title: Considerations for an Individual-Level Population Notification System for Pandemic Response: A Review and Prototype

text: The outbreak of the coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, spread worldwide after its emergence in China. Whether rich or poor, all nations are struggling to cope with this new global health crisis. The speed of the threat’s emergence and the quick response required from public health authorities and the public itself makes evident the need for a major reform in pandemic surveillance and notification systems. The development and implementation of a graded, individual-level pandemic notification system could be an effective tool to combat future threats of epidemics. This paper describes a prototype model of such a notification system and its potential advantages and challenges for implementation. Similar to other emergency alerts, this system would include a number of threat levels (level 1-5) with a higher level indicating increasing severity and intensity of safety measures (eg, level 1: general hygiene, level 2: enhanced hygiene, level 3: physical distancing, level 4: shelter in place, and level 5: lockdown). The notifications would be transmitted to cellular devices via text message (for lower threat levels) or push notification (for higher threat levels). The notification system would allow the public to be informed about the threat level in real time and act accordingly in an organized manner. New Zealand and the United Kingdom have recently launched similar alert systems designed to coordinate the ongoing COVID-19 pandemic response more efficiently. Implementing such a system, however, faces multiple challenges. Extensive preparation and coordination among all levels of government and relevant sectors are required. Additionally, such systems may be effective primarily in countries where there exists at least moderate trust in government. Advance and ongoing public education about the nature of the system and its steps would be an essential part of the system, such that all members of the public understand the meaning of each step in advance, similar to what has been established in systems for other emergency responses. This educational component is of utmost importance to minimize adverse public reaction and unintended consequences. The use of mass media and local communities could be considered where mobile phone penetration is low. The implementation of such a notification system would be more challenging in developing countries for several reasons, including inadequate technology, limited use of data plans, high population density, poverty, mistrust in government, and tendency to ignore or failure to understand the warning messages. Despite the challenges, an individual-level pandemic notification system could provide added benefits by giving an additional route for notification that would be complementary to existing platforms.


Risk Perceptions and Behaviour: Towards Pandemic Control of Emerging Infectious Diseases: International Research on Risk Perception in the Control of Emerging Infectious Diseases


ECHOCARDIOGRAPHY DURING PRONE POSITION MECHANICAL VENTILATION IN COVID-19 PATIENTS: A PROPOSAL FOR A NEW APPROACH


title: The Role of the Adeno-Associated Virus Capsid in Gene Transfer

text: Adeno-associated virus (AAV) is one of the most promising viral gene transfer vectors that has been shown to effect long-term gene expression and disease correction with low toxicity in animal models, and is well tolerated in human clinical trials. The surface of the AAV capsid is an essential component that is involved in cell binding, internalization, and trafficking within the targeted cell. Prior to developing a gene therapy strategy that utilizes AAV, the serotype should be carefully considered since each capsid exhibits a unique tissue tropism and transduction efficiency. Several approaches have been undertaken in an effort to target AAV vectors to specific cell types, including utilizing natural serotypes that target a desired cellular receptor, producing pseudotyped vectors, and engineering chimeric and mosaic AAV capsids. These capsid modifications are being incorporated into vector production and purification methods that provide for the ability to scale-up the manufacturing process to support human clinical trials. Protocols for small-scale and large-scale production of AAV, as well as assays to characterize the final vector product, are presented here. The structures of AAV2, AAV4, and AAV5 have been solved by X-ray crystallography or cryo-electron microscopy (cryo-EM), and provide a basis for rational vector design in developing customized capsids for specific targeting of AAV vectors. The capsid of AAV has been shown to be remarkably stable, which is a desirable characteristic for a gene therapy vector; however, recently it has been shown that the AAV serotypes exhibit differential susceptibility to proteases. The capsid fragmentation pattern when exposed to various proteases, as well as the susceptibility of the serotypes to a series of proteases, provides a unique fingerprint for each serotype that can be used for capsid identity validation. In addition to serotype identification, protease susceptibility can also be utilized to study dynamic structural changes that must occur for the AAV capsid to perform its various functions during the virus life cycle. The use of proteases for structural studies in solution complements the crystal structural studies of the virus. A generic protocol based on proteolysis for AAV serotype identification is provided here.


title: Epidemiology of respiratory viral infections in children enrolled in a study of influenza vaccine effectiveness

text: BACKGROUND: Influenza-like illness (ILI) confers a high annual morbidity in young children. We report the epidemiology of ILIs in children who participated in an influenza vaccine effectiveness study during the 2010 Southern Hemisphere influenza season in Sydney, Australia. METHODS: Children aged 0·5–3 years were prospectively recruited from child care centres (CCCs). We classified them as fully vaccinated, partially vaccinated and unvaccinated according to their receipt of unadjuvanted vaccines containing influenza A (H1N1)pdm09. For 13 weeks commencing 30 July 2010, parents reported when their children developed an ILI (fever ≥37·8°C/feverishness plus ≥1 respiratory symptom) and collected nose and/or throat swabs for multiplex respiratory virus polymerase chain reaction (PCR) testing. Health impacts were assessed by telephone interview at enrolment and two weeks after each ILI. RESULTS: There were 124 ILIs reported in 105 of 381 enrolled children. Swabs were taken in 117 ILIs: 175 viruses were identified from 103 swabs. Adeno- and rhinoviruses were most frequently identified; 44% of swabs yielded multiple viruses. No virus was associated with more severe symptoms, although rhinovirus-related ILIs lasted longer. Nose swabs had a higher virus detection rate than throat swabs. Influenza-vaccinated children were 1·6 times (P = 0·001) more likely than unvaccinated children to have a non-influenza ILI. CONCLUSION: Adeno- and rhinoviruses were the most common viruses causing ILI. Swabs taken by parents are an effective method for sample collection. Influenza-like illness was more common in children vaccinated against influenza in this observational study, but prior health-seeking behaviour may have contributed to this difference.


title: Extension of the known distribution of a novel clade C betacoronavirus in a wildlife host

text: Disease surveillance in wildlife populations presents a logistical challenge, yet is critical in gaining a deeper understanding of the presence and impact of wildlife pathogens. Erinaceus coronavirus (EriCoV), a clade C Betacoronavirus, was first described in Western European hedgehogs (Erinaceus europaeus) in Germany. Here, our objective was to determine whether EriCoV is present, and if it is associated with disease, in Great Britain (GB). An EriCoV-specific BRYT-Green(®) real-time reverse transcription PCR assay was used to test 351 samples of faeces or distal large intestinal tract contents collected from casualty or dead hedgehogs from a wide area across GB. Viral RNA was detected in 10.8% (38) samples; however, the virus was not detected in any of the 61 samples tested from Scotland. The full genome sequence of the British EriCoV strain was determined using next generation sequencing; it shared 94% identity with a German EriCoV sequence. Multivariate statistical models using hedgehog case history data, faecal specimen descriptions and post-mortem examination findings found no significant associations indicative of disease associated with EriCoV in hedgehogs. These findings indicate that the Western European hedgehog is a reservoir host of EriCoV in the absence of apparent disease.


title: Peroral immunotheraphy with yolk antibodies for the prevention and treatment of enteric infections

text: Oral administration of specific antibodies is an attractive approach to establish protective immunity against gastrointestinal pathogens in humans and animals. The increasing number of antibiotic-resistant bacteria emphasize the need to find alternatives to antibiotics. Immunotherapy can also be used against pathogens that are difficult to treat with traditional antibiotics. Laying hens are very good producers of specific antibodies. After immunization, the specific antibodies are transported to the egg yolk from which the antibodies then can be purified. A laying hen produces more than 20 g of yolk antibodies (IgY) per year. These antibodies also have biochemical properties that make them attractive for peroral immunotherapy: They neither activate mammalian complement nor interact with mammalian Fc receptors that could mediate inflammatory response in the gastrointestinal tract. Eggs are also normal dietary components and thus there is practically no risk of toxic side effects of IgY. Yolk antibodies have been shown in several studies to prevent bacterial and viral infections.


title: Twenty Years of Active Bacterial Core Surveillance

text: Active Bacterial Core surveillance (ABCs) was established in 1995 as part of the Centers for Disease Control and Prevention Emerging Infections Program (EIP) network to assess the extent of invasive bacterial infections of public health importance. ABCs is distinctive among surveillance systems because of its large, population-based, geographically diverse catchment area; active laboratory-based identification of cases to ensure complete case capture; detailed collection of epidemiologic information paired with laboratory isolates; infrastructure that allows for more in-depth investigations; and sustained commitment of public health, academic, and clinical partners to maintain the system. ABCs has directly affected public health policies and practices through the development and evaluation of vaccines and other prevention strategies, the monitoring of antimicrobial drug resistance, and the response to public health emergencies and other emerging infections.


Re: Ming-Chun Chan, Sharon E.K. Yeo, Yew-Lam Chong, Yee-Mun Lee. Stepping Forward: Urologists’ Efforts During the COVID-19 Outbreak in Singapore. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2020.03.004


title: Sequence analysis of a reovirus isolated from the winter moth Operophtera brumata (Lepidoptera: Geometridae) and its parasitoid wasp Phobocampe tempestiva (Hymenoptera: Ichneumonidae)

text: Abstract A reovirus was isolated from Operophtera brumata (ObRV) and its parasitoid wasp Phobocampe tempestiva. Each of the 10 dsRNA genome segments of ObRV was sequenced and shown to contain a single open reading frame (ORF). Conserved motifs ([+ve] 5′-AAATAAA … G/TAGGTT-3′) were found at the termini of each segment, with the exception of Seg-6 and Seg-8, where the 5′ termini were 5′-AACAAA…-3′. The putative proteins encoded by each segment were compared with those of other members of the family Reoviridae. Phylogenetic comparisons to published sequences for the RNA-dependent RNA polymerase genes from other reoviruses indicated that ObRV is most closely related to members of the genus Cypovirus. However, unlike the cypoviruses, ObRV has a double-layered capsid structure. When the protein encoded by ObRV Seg-10 was expressed (by inserting the open reading frame into a baculovirus expression vector) no ‘occlusion bodies’ were observed in the recombinant baculovirus infected insect cell cultures. This suggests that unlike the cypoviruses, Seg-10 of ObRV does not contain a polyhedrin gene. Further phylogenetic comparisons also identified relationships between Seg-2 and Seg-10 of ObRV, and genes of Diadromus pulchellus Idnoreovirus 1 (DpIRV1), suggesting that ObRV represents a new species from the genus Idnoreovirus.


title: Facing the Next Pandemic: Ready or Not

text: Abstract Influenza pandemics generally occur at 30-40 year intervals and it has been nearly 40 years since the last one. A global pandemic will result in devastating social, economical, and health consequences. Preparedness is crucial to minimize the threat to hematopoietic stem cell transplant (HSCT) patients. Vaccines, antivirals, and infection control measures are important elements of prevention. Antivirals, often given presumptively, are the mainstay of therapy.


title: Crimean-Congo haemorrhagic fever in travellers: A systematic review

text: Summary Background The recent Ebola epidemic has increased public awareness of the risk of travel associated viral haemorrhagic fever (VHF). International preparedness to manage imported cases Ebola virus infection was inadequate, highlighted by cases of nosocomial transmission. Crimean-Congo haemorrhagic fever (CCHF) is a re-emerging tick-borne VHF centred in the Eurasian region, affecting a large geographical area and with human-to-human transmission reported, especially in the healthcare setting. Objectives To systematically review the characteristics of travel associated Crimean-Congo haemorrhagic fever. Methods A systematic review of travel-associated cases of CCHF was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement protocol. PubMed, SCOPUS, Science Citation Index (SCI) and ProMED databases were searched for reports published between January 1960 and January 2016. Three independent reviewers selected and reviewed studies and extracted data. Results 21 cases of travel associated CCHF were identified, of which 12 died (3 outcome unknown) and 4 secondary (nosocomial) infections were reported. Risk occupations or activities for CCHF infection were reported in 8/12 cases when data were available. Travel from Asia to Asia occurred in 9 cases, Africa to Africa occurred in 5 cases, Africa to Europe in 3 cases, Asia to Europe in 2 cases and Europe to Europe in 2 cases. Conclusion CCHF related to travel is rare, is generally associated with at risk activities/occupation and is frequently fatal. Key to early diagnosis and prevention of nosocomial transmission is an understanding of CCHF risk factors and the geographical distribution of CCHF. International travel to CCHF endemic areas is increasing and clinicians and laboratory personnel managing returning travellers should maintain a high index of suspicion.


title: COVID‐19: A global transplant perspective on successfully navigating a pandemic

text: The COVID‐19 pandemic has rapidly evolved and changed our way of life in an unprecedented manner. The emergence of COVID‐19 has impacted transplantation worldwide. The impact has not been just restricted to issues pertaining to donors or recipients, but also health‐care resource utilization as the intensity of cases in certain jurisdictions exceeds available capacity. Here we provide a personal viewpoint representing different jurisdictions from around the world in order to outline the impact of the current COVID‐19 pandemic on organ transplantation. Based on our collective experience, we discuss mitigation strategies such as donor screening, resource planning, and a staged approach to transplant volume considerations as local resource issues demand. We also discuss issues related to transplant‐related research during the pandemic, the role of transplant infectious diseases, and the influence of transplant societies for education and disseminating current information.


title: Construction of Simple and Efficient siRNA Validation Systems for Screening and Identification of Effective RNAi-Targeted Sequences from Mammalian Genes

text: RNA interference (RNAi) is an evolutionarily conserved mechanism of gene silencing induced by double-stranded RNAs (dsRNAs). Among the widely used dsRNAs, small interfering RNAs (siRNAs) and short hairpin RNAs have evolved as extremely powerful and the most popular gene silencing reagents. The key challenge to achieving efficient gene silencing especially for the purpose of therapeutics is mainly dependent on the effectiveness and specificity of the selected RNAi-targeted sequences. Practically, only a small number of dsRNAs are capable of inducing highly effective and sequence-specific gene silencing via RNAi mechanism. In addition, the efficiency of gene silencing induced by dsRNAs can only be experimentally examined based on inhibition of the target gene expression. Therefore, it is essential to develop a fully robust and comparative validation system for measuring the efficacy of designed dsRNAs. In this chapter, we focus our discussion on a reliable and quantitative reporter-based siRNA validation system that has been previously established in our laboratory. The system consists of a short synthetic DNA fragment containing an RNAi-targeted sequence of interest and two expression vectors for targeting reporter and triggering siRNA expressions. The efficiency of siRNAs is determined by their abilities to inhibit expression of the targeting reporters with easily quantified readouts including enhanced green fluorescence protein and firefly luciferase. Since only a readily available short synthetic DNA fragment is needed for constructing this reliable and efficient reporter-based siRNA validation system, this system not only provides a powerful strategy for screening highly effective RNAi-targeted sequences from mammalian genes but also implicates the use of RNAi-based dsRNA reagents for reverse functional genomics and molecular therapeutics.


title: Impacts of rapid flu clinic services at an emergency department during the pandemic flu season

text: BACKGROUND: We performed an assessment of an independent rapid flu clinic service (RFCS) unit, which was set up outside the emergency department (ED) during the 2009 H1N1 pandemic season. The unit was able to relieve the crowding of regular ambulatory and emergency services. METHODS: Between August and December 2009, a total of 6,152 patients with influenza-like illness were enrolled in this observational retrospective study. Patients with positive influenza tests were interviewed to evaluate the efficiency of RFCS. RESULTS: The mean length of stay (LOS) for the RFCS was 50 minutes, which was shorter than the LOS for ambulatory services (1 hour) and regular ED services (3.5 hours). Overall, 88% of patients were satisfied with the RFCS. Of 6,152 patients receiving flu tests, 1,235 (20%) had a positive result. Fever (odds ratio [OR], 4.28, 95% confidence interval [CI]: 3.11-5.89), fever combined with cough and sore throat (OR, 2.52; 95% CI: 2.18-2.92), fever combined with sore throat (OR, 2.42; 95% CI: 2.13-2.75), history of contacting confirmed flu patients within 7 days (OR, 2.40; 95% CI: 2.07-2.78), fever combined with cough (OR, 2.19; 95% CI: 1.92-2.47), sore throat (OR, 2.03, 95% CI: 1.79-2.30); and cough (OR, 1.91, 95% CI: 1.69-2.17) were significantly associated with positive influenza tests. CONCLUSION: Setting up the RFSC was beneficial to health care facilities during a pandemic flu season.


title: Childhood community-acquired pneumonia: A review of etiology- and antimicrobial treatment studies

text: Abstract Community acquired pneumonia (CAP) is a leading cause of childhood morbidity worldwide. Because of the rising antimicrobial resistance rates and adverse effects of childhood antibiotic use on the developing microbiome, rational prescribing of antibiotics for CAP is important. This review summarizes and critically reflects on the available evidence for the epidemiology, etiology and antimicrobial management of childhood CAP. Larger prospective studies on antimicrobial management derive mostly from low- or middle-income countries as they have the highest burden of CAP. Optimal antimicrobial management depends on the etiology, age, local vaccination policies and resistance patterns. As long as non-rapid surrogate markers are used to distinguish viral- from bacterial pneumonia, the management is probably suboptimal. For a young child with signs of non-severe pneumonia (with or without wheezing), watchful waiting is recommended because of probable viral etiology. For children with more severe CAP with fever, a five-day oral amoxicillin course would be the first choice therapy and dosage will depend on local resistance rates. There is no clear evidence yet for superiority of a macrolide-based regimen for all ages. For cases with CAP requiring hospitalization, several studies have shown that narrow-spectrum IV beta-lactam therapy is as effective as a broad-spectrum cephalosporin therapy. For most severe disease, broad-spectrum therapy with or without a macrolide is suggested. In case of empyema, rapid IV-to-oral switch seems to be equivalent to prolonged IV treatment.


COVID-19 precautions and recommendations


title: Determining training and education needs pertaining to highly infectious disease preparedness and response: A gap analysis survey of US emergency medical services practitioners

text: BACKGROUND: The Ebola virus disease outbreak highlighted the lack of consistent guidelines and training for workers outside of hospital settings. Specifically, emergency medical services (EMS) workers, who are frequently the first professionals to evaluate patients, often do not have advanced notice of patient diagnosis, and have limited time in their national curricula devoted to highly infectious disease (HID) identification and containment. All of these can place them at increased risk. To explore the depth of US EMS practitioners' HID training and education, a pilot gap analysis survey was distributed to determine where the aforementioned can be bolstered to increase occupational safety. METHODS: Electronic surveys were distributed to EMS organization members. The survey collected respondent willingness to encounter HID scenarios; current policies and procedures; and levels of knowledge, training, and available resources to address HIDs. RESULTS: A total of 2,165 surveys were initiated and collected. Eighty percent of frontline personnel were aware that their agency had an HID standard operating guideline. Almost 85% of respondents correctly marked routes of exposure for select HIDs. More than half of respondents indicated no maximum shift times in personal protective equipment. DISCUSSION: This research suggests EMS practitioners could benefit from enhanced industry-specific education, training, and planning on HID mitigation and management. CONCLUSION: Strengthening EMS preparedness in response to suspected or confirmed HID cases may not only improve patient outcomes, but also worker and community safety.


title: Development of loop-mediated isothermal amplification assay for detection of human coronavirus-NL63

text: Abstract Human coronavirus NL63 was identified in 2004 in the Netherlands. Due to the high prevalence and world-wide distribution of this pathogen, it is essential to develop a sensitive and specific detection assay suitable for use in a routine diagnostic laboratory. Techniques based on PCR or real-time PCR are laborious and expensive. Detailed analysis of the HCoV-NL63 genome permitted the identification of a conserved nucleic acid sequential motif, which was sufficient for the design of a loop-mediated isothermal amplification (LAMP) assay. Evaluation of the method showed that the test is specific to HCoV-NL63 and that it does not cross-react with other respiratory viruses. The detection limit was found to be 1 copy of RNA template per reaction in cell culture supernatants and clinical specimens.


title: COVID-19 and social distancing

text: AIM: COVID-19 has spread rapidly worldwide since it began, greatly affecting peoples' lives, social economies and medical systems. At present, little is known about the disease, and vaccines are still under development. Therefore, in the face of severe outbreaks, previous effective experience can help people better protect themselves and their families. The aim of this article is to discuss the social distancing measures for COVID-19. SUBJECTS AND METHODS: Literature and document search. RESULTS: Recent research and a novel coronavirus pneumonia prediction model revealed social distancing measures and wearing masks are required to mitigate hospital system overload and prevent pathogen exposure. After a series of social distancing measures, there are 309 cities with zero cases and 34 cities with confirmed cases in China as of April 13, 2020. CONCLUSION: From China's experience with novel coronavirus pneumonia, we know that social distancing is the most effective measure at present. We need to win more time to allow limited medical resources to save lives.


title: Identification and Comparison of Receptor Binding Characteristics of the Spike Protein of Two Porcine Epidemic Diarrhea Virus Strains

text: Porcine epidemic diarrhea virus (PEDV), a member of Alphacoronavirus, has caused huge economic losses for the global pork industry recently. The spike (S) protein mediates PEDV entry into host cells. Herein, we investigated the interactions between the S protein and its receptor porcine aminopeptidase N (pAPN) or co-receptor sugars. The C-terminal domain (CTD) of the S1 domain is bound to pAPN. The prototype strain demonstrated similar receptor-binding activity compared with the variant field isolate. Three loops at the tips of the β-barrel domains did not play crucial roles in the PEDV S-pAPN association, indicating that PEDV conforms to a different receptor recognition model compared with transmissible gastroenteritis virus (TGEV), porcine respiratory CoV (PRCV), and human coronavirus NL63 (HCoV-NL63). The N-terminal domain (NTD) of the PEDV S1 domain could bind sugar, a possible co-receptor for PEDV. The prototype strain exhibited weaker sugar-binding activity compared with the variant field isolate. Strategies targeting the receptor binding domain (RBD) may be helpful for developing vaccines or antiviral drugs for PEDV. Understanding the differences in receptor binding between the prototype and the variant strains may provide insight into PEDV pathogenesis.


title: Effect of a quadrivalent vaccine against respiratory virus on the incidence of respiratory disease in weaned beef calves

text: Abstract We investigated the effect of vaccination of male beef calves (mean age±S.D.: 158±31days) against bovine herpes virus (BHV-1 or IBR virus), bovine respiratory syncitial virus (BRSV), bovine viral diarrhea (BVD) virus and para-influenza (PI3) virus on the incidence of respiratory disease during the first forty days after weaning and entering a feed-lot in Portugal. In May 2003, Mertolenga, Preta and mixed-breed calves from 10 different beef herds, were systematically assigned (by order of entrance in a chute) to two treatment groups, before moving to a common feed-lot. One hundred and twenty five male calves were vaccinated with a quadrivalent vaccine (Rispoval 4®) and revaccinated after 21–27 days while 148 herdmates were injected with saline (0.9% NaCl) on the same occasions. The incidence and severity of clinical cases of “bovine respiratory disease” (BRD) were evaluated every day during the first 40 days after entering the feed-lot. Morbidity (3% vs. 14%) and mortality (0% vs. 4%) due to BRD were significantly lower in the vaccinated group. Ten days after revaccination, the calves were treated with an antimicrobial – ending the study – after an outbreak of BRD caused a high incidence of disease in the non-vaccinated group. In conclusion, our results showed that Rispoval 4®, a quadrivalent vaccine against respiratory viruses, under field conditions, reduces morbidity and mortality due to BRD in beef calves after weaning.


title: Utilizing Technology to Enhance Screening for Highly Infectious Diseases

text: • Digital survey applications can be used to create highly infectious disease screening tools; • Digital screening tools simplify patient screening for non-clinical staff at facility entrances; • Digital screening tools can be monitored remotely to assist with compliance. Quick identification and isolation of patients with highly infectious diseases is extremely important in healthcare settings today. This study focused on the creation of a digital screening tool using a free and publicly available digital survey application to screen patients during a measles outbreak in New York City. The results indicate that digital tools are an effective alternative to paper tools due to their ease of use and remote compliance monitoring capabilities.


title: Inborn errors of human STAT1: allelic heterogeneity governs the diversity of immunological and infectious phenotypes

text: The genetic dissection of various human infectious diseases has led to the definition of inborn errors of human STAT1 immunity of four types, including (i) autosomal recessive (AR) complete STAT1 deficiency, (ii) AR partial STAT1 deficiency, (iii) autosomal dominant (AD) STAT1 deficiency, and (iv) AD gain of STAT1 activity. The two types of AR STAT1 defect give rise to a broad infectious phenotype with susceptibility to intramacrophagic bacteria (mostly mycobacteria) and viruses (herpes viruses at least), due principally to the impairment of IFN-γ-mediated and IFN-α/β-mediated immunity, respectively. Clinical outcome depends on the extent to which the STAT1 defect decreases responsiveness to these cytokines. AD STAT1 deficiency selectively predisposes individuals to mycobacterial disease, owing to the impairment of IFN-γ-mediated immunity, as IFN-α/β-mediated immunity is maintained. Finally, AD gain of STAT1 activity is associated with autoimmunity, probably owing to an enhancement of IFN-α/β-mediated immunity. More surprisingly, it is also associated with chronic mucocutaneous candidiasis, through as yet undetermined mechanisms involving an inhibition of the development of IL-17-producing T cells. Thus, germline mutations in human STAT1 define four distinct clinical disorders. Various combinations of viral, mycobacterial and fungal infections are therefore allelic at the human STAT1 locus. These experiments of Nature neatly highlight the clinical and immunological impact of the human genetic dissection of infectious phenotypes.


title: Differential transcriptional profiles identify microglial- and macrophage-specific gene markers expressed during virus-induced neuroinflammation

text: BACKGROUND: In the healthy central nervous system (CNS), microglia are found in a homeostatic state and peripheral macrophages are absent from the brain. Microglia play key roles in maintaining CNS homeostasis and acting as first responders to infection and inflammation, and peripheral macrophages infiltrate the CNS during neuroinflammation. Due to their distinct origins and functions, discrimination between these cell populations is essential to the comprehension of neuroinflammatory disorders. Studies comparing the gene profiles of microglia and peripheral macrophages, or macrophages in vitro-derived from bone marrow, under non-infectious conditions of the CNS, have revealed valuable microglial-specific genes. However, studies comparing gene profiles between CNS-infiltrating macrophages and microglia, when both are isolated from the CNS during viral-induced neuroinflammation, are lacking. METHODS: We isolated, via flow cytometry, microglia and infiltrating macrophages from the brains of Theiler’s murine encephalomyelitis virus-infected C57BL/6 J mice and used RNA-Seq, followed by validation with qPCR, to examine the differential transcriptional profiles of these cells. We utilized primary literature defining subcellular localization to determine whether or not particular proteins extracted from the transcriptional profiles were expressed at the cell surface. The surface expression and cellular specificity of triggering receptor expressed on myeloid cells 1 (TREM-1) protein were examined via flow cytometry. We also examined the immune response gene profile within the transcriptional profiles of these isolated microglia and infiltrating macrophages. RESULTS: We have identified and validated new microglial- and macrophage-specific genes, encoding cell surface proteins, expressed at the peak of neuroinflammation. TREM-1 protein was confirmed to be expressed by infiltrating macrophages, not microglia, at the peak of neuroinflammation. We also identified both unique and redundant immune functions, through examination of the immune response gene profiles, of microglia and infiltrating macrophages during neurotropic viral infection. CONCLUSIONS: The differential expression of cell surface-specific genes during neuroinflammation can potentially be used to discriminate between microglia and macrophages as well as provide a resource that can be further utilized to target and manipulate specific cell responses during neuroinflammation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12974-019-1545-x) contains supplementary material, which is available to authorized users.


title: Practice recommendations for lung cancer radiotherapy during the COVID-19 pandemic: An ESTRO-ASTRO consensus statement

text: BACKGROUND: The COVID-19 pandemic has caused radiotherapy resource pressures and led to increased risks for lung cancer patients and healthcare staff. An international group of experts in lung cancer radiotherapy established this practice recommendation pertaining to whether and how to adapt radiotherapy for lung cancer in the COVID-19 pandemic. METHODS: For this ESTRO & ASTRO endorsed project, 32 experts in lung cancer radiotherapy contributed to a modified Delphi consensus process. We assessed potential adaptations of radiotherapy in two pandemic scenarios. The first, an early pandemic scenario of risk mitigation, is characterized by an altered risk–benefit ratio of radiotherapy for lung cancer patients due to their increased susceptibility for severe COVID-19 infection, and minimization of patient travelling and exposure of radiotherapy staff. The second, a later pandemic scenario, is characterized by reduced radiotherapy resources requiring patient triage. Six common lung cancer cases were assessed for both scenarios: peripherally located stage I NSCLC, locally advanced NSCLC, postoperative radiotherapy after resection of pN2 NSCLC, thoracic radiotherapy and prophylactic cranial irradiation for limited stage SCLC and palliative thoracic radiotherapy for stage IV NSCLC. RESULTS: In a risk-mitigation pandemic scenario, efforts should be made not to compromise the prognosis of lung cancer patients by departing from guideline-recommended radiotherapy practice. In that same scenario, postponement or interruption of radiotherapy treatment of COVID-19 positive patients is generally recommended to avoid exposure of cancer patients and staff to an increased risk of COVID-19 infection. In a severe pandemic scenario characterized by reduced resources, if patients must be triaged, important factors for triage include potential for cure, relative benefit of radiation, life expectancy, and performance status. Case-specific consensus recommendations regarding multimodality treatment strategies and fractionation of radiotherapy are provided. CONCLUSION: This joint ESTRO-ASTRO practice recommendation established pragmatic and balanced consensus recommendations in common clinical scenarios of radiotherapy for lung cancer in order to address the challenges of the COVID-19 pandemic.


title: Treatment of Severe Pneumonia due to COVID-19 with Peginterferon alfa 2a

text: The outbreak of the new coronavirus disease 2019 (COVID-19) has spread rapidly worldwide. Until now, no definite effective treatment has been identified. We reported 3 patients with severe COVID-19 treated with pegylated interferon alfa 2a with satisfactory recovery. Based on these observations, randomized studies with interferons should be considered in deteriorating patients infected with COVID-19.


title: High success and low mortality rates with non-invasive ventilation in influenza A H1N1 patients in a tertiary hospital

text: BACKGROUND: In 2009, an outbreak of respiratory illness caused by influenza A H1N1 virus occurred worldwide. Some patients required Intensive Care Unit (ICU) admission. The use of non-invasive ventilation (NIV) in these patients is controversial, as the aerosol dispersion may contaminate the environment and health-care co-workers. METHODS: Describe the respiratory profile, the mortality rate, and the benefit of using NIV in patients with confirmed diagnosis of influenza AH1N1 who were admitted in the ICU during the year 2009. RESULTS: A total of 1, 401 cases of influenza A H1N1 were confirmed in our hospital by real-time RT-PCR in 2009, and 20 patients were admitted to the ICU. The patients' ages ranged from 18 to 74 years (median of 42). Acute Respiratory Failure (ARF) was present in 70% of patients. The median Acute Physiology and Chronic Health Evaluation II score was 7 (range 7 to 25). Of the 14 patients who developed ARF, 85.7% needed NIV and 14% needed invasive MV at admission. Our success rate (41.6%) with NIV was higher than that described by others. The hospital mortality rate was 2.1%. When influenza A H1N1 arrived in Brazil, the disease was already on endemic alert in other countries. The population was already aware of the symptoms and the health-care system of the treatment. This allowed patients to be properly and promptly treated for influenza A H1N1, while health-care workers took protective measures to avoid contamination. CONCLUSION: In our study we found a high success and low mortality rates with non-invasive ventilation in patients with influenza A H1N1.


Genome editing for disease resistance in pigs and chickens


title: Common Respiratory Diseases

text: The self-medication phenomenon in upper respiratory tract infections, rhinosinusitis, asthma, and chronic obstructive pulmonary disease are significant and will continue to increase. Current level of evidence is poor because of the small number of good quality studies, small sample size, short duration, and variation in the composition of the herbal interventions or therapies. The current review points to several potential therapies that could be effective either alone, or as adjuncts to conventional therapies.


title: Insights into the development of chemical probes for RNA

text: Over the past decade, the RNA revolution has revealed thousands of non-coding RNAs that are essential for cellular regulation and are misregulated in disease. While the development of methods and tools to study these RNAs has been challenging, the power and promise of small molecule chemical probes is increasingly recognized. To harness existing knowledge, we compiled a list of 116 ligands with reported activity against RNA targets in biological systems (R-BIND). In this survey, we examine the RNA targets, design and discovery strategies, and chemical probe characterization techniques of these ligands. We discuss the applicability of current tools to identify and evaluate RNA-targeted chemical probes, suggest criteria to assess the quality of RNA chemical probes and targets, and propose areas where new tools are particularly needed. We anticipate that this knowledge will expedite the discovery of RNA-targeted ligands and the next phase of the RNA revolution.


Health status of patients with Autoimmune Liver Disease during SARS-CoV-2 outbreak in northern Italy


title: Genetic diversity and cross-species transmission of kobuviruses in Vietnam

text: Cross-species transmission of viruses poses a sustained threat to public health. Due to increased contact between humans and other animal species the possibility exists for cross-species transmissions and ensuing disease outbreaks. By using conventional PCR amplification and next generation sequencing, we obtained 130 partial or full genome kobuvirus sequences from humans in a sentinel cohort in Vietnam and various mammalian hosts including bats, rodents, pigs, cats, and civets. The evolution of kobuviruses in different hosts was analysed using Bayesian phylogenetic methods. We estimated and compared time of origin of kobuviruses in different host orders; we also examined the cross-species transmission of kobuviruses within the same host order and between different host orders. Our data provide new knowledge of rodent and bat kobuviruses, which are most closely related to human kobuviruses. The novel bat kobuviruses isolated from bat roosts in Southern Vietnam were genetically distinct from previously described bat kobuviruses, but closely related to kobuviruses found in rodents. We additionally found evidence of frequent cross-species transmissions of kobuviruses within rodents. Overall, our phylogenetic analyses reveal multiple cross-species transmissions both within and among mammalian species, which increases our understanding of kobuviruses genetic diversity and the complexity of their evolutionary history.


title: Infecciones virales de las vías respiratorias en la Unidad de Cuidados Intensivos Neonatales

text: Resumen Introducción Las infecciones virales respiratorias son causa de importante morbimortalidad en recién nacidos prematuros. Hemos realizado un estudio prospectivo en nuestra unidad de cuidados intensivos neonatales (UCIN) para determinar la incidencia de infecciones respiratorias, su impacto, epidemiología y pronóstico en neonatos de alto riesgo. Pacientes y métodos Estudio prospectivo realizado entre septiembre del 2011 y mayo del 2013 entre todos los recién nacidos < 32 semanas de edad gestacional y aquellos niños cuya patología pudiera dar lugar a pensar en un ingreso superior a las 2 semanas. Se recogieron aspirados nasofaríngeos (ANF) el primer día de vida y semanalmente hasta el alta para estudio virológico mediante reacción en cadena de polimerasa. En los casos en los que los niños presentaban síntomas respiratorios, se procedió a recoger un nuevo ANF. El pediatra cumplimentó un cuestionario con los datos clínicos. Resultados Se estudió a 60 niños; 30 (50%) de ellos con una edad gestacional < 32 semanas y 36 (60%) con un peso < 1.500 g. Se recogió un total de 256 ANF, 24 de los cuales resultaron positivos (9,3%). Estas 24 muestras positivas correspondieron solo a 13 niños (21,6% de los pacientes). De ellos, 9 resultaron sintomáticos y presentaron 11 episodios de infección (2 pacientes experimentaron 2 episodios diferentes con control negativo entre ellos). El virus más frecuentemente identificado —el 79% de las muestras (19)— fue el rinovirus (RV). El dato clínico más frecuente fue la presencia o incremento de apneas (75%) y la necesidad de oxigenoterapia. Conclusiones Las infecciones por RV son frecuentes en la UCIN y los recién nacidos pretérmino tienen un alto riesgo de presentar infecciones de relevancia clínica. Abstract Introduction Viral respiratory infections cause major morbidity and mortality in preterm infants. We have performed a prospective study in our neonatal intensive care unit (NICU) to determine the incidence of respiratory infections, their impact and the epidemiology and outcome in high risk neonates. Patients and methods From September 2011 to May 2013 a prospective study was conducted in all preterm infants < 32 weeks gestational age and in all term newborns admitted to NICU for any pathology that are anticipated to have an income exceeding two weeks. A nasopharyngeal aspirate (NPA) was collected the first day of life and weekly until discharge for virologic study with polymerase chain reaction. When these babies presented respiratory symptoms a new NPA was collected in this moment. A clinical form was filled by the physician. Results A total of 60 infants were analyzed: 30 (50%) had a gestational age < 32 weeks and 36 (60%) weighing less than 1500 grams. We collected a total of 256 nasopharyngeal aspirate samples, 24 of them being positive (9.3%). These 24 positive samples corresponded to 13 infants in our cohort (21.6% of the patients). Of them, 9 were symptomatic and had 11 episodes of infection (2 patients had two different episodes with negative control between them). The most frequently identified virus was rhinovirus in (19) 79% of cases. The most frequent clinical data was the presence or increased of apneas (75%) and the needed of oxygenotherapy. Conclusions HRV infections are prevalent in the NICU, and preterm infants have a high risk of infections with clinical relevance.


Thirty Years into the Genomics Era: Tumor Viruses Led the Way


title: Genotyping of clinically relevant human adenoviruses by array-in-well hybridization assay

text: A robust oligonucleotide array-in-well hybridization assay using novel up-converting phosphor reporter technology was applied for genotyping clinically relevant human adenovirus types. A total of 231 adenovirus-positive respiratory, ocular swab, stool and other specimens from 219 patients collected between April 2010 and April 2011 were included in the study. After a real-time PCR amplification targeting the adenovirus hexon gene, the array-in-well assay identified the presence of B03 (n = 122; 57.5% of patients), E04 (29; 13.7%), C02 (21; 9.9%), D37 (14; 6.6%), C01 (12; 5.7%), C05 (5; 2.4%), D19 (4; 1.9%), C06 (2; 0.9%), D08 (1; 0.5%), A31 (1; 0.5%) and F41 (1; 0.5%) genotypes among the clinical sample panel. The typing result was obtained for all specimens that could be amplified (n = 223; 97%), and specificity of the typing was confirmed by sequencing specimens representing each of the different genotypes. No hybridization signal was obtained in adenovirus-negative specimens or specimens with other viruses (n = 30). The array-in-well hybridization assay has great potential as a rapid and multiplex platform for the typing of clinically relevant human adenovirus genotypes in different specimen types.


title: The Glycoproteins of All Filovirus Species Use the Same Host Factors for Entry into Bat and Human Cells but Entry Efficiency Is Species Dependent

text: Ebola and marburgviruses, members of the family Filoviridae, can cause severe hemorrhagic fever in humans. The ongoing Ebola virus (EBOV) disease epidemic in Western Africa claimed more than 11,300 lives and was associated with secondary cases outside Africa, demonstrating that filoviruses pose a global health threat. Bats constitute an important natural reservoir of filoviruses, including viruses of the recently identified Cuevavirus genus within the Filoviridae family. However, the interactions of filoviruses with bat cells are incompletely understood. Here, we investigated whether filoviruses employ different strategies to enter human and bat cells. For this, we examined host cell entry driven by glycoproteins (GP) from all filovirus species into cell lines of human and fruit bat origin. We show that all GPs were able to mediate entry into human and most fruit bat cell lines with roughly comparable efficiency. In contrast, the efficiency of entry into the cell line EidNi/41 derived from a straw-colored fruit bat varied markedly between the GPs of different filovirus species. Furthermore, inhibition studies demonstrated that filoviruses employ the same host cell factors for entry into human, non-human primate and fruit bat cell lines, including cysteine proteases, two pore channels and NPC1 (Niemann-Pick C1 molecule). Finally, processing of GP by furin and the presence of the mucin-like domain in GP were dispensable for entry into both human and bat cell lines. Collectively, these results show that filoviruses rely on the same host cell factors for entry into human and fruit bat cells, although the efficiency of the usage of these factors might differ between filovirus species.


title: Nanotechnology in vaccine delivery

text: Abstract With very few adjuvants currently being used in marketed human vaccines, a critical need exists for novel immunopotentiators and delivery vehicles capable of eliciting humoral, cellular and mucosal immunity. Such crucial vaccine components could facilitate the development of novel vaccines for viral and parasitic infections, such as hepatitis, HIV, malaria, cancer, etc. In this review, we discuss clinical trial results for various vaccine adjuvants and delivery vehicles being developed that are approximately nanoscale (<1000 nm) in size. Humoral immune responses have been observed for most adjuvants and delivery platforms while only viral vectors, ISCOMs and Montanide™ ISA 51 and 720 have shown cytotoxic T cell responses in the clinic. MF59 and MPL® have elicited Th1 responses, and virus-like particles, non-degradable nanoparticles and liposomes have also generated cellular immunity. Such vaccine components have also been evaluated for alternative routes of administration with clinical successes reported for intranasal delivery of viral vectors and proteosomes and oral delivery of a VLP vaccine.


title: Precision-cut intestinal slices as a culture system to analyze the infection of differentiated intestinal epithelial cells by avian influenza viruses

text: Abstract Many viruses infect and replicate in their host via the intestinal tract, e.g. many picornaviruses, several coronaviruses and avian influenza viruses of waterfowl. To analyze infection of enterocytes is a challenging task as culture systems for differentiated intestinal epithelial cells are not readily available and often have a life span that is too short for infection studies. Precision-cut intestinal slices (PCIS) from chicken embryos were prepared and shown that the epithelial cells lining the lumen of the intestine are viable for up to 4 days. Using lectin staining, it was demonstrated that α2,3-linked sialic acids, the preferred receptor determinants of avian influenza viruses, are present on the apical side of the epithelial cells. Furthermore, the epithelial cells (at the tips) of the villi were shown to be susceptible to infection by an avian influenza virus of the H9N2 subtype. This culture system will be useful to analyze virus infection of intestinal epithelial cells and it should be applicable also to the intestine of other species.


Environmental Contamination and Viral Shedding in MERS Patients


BK 3101: COVID-19-Infektion des HNO-Arztes ist Berufskrankheit, kein Arbeitsunfall


title: Therapeutic potentials of Houttuynia cordata Thunb. against inflammation and oxidative stress: A review

text: Abstract Ethnopharmacological relevance Houttuynia cordata Thunb. (Family: Saururaceae) is an herbaceous perennial plant that grows in moist and shady places. The plant is well known among the people of diverse cultures across Japan, Korea, China and North-East India for its medicinal properties. Traditionally the plant is used for its various beneficial properties against inflammation, pneumonia, severe acute respiratory syndrome, muscular sprain, stomach ulcer etc. Oxidative stress and inflammation were found to be linked with most of the diseases in recent times. Many ancient texts from Chinese Traditional Medicine, Ayurveda and Siddha, and Japanese Traditional medicine have documented the efficacy of H. cordata against oxidative stress and inflammation. Aim of the study This review aims to provide up-to-date and comprehensive information on the efficacy of H. cordata extracts as well as its bioactive compounds both in vitro and in vivo, against oxidative stress and inflammation Materials and methods Relevant information on H. cordata against oxidative stress and inflammation were collected from the established scientific databases such as NCBI, Web of Science, ScienceDirect, Elsevier, and Springer. Additionally, a few books and magazines were also consulted to get the important information. Results Herbal medicines or plant products were traditionally being used for treating the oxidative stress and inflammation related diseases in diverse communities across the world. Scientifically, H. cordata has shown to target several signaling pathways and found to effectively reduce the oxidative stress and inflammation. Phyto-constituents such as afzelin, hyperoside and quercitrin have shown to reduce inflammation both in vitro and in vivo models. These molecules were also shown to have strong antioxidant properties both in vivo and in vitro models. Conclusions H. cordata extracts and its bioactive molecules were shown to have both anti-inflammatory and anti-oxidative properties. As both in vitro and in vivo studies were shown that H. cordata did not have any toxicity on the various model systems used, future clinical studies will hopefully make an impact on the future direction of treating inflammation-related diseases.


title: Virus-like particles associated with porcine epidemic diarrhoea

text: Porcine epidemic diarrhoea type II was reproduced in experimental pigs of various ages by oral dosing with minced intestine from a naturally occurring case of the disease. Virus-like particles which probably represent an unidentified coronavirus were seen by electron microscopy in the faeces and intestinal epithelium of infected animals.


title: Detection and pathogenicity of human metapneumovirus respiratory infection in pediatric Italian patients during a winter–spring season

text: Abstract Background Some diagnostic, epidemiological and clinical features of the recently discovered human metapneumovirus remain to be investigated. Objectives To study the best approach for the diagnosis of human metapneumovirus infections by both conventional and molecular methods, along with the human metapneumovirus circulation rate in northern Italy and the severity of human metapneumovirus respiratory infections in a pediatric patient population. Study design Nasopharyngeal aspirates (NPA) were taken from 306 pediatric patients during the winter–spring season 2003–2004, and examined for conventional respiratory viruses by direct fluorescent staining and cell culture, while human coronavirus and human metapneumovirus were sought by RT-PCR. Results RT-PCR detected human metapneumovirus in 40/306 (13.1%) children positive for respiratory viruses, with an incidence intermediate between that of respiratory syncytial virus (58 patients, 18.9%) and that of influenzavirus infections (29 patients, 9.5%). Phylogenetic analysis showed cocirculation of both human metapneumovirus types (A and B) as well as their relevant subtypes (A1–A2 and B1–B2). Clinically, human metapneumovirus was found to be second to human respiratory syncytial virus alone, as a cause of respiratory tract infections, while duration of virus excretion appeared to correlate with severity of infection, and virus load in NPA with the stage of respiratory infection. Conclusion (i) Human metapneumovirus is a major viral pathogen in the Italian pediatric patient population; (ii) the severity of lower respiratory tract infections approaches that of human respiratory syncytial virus; (iii) there are preliminary indications that the duration of virus excretion may reach 2–3 weeks and that the level of viral load in NPA correlates with the clinical stage of human metapneumovirus infection.


title: OC43 strain‐related coronavirus antibodies in different age groups

text: Serum antibodies against human coronavirus OC43 in different age groups were measured by complement fixation (CF), haemagglutination inhibition (HI), radial diffusion haemolysis‐in‐gel (HIG), and solid‐phase radioimmunoassay (RIA) methods. Antigen grown in suckling mouse brain was used in all tests. Results obtained by the CF and HIG tests, and the RIA, were in good agreement with regard to the presence or absence of antibodies. Similar results were also obtained with the HI test if nonspecific haemagglutination inhibitors were first removed by treatment with phospholipase C and only titers of 1:20 or greater were considered positive. Children 6–23 months of age (n = 45) were without measurable coronavirus antibodies in all four assays. A rapid increase in the prevalence of antibodies then occurred in subsequent age groups, and practically all persons 6 years of age or older were found to have OC43 antibodies as measured by the HIG test or the RIA. The mean antibody levels determined by these two methods continued to increase, however, up to the age group of 10–14 years. This increase in antibody levels after the initial antibody incidence plateau may be due to boosting effects caused by related coronavirus strains, since OC43 antigens are known to cross‐react with antibodies induced by other human coronaviruses. Taken together, these data suggest that OC43 virus, or an antigenically related coronavirus strain, is very common in Finland.


title: Hundreds of severe pediatric COVID-19 infections in Wuhan prior to the lockdown

text: Before January 22, 2020, only one pediatric case of COVID-19 was reported in mainland China. However, a retrospective surveillance study identified six children who had been hospitalized for COVID-19 in one of three central Wuhan hospitals between January 7th and January 15th. Given that Wuhan has over 395 other hospitals, there may have been far more severe pediatric cases than reported. There were six and 43 children out of 336 who tested positive for COVID-19 and influenza, respectively among all pediatric admissions during the 9-day period. By using this ratio in a detailed analysis of influenza surveillance data and COVID-19 epidemic dynamics (see Appendix), we estimate that there were 313 [95% CI: 171-520] children hospitalized for COVID-19 in Wuhan during January 7-15, 2020 (Figure). Under an epidemic doubling time of 7.31 days4, we estimate that there were 1105 [95% CI: 592, 1829] cumulative pediatric COVID-19 hospitalizations prior to the January 23rd lockdown, which far surpasses the 425 confirmed cases reported across all age groups, none of which were children under age 15. Children are strikingly absent from COVID-19 reports and limited data suggest that pediatric infections are overwhelmingly mild5. Thus, our estimates for hundreds of severe pediatric cases likely translates to thousands or even tens of thousands of mildly infected children, suggesting that the force of infection from children may be grossly underestimated and the infection fatality rate overestimated from confirmed case counts alone. This highlights the urgent need for more robust surveillance to gauge the true extent and severity of COVID-19 in all ages.


title: Wearable IoT sensor based healthcare system for identifying and controlling chikungunya virus

text: Abstract Chikungunya is a vector borne disease that spreads quickly in geographically affected areas. Its outbreak results in acute illness that may lead to chronic phase. Chikungunya virus (CHV) diagnosis solutions are not easily accessible and affordable in developing countries. Also old approaches are very slow in identifying and controlling the spread of CHV outbreak. The sudden development and advancement of wearable internet of things (IoT) sensors, fog computing, mobile technology, cloud computing and better internet coverage have enhanced the quality of remote healthcare services. IoT assisted fog health monitoring system can be used to identify possibly infected users from CHV in an early phase of their illness so that the outbreak of CHV can be controlled. Fog computing provides many benefits such as low latency, minimum response time, high mobility, enhanced service quality, location awareness and notification service itself at the edge of the network. In this paper, IoT and fog based healthcare system is proposed to identify and control the outbreak of CHV. Fuzzy-C means (FCM) is used to diagnose the possibly infected users and immediately generate diagnostic and emergency alerts to users from fog layer. Furthermore on cloud server, social network analysis (SNA) is used to represent the state of CHV outbreak. Outbreak role index is calculated from SNA graph which represents the probability of any user to receive or spread the infection. It also generates warning alerts to government and healthcare agencies to control the outbreak of CHV in risk prone or infected regions. The experimental results highlight the advantages of using both fog computing and cloud computing services together for achieving network bandwidth efficiency, high quality of service and minimum response time in generation of real time notification as compared to a cloud only model.


title: Fine level epitope mapping and conservation analysis of two novel linear B-cell epitopes of the avian infectious bronchitis coronavirus nucleocapsid protein

text: Abstract The nucleocapsid (N) protein of the infectious bronchitis virus (IBV) may play an essential role in the replication and translation of viral RNA. The N protein can also induce high titers of cross-reactive antibodies and cell-mediated immunity, which protects chickens from acute infection. In this study, we generated two monoclonal antibodies (mAbs), designated as 6D10 and 4F10, which were directed against the N protein of IBV using the whole viral particles as immunogens. Both of the mAbs do not cross react with Newcastle disease virus (NDV), infectious laryngotracheitis virus (ILTV) and subtype H9 avian influenza virus (AIV). After screening a phage display peptide library and peptide scanning, we identified two linear B-cell epitopes that were recognized by the mAbs 6D10 and 4F10, which corresponded to the amino acid sequences 242FGPRTK247 and 195DLIARAAKI203, respectively, in the IBV N protein. Alignments of amino acid sequences from a large number of IBV isolates indicated that the two epitopes, especially 242FGPRTK247, were well conserved among IBV strains. This conclusion was further confirmed by the relationships of 18 heterologous sequences to the 2 mAbs. The novel mAbs and the epitopes identified will be useful for developing diagnostic assays for IBV infections.


title: Isothermal Nucleic Acid Amplification Techniques and Their Use in Bioanalysis

text: Recently, there has been a rapid progress in the development of techniques for isothermal amplification of nucleic acids as an alternative to polymerase chain reaction (PCR). The advantage of these methods is that the nucleic acids amplification can be carried out at constant temperature, unlike PCR, which requires cyclic temperature changes. Moreover, isothermal amplification can be conducted directly in living cells. This review describes the principles of isothermal amplification techniques and demonstrates their high efficiency in designing new highly sensitive detection methods of nucleic acids and enzymes involved in their modifications. The data on successful application of isothermal amplification methods for the analysis of cells and biomolecules with the use of DNA/RNA aptamers are presented.


title: Intervention strategies for emerging viruses: use of antivirals

text: Today, small molecule antiviral drugs are available for the treatment of infections with herpesviruses, HIV, HBV and HCV as well as with influenza viruses. Ribavirin, a broad-spectrum (but aspecific) antiviral, has been approved for the treatment of infections with respiratory syncytial virus, HCV and Lassa virus. Yet, for many other viruses that cause life-threatening infections [most of which are considered emerging and/or neglected] there are no drugs available. Ideally, potent and broad-spectrum (i.e., pan-genus or pan-family virus activity) antiviral drugs should be developed whereby one drug could be used for the treatment of a number of such viral infections. We here review recent evolutions in the search for inhibitors of emerging and neglected RNA viruses.


title: IFN-lambda preferably inhibits PEDV infection of porcine intestinal epithelial cells compared with IFN-alpha

text: Abstract In contrast to type I interferons that target various types of cells and organs, interferon lambda (IFN-L) primarily acts on mucosal epithelial cells and exhibits robust antiviral activity within the mucosal surface. Porcine epidemic diarrhea virus (PEDV), which causes high morbidity and mortality in piglets, is an enteropathogenic coronavirus with economic importance. Here, we demonstrated that both recombinant porcine IFN-L1 (rpIFN-L1) and rpIFN-L3 have powerful antiviral activity against PEDV infection of both Vero E6 cells and the intestinal porcine epithelial cell line J2 (IPEC-J2). Both forms of rpIFN-L inhibited two genotypes of PEDV (strain CV777 of genotype 1 and strain LNCT2 of genotype 2). rpIFN-L1 primarily controlled viral infection in the early stage and had less antiviral activity in IPEC-J2 than in rpIFN-L3 cells infected with PEDV. In addition, rpIFN-L1 exhibited greater antiviral activity against PEDV infection of IPEC-J2 cells than that of porcine IFN-alpha. Consistent with this finding, rpIFN-L1 triggered higher levels of certain antiviral IFN-stimulated genes (ISGs) (ISG15, OASL, and MxA) in IPEC-J2 cells than porcine IFN-alpha. Although IPEC-J2 cells responded to both IFN-alpha and lambda, transcriptional profiling of ISGs (specifically ISG15, OASL, MxA, and IFITMs) differed when induced by either IFN-alpha or rpIFN-L. Therefore, our data provide the experimental evidence that porcine IFN-L suppresses PEDV infection of IPEC-J2 cells, which may offer a promising therapeutic for combating PED in piglets.


title: Hepatitis E Virus Strains in Rabbits and Evidence of a Closely Related Strain in Humans, France

text: Hepatitis E virus (HEV) strains from rabbits indicate that these mammals may be a reservoir for HEVs that cause infection in humans. To determine HEV prevalence in rabbits and the strains’ genetic characteristics, we tested bile, liver, and additional samples from farmed and wild rabbits in France. We detected HEV RNA in 7% (14/200) of bile samples from farmed rabbits (in 2009) and in 23% (47/205) of liver samples from wild rabbits (in 2007–2010). Full-length genomic sequences indicated that all rabbit strains belonged to the same clade (nucleotide sequences 72.2%–78.2% identical to HEV genotypes 1–4). Comparison with HEV sequences of human strains and reference sequences identified a human strain closely related to rabbit strain HEV. We found a 93-nt insertion in the X domain of open reading frame 1 of the human strain and all rabbit HEV strains. These findings indicate that the host range of HEV in Europe is expanding and that zoonotic transmission of HEV from rabbits is possible.


title: Characterization of the nasopharyngeal microbiota in health and during rhinovirus challenge

text: BACKGROUND: The bacterial communities of the nasopharynx play an important role in upper respiratory tract infections (URTIs). Our study represents the first survey of the nasopharynx during a known, controlled viral challenge. We aimed to gain a better understanding of the composition and dynamics of the nasopharyngeal microbiome during viral infection. METHODS: Rhinovirus illnesses were induced by self-inoculation using the finger to nose or eye natural transmission route in ten otherwise healthy young adults. Nasal lavage fluid samples (NLF) samples were collected at specific time points before, during, and following experimental rhinovirus inoculation. Bacterial DNA from each sample (N = 97 from 10 subjects) was subjected to 16S rRNA sequencing by amplifying the V1-V2 hypervariable region followed by sequencing using the 454-FLX platform. RESULTS: This survey of the nasopharyngeal microbiota revealed a highly complex microbial ecosystem. Taxonomic composition varied widely between subjects and between time points of the same subject. We also observed significantly higher diversity in not infected individuals compared to infected individuals. Two genera – Neisseria and Propionibacterium – differed significantly between infected and not infected individuals. Certain phyla, including Firmicutes, Actinobacteria, and Proteobacteria, were detected in all samples. CONCLUSIONS: Our results reveal the complex and diverse nature of the nasopharyngeal microbiota in both healthy and viral-challenged adults. Although some phyla were common to all samples, differences in levels of diversity and selected phyla were detected between infected and uninfected participants. Deeper, species-level metagenomic sequencing in a larger sample is warranted.


title: Occurrence of HSV-1-induced pneumonitis in patients under standard immunosuppressive therapy for rheumatic, vasculitic, and connective tissue disease

text: BACKGROUND: Herpes simplex virus type-1 (HSV-1) has been described to cause respiratory tract infections in critically ill patients or in individuals that are immunocompromised. It is a continuing matter of debate under which circumstances HSV-1 is a relevant pathogen for pneumonitis. While its role during critical illness has been investigated by prospective interventional studies, comparatively little systematic data is available on the role of HSV-1 for pneumonitis in outpatients with autoimmune disease under a maintenance regimen of immunosuppression. METHODS: We retrospectively reviewed the charts of ~1400 patients with rheumatoid arthritis, vasculitis, and systemic lupus erythematosus (SLE) that were followed at the outpatient clinic of a German University hospital during the years 2000–2007. Episodes of admission to a ward resulting in the diagnosis of pneumonia/pneumonitis were identified, and the type of pneumonia and clinical features retrospectively studied. RESULTS: 63 patients with rheumatoid arthritis, vasculitis, or SLE were admitted to a ward and diagnosed to have pneumonia/pneumonitis. Using bronchoscopy a total of 6 cases of pulmonary infection associated with HSV-1 in the lower respiratory tract were identified. Among those, 2 cases suggested a causative role of HSV-1 as the sole agent causing pneumonitis that proved clinically responsive to antiviral treatment. In the remaining 4 cases HSV-1 appeared as a bystander of bacterial infection. Maintenance therapy with leflunomide, which inhibits HSV-1 assembly in vitro, was associated with a milder course of pneumonitis in one patient. Detection of HSV-1 was associated with stronger immunosuppressive regimens and vasculitic disease. CONCLUSION: The present study analyzed the frequency and hallmarks of cases of HSV-1 associated pneumonitis that occurred in a comparatively large cohort of patients with rheumatologic autoimmune diseases. In an area of controversy, this study provides further evidence that HSV-1 causes isolated pneumonitis in the immunocompromised. The study may provide an estimate on the frequency of relevant HSV-1 infection and bacterial agents in outpatients with autoimmune disease.


Novel targeted drugs approved by the NMPA and FDA in 2019


title: Initial CT imaging characters of an imported family cluster of COVID-19

text: Abstract The objective of this report is to better understand the initial CT imaging spectrum and the relationship between clinical characteristics and initial CT imaging features of an imported family cluster cases involving 7 laboratory-confirmed COVID-19 patients. We find that initial CT findings of 4 patients were positive within one week after the onset of symptoms and 1 patient was negative before the onset of symptoms. Two asymptomatic patients had typical CT abnormalities. The initial CT imaging manifestations are mainly peripheral or subpleural ground-glass opacities and ground-glass with consolidation. Our report is of potential guiding value for the initial CT screening of imported familial cluster cases since the imported cases have an identified time of infection.


title: Liver Sinusoidal Endothelial Cell Lectin, LSECtin, Negatively Regulates Hepatic T-Cell Immune Response

text: Background & Aims The liver is an organ with paradoxic immunologic properties and is known for its tolerant microenvironment, which holds important implications for hepatic diseases. The molecular basis for this local immune suppression, however, is poorly understood. In this study, we aimed to determine the role of liver sinusoidal endothelial cell lectin (LSECtin), a recently identified member of the dendritic cell-specific ICAM-3 grabbing nonintegrin (DC-SIGN) family, in the regulation of hepatic T-cell immune response. Methods The regulation of T-cell effector function by LSECtin was determined by co-stimulated T cells with anti-CD3/CD28 monoclonal antibody and LSECtin protein, or co-culture of T-cell receptor transgenic T cells with mouse LSECs in vitro. We generated LSECtin knockout mice and prepared recombinant LSECtin protein and complementary DNA plasmids to analyze the role of LSECtin in hepatic T-cell immune regulation in vivo. Results We showed that LSECtin specifically recognized activated T cells and negatively regulated their immune responses. In mice with T-cell–mediated acute liver injury, the lack of LSECtin accelerated the disease owing to an increased T-cell immune response, whereas the exogenous administration of recombinant LSECtin protein or plasmid ameliorated the disease via down-regulation of T-cell immunity. Conclusions Our results reveal that LSECtin is a novel regulator of T cells and expose a crucial mechanism for hepatic T-cell immune suppression, perhaps opening up a new approach for treatment of inflammatory diseases in the liver.


title: Respiratory Viral Infections in Transplant and Oncology Patients

text: Respiratory viral infections are a significant cause of morbidity and mortality in the immunocompromised host. In the last two decades, there has been significant advancement in the epidemiology and laboratory diagnosis of respiratory viral infections. In addition, the clinical consequences of many respiratory viruses in the immunocompetent and immunocompromised host continue to be studied. Many therapeutics have also now become available, although their efficacy in transplant recipients remains uncertain. This article describes the current knowledge about respiratory viral infections as it relates to solid organ transplant, hematopoietic stem cell transplant, and oncology settings.


title: Relationships among lymphocyte subsets, cytokines, and the pulmonary inflammation index in coronavirus (COVID‐19) infected patients

text: We explored the relationships between lymphocyte subsets, cytokines, pulmonary inflammation index (PII) and disease evolution in patients with (corona virus disease 2019) COVID‐19. A total of 123 patients with COVID‐19 were divided into mild and severe groups. Lymphocyte subsets and cytokines were detected on the first day of hospital admission and lung computed tomography results were quantified by PII. Difference analysis and correlation analysis were performed on the two groups. A total of 102 mild and 21 severe patients were included in the analysis. There were significant differences in cluster of differentiation 4 (CD4(+ )T), cluster of differentiation 8 (CD8(+ )T), interleukin 6 (IL‐6), interleukin 10 (IL‐10) and PII between the two groups. There were significant positive correlations between CD4(+ )T and CD8(+ )T, IL‐6 and IL‐10 in the mild group (r (2) = 0·694, r ( 2) = 0·633, respectively; P < 0·01). After ‘five‐in‐one’ treatment, all patients were discharged with the exception of the four who died. Higher survival rates occurred in the mild group and in those with IL‐6 within normal values. CD4(+ )T, CD8(+ )T, IL‐6, IL‐10 and PII can be used as indicators of disease evolution, and the PII can be used as an independent indicator for disease progression of COVID‐19.


title: Doxycycline as a potential partner of COVID-19 therapies

text: Coronavirus disease 2019 (COVID-19) is a major public health challenge, and the current antiviral arsenal for treatment is limited, with questionable efficacy. Major efforts are under way for discovery of new effective agents, but the validation of new potential treatments for COVID-19 may take a long time. Therefore, the repurposing of existing drugs for new indications is needed. In this article, we argue for the potential benefits of using doxycycline with either hydroxycholoroquine or other putative agents for COVID-19 treatment, as doxycycline has antiviral and anti-inflammatory activities by dampening the cytokine storm and to prevent lung damage.


To the Lighthouse: Embracing a Grand Challenge for Cancer Education in the Digital Age


Excitement around hydroxychloroquine for treating COVID-19 causes challenges for rheumatology


title: Modeling serological testing to inform relaxation of social distancing for COVID-19 control

text: The value of serological testing to inform the public health response to the SARS-CoV-2 pandemic is debated. Using a transmission model, we examined how serology can be implemented to allow seropositive individuals to resume more normal levels of social interaction while offsetting the risks. We simulated the use of widespread serological testing with realistic assay characteristics, in which seropositive individuals partially restore their social contacts and act as immunological ‘shields’. If social distancing is relaxed by 50% at the same time that quarterly serological screening is initiated, approximately 120,000 deaths could be averted and a quarter of the US population could be released from social distancing in the first year of the epidemic, compared to a scenario without serological testing. This strategy has the potential to substantially flatten the COVID-19 epidemic curve while also allowing a substantial number of individuals to safely return to social and economic interactions.


title: Clinical management and infection control of SARS: Lessons learned

text: Abstract The outbreak of severe acute respiratory syndrome (SARS) in 2003 was the first emergence of an important human pathogen in the 21st century. Responding to the epidemic provided clinicians with extensive experience in diagnosing and treating a novel respiratory viral disease. In this article, we review the experience of the SARS epidemic, focusing on measures taken to identify and isolate patients, prevent the transmission of infection to healthcare workers and develop effective therapies. Lessons learned from the SARS epidemic will be especially important in responding to the current emergence of another highly pathogenic human coronavirus, the agent of Middle East respiratory syndrome (MERS), and to the recently emerging H7N9 influenza A virus in China. This paper forms part of a symposium in Antiviral Research on “From SARS to MERS: 10years of research on highly pathogenic human coronaviruses.”


title: Characterization of HCoV-229E fusion core: Implications for structure basis of coronavirus membrane fusion

text: Abstract Human coronavirus 229E (HCoV-229E), a member of group I coronaviruses, has been identified as one of the major viral agents causing respiratory tract diseases in humans for nearly 40 years. However, the detailed molecular mechanism of the membrane fusion mediated by the spike (S) protein of HCoV-229E remains elusive. Here, we report, for the first time, a rationally designed fusion core of HCoV-229E (HR1-SGGRGG-HR2), which was in vitro produced in GST prokaryotic expression system. Multiple lines of experimental data including gel-filtration, chemical cross-linking, and circular diagram (CD) demonstrated that the HCoV-229E fusion core possesses the typical properties of the trimer of coiled-coil heterodimer (six α-helix bundle). 3D structure modeling presents its most-likely structure, similar to those of coronaviruses that have been well-documented. Collectively, HCoV-229E S protein belongs to the type I fusion protein, which is characterized by the existence of two heptad-repeat regions (HR1 and HR2), furthermore, the available knowledge concerning HCoV-229E fusion core may make it possible to design small molecule or polypeptide drugs targeting the membrane fusion, a crucial step of HCoV-229E infection.


title: A novel human coronavirus: Middle East respiratory syndrome human coronavirus

text: In 2012, a novel coronavirus, initially named as human coronavirus EMC (HCoV-EMC) but recently renamed as Middle East respiratory syndrome human coronavirus (MERS-CoV), was identified in patients who suffered severe acute respiratory infection and subsequent renal failure that resulted in death. Ongoing epidemiological investigations together with retrospective studies have found 61 laboratory-confirmed cases of infection with this novel coronavirus, including 34 deaths to date. This novel coronavirus is culturable and two complete genome sequences are now available. Furthermore, molecular detection and indirect immunofluorescence assay have been developed. The present paper summarises the limited recent advances of this novel human coronavirus, including its discovery, genomic characterisation and detection.


title: Diverse Functions of Polyamines in Virus Infection

text: As obligate intracellular parasites, viruses rely on host cells for the building blocks of progeny viruses. Metabolites such as amino acids, nucleotides, and lipids are central to viral proteins, genomes, and envelopes, and the availability of these molecules can restrict or promote infection. Polyamines, comprised of putrescine, spermidine, and spermine in mammalian cells, are also critical for virus infection. Polyamines are small, positively charged molecules that function in transcription, translation, and cell cycling. Initial work on the function of polyamines in bacteriophage infection illuminated these molecules as critical to virus infection. In the decades since early virus-polyamine descriptions, work on diverse viruses continues to highlight a role for polyamines in viral processes, including genome packaging and viral enzymatic activity. On the host side, polyamines function in the response to virus infection. Thus, viruses and hosts compete for polyamines, which are a critical resource for both. Pharmacologically targeting polyamines, tipping the balance to favor the host and restrict virus replication, holds significant promise as a broad-spectrum antiviral strategy.


title: Nutrition Therapy in Critically Ill Patients with Coronavirus Disease (COVID‐19)

text: In the midst of a worldwide pandemic of the Coronavirus Disease 2019 (COVID‐19), a paucity of data precludes derivation of COVID‐19‐specific recommendations for nutritional therapy. Until more data are available, the focus needs to center on principles of critical care nutrition modified for the constraints of this disease process, i.e., COVID‐19‐relevant recommendations. Delivery of nutritional therapy must include strategies to reduce exposure and spread of the disease by providing clustered care, adequate protection of healthcare providers, and preservation of personal protective equipment. Enteral nutrition (EN) should be initiated early after admission to the intensive care unit (ICU) using a standard isosmolar polymeric formula, starting at trophic doses and advancing as tolerated while monitoring for gastrointestinal intolerance, hemodynamic instability, and metabolic derangements. Intragastric EN may be provided safely, even with use of prone positioning and extracorporeal membrane oxygenation. Clinicians, though, should have a lower threshold for switching to parenteral nutrition in cases of intolerance, high risk of aspiration, or escalating vasopressor support. While data extrapolated from experience in Acute Respiratory Distress Syndrome (ARDS) warrants use of fiber additives and probiotic organisms. The lack of demonstrated benefit precludes a recommendation for micronutrient supplementation. Practices which increase exposure or contamination of equipment, such as use of gastric residual volumes as a monitor, indirect calorimetry to calculate requirements, endoscopy or fluoroscopy to achieve enteral access, or transport out of the ICU for additional imaging should be avoided. At all times, strategies for nutritional therapy need to be assessed on a risk/benefit basis, paying attention to risk for both the patient and the healthcare provider. This article is protected by copyright. All rights reserved


title: Chemical microarray: a new tool for drug screening and discovery

text: HTS with microtiter plates has been the major tool used in the pharmaceutical industry to explore chemical diversity space and to identify active compounds and pharmacophores for specific biological targets. However, HTS faces a daunting challenge regarding the fast-growing numbers of drug targets arising from genomic and proteomic research, and large chemical libraries generated from high-throughput synthesis. There is an urgent need to find new ways to profile the activity of large numbers of chemicals against hundreds of biological targets in a fast, low-cost fashion. Chemical microarray can rise to this challenge because it has the capability of identifying and evaluating small molecules as potential therapeutic reagents. During the past few years, chemical microarray technology, with different surface chemistries and activation strategies, has generated many successes in the evaluation of chemical–protein interactions, enzyme activity inhibition, target identification, signal pathway elucidation and cell-based functional analysis. The success of chemical microarray technology will provide unprecedented possibilities and capabilities for parallel functional analysis of tremendous amounts of chemical compounds.


title: Receptor-binding domain of SARS-CoV spike protein induces long-term protective immunity in an animal model

text: Development of effective vaccines against severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) is still a priority in prevention of re-emergence of SARS. Our previous studies have shown that the receptor-binding domain (RBD) of SARS-CoV spike (S) protein elicits highly potent neutralizing antibody responses in the immunized animals. But it is unknown whether RBD can also induce protective immunity in an animal model, a key aspect for vaccine development. In this study, BALB/c mice were vaccinated intramuscularly (i.m.) with 10 μg of RBD-Fc (RBD fused with human IgG1 Fc) and boosted twice at 3-week intervals and one more time at 12th month. Humoral immune responses of vaccinated mice were investigated for up to 12 months at a 1-month interval and the neutralizing titers of produced antibodies were reported at months 0, 3, 6 and 12 post-vaccination. Mice were challenged with the homologous strain of SARS-CoV 5 days after the last boost, and sacrificed 5 days after the challenge. Mouse lung tissues were collected for detection of viral load, virus replication and histopathological effects. Our results showed that RBD-Fc vaccination induced high titer of S-specific antibodies with long-term and potent SARS-CoV neutralizing activity. Four of five vaccinated mice were protected from subsequent SARS-CoV challenge because no significant virus replication, and no obvious histopathological changes were found in the lung tissues of the vaccinated mice challenged with SARS-CoV. Only one vaccinated mouse had mild alveolar damage in the lung tissues. In contrast, high copies of SARS-CoV RNA and virus replication were detected, and pathological changes were observed in the lung tissues of the control mice. In conclusion, our findings suggest that RBD, which can induce protective antibodies to SARS-CoV, may be further developed as a safe and effective SARS subunit vaccine.


title: Parallel problems

text: Our fight against climate change offers useful lessons for tackling the coronavirus


title: Chapter 11 Health effects

text: Abstract There are beneficial as well as harmful aerosols. According to their nature, harmful particles can be classified into three categories: chemically toxic, infectious, and radioactive. In general, there is a relationship between the response and the dose received. A biochemically active particle may contain only a small amount of active agents. In this respect, an inhaled particle simply acts as a carrier that facilitates delivery of deleterious or beneficial components to specific surface areas of lung airways. In view of the tortuous narrow passageways and sharp turns they have to go through, aerosol particles are an effective carrier. As an indication of their effectiveness, about one half of all 3-m particles inhaled through the mouth deposit in the alveolar region.


title: Effects of indole alkaloids from leaf of Alstonia scholaris on post-infectious cough in mice

text: Abstract Ethnopharmacological relevance Leaf of Alstonia scholaris (L.) R. Br. (Apocynaceae), a wide used ethic-medicine in many Asia and Africa counties, has also been recorded as the common traditional Chinese medicine for treatment of illnesses in respiratory system by Dai people. Aim of the study To provide experimental data of clinical adaption of total indole alkaloids (TA) from leaf of A. scholaris for treating post-infectious cough in phase II clinical trial. Materials and methods To model post-infectious cough, all animals except control group were instilled intra-tracheal with lipopolysaccharide (LPS) (80 μg/50 µL/mouse), followed by subsequent exposure to cigarette smoke (CS) for 30 min per day for a total of 30 days. Mice were orally given TA at dose of 10, 25, 50 mg/kg, and four main alkaloids (Sch: scholaricine, Epi: 19-epischolaricine, Val: vallesamine, Pic: picrinine) once daily. Cellular infiltration was assessed in the broncho-alveolar lavage fluid (BALF). Expression of interleukin-6 (IL-6) and C-reactive protein (CRP) in the serum was determined, the superoxide dismutase (SOD) activity as well as malondialdehyde (MDA) content in the serum and homogenate were examined. Finally, histopathological examination in the lungs was assessed by H. E. staining. Results After administration of TA and four major alkaloids respectively, the symptoms of cough in mice were obviously attenuated. Total white blood cells (WBC) and neutrophils (NEU) amounts in BALF were reduced obviously and the pathological damage of lung was also attenuated. There was also significant reduction in IL-6, CRP, MDA and a marked improvement in SOD. Conclusions The efficacy of indole alkaloids against post-infectious cough (PIC) was shown in the down-regulation of inflammatory cells, cytokines, and the balance of antioxidants. What's more, the pharmacological effects of TA were better than single indole alkaloid, which might be related to the synergic effect of four major alkaloids.


title: Autoregulation of thromboinflammation on biomaterial surfaces by a multicomponent therapeutic coating

text: Activation of the thrombotic and complement systems is the main recognition and effector mechanisms in the multiple adverse biological responses triggered when biomaterials or therapeutic cells come into blood contact. We have created a surface which is auto-protective to human innate immunity by combining three fundamentally different strategies, all developed by us previously, which have been shown to induce substantial, but incomplete hemocompatibility when used separately. In summary, we have conjugated a factor H –binding peptide; and an ADP-degrading enzyme; using a PEG linker on both material and cellular surfaces. When exposed to human whole blood, factor H was specifically recruited to the modified surfaces and inhibited complement attack. In addition, activation of platelets and coagulation was efficiently attenuated, by degrading ADP. Thus, by inhibiting thromboinflammation using a multicomponent approach, we have created a hybrid surface with the potential to greatly reduce incompatibility reactions involving biomaterials and transplantation.


title: Simulated Pediatric Resuscitation Use for Personal Protective Equipment Adherence Measurement and Training During the 2009 Influenza (H1N1) Pandemic

text: Article-at-a-Glance Background Previous experience with simulated pediatric cardiac arrests (that is, mock codes) suggests frequent deviation from American Heart Association (AHA) basic and advanced life support algorithms. During highly infectious outbreaks, acute resuscitation scenarios may also increase the risk of insufficient personal protective equipment (PPE) use by health care workers (HCWs). Simulation was used as an educational tool to measure adherence with PPE use and pediatric resuscitation guidelines during simulated cardiopulmonary arrests of 2009 influenza A patients. Methods A retrospective, observational study was performed of 84 HCWs participating in 11 in situ simulations in June 2009. Assessment included (1) PPE adherence, (2) confidence in PPE use, (3) elapsed time to specific resuscitation maneuvers, and (4) deviation from AHA guidelines. Results Observed adherence with PPE use was 61% for eye shields, 81% for filtering facepiece respirators or powered air-purifying respirators, and 87% for gown/gloves. Use of a “gatekeeper” to control access and facilitate donning of PPE was associated with 100% adherence with gown and respirator precautions and improved respirator adherence. All simulations showed deviation from pediatric basic life support protocols. The median time to bag-valve-mask ventilation improved from 4.3 to 2.7minutes with a gatekeeper present. Rapid isolation carts appeared to improve access to necessary PPE. Confidence in PPE use improved from 64% to 85% after the mock code and structured debriefing. Conclusions Large gaps exist in the use of PPE and self-protective behaviors, as well as adherence to resuscitation guidelines, during simulated resuscitation events. Intervention opportunities include use of rapid isolation measures, use of gatekeepers, reinforcement of first responder roles, and further simulation training with PPE.


title: Persistent prion infection disturbs the function of Oct-1, resulting in the down-regulation of murine interferon regulatory factor-3

text: As a prompt response against invasion of various viruses, interferon regulatory factor-3 (IRF-3) is initially phosphorylated to become activated and upregulates mainly Type I Interferons (IFN-I) in most cell types. We previously reported that IRF-3-dependent host innate immune responses partially interfere in infection of prions. Here, we found that stable infection of prion suppressed IRF-3 gene-expression. The decreased promoter activity of IRF-3 was significantly restored along with treatment of anti-prion drugs in the prion-infected cells, suggesting that infection of prion directly influence the regulation of IRF-3 transcription. We further investigated promoter activity of 5′- flanking region of murine IRF-3 using a luciferase reporter system and found that the nucleotides -119 to -1 were indispensable for the promoter activity. Within this region, mutations in the Oct-1 binding site significantly reduced the promoter activity and chromatin immunoprecipitation (ChIP) assay revealed that Oct-1 indeed binds to the region. In addition, overexpression of Oct-1 increased the promoter activity of IRF-3. Intriguingly, Oct-1 protein was significantly reduced in prion-infected cells and mice brains compared with uninfected groups. Taken together, we concluded that prion infection could interfere in the function of Oct-1, resulting in the down-regulation of IRF-3.


title: Glycyrrhizic acid derivatives as influenza A/H1N1 virus inhibitors

text: Abstract This Letter describes the synthesis and antiviral activity study of some glycyrrhizic acid (GL) derivatives against influenza A/H1N1/pdm09 virus in MDCK cells. Conjugation of GL with l-amino acids or their methyl esters, and amino sugar (d-galactose amine) dramatically changed its activity. The most active compounds were GL conjugates with aromatic amino acids methyl esters (phenylalanine and tyrosine) (SI=61 and 38), and S-benzyl-cysteine (SI=71). Thus modification of GL is a perspective route in the search of new antivirals, and some of GL derivatives are potent as anti-influenza A/H1N1 agents.


The pathogens


title: Sovereign rating after private and official restructuring

text: This paper studies the relationship between sovereign debt (final) restructuring and sovereign ratings, by distinguishing between commercial and official debt and by considering the creditors’ loss (haircut). Institutional Investor’s index is taken as a measure of a country’s creditworthiness. We find that while a restructuring with private creditors seems to involve some reputational costs, ”official defaulters” are not affected (or may even benefit) by the restructuring episodes. Using the Synthetic Control Method, we find further evidence for the heterogeneity of the economic impact of debt restructurings, confirming that official and private restructurings may have different costs and then induce selective defaults.


title: “Alteración del nivel de conciencia puerperal: ¿puede el covid-19 ser causa de síndrome de encefalopatía posterior reversible?”

text: SUMMARY We describe the case of a 24-year-old pregnant woman with no history of note who was admitted with a diagnosis of bilateral pneumonia caused by the new coronavirus.Due to clinical worsening, she required urgent cesarean section with general anaesthesia and intubationfor decubitus intolerance. After extubation, she presented altered mental statethat required a differential diagnosis of encephalitis/meningitis secondary to SARS-CoV-2.CT and CT-angiography were normal, spinal fluid tests were non-specific, and magnetic resonance imaging reported posterior reversible encephalopathy syndrome (PRES) (due to radiological features suggestive of white matter vasogenic edema affecting the parietal, temporal and occipital lobes, along with altered mental state) secondary to gestational hypertension. Eleven days after the cesarean section the patient began to develop hypertension that required treatment. PRES is associated with certain clinical (headache, altered mental state, visual disturbances and convulsions) and radiological (reversible changes in white substance mainly affecting the parietal, temporal, and occipital lobes) characteristics suggestive of vasogenic oedema In pregnant SARS-CoV-2 patients, the differential diagnosis of hypertension and altered mental state is often extremely complicated because complementary tests can be normal and there is no immediate sign of peripartum hypertension. SARS CoV-2 genome sequencing in spinal fluid could have provided a definitive diagnosis, but the treatment would not have differed.