of sick, hospitalized and dead as a result of the outbreak. Currently, this tool has been deployed in Indiana State Department of Health planning and preparedness exercises, and as an educational tool for demonstrating the impact of social distancing strategies during the recent H1N1 (swine flu) outbreak.


title: The design and application of DNA chips for early detection of SARS-CoV from clinical samples

text: Abstract Background: SARS coronavirus has been identified as the cause of severe acute respiratory syndrome (SARS). Few tests allow confirmation or exclusion of SARS within the first few days of infection. A gene chip is a useful tool for the study of microbial infections mainly for its capability of performing multi-target analysis in a single test. Objectives: Investigate the possibility of early detection of SARS virus from clinical samples using the gene chip-based method. Study design: We purified RNA from SARS-CoV obtained from routinely collected peripheral blood and sputum samples of 34 patients who had been identified as probable SARS patients by following the interim U.S. case definition. Four segments of the SARS-CoV were amplified using reverse transcription-nested PCR and the products examined using the 70-mer gene chips for SARS-CoV detection. Results: A blind-test of both peripheral blood and sputum specimens lead to the positive detection of SARS-CoV in 31 out of 34 patients. SARS-CoV was not found in peripheral blood or sputum specimens from three patients. Two of the 34 patients were only 3 days post-onset of symptoms and were subsequently confirmed to be SARS positive. Our results indicate that the gene chip-based molecular test is specific for SARS-CoV and allows early detection of patients with SARS with detection rate about 8% higher than the single PCR test when the sputum sample is available.


title: Severe acute respiratory syndrome from the trenches, at a Singapore university hospital

text: Summary The epidemiology and virology of severe acute respiratory syndrome (SARS) have been written about many times and several guidelines on the infection control and public health measures believed necessary to control the spread of the virus have been published. However, there have been few reports of the problems that infectious disease clinicians encounter when dealing with the protean manifestations of this pathogen. This is a qualitative account of some of the issues faced by an infectious disease physician when identifying and treating patients with SARS as well as protecting other healthcare workers and patients, including: identification of the chain of contagion, early recognition of the disease in the absence of a reliable and rapid diagnostic test, appropriate use of personal protective equipment, and the use of isolation to prevent super-spreading events. Many issues need to be addressed if clinicians are to be able to manage the virus should it reappear.


title: Can Bats Serve as Reservoirs for Arboviruses?

text: Bats are known to harbor and transmit many emerging and re-emerging viruses, many of which are extremely pathogenic in humans but do not cause overt pathology in their bat reservoir hosts: henipaviruses (Nipah and Hendra), filoviruses (Ebola and Marburg), and coronaviruses (SARS-CoV and MERS-CoV). Direct transmission cycles are often implicated in these outbreaks, with virus shed in bat feces, urine, and saliva. An additional mode of virus transmission between bats and humans requiring further exploration is the spread of disease via arthropod vectors. Despite the shared ecological niches that bats fill with many hematophagous arthropods (e.g., mosquitoes, ticks, biting midges, etc.) known to play a role in the transmission of medically important arboviruses, knowledge surrounding the potential for bats to act as reservoirs for arboviruses is limited. To this end, a comprehensive literature review was undertaken examining the current understanding and potential for bats to act as reservoirs for viruses transmitted by blood-feeding arthropods. Serosurveillance and viral isolation from either free-ranging or captive bats are described in relation to four arboviral groups (Bunyavirales, Flaviviridae, Reoviridae, Togaviridae). Further, ecological associations between bats and hematophagous viral vectors are characterized (e.g., bat bloodmeals in mosquitoes, ingestion of mosquitoes by bats, etc). Lastly, knowledge gaps related to hematophagous ectoparasites (bat bugs and bed bugs (Cimicidae) and bat flies (Nycteribiidae and Streblidae)), in addition to future directions for characterization of bat-vector-virus relationships are described.


Convert to open: the new paradigm for surgery during COVID‐19?


Editorial Commentary: Plethora of Respiratory Viruses and Respiratory Virus Data


title: 1-[2-(2-Benzoyl- and 2-benzylphenoxy)ethyl]uracils as potent anti-HIV-1 agents

text: Abstract Non-nucleoside reverse transcriptase inhibitors (NNRTI) are key components in highly active antiretroviral therapy for treating HIV-1. Herein we present the synthesis for a series of N1-alkylated uracil derivatives bearing ω-(2-benzyl- and 2-benzoylphenoxy)alkyl substituents as novel NNRTIs. These compounds displayed anti-HIV activity similar to that of nevirapine and several of them exhibited activity against the K103N/Y181C RT mutant HIV-1 strain. Further evaluation revealed that the inhibitors were active against most nevirapine-resistant mono- and di-substituted RTs with the exception of the V106A RT. Thus, the candidate compounds can be regarded as potential lead compounds against the wild-type virus and drug-resistant forms.


title: Should cyclosporine be useful in renal transplant recipients affected by SARS‐CoV‐2?

text: Minimization of immunosuppression and administration of antiretrovirals have been recommended for kidney transplant recipients (KTRs) with COVID‐19. However, outcomes remain poor. Given the likely benefit of cyclosporine due to its antiviral and immunomodulatory effect, we have been using it as a strategy in KTRs diagnosed with SARS‐CoV‐2. We studied 29 kidney transplant recipients (KTRs) who were admitted to our institution with COVID‐19 between March,15‐ April, 24(th), 2020. Mycophenolate and/or mTORi were discontinued in all patients. Two therapeutic strategies were compared: Group 1) minimization of calcineurin inhibitors (N=6); Group 2) cyclosporine‐based therapy (N=23), with 15 patients switched from tacrolimus. Hydroxychloroquine was considered in both strategies but antivirals in none. Six patients died after a respiratory distress (20.6%). Five required mechanical ventilation (17.2 %), and three could be weaned. Nineteen patients had an uneventful recovery (65.5%). In group 1, 3/6 patients died (50%) and 1/6 required invasive mechanical ventilation (IVM) (16.7%). In group 2, three patients died 3/23 (12.5%). Renal function did not deteriorate and signs of rejection were not observed in any patient on the second treatment regime. In conclusion, immunosuppressant treatment based on cyclosporine could be safe and effective for KTRs diagnosed with COVID‐19.


title: Researching the Future of Purchasing and Supply Management: The purpose and potential of scenarios

text: ABSTRACT Drawing on prior research, the value of scenario planning as a methodology for future research on the future of purchasing and supply management (PSM) is explored. Using three criteria of research quality – rigour, originality and significance – it is shown how developing scenarios and analysing their implications present new, important research opportunities for PSM academics, practitioners, and leaders of the profession. Researching the future of PSM supports the identification of uncertainties and anticipates change across many units and levels of analysis of interest to PSM scholars and practitioners, such as the profession/discipline, markets/sectors, or organizations. Scenarios are particularly effective for: considering how the complex interaction of macro-environmental factors affects the PSM context; avoiding incremental thinking; surfacing assumptions and revealing significant blind spots. PSM research using scenarios aligns with Corley and Gioia’s (2011) call for prescience-oriented research in which academics aim for more impactful research, enhancing sense-giving potential and theoretical relevance to practice to better perform their adaptive role in society.


Prevalence of antibodies against the Middle East Respiratory Syndrome coronavirus, influenza A and B viruses among blood donors, Saudi Arabia


title: Evaluation of the sentinel surveillance system for influenza-like illnesses in the Greater Accra region, Ghana, 2018

text: BACKGROUND: Influenza-like Illness (ILI) is a medical diagnosis of possible influenza or another respiratory illness with a common set of symptoms. The deaths of four schoolchildren, during a pandemic influenza outbreak in December 2017 in Ghana, raised doubts about the ILI surveillance system’s performance. We evaluated the ILI surveillance system in the Greater Accra region, Ghana, to assess the system’s attributes and its performance on set objectives. METHODS: CDC guidelines were used to evaluate the data of the ILI surveillance system between 2013 and 2017. We interviewed the surveillance personnel on the system’s description and operation. Additionally, routinely entered ILI data from the National Influenza Center provided by the six sentinel sites in Accra was extracted. We sampled and reviewed 120 ILI case-investigation forms from these sites. Surveillance activities were examined on system’s performance indicators, each being scored on a scale of 1 to 3 (poorest to best performance). RESULTS: All population and age groups were under ILI surveillance over the period evaluated. Overall, 2948 suspected case-patients, including 392 (13.3%) children under-five were reported, with 219 being positive for influenza virus (Predictive value positive = 7.4%). The predominant influenza subtype was H3N2, recorded in 90 (41.1%) of positive case-patients. The system only met two out of its four objectives. None of the six sentinel sites consistently met their annual 260 suspected case-detection quota. Samples reached the laboratory on average 48 hours after collection and results were disseminated within 7 days. Of 120 case-investigation forms sampled, 91 (76.3%) were completely filled in. CONCLUSIONS: The ILI surveillance system in the Greater Accra region is only partially meeting its objectives. While it is found to be sensitive, representative and timely, the data quality was sub-optimal. We recommend the determination of thresholds for alert and outbreak detection and ensuring that sentinel sites meet their weekly case-detection targets.


title: The intracellular sites of early replication and budding of SARS-coronavirus

text: Abstract In this study, we analyzed the replication and budding sites of severe acute respiratory syndrome coronavirus (SARS-CoV) at early time points of infection. We detected cytoplasmic accumulations containing the viral nucleocapsid protein, viral RNA and the non-structural protein nsp3. Using EM techniques, we found that these putative viral replication sites were associated with characteristic membrane tubules and double membrane vesicles that most probably originated from ER cisternae. In addition to its presence at the replication sites, N also accumulated in the Golgi region and colocalized with the viral spike protein. Immuno-EM revealed that budding occurred at membranes of the ERGIC (ER–Golgi intermediate compartment) and the Golgi region as early as 3 h post infection, demonstrating that SARS-CoV replicates surprisingly fast. Our data suggest that SARS-CoV establishes replication complexes at ER-derived membranes. Later on, viral nucleocapsids have to be transported to the budding sites in the Golgi region where the viral glycoproteins accumulate and particle formation occurs.


title: Coinfection of avian influenza virus (H9N2 subtype) with infectious bronchitis live vaccine

text: Avian influenza virus of H9N2 subtype is pathotyped as a non-highly pathogenic virus. However, frequent incidences of avian influenza of high mortality that are caused by H9N2 viruses have been observed in broiler chicken farms in Iran and some other Asian countries. Coinfections or environmental factors may be involved in such cases. Infectious microorganisms have been implicating in taking part in the cases of coinfection. We studied the effect of experimental coinfection of H9N2 avian influenza virus with infectious bronchitis live vaccine, which is used extensively in chicken farms in Iran. Clinical signs, gross lesions, viral shedding and mortality rate of the experimentally infected birds were examined. Coinfection of infectious bronchitis live vaccine and H9N2 avian influenza virus led to an extension of the shedding period of H9N2 virus, increasing the severity of clinical signs and mortality rates, causing macroscopic lesions in the embryos.


title: Les effets de confinement SARS-CoV-2 sur le sommeil: enquête en ligne au cours de la quatrième semaine de confinement

text: Abstract Objectives: Explore the evolution of sleep during the SARS-CoV-2 quarantine period and define associated factors. Methods: an online survey of patients in quarantine. Questions targeted the conditions of quarantine, sleep related behaviours and exposure to factors known to affect sleep and circadian rhythms (light exposure and sport). Results: 1 777 participants were included: 77% women and 72 % aged 25-54 years. Quarantine conditions were most frequently in couples with children (36 %) and in a house with a garden (51 %). 47 % of participants reported a decrease in sleep quality during quarantine. Factors associated with a reduction in sleep quality by logistic regression were sleep reduction (OR 15.52 p<0.001), going to bed later (OR 1.72 p<0.001), getting up earlier (2.18 p=0.01), an increase in sleep-wake irregularity (OR 2.29 p<0.001), reduced exposure to daylight (OR 1.46 p=0.01) and increased screen use in the evenings (OR 1.33 p=0.04). Conclusion: Sleep quality tended to reduce during quarantine and this was associated with changes in sleep behaviours and light exposure, especially in the evening. In order to optimise sleep during quarantine, regular sleep and wake times, at least 1 hour exposure to daylight and a reduction of screen use in the evenings are suggested.


title: Hepatitis E virus infection during pregnancy

text: BACKGROUND: Hepatitis E virus (HEV) generally causes self-limiting viral hepatitis. However, in pregnant women, HEV infection can be severe and has been associated with up to 30% mortality in the third trimester. Additionally, HEV infection in pregnancy is also associated with high rates of preterm labor and vertical transmission. MAIN BODY: HEV is now recognized as a global health problem in both developing and industrialized countries. HEV can be transmitted via the fecal-oral route, zoonotic route, and blood transfusion route. An altered immune status, hormonal levels, and viral factors may be related to the severity of the disease. Currently, no established treatment is available for HEV in pregnant women. A Chinese vaccine has been demonstrated to be protective against HEV in the general population and seems to be safe in pregnancy; however, its safety and efficacy in a large population of pregnant women remain to be determined. CONCLUSION: This review summarizes the current knowledge about HEV infection during pregnancy and focuses on the epidemiology, clinical manifestations, mechanisms underlying severe liver injury, and management and prevention of HEV infection during pregnancy. Considering that HEV infection during pregnancy may result in poor outcomes, screening for and monitoring HEV infection early in pregnancy should be taken into account. In addition, a better understanding of the pathogenesis will help to develop potential treatment strategies targeting HEV infection in pregnancy.


title: Detection of substantial porcine group B rotavirus genetic diversity in the United States, resulting in a modified classification proposal for G genotypes

text: Abstract Rotavirus (RV) is an important cause of gastrointestinal disease in animals and humans. In this study, we developed an RT-PCR to detect RV group B (RVB) and characterized the VP7 (G) gene segment detected in porcine samples. One hundred seventy three samples were tested for RV group A (RVA), RVB, and C (RVC) by RT-PCR and examined for RV-like lesion using histopathology. A majority (86.4%) of the samples had mixed RV infections and co-infections of RVA/RVB/RVC were detected at a higher rate (24.3%) than previously reported. RVB was identified in 46.8% of the 173 samples. An adapted VP7 classification was developed using previously published (n=57) and newly sequenced (n=68) RVB strains, resulting in 20 G genotypes based on an 80% nucleotide identity cutoff value. Our results revealed a broad genetic diversity of porcine RVB strains, suggesting RVB has been the cause of common/pre-existing, yet undiagnosed, disease in pigs.


title: Conservation of pregnancy-specific glycoprotein (PSG) N domains following independent expansions of the gene families in rodents and primates

text: BACKGROUND: Rodent and primate pregnancy-specific glycoprotein (PSG) gene families have expanded independently from a common ancestor and are expressed virtually exclusively in placental trophoblasts. However, within each species, it is unknown whether multiple paralogs have been selected for diversification of function, or for increased dosage of monofunctional PSG. We analysed the evolution of the mouse PSG sequences, and compared them to rat, human and baboon PSGs to attempt to understand the evolution of this complex gene family. RESULTS: Phylogenetic tree analyses indicate that the primate N domains and the rodent N1 domains exhibit a higher degree of conservation than that observed in a comparison of the mouse N1 and N2 domains, or mouse N1 and N3 domains. Compared to human and baboon PSG N domain exons, mouse and rat PSG N domain exons have undergone less sequence homogenisation. The high non-synonymous substitution rates observed in the CFG face of the mouse N1 domain, within a context of overall conservation, suggests divergence of function of mouse PSGs. The rat PSG family appears to have undergone less expansion than the mouse, exhibits lower divergence rates and increased sequence homogenisation in the CFG face of the N1 domain. In contrast to most primate PSG N domains, rodent PSG N1 domains do not contain an RGD tri-peptide motif, but do contain RGD-like sequences, which are not conserved in rodent N2 and N3 domains. CONCLUSION: Relative conservation of primate N domains and rodent N1 domains suggests that, despite independent gene family expansions and structural diversification, mouse and human PSGs retain conserved functions. Human PSG gene family expansion and homogenisation suggests that evolution occurred in a concerted manner that maintains similar functions of PSGs, whilst increasing gene dosage of the family as a whole. In the mouse, gene family expansion, coupled with local diversification of the CFG face, suggests selection both for increased gene dosage and diversification of function. Partial conservation of RGD and RGD-like tri-peptides in primate and rodent N and N1 domains, respectively, supports a role for these motifs in PSG function.


title: N-Linked glycosylation of the membrane protein ectodomain regulates infectious bronchitis virus-induced ER stress response, apoptosis and pathogenesis

text: Abstract Coronavirus membrane (M) protein is the most abundant structural protein playing a critical role in virion assembly. Previous studies show that the N-terminal ectodomain of M protein is modified by glycosylation, but its precise functions are yet to be thoroughly investigated. In this study, we confirm that N-linked glycosylation occurs at two predicted sites in the M protein ectodomain of infectious bronchitis coronavirus (IBV). Dual mutations at the two sites (N3D/N6D) did not affect particle assembly, virus-like particle formation and viral replication in culture cells. However, activation of the ER stress response was significantly reduced in cells infected with rN3D/N6D, correlated with a lower level of apoptosis and reduced production of pro-inflammatory cytokines. Taken together, this study demonstrates that although not essential for replication, glycosylation in the IBV M protein ectodomain plays important roles in activating ER stress, apoptosis and proinflammatory response, and may contribute to the pathogenesis of IBV.


title: SARS: clinical features and diagnosis

text: Severe acute respiratory syndrome (SARS) is a highly infectious disease with a significant morbidity and case fatality. The major clinical features include persistent fever, chills/rigor, myalgia, malaise, dry cough, headache and dyspnoea. Less common symptoms include sputum production, sore throat, coryza, dizziness, nausea, vomiting and diarrhoea. Older subjects may present with decrease in general well‐being, poor feeding, fall/fracture and delirium, without the typical febrile response. Common laboratory features include lymphopenia with depletion of CD4 and CD8 lymphocytes, thrombocytopenia, prolonged activated partial thromboplastin time, elevated D‐Dimer, elevated alanine transminases, lactate dehydrogenase and creatinine kinase. The constellation of compatible clinical and laboratory findings, together with the rather characteristic radiological features especially on HRCT and the lack of clinical response to broad‐spectrum antibiotics, should quickly arouse suspicion of SARS. The positivity rates of urine, nasophargyngeal aspirate and stool specimen have been reported to be 42%, 68% and 97%, respectively, on day 14 of illness, whereas serology for confirmation may take 28 days to reach a detection rate above 90%. Recently, quantitative measurement of blood SARS CoV RNA with real‐time RT‐PCR technique has been developed with a detection rate of 80% as early as day 1 of hospital admission but the detection rates drop to 75% and 42% on day 7 and day 14, respectively.


title: Correlates of Viral Richness in Bats (Order Chiroptera)

text: Historic and contemporary host ecology and evolutionary dynamics have profound impacts on viral diversity, virulence, and associated disease emergence. Bats have been recognized as reservoirs for several emerging viral pathogens, and are unique among mammals in their vagility, potential for long-distance dispersal, and often very large, colonial populations. We investigate the relative influences of host ecology and population genetic structure for predictions of viral richness in relevant reservoir species. We test the hypothesis that host geographic range area, distribution, population genetic structure, migratory behavior, International Union for Conservation of Nature and Natural Resources (IUCN) threat status, body mass, and colony size, are associated with known viral richness in bats. We analyze host traits and viral richness in a generalized linear regression model framework, and include a correction for sampling effort and phylogeny. We find evidence that sampling effort, IUCN status, and population genetic structure correlate with observed viral species richness in bats, and that these associations are independent of phylogeny. This study is an important first step in understanding the mechanisms that promote viral richness in reservoir species, and may aid in predicting the emergence of viral zoonoses from bats.


title: Recent advances in the chemistry of imine-based multicomponent reactions (MCRs)

text: [Figure: see text]


Impact of COVID-19 on Madrid hospital system


Communication with Healthcare Workers Regarding Healthcare Associated Exposure to Coronavirus 2019: A Checklist to Facilitate Disclosure


Coronavirus JHM induced demyelinating encephalomyelitis in rats: Analysis of the intrathecal immune response


title: Covid-19 and cardiovascular risk: susceptibility to infection to SARS-CoV-2, severity and prognosis of Covid-19 and blockade of the renin-angiotensin-aldosterone system. An evidence-based viewpoint

text: Abstract The presence of cardiovascular co-morbidities and the known effects of coronaviruses on the cardiovascular system have called attention to the potential implications for patients with cardiovascular risk factors. This evidence-based viewpoint will address two questions: (a) are individuals with underlying cardiovascular risk factors (e.g. high blood pressure or diabetes) or overt disease (e.g. coronary heart disease, heart failure, kidney disease) more likely to develop severe Covid-19 and to die than those without underlying conditions? (b) does the regular use of angiotensin-converting enzyme inhibitors (ACE-i) or angiotensin-receptor blockers (ARB) make patients more likely to get infected and to die of Covid-19? With a necessary cautionary note that the evidence around the links between Covid-19 and cardiovascular disease is accruing at a fast pace, to date we can conclude that: (a) the greater susceptibility of individuals with underlying cardiovascular conditions to develop more severe Covid-19 with higher mortality rate is likely to be confounded, in part, by age and the type of co-morbidities. Patients with heart failure or chronic kidney disease might show an excess risk; (b) neither ACE-i nor ARB are associated with greater risk of SARS-Cov2 infection, or severity or risk of death in patients with Covid-19. Patients on these drugs should not stop them, unless under strict medical supervision and with the addition of a suitable replacement medicine.


title: Type I interferon and HIV: Subtle balance between antiviral activity, immunopathogenesis and the microbiome

text: Abstract Type I interferon (IFN) response initially limits HIV-1 spread and may delay disease progression by stimulating several immune system components. Nonetheless, persistent exposure to type I IFN in the chronic phase of HIV-1 infection is associated with desensitization and/or detrimental immune activation, thereby hindering immune recovery and fostering viral persistence. This review provides a basis for understanding the complexity and function of IFN pleiotropic activity in HIV-1 infection. In particular, the dichotomous role of the IFN response in HIV-1 immunopathogenesis will be discussed, highlighting recent advances in the dynamic modulation of IFN production in acute versus chronic infection, expression signatures of IFN subtypes, and viral and host factors affecting the magnitude of IFN response during HIV-1 infection. Lastly, the review gives a forward-looking perspective on the interplay between microbiome compositions and IFN response.


title: A novel bat coronavirus closely related to SARS-CoV-2 contains natural insertions at the S1/S2 cleavage site of the spike protein

text: Summary The unprecedented pandemic of pneumonia caused by a novel coronavirus, SARS-CoV-2, in China and beyond has had major public health impacts on a global scale [1,2]. Although bats are regarded as the most likely natural hosts for SARS-CoV-2 [3], the origins of the virus remain unclear. Here, we report a novel bat-derived coronavirus, denoted RmYN02, identified from a metagenomics analysis of samples from 227 bats collected from Yunnan Province in China between May and October, 2019. Notably, RmYN02 shares 93.3% nucleotide identity with SARS-CoV-2 at the scale of the complete virus genome and 97.2% identity in the 1ab gene, in which it is the closest relative of SARS-CoV-2 reported to date. In contrast, RmYN02 showed low sequence identity (61.3%) to SARS-CoV-2 in the receptor binding domain (RBD) and might not bind to angiotensin-converting enzyme 2 (ACE2). Critically, and in a similar manner to SARS-CoV-2, RmYN02 was characterized by the insertion of multiple amino acids at the junction site of the S1 and S2 subunits of the spike (S) protein. This provides strong evidence that such insertion events can occur naturally in animal betacoronaviruses.