docid: panntacm

title: The selection pressures induced non-smooth infectious disease model and bifurcation analysis

text: Abstract Mathematical models can assist in the design strategies to control emerging infectious disease. This paper deduces a non-smooth infectious disease model induced by selection pressures. Analysis of this model reveals rich dynamics including local, global stability of equilibria and local sliding bifurcations. Model solutions ultimately stabilize at either one real equilibrium or the pseudo-equilibrium on the switching surface of the present model, depending on the threshold value determined by some related parameters. Our main results show that reducing the threshold value to a appropriate level could contribute to the efficacy on prevention and treatment of emerging infectious disease, which indicates that the selection pressures can be beneficial to prevent the emerging infectious disease under medical resource limitation.


Is there a better future of healthy aging?


title: Efficacy and Adverse Events During Janus Kinase Inhibitor Treatment of SAVI Syndrome

text: OBJECTIVES: Mutations affecting the TMEM173 gene cause STING-associated vasculopathy with onset in infancy (SAVI). No standard immunosuppressive treatment approach is able to control disease progression in patients with SAVI. We studied the efficacy and safety of targeting type I IFN signaling with the Janus kinase inhibitor, ruxolitinib. METHODS: We used DNA sequencing to identify mutations in TMEM173 in patients with peripheral blood type I IFN signature. The JAK1/2 inhibitor ruxolitinib was administered on an off-label basis. RESULTS: We identified three patients with SAVI presenting with skin involvement and progressive severe interstitial lung disease. Indirect echocardiographic signs of pulmonary hypertension were present in one case. Following treatment with ruxolitinib, we observed improvements of respiratory function including increased forced vital capacity in two patients, with discontinuation of oxygen therapy and resolution of echocardiographic abnormalities in one case. Efficacy was persistent in one patient and only transitory in the other two patients. Clinical control of skin complications was obtained, and one patient discontinued steroid treatment. One patient, who presented with kidney involvement, showed resolution of hematuria. One patient experienced increased recurrence of severe viral respiratory infections. Monitoring of peripheral blood type I interferon signature during ruxolitinib treatment did not show a stable decrease. CONCLUSIONS: We conclude that targeting type I IFN receptor signaling may represent a promising therapeutic option for a subset of patients with SAVI syndrome and severe lung involvement. However, the occurrence of viral respiratory infection might represent an important cautionary note for the application of such form of treatment. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10875-019-00645-0) contains supplementary material, which is available to authorized users.


title: RNA-Seq Data-Mining Allows the Discovery of Two Long Non-Coding RNA Biomarkers of Viral Infection in Humans

text: There is a growing interest in unraveling gene expression mechanisms leading to viral host invasion and infection progression. Current findings reveal that long non-coding RNAs (lncRNAs) are implicated in the regulation of the immune system by influencing gene expression through a wide range of mechanisms. By mining whole-transcriptome shotgun sequencing (RNA-seq) data using machine learning approaches, we detected two lncRNAs (ENSG00000254680 and ENSG00000273149) that are downregulated in a wide range of viral infections and different cell types, including blood monocluclear cells, umbilical vein endothelial cells, and dermal fibroblasts. The efficiency of these two lncRNAs was positively validated in different viral phenotypic scenarios. These two lncRNAs showed a strong downregulation in virus-infected patients when compared to healthy control transcriptomes, indicating that these biomarkers are promising targets for infection diagnosis. To the best of our knowledge, this is the very first study using host lncRNAs biomarkers for the diagnosis of human viral infections.


title: Tratamiento antigripal: fármacos actualmente utilizados y nuevos agentes en desarrollo

text: Resumen La gripe es una enfermedad contagiosa altamente prevalente y con significativa morbimortalidad. El tratamiento disponible con fármacos antivirales, de ser administrado de forma precoz, puede reducir el riesgo de complicaciones severas; sin embargo, muchos tipos de virus desarrollan resistencia a estos fármacos, reduciendo notablemente su efectividad. Ha habido un gran interés en el desarrollo de nuevas opciones terapéuticas para combatir la enfermedad. Una gran variedad de fármacos han demostrado tener actividad antiinfluenza, pero aún no están disponibles para su uso en la clínica. Muchos de ellos tienen como objetivo componentes del virus, mientras que otros son dirigidos a elementos de la célula huésped que participan en el ciclo viral. Modular los componentes del huésped es una estrategia que minimiza el desarrollo de cepas resistentes, dado que estos no están sujetos a la variabilidad genética que tiene el virus. Por otro lado, la principal desventaja es que existe un mayor riesgo de efectos secundarios asociados al tratamiento. El objetivo de la presente revisión es describir los principales agentes farmacológicos disponibles en la actualidad, así como los nuevos fármacos en estudio con potencial beneficio en el tratamiento de la gripe. Abstract Influenza is a very common contagious disease that carries significant morbidity and mortality. Treatment with antiviral drugs is available, which if administered early, can reduce the risk of severe complications. However, many virus types develop resistance to those drugs, leading to a notable loss of efficacy. There has been great interest in the development of new drugs to combat this disease. A wide range of drugs has shown anti-influenza activity, but they are not yet available for use in the clinic. Many of these target viral components, which others are aimed at elements in the host cell which participate in the viral cycle. Modulating host components is a strategy which minimizes the development of resistance, since host components are not subject to the genetic variability of the virus. The main disadvantage is the risk of treatment-related side effects. The aim of this review is to describe the main pharmacological agents currently available and new drugs in the pipeline with potential benefit in the treatment of influenza.


title: The SARS-Coronavirus Membrane protein induces apoptosis through modulating the Akt survival pathway

text: A number of viral gene products are capable of triggering apoptotic cell death through interfering with cellular signaling cascades, including the Akt kinase pathway. In this study, the pro-apoptotic role of the SARS-CoV Membrane (M) structural protein is described. We found that the SARS-CoV M protein induced apoptosis in both HEK293T cells and transgenic Drosophila. We further showed that M protein-induced apoptosis involved mitochondrial release of cytochrome c protein, and could be suppressed by caspase inhibitors. Over-expression of M caused a dominant rough-eye phenotype in adult Drosophila. By performing a forward genetic modifier screen, we identified phosphoinositide-dependent kinase-1 (PDK-1) as a dominant suppressor of M-induced apoptotic cell death. Both PDK-1 and Akt kinases play essential roles in the cell survival signaling pathway. Altogether, our data show that SARS-CoV M protein induces apoptosis through the modulation of the cellular Akt pro-survival pathway and mitochondrial cytochrome c release.


title: CORONAVIRUS REVERSE GENETIC SYSTEMS: INFECTIOUS CLONES AND REPLICONS

text: Coronaviruses (CoVs) infect humans and many animal species, and are associated with respiratory, enteric, hepatic, and central nervous system diseases. The large size of the CoV genome and the instability of some CoV replicase gene sequences during its propagation in bacteria, represent serious obstacles for the development of reverse genetic systems similar to those used for smaller positive sense RNA viruses. To overcome these limitations, several alternatives to more conventional plasmid-based approaches have been established in the last thirteen years. In this report, we briefly review and discuss the different reverse genetic systems developed for CoVs, paying special attention to the severe acute respiratory syndrome CoV (SARS-CoV).


title: Propagation of respiratory viruses in human airway epithelia reveals persistent virus-specific signatures

text: Background The leading cause of acute illnesses, respiratory viruses, typically cause self-limited diseases, although severe complications can occur in fragile patients. Rhinoviruses (RVs), respiratory enteroviruses (EVs), influenza virus, respiratory syncytial viruses (RSVs), and coronaviruses are highly prevalent respiratory pathogens, but because of the lack of reliable animal models, their differential pathogenesis remains poorly characterized. Objective We sought to compare infections by respiratory viruses isolated from clinical specimens using reconstituted human airway epithelia. Methods Tissues were infected with RV-A55, RV-A49, RV-B48, RV-C8, and RV-C15; respiratory EV-D68; influenza virus H3N2; RSV-B; and human coronavirus (HCoV)–OC43. Replication kinetics, cell tropism, effect on tissue integrity, and cytokine secretion were compared. Viral adaptation and tissue response were assessed through RNA sequencing. Results RVs, RSV-B, and HCoV-OC43 infected ciliated cells and caused no major cell death, whereas H3N2 and EV-D68 induced ciliated cell loss and tissue integrity disruption. H3N2 was also detected in rare goblet and basal cells. All viruses, except RV-B48 and HCoV-OC43, altered cilia beating and mucociliary clearance. H3N2 was the strongest cytokine inducer, and HCoV-OC43 was the weakest. Persistent infection was observed in all cases. RNA sequencing highlighted perturbation of tissue metabolism and induction of a transient but important immune response at 4 days after infection. No majority mutations emerged in the viral population. Conclusion Our results highlight the differential in vitro pathogenesis of respiratory viruses during the acute infection phase and their ability to persist under immune tolerance. These data help to appreciate the range of disease severity observed in vivo and the occurrence of chronic respiratory tract infections in immunocompromised hosts.


title: Diabetic patients with COVID-19 infection are at higher risk of ICU admission and poor short-term outcome

text: Abstract Background The prognostic significance of diabetes mellitus (DM) in patients with coronavirus 2019 disease (COVID-19) remains unknown. Objectives To assess the risk of ICU admission and morality risk in diabetic COVID-19 patients. Study desing A database search was conducted to identify studies comparing diabetic COVID-19 patients hospitalized in intensive care unit (ICU) and those reporting the overall mortality of these patients published up to March 25, 2020 within MEDLINE, Scopus and Web of Science. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed in abstracting data and assessing validity. Quality assessment was performed using the Newcastle-Ottawa quality assessment scale. The main outcome was the risk of ICU admission in diabetic patients with COVID-19 infection while the second was the mortality risk in overall diabetic COVID-19 patients. Data were pooled using the Mantel-Haenszel random effects models with odds ratio (OR) as the effect measure with the related 95 % confidence interval (CI). Statistical heterogeneity between groups was measured using the Higgins I2 statistic. Results Among 1382 patients (mean age 51.5 years, 798 males), DM resulted to be the second more frequent comorbidities. Diabetic patients resulted to have a significant increased risk of ICU admission (OR: 2.79, 95 % CI 1.85–4.22, p < 0.0001, I2 = 46 %). In 471 patients (mean age 56.6 years, 294 males) analysed for the secondary outcome diabetic subjects resulted to be at higher mortality risk (OR 3.21, 95 % CI 1.82–5.64, p < 0.0001, I2 = 16 %). Conclusions Diabetic patients with COVID-19 patients are at higher risk of ICU admission and show an higher mortality risk.


title: Using air curtains to reduce short-range infection risk in consulting ward: A numerical investigation

text: Air curtains is promising in reducing the short-range infection risk in hospitals. To quantitatively evaluate its performance, this paper explores air curtains equipped on normal consulting desk to avoid doctor’s direct exposure to the patient exhaled pollutants. A numerical investigation is conducted to evaluate the effects of supply air velocity and angle on cutting off performance. Simulation results show that the average mass fraction of exhaled pollutants decreases significantly (70%–90%) in the consulting ward, indicating satisfying performance of air curtains. Increasing supply air velocity is demonstrated to be conducive in forming full air curtains, whereas an excessively high supply air velocity may be of adverse effects by entraining exhaled flow. Besides, the supply air angle is also critical due to its coupling with supply air velocity. It is found that larger angle (0°–40°) is better where velocity is less than 3 m/s, otherwise a small angle (20°) is preferable where velocity is larger than 3 m/s. Exhaled flow could be well suppressed at the supply air angle 20° but moves over air curtains at 40°. This study can provide effective and intuitive guidance in applying air curtains in consulting wards. ELECTRONIC SUPPLEMENTARY MATERIAL (ESM): supplementary material is available in the online version of this article at 10.1007/s12273-020-0649-7. The ESM files include the animation of patient exhaled droplets from the droplet birth at 0 s to 5 s under the supply air angle 0°, 20°, 40°, at supply air velocity 3 m/s.


title: Psychological impact of 2019 novel coronavirus (2019-nCoV) outbreak in health workers in China

text: The first case of 2019-nCoV pneumonia infection occurred in Wuhan, Hubei Province, South China Seafood Market in December 2019. As a group with a high probability of infection, health workers are faced with a certain degree of psychological challenges in the process of facing the epidemic. This study attempts to evaluate the impact of 2019-nCoV outbreak on the psychological state of Chinese health workers and to explore the influencing factors. During the period from 31 January 2020 to 4 February 2020, the ‘Questionnaire Star’ electronic questionnaire system was used to collect data. The 2019-nCoV impact questionnaire and The Impact of Event Scale (IES) were used to check the psychological status of health workers in China. A total of 442 valid data were collected in this study. Seventy-four (16.7%) male and 368 (83.3%) female individuals participated in this study. The average score of high arousal dimension was 5.15 (s.d. = 4.71), and the median score was 4.0 (IQR 2.0, 7.0). The average score of IES was 15.26 (s.d. = 11.23), and the median score was 13.5 (IQR 7.0, 21.0). Multiple regression analysis showed that there were critical statistical differences in high arousal scores among different gender groups (male 3.0 vs. female 5.0, P = 0.075). Whether being quarantined had significant statistical differences of IES scores (being quarantined 16.0 vs. not being quarantined 13.0, P = 0.021). The overall impact of the 2019-nCoV outbreak on health workers is at a mild level. Chinese health workers have good psychological coping ability in the face of public health emergencies.


Alone, Together: Social Isolation, Quarantine, and the Coronavirus Pandemic


title: Viral Sepsis in Children

text: Sepsis in children is typically presumed to be bacterial in origin until proven otherwise, but frequently bacterial cultures ultimately return negative. Although viruses may be important causative agents of culture-negative sepsis worldwide, the incidence, disease burden and mortality of viral-induced sepsis is poorly elucidated. Consideration of viral sepsis is critical as its recognition carries implications on appropriate use of antibacterial agents, infection control measures, and, in some cases, specific, time-sensitive antiviral therapies. This review outlines our current understanding of viral sepsis in children and addresses its epidemiology and pathophysiology, including pathogen-host interaction during active infection. Clinical manifestation, diagnostic testing, and management options unique to viral infections will be outlined.


Chinese premier rallies medics in coronavirus fight


docid: tglutbhq

title: Newly identified respiratory viruses associated with acute lower respiratory tract infections in children in Lanzou, China, from 2006 to 2009

text: Nasopharyngeal aspirates were collected from 813 children <14 years old with acute lower respiratory tract infections in Lanzhou, China, from December 2006 to November 2009. PCR or RT-PCR was used to screen for the presence of 10 respiratory viruses. Viral agents were identified in 73.92% (601/813) of specimens, including RSV in 40.71%, hMPV in 6.15%, IFVA in 7.13%, IFVB in 0.98%, PIV1-3 in 7.87%, HCoV-HKU1 in 2.21%, HCoV-NL63 in 3.81%, HRV in 19.93%, AdV in 7.50% and HBoV in 11.56%. Two or more viruses were detected in 34.44% (280/813) of cases. The newly identified respiratory viruses, HBoV, hMPV, HCoV-HKU1 and HCoV-NL63, accounted for 22.01% of the detected viral pathogens. RSV and HRV were frequently detected in patients with bronchiolitis, and hMPV was frequently associated with pneumonia. HCoV-NL63 was found to be one of the causative agents of acute respiratory wheezing in young children. No seasonal variation was found in the incidence of detection of HCoV-HKU1, HCoV-NL63 or HBoV. This 3-year study demonstrated that viral pathogens play an important role in children with ALRTIs, and more attention should be paid to these newly identified viral agents.


title: Crosstalk between autophagy and inflammatory signaling pathways: balancing host defence and homeostasis

text: Autophagy has broad functions in immunity ranging from cell autonomous defense to coordination of complex multicellular responses. The successful resolution of infection and avoidance of autoimmunity necessitates efficient and timely communication between autophagy and pathways that sense the immune environment. In this article, progress in elucidating mechanisms of crosstalk between autophagy and inflammatory signaling cascades will be reviewed. The recent literature indicates that a variety of immune mediators induce or repress autophagy. It is also becoming increasing clear that immune signaling cascades are subject to regulation by autophagy, and that a return to homeostasis following a robust immune response is critically dependent on this pathway. Importantly, examples of non-canonical forms of autophagy in mediating immunity are pervasive. Improved mechanistic understanding of the autophagy machinery offers hope for treating infectious and inflammatory diseases.


title: Role of vitamin D in preventing of COVID-19 infection, progression and severity

text: The outbreak of COVID-19 has created a global public health crisis. Little is known about the protective factors of this infection. Therefore, preventive health measures that can reduce the risk of infection, progression and severity are desperately needed. This review discussed the possible roles of vitamin D in reducing the risk of COVID-19 and other acute respiratory tract infections and severity. Moreover, this study determined the correlation of vitamin D levels with COVID-19 cases and deaths in 20 European countries as of 20 May 2020. A significant negative correlation (p = 0.033) has been observed between mean vitamin D levels and COVID-19 cases per one million population in European countries. However, the correlation of vitamin D with COVID-19 deaths of these countries was not significant. Some retrospective studies demonstrated a correlation between vitamin D status and COVID-19 severity and mortality, while other studies did not find the correlation when confounding variables are adjusted. Several studies demonstrated the role of vitamin D in reducing the risk of acute viral respiratory tract infections and pneumonia. These include direct inhibition with viral replication or with anti-inflammatory or immunomodulatory ways. In the meta-analysis, vitamin D supplementation has been shown as safe and effective against acute respiratory tract infections. Thus, people who are at higher risk of vitamin D deficiency during this global pandemic should consider taking vitamin D supplements to maintain the circulating 25(OH)D in the optimal levels 75-125 nmol/L. In conclusion, there not enough evidence on the association between vitamin D levels and COVID-19 severity and mortality. Therefore, randomized control trials and cohort studies are necessary to test this hypothesis.


The COVID-19 Pandemic: Changing Lives and Lessons Learned


title: Chapter 17 Family Coronaviridae

text: Abstract Members of the family Coronaviridae are large, enveloped, single-stranded RNA viruses. They are the largest known RNA viruses, with genomes ranging from 25 to 32kb and virions of 118–140nm in diameter. The family is divided into two subfamilies, the Coronavirinae and the Torovirinae. They can be distinguished on the basis of their nucleocapsids as the toroviruses have unique doughnut-shaped nucleocapsids. Virions are roughly spherical and are notable for the large spike (S) glycoprotein that extends from the virus envelope. Current taxonomy places the family in the order Nidovirales. Within the subfamily Coronavirinae are four genera, the alpha-, beta-, gamma-, and deltacoronaviruses. All family members share the same unique strategy for mRNA synthesis whereby the polymerase complex jumps or moves from one region of the template to a more distant region. The need for the polymerase complex to dissociate from the template may explain the high rate of RNA recombination that occurs during genome replication. Both the coronaviruses and toroviruses are enteric and respiratory tract pathogens, usually associated with only mild disease (or inapparent infection). However the human severe acute respiratory syndrome (SARS) coronavirus and the Middle East respiratory syndrome (MERS) coronavirus cause severe respiratory diseases.


Virological ultrastructural investigation in 1262 cases of children gastroenteritis


docid: slfzygdv

title: Vaccinations in rheumatic diseases


title: A multidisciplinary investigation of a cluster of deaths on a paediatric intensive care unit

text: Abstract During late December 1989 and early January 1990, a cluster of six unexplained deaths occurred on a paediatric intensive care unit (PICU) among children with congenital heart disease who had undergone cardiac surgical procedures. The children were all aged three years or less. In each case death was preceded by an unexpected increase in ventilatory pressure requirement followed by the development of a similar pulmonary shadowing on chest radiography. The radiological abnormality was felt to be consistent with a pneumonitis associated with some small airway disease. The clustering of these deaths, occurring in a similar unusual manner, was felt to constitute an outbreak warranting investigation. An Incident Committee was established to plan and manage a large multidisciplinary investigation during which the unit was temporarily closed. Following extensive investigation no bacterium, virus, fungus or other pathogen, toxic agent, or any other explanation for the cluster of deaths could be found. The possibility that the cluster occurred by chance remains although this was felt to be unlikely.


title: Caring for Frail Older Adults During COVID‐19: integrating public health ethics into clinical practice

text: During the COVID‐19 pandemic, principles from both clinical and public health ethics cue clinicians and health care administrators to plan alternatives for frail older adults who prefer to avoid critical care, and for when critical care is not available due to crisis triaging. This paper will explore the COVID‐19 Ethical Decision Making Framework, published in British Columbia, Canada, to familiarize clinicians and policy makers with how ethical principles can guide systems change, in the service of frail older adults. In British Columbia, the health care system has launched resources to support clinicians in proactive advance care planning discussions, and is providing enhanced supportive and palliative care options to residents of long term care facilities. If the pandemic truly overwhelms the healthcare system, frailty, but not age alone, provides a fair and evidence‐based means of triaging patients for critical care and could be included into ventilator allocation frameworks. This article is protected by copyright. All rights reserved.


title: Epidemiology, Prevention, and Control of the Number One Foodborne Illness Human Norovirus

text: Human norovirus (NoV) is the number one cause of foodborne illness. Despite tremendous research efforts, human NoV is still poorly understood and understudied. There is no effective measure to eliminate this virus from food and the environment. Future research efforts should focus on developing: (1) an efficient cell culture system and a robust animal model, (2) rapid and sensitive detection methods, (3) novel sanitizers and control interventions, and (4) vaccines and antiviral drugs. Furthermore, there is an urgent need to build multidisciplinary and multi-institutional teams to combat this important biodefense agent.


Concerns about intensive therapies for critically ill COVID-19: Summary of a panel discussion by global intensivists


title: Therapeutic pulmonary telerehabilitation protocol for patients affected by COVID-19, confined to their homes: study protocol for a randomized controlled trial

text: BACKGROUND: In December 2019, 27 cases of pneumonia, of unknown cause, were identified in the province of Hubei (China). The WHO declared the situation as a Public Health Emergency of International Concern, and it was finally declared a global pandemic on March 11, 2020. The Spanish Government obliges the entire population to remain confined to their homes, with the exception of essential basic services, to stop the spread of COVID-19. Home isolation implies a notable physical deconditioning. Telerehabilitation methods have reported positive experiences, and we propose to study in affected patients of COVID-19, due to the general house confinement of the entire Spanish population. METHODS: Patients will be recruited in the regions of Andalusia, Murcia, and Valencia (Spain). Patients will remain confined to their homes, and there, they will carry out their assigned exercise program, which will be controlled telematically. Evaluators will attend to carry out all measurements at the beginning, during, and end of the study, telematically controlled. The patients will be randomly divided into three groups, two of them will perform a home exercise program (breathing exercises or non-specific exercises for muscle toning) and the third group will perform sedentary activities, using mental activation techniques, and will act as a sham group. We will evaluate respiratory variables and other variables of the physical state through physical tests, effort, and perceived fatigue. The data will be statistically analyzed, and the hypotheses will be tested between the groups, using the SPSS software, v.24, considering a 95% confidence interval. DISCUSSION: We will analyze the results, in terms of the level of fatigue and perceived exertion, physical health, and maintenance of respiratory activity of two types of exercise programs, toning and respiratory, applied in patients affected by COVID-19 during the period of home confinement. We intend to investigate a field not previously studied, such as the repercussion of carrying out a toning and respiratory exercise program in these patients, in historical circumstances that no one had previously observed in Spain, since the general population has never been forced to remain confined in their homes, due to a pandemic infection, by a coronavirus (COVID-19). Observing the effects that these two home exercise programs could produce in patients infected with COVID-19, we will try to better analyze and understand the mechanisms that are associated with the worsening of breathing in this type of patient. TRIAL REGISTRATION: Brazilian Clinical Trial Registry RBR-6m69fc. Registered on March 31, 2020.


docid: kkrqtcvg

title: GSK983: A novel compound with broad-spectrum antiviral activity

text: Abstract GSK983, a novel tetrahydrocarbazole, inhibits the replication of a variety of unrelated viruses in vitro with EC50 values of 5–20nM. Both replication of the adenovirus Ad-5 and the polyoma virus SV-40, and episomal maintenance of human papillomaviruses (HPV) and Epstein-Barr virus (EBV) are susceptible to GSK983. The compound does not inhibit all viruses; herpes simplex virus (HSV-1), human immunodeficiency virus (HIV), and lytic replication of EBV were not susceptible at concentrations below 1μM. GSK983 does inhibit the growth of cell lines immortalized by HTLV-1, EBV, HPV, SV40 and Ad-5, with EC50 values in the range of 10–40nM. Depending on the cell line, the compound induces either apoptosis or cytostasis at concentrations over 20nM. GSK983 also inhibits cell lines immortalized by non-viral mechanisms, but has little effect on primary cells. The CC50 values for keratinocytes, fibroblasts, lymphocytes, endothelial, and bone marrow progenitor cells are all above 10μM. The pattern of inhibition, which includes diverse viruses as well as growth of immortalized cells of varied origins, suggests the target is a host cell protein, rather than a viral protein. Preliminary mechanism studies indicate that GSK983 acts by inducing a subset of interferon-stimulated genes.


title: Sensitive detection and typing of porcine reproductive and respiratory syndrome virus by RT-PCR amplification of whole viral genes

text: Abstract Following the recent use of a live vaccine against porcine reproductive and respiratory syndrome virus (PRRSV) in Denmark, both American (vaccine) and European-type PRRSV now coexist in Danish herds. This situation highlighted a requirement for supplementary tests for precise virus-typing. As a result, we developed a RT-PCR assay able to detect as well as type PRRSV. To provide maximal sequence information, complete viral open reading frames (ORFs 5 and 7) were targeted for amplification. The RT-PCR test was able to amplify complete PRRSV ORFs from complex materials such as boar semen containing as little as 1 TCID50 ml−1 of PRRSV. Typing of viruses was accomplished by any one of three strategies: (i) use of type-specific PCR primers, (ii) size determination of ORF 7 amplicons, (iii) DNA sequencing. All three typing strategies showed complete concordance with the currently used method of typing with monoclonal antibodies (MAbs) when used on a panel of PRRSV field isolates covering the period 1992–1997. The ORF 7-based test had particularly desirable characteristics, namely, highly sensitive detection of PRRSV without apparent type bias, typing of the detected virus, discrimination between pure and mixed virus populations, and semi-quantitative assessment of type ratios in mixed populations, all in a single PCR reaction. In addition, the obtained sequence data were used to predict two simple and rapid strategies (single-enzyme restriction length polymorphy analysis and oligonucleotide hybridization) for confirmation of the specificity of ORF 7 RT-PCR reactions. As such, the RT-PCR assay provides a new, powerful diagnostic tool to study the population dynamics between present and emerging PRRSV-types.


title: Chapter 27 Emergence and Reemergence of Viral Zoonotic Diseases: Concepts and Factors of Emerging and Reemerging Globalization of Health Threats

text: Abstract The unpredictable emergence of new zoonotic diseases with viral etiology is currently a hot issue in the scientific and political circles. Viral emergence and reemergence, as a sanitary event, are only the visible part of the iceberg, while the hidden one corresponds to a multitude of complex and interrelated factors, including societal and environmental factors favoring the advent of the state of viral emergence and reemergence. According to the World Health Organization, 60% of the agents recognized as human pathogens come from the animal kingdom, and 75% of the pathogens responsible for emerging and reemerging animal diseases present a potential transgression of interface between interspecies establishing favorable conditions for genetic exchange leading to the emergence of new highly pathogenic variants and strains of which the animal is often the host reservoir. Therefore any public health prophylactic strategy requires a holistic approach to the health problem, taking into account the interaction between the triad elements of the human, animal, and environment. This globalized approach has been realized by the international community through the new recently established concept of “One Health, One World,” making the old bipolar concept of separated human and animal health issues avoided and obsolete. The extreme diversity of emerging and reemerging viral pathogens, the change of human lifestyle, the globalization of travel, business exchanges, and tourism potentiate the risk of emergence of highly pathogenic zoonotic diseases. Promoting intersectorial collaboration will allow to unify the health and safety policies. The cross-cutting ecological and health data at the national and global scales are effective means for sustaining good health in human, animal, and ecosystem (in particular the viral ecology).


title: Rapid response research to emerging infectious diseases: lessons from SARS

text: New and emerging infectious diseases continue to plague the world, and there is significant concern that recombinant infectious agents can be used as bioterrorism threats. Microbiologists are increasingly being asked to apply their scientific knowledge to respond to these threats. The recent pandemic caused by the severe acute respiratory syndrome (SARS) coronavirus illustrated not only how a newly evolved pathogen can rapidly spread throughout the world but also how the global community can unite to identify the causative agent and control its spread. Rapid response research mechanisms, such as those used by the SARS Accelerated Vaccine Initiative (SAVI), have shown that the application of emergency management techniques, together with rapid response research, can be highly effective when applied appropriately to new infectious diseases.


title: Hypertension prevalence in human Coronavirus: The role of ACE system in infection spread and severity

text: Summary The prevalence of hypertension is high in patients affected by COVID infection and it appears related to increased risk of mortality in many epidemiological studies. The ACE system is not uniformly expressed in all the human races, and current differences could hypothesize some geographical discrepancies of infection around the world. However, animal studies showed that ACE2 receptor is a potential pathway for host infection. Because two third of the hypertensive patients take ACE-i/ARB, several concerns have been raised about the detrimental role of current drugs. In this report we summarized the current evidences in favour or against the administration of ACE blockade in the COVID era.


title: Identification of specific histidines as pH sensors in flavivirus membrane fusion

text: The flavivirus membrane fusion machinery, like that of many other enveloped viruses, is triggered by the acidic pH in endosomes after virus uptake by receptor-mediated endocytosis. It has been hypothesized that conserved histidines in the class II fusion protein E of these viruses function as molecular switches and, by their protonation, control the fusion process. Using the mutational analysis of recombinant subviral particles of tick-borne encephalitis virus, we provide direct experimental evidence that the initiation of fusion is crucially dependent on the protonation of one of the conserved histidines (His323) at the interface between domains I and III of E, leading to the dissolution of domain interactions and to the exposure of the fusion peptide. Conserved histidines located outside this critical interface were found to be completely dispensable for triggering fusion.


title: Peptide entry inhibitors of enveloped viruses: The importance of interfacial hydrophobicity

text: Abstract There are many peptides known that inhibit the entry of enveloped viruses into cells, including one peptide that is successfully being used in the clinic as a drug. In this review, we discuss the discovery, antiviral activity and mechanism of action of such peptides. While peptide entry inhibitors have been discovered by a wide variety of approaches (structure-based, accidental, intentional, rational and brute force) we show here that they share a common physical chemical property: they are at least somewhat hydrophobic and/or amphipathic and have a propensity to interact with membrane interfaces. We propose that this propensity drives a shared mechanism of action for many peptide entry inhibitors, involving direct interactions with viral and cellular membranes, as well as interactions with the complex hydrophobic protein/lipid interfaces that are exposed, at least transiently, during virus–cell fusion. By interacting simultaneously with the membrane interfaces and other critical hydrophobic surfaces, we hypothesize that peptide entry inhibitors can act by changing the physical chemistry of the membranes, and the fusion protein interfaces bridging them, and by doing so interfere with the fusion of cellular and viral membranes. Based on this idea, we propose that an approach that focuses on the interfacial hydrophobicity of putative entry inhibitors could lead to the efficient discovery of novel, broad-spectrum viral entry inhibitors. This article is part of a Special Issue entitled: Interfacially Active Peptides and Proteins. Guest Editors: William C. Wimley and Kalina Hristova.


title: Etiology and Clinical Outcomes of Acute Respiratory Virus Infection in Hospitalized Adults

text: BACKGROUND: Etiologies and clinical profiles of acute respiratory viral infections need to be clarified to improve preventive and therapeutic strategies. MATERIALS AND METHODS: A retrospective observational study at a single, university-affiliated center was performed to evaluate the respiratory viral infection etiologies in children compared to that in adults and to document the clinical features of common viral infections for adults from July 2009 to April 2012. RESULTS: The common viruses detected from children (2,800 total patients) were human rhinovirus (hRV) (31.8%), adenovirus (AdV) (19.2%), respiratory syncytial virus (RSV) A (17.4%), RSV B (11.7%), and human metapneumovirus (hMPV) (9.8%). In comparison, influenza virus A (IFA) had the highest isolation rate (28.5%), followed by hRV (15.5%), influenza virus B (IFB) (15.0%), and hMPV (14.0%), in adults (763 total patients). Multiple viruses were detected in single specimens from 22.4% of children and 2.0% of adults. IFA/IFB, RSV A/B, and hMPV exhibited strong seasonal detection and similar circulating patterns in children and adults. Adult patients showed different clinical manifestations according to causative viruses; nasal congestion and rhinorrhea were more common in hRV and human coronavirus (hCoV) infection. Patients with RSV B, hRV, or AdV tended to be younger, and those infected with RSV A and hMPV were likely to be older. Those with RSV A infection tended to stay longer in hospital, enter the intensive care unit more frequently, and have a fatal outcome more often. The bacterial co-detection rate was 26.5%, and those cases were more likely to have lower respiratory tract involvement (P = 0.001), longer hospital stay (P = 0.001), and higher mortality (P = 0.001). CONCLUSIONS: The etiologic virus of an acute respiratory infection can be cautiously inferred based on a patient's age and clinical features and concurrent epidemic data. Large-scale prospective surveillance studies are required to provide more accurate information about respiratory viral infection etiology, which could favorably influence clinical outcomes.


title: Dissecting the Interaction between Coronavirus Disease 2019 and Diabetes Mellitus

text: Coronavirus disease 2019 (COVID‐19) is a global pandemic that is caused by a novel coronavirus, severe acute respiratory syndrome‐coronavirus‐2 (SARS‐CoV‐2). Data from several countries have demonstrated higher morbidity and mortality among individuals with chronic metabolic diseases such as diabetes mellitus (DM). In this review, we explore the contributing factors for poorer prognosis in these individuals. As a significant proportion of patients with COVID‐19 also have DM, this adds another layer of complexity to their management. We explore potential interactions between anti‐diabetic medications and renin‐angiotensin‐aldosterone‐system inhibitors with COVID‐19. Suggested recommendations for the use of anti‐diabetic medications in COVID‐19 patients with DM are provided. We also review pertinent clinical considerations in the management of diabetic ketoacidosis in the COVID‐19 patient. In addition, we aim to increase the awareness of clinicians to the metabolic effects of promising drug therapies for COVID‐19. Finally, we highlight the importance of timely vaccinations for patients with DM.


title: The Impact of Isolation Measures Due to COVID-19 on Energy Intake and Physical Activity Levels in Australian University Students

text: The coronavirus disease 2019 (COVID-19) pandemic resulted in physical isolation measures in many parts of the world. In Australia, nationwide restrictions included staying at home, unless seeking medical care, providing care, purchasing food, undertaking exercise, or attending work in an essential service. All undergraduate university classes transitioned to online, mostly home-based learning. We, therefore, examined the effect of isolation measures during the early phase of the COVID-19 pandemic in Australia (March/April) on diet (24-h recall) and physical activity (Active Australia Survey) patterns in third-year biomedical students. Findings were compared with students enrolled in the same course in the previous two years. In females, but not males, energy intake was ~20% greater during the pandemic, and snacking frequency and energy density of consumed snacks also increased compared with 2018 and 2019. Physical activity was impacted for both sexes during the pandemic with ~30% fewer students achieving “sufficient” levels of activity, defined by at least 150 min over at least five sessions, compared with the previous two years. In a follow-up study six to eight weeks later (14–18% response rate), during gradual easing of nationwide restrictions albeit continued gym closures and online learning, higher energy intake in females and reduced physical activity levels in both sexes persisted. These data demonstrate the health impacts of isolation measures, with the potential to affect long-term diet and activity behaviours.


title: Reusability Comparison of Melt-Blown vs Nanofiber Face Mask Filters for Use in the Coronavirus Pandemic

text: [Image: see text] Shortage of face masks is a current critical concern since the emergence of coronavirus-2 or SARS-CoV-2 (COVID-19). In this work, we compared the melt-blown (MB) filter, which is commonly used for the N95 face mask, with nanofiber (NF) filter, which is gradually used as an effective mask filter, to evaluate their reusability. Extensive characterizations were performed repeatedly to evaluate some performance parameters, which include filtration efficiency, airflow rate, and surface and morphological properties, after two types of cleaning treatments. In the first cleaning type, samples were dipped in 75% ethanol for a predetermined duration. In the second cleaning type, 75% ethanol was sprayed on samples. It was found that filtration efficiency of MB filter was significantly dropped after treatment with ethanol, while the NF filter exhibited consistent high filtration efficiency regardless of cleaning types. In addition, the NF filter showed better cytocompatibility than the MB filter, demonstrating its harmlessness on the human body. Regardless of ethanol treatments, surfaces of both filter types maintained hydrophobicity, which can sufficiently prevent wetting by moisture and saliva splash to prohibit not only pathogen transmission but also bacterial growth inside. On the basis of these comparative evaluations, the wider use of the NF filter for face mask applications is highly recommended, and it can be reused multiple times with robust filtration efficiency. It would be greatly helpful to solve the current shortage issue of face masks and significantly improve safety for front line fighters against coronavirus disease.


title: The role of gamma interferon in infection of susceptible mice with murine coronavirus, MHV-JHM

text: Infection of BALB/c mice with mouse hepatitis virus, strain JHM (MHV-JHM), at any of several intervals relative to ovalbumin (OVA) administration resulted in elevated OVA-specific IgG 2 a titers. Since gamma interferon (IFN) has been implicated as an up-regulator of IgG 2 a production, attempts were made to determine whether levels of this cytokine were modified in sera of infected mice. Serum IFN-γ was not detected, but treatment of MHV-JHM-infected mice with monoclonal anti-IFN-γ antibody resulted in high mortality with decreased survival times, enhanced virus titers in liver and spleen, and more severe virus-associated pathology, compared to mock-treated, infected mice. Immunotherapy with recombinant IFN-γ ameliorated disease as reflected by mortality rates and virus titers in target organs.


title: Higher level of neutrophil-to-lymphocyte is associated with severe COVID-19

text: In December 2019, cases of severe coronavirus 2019 (COVID-19) infection rapidly progressed to acute respiratory failure. This study aims to assess the association between the neutrophil-to-lymphocyte ratio (NLR) and the incidence of severe COVID-19 infection. A retrospective cohort study was conducted on 210 patients with COVID-19 infection who were admitted to the Central Hospital of Wuhan from 27 January 2020 to 9 March 2020. Peripheral blood samples were collected and examined for lymphocyte subsets by flow cytometry. Associations between tertiles of NLR and the incidence of severe illness were analysed by logistic regression. Of the 210 patients with COVID-19, 87 were diagnosed as severe cases. The mean NLR of the severe group was higher than that of the mild group (6.6 vs. 3.3, P < 0.001). The highest tertile of NLR (5.1–19.7) exhibited a 5.9-fold (95% CI 1.3–28.5) increased incidence of severity relative to that of the lowest tertile (0.6–2.5) after adjustments for age, diabetes, hypertension and other confounders. The number of T cells significantly decreased in the severe group (0.5 vs. 0.9, P < 0.001). COVID-19 might mainly act on lymphocytes, particularly T lymphocytes. NLR was identified as an early risk factor for severe COVID-19 illness. Patients with increased NLR should be admitted to an isolation ward with respiratory monitoring and supportive care.


After Malaria Is Controlled, What's Next?†


European National News


Resumption of work in the building and public works sector


title: Managing tourism emissions through optimizing the tourism demand mix: Concept and analysis

text: Carbon mitigation strategies are an urgent and overdue tourism industry imperative. The tourism response to climate action has been to engage businesses in technology adoption, and to encourage more sustainable visitor behaviour. These strategies however are insufficient to mitigate the soaring carbon footprint of tourism. Building upon the concepts of optimization and eco-efficiency, we put forward a novel carbon mitigation approach, which seeks to pro-actively determine, foster, and develop a long-term tourist market portfolio. This can be achieved through intervening and reconfiguring the demand mix with the fundamental aim of promoting low carbon travel markets. The concept and the analytical framework that quantitatively inform optimization of the desired market mix are presented. Combining the “de-growth” and “optimization” strategies, it is demonstrated that in the case study of Taiwan, great potential exists to reduce emissions and sustain economic yields. The implications for tourism destination managers and wider industry stakeholders are discussed.


Neurogenetics: Gene implicated in apes' brain growth


title: Development of transgenic mouse model expressing porcine aminopeptidase N and its susceptibility to porcine epidemic diarrhea virus

text: Abstract Porcine coronavirus infections have known as they are specific to pigs with predominantly enteric or respiratory diseases. No laboratory animal model is yet been developed in porcine coronaviruses study. Here, we report that development of a transgenic mouse model expressing porcine APN which is susceptible to porcine coronavirus infection. The porcine APN transgene was constructed by fusing with mouse proximal APN promoter at 5′ terminus and bovine growth hormone polyadenylation site at its 3′ terminus. After screen on pubs from the microinjected mice, we confirmed two transgenic lines expressing porcine APN in various organs. We confirmed the susceptibility to porcine epidemic diarrhea virus, one of the porcine coronaviruses. These transgenic mice will be an important tool for research into the porcine coronaviruses.


title: PAMPs and DAMPs: Signal 0s that Spur Autophagy and Immunity

text: Pathogen-associated molecular pattern molecules (PAMPs) are derived from microorganisms and recognized by pattern recognition receptor (PRR)-bearing cells of the innate immune system as well as many epithelial cells. In contrast, damage-associated molecular pattern molecules (DAMPs) are cell-derived and initiate and perpetuate immunity in response to trauma, ischemia, and tissue damage, either in the absence or presence of pathogenic infection. Most PAMPs and DAMPs serve as so-called ‘Signal 0s’ that bind specific receptors [Toll-like receptors, NOD-like receptors, RIG-I-like receptors, AIM2-like receptors, and the receptor for advanced glycation end products (RAGE)] to promote autophagy. Autophagy, a conserved lysosomal degradation pathway, is a cell survival mechanism invoked in response to environmental and cellular stress. Autophagy is inferred to have been present in the last common eukaryotic ancestor and only to have been lost by some obligatory intracellular parasites. As such, autophagy represents a unifying biology, subserving survival and the earliest host defense strategies, predating apoptosis, within eukaryotes. Here, we review recent advances in our understanding of autophagic molecular mechanisms and functions in emergent immunity.


title: Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals

text: Summary Understanding adaptive immunity to SARS-CoV-2 is important for vaccine development, interpreting coronavirus disease 2019 (COVID-19) pathogenesis, and calibration of pandemic control measures. Using HLA class I and II predicted peptide ‘megapools’, circulating SARS-CoV-2−specific CD8+ and CD4+ T cells were identified in ∼70% and 100% of COVID-19 convalescent patients, respectively. CD4+ T cell responses to spike, the main target of most vaccine efforts, were robust and correlated with the magnitude of the anti-SARS-CoV-2 IgG and IgA titers. The M, spike and N proteins each accounted for 11-27% of the total CD4+ response, with additional responses commonly targeting nsp3, nsp4, ORF3a and ORF8, among others. For CD8+ T cells, spike and M were recognized, with at least eight SARS-CoV-2 ORFs targeted. Importantly, we detected SARS-CoV-2−reactive CD4+ T cells in ∼40-60% of unexposed individuals, suggesting cross-reactive T cell recognition between circulating ‘common cold’ coronaviruses and SARS-CoV-2.


title: Ocular screening in severe acute respiratory syndrome

text: Abstract To investigate the ocular manifestations of patients with severe acute respiratory syndrome (SARS) and to monitor the possible ocular complications arising from the treatment regimen with high-dose systemic corticosteroid drugs. Design Prospective, observational cohort case series. Methods Ninety eyes from 45 patients with the diagnosis of SARS during an epidemic outbreak in Hong Kong were analyzed. Relevant medical and ophthalmic histories were taken. Ophthalmic examinations, including best-corrected visual acuity, intraocular pressure, slit-lamp, and indirect ophthalmoscopy examination, were performed at baseline and at 2-month and 3-month follow-up. Setting Faculty practice in university hospital. Results Only two patients had mild elevated intraocular pressure at baseline and at subsequent follow-up. There was no loss of visual acuity, cataract progression, or increased cup–disk ratio. Fundus examinations were unremarkable in all patients. Conclusions Our study did not demonstrate any ocular manifestations in patients with SARS. The treatment regimen of high-dose corticosteroid also did not show any significant ocular complications. Routine ocular screening of patients with SARS for diagnosis or for complications might not be indicated.


title: The knowledge level and precautionary measures taken by older adults during the SARS outbreak in Hong Kong

text: Abstract The study aims to examine the knowledge and the practice of the precautionary measures taken by older adults in Hong Kong against the outbreak of severe acute respiratory syndrome (SARS). Overall, more than half the participants responded correctly that droplet transmission is one of the main transmission routes of SARS. Those who received formal education demonstrated that they acquired greater knowledge of the sources and precautionary measures for SARS. The types of precautionary measures used and the factors affecting their behaviours were discussed. The results of the study could help the health-care professionals develop appropriate health promotion and disease prevention programmes for older adults.


title: Immunization with vesicular stomatitis virus vaccine expressing the Ebola glycoprotein provides sustained long-term protection in rodents

text: Abstract Ebola virus (EBOV) infections cause lethal hemorrhagic fever in humans, resulting in up to 90% mortality. EBOV outbreaks are sporadic and unpredictable in nature; therefore, a vaccine that is able to provide durable immunity is needed to protect those who are at risk of exposure to the virus. This study assesses the long-term efficacy of the vesicular stomatitis virus (VSV)-based vaccine (VSVΔG/EBOVGP) in two rodent models of EBOV infection. Mice and guinea pigs were first immunized with 2×104 or 2×105 plaque forming units (PFU) of VSVΔG/EBOVGP, respectively. Challenge of mice with a lethal dose of mouse-adapted EBOV (MA-EBOV) at 6.5 and 9 months after vaccination provided complete protection, and 80% (12 of 15 survivors) protection at 12 months after vaccination. Challenge of guinea pigs with a lethal dose of guinea pig-adapted EBOV (GA-EBOV) at 7, 12 and 18 months after vaccination resulted in 83% (5 of 6 survivors) at 7 months after vaccination, and 100% survival at 12 and 18 months after vaccination. No weight loss or clinical signs were observed in the surviving animals. Antibody responses were analyzed using sera from individual rodents. Levels of EBOV glycoprotein-specific IgG antibody measured immediately before challenge appeared to correlate with protection. These studies confirm that vaccination with VSVΔG/EBOVGP is able to confer long-term protection against Ebola infection in mice and guinea pigs, and support follow-up studies in non-human primates.


title: Emergence of genomic diversity and recurrent mutations in SARS-CoV-2

text: Abstract SARS-CoV-2 is a SARS-like coronavirus of likely zoonotic origin first identified in December 2019 in Wuhan, the capital of China's Hubei province. The virus has since spread globally, resulting in the currently ongoing COVID-19 pandemic. The first whole genome sequence was published on January 52,020, and thousands of genomes have been sequenced since this date. This resource allows unprecedented insights into the past demography of SARS-CoV-2 but also monitoring of how the virus is adapting to its novel human host, providing information to direct drug and vaccine design. We curated a dataset of 7666 public genome assemblies and analysed the emergence of genomic diversity over time. Our results are in line with previous estimates and point to all sequences sharing a common ancestor towards the end of 2019, supporting this as the period when SARS-CoV-2 jumped into its human host. Due to extensive transmission, the genetic diversity of the virus in several countries recapitulates a large fraction of its worldwide genetic diversity. We identify regions of the SARS-CoV-2 genome that have remained largely invariant to date, and others that have already accumulated diversity. By focusing on mutations which have emerged independently multiple times (homoplasies), we identify 198 filtered recurrent mutations in the SARS-CoV-2 genome. Nearly 80% of the recurrent mutations produced non-synonymous changes at the protein level, suggesting possible ongoing adaptation of SARS-CoV-2. Three sites in Orf1ab in the regions encoding Nsp6, Nsp11, Nsp13, and one in the Spike protein are characterised by a particularly large number of recurrent mutations (>15 events) which may signpost convergent evolution and are of particular interest in the context of adaptation of SARS-CoV-2 to the human host. We additionally provide an interactive user-friendly web-application to query the alignment of the 7666 SARS-CoV-2 genomes.


title: On the Origin of Cells and Viruses: Primordial Virus World Scenario

text: It is proposed that the precellular stage of biological evolution unraveled within networks of inorganic compartments that harbored a diverse mix of virus‐like genetic elements. This stage of evolution might makes up the Last Universal Cellular Ancestor (LUCA) that more appropriately could be denoted Last Universal Cellular Ancestral State (LUCAS). Such a scenario recapitulates the ideas of J. B. S. Haldane sketched in his classic 1928 essay. However, unlike in Haldane's day, considerable support for this scenario exits today: lack of homology between core DNA replication system components in archaea and bacteria, distinct membrane chemistries and enzymes of lipid biosynthesis in archaea and bacteria, spread of several viral hallmark genes among diverse groups of viruses, and the extant archaeal and bacterial chromosomes appear to be shaped by accretion of diverse, smaller replicons. Under the viral model of precellular evolution, the key components of cells originated as components of virus‐like entities. The two surviving types of cellular life forms, archaea and bacteria, might have emerged from the LUCAS independently, along with, probably, numerous forms now extinct.


title: Physiotherapy management for COVID-19 in the acute hospital setting: clinical practice recommendations

text: Abstract This document outlines recommendations for physiotherapy management for COVID-19 in the acute hospital setting. It includes: recommendations for physiotherapy workforce planning and preparation; a screening tool for determining requirement for physiotherapy; and recommendations for the selection of physiotherapy treatments and personal protective equipment. It is intended for use by physiotherapists and other relevant stakeholders in the acute care setting caring for adult patients with confirmed or suspected COVID-19.


title: A new mouse-adapted strain of SARS-CoV as a lethal model for evaluating antiviral agents in vitro and in vivo

text: Severe acute respiratory syndrome (SARS) is a highly lethal emerging disease caused by coronavirus SARS-CoV. New lethal animal models for SARS were needed to facilitate antiviral research. We adapted and characterized a new strain of SARS-CoV (strain v2163) that was highly lethal in 5–6 week old BALB/c mice. It had nine mutations affecting 10 amino acid residues. Strain v2163 increased IL-1α, IL-6, MIP-1α, MCP-1, and RANTES in mice, and high IL-6 expression correlated with mortality. The infection largely mimicked human disease, but lung pathology lacked hyaline membrane formation. In vitro efficacy against v2163 was shown with known inhihibitors of SARS-CoV replication. In v2163-infected mice, Ampligen™ was fully protective, stinging nettle lectin (UDA) was partially protective, ribavirin was disputable and possibly exacerbated disease, and EP128533 was inactive. Ribavirin, UDA and Ampligen™ decreased IL-6 expression. Strain v2163 provided a valuable model for anti-SARS research.


title: Xenotransplantation panel for the detection of infectious agents in pigs

text: Recent advances in xenotransplantation have produced organs from pigs that are well tolerated in primate models because of genetic changes engineered to delete major antigens from donor animals. To ensure the safety of human transplant recipients, it will be essential to understand both the spectrum of infectious agents in donor pigs and their potential to be transmitted to immunocompromised transplant recipients. Equally important will be the development of new highly sensitive diagnostic methods for use in the detection of these agents in donor animals and for the monitoring of transplant recipients. Herein, we report results from a panel of 30 quantitative polymerase chain reaction (qPCR) assays for infectious agents with the potential to be transmitted to the human host. The reproducibility, sensitivity and specificity of each assay were evaluated and were found to exhibit analytic sensitivity that was similar to that of quantitative assays used to perform viral load testing of human viruses in clinical laboratories. This analytical approach was used to detect nucleic acids of infectious agents present in specimens from 9 sows and 22 piglets derived by caesarean section. The most commonly detected targets in adult animals were Mycoplasma species and two distinct herpesviruses, porcine lymphotrophic herpesvirus 2 and 3. A total of 14 piglets were derived from three sows infected with either or both herpesviruses, yet none tested positive for the viruses indicating that vertical transmission of these viruses is inefficient.


title: Primaquine derivatives: Modifications of the terminal amino group

text: Numerous modifications of the well-known antimalarial drug primaquine, both at the quinoline ring and at the primary amino group, have been reported, mostly to obtain antimalarial agents with improved bioavailability, reduced toxicity and/or prolonged activity. Modifications of the terminal amino group were made with the main idea to prevent the metabolic pathway leading to inactive and toxic carboxyprimaquine (follow-on strategy), but also to get compounds with different activity (repurposing strategy). The modifications undertaken until 2009 were included in a review published in the same year. The present review covers various classes of primaquine N-derivatives with diverse biological profiles, prepared in the last decade by our research group as well as the others. We have summarized the synthetic procedures applied for their preparation and discussed the main biological results. Several hits for the development of novel antiplasmodial, anticancer, antimycobacterial and antibiofilm agents were identified.


title: Tools for Model Building and Optimization into Near-Atomic Resolution Electron Cryo-Microscopy Density Maps

text: Electron cryo-microscopy (cryoEM) has advanced dramatically to become a viable tool for high-resolution structural biology research. The ultimate outcome of a cryoEM study is an atomic model of a macromolecule or its complex with interacting partners. This chapter describes a variety of algorithms and software to build a de novo model based on the cryoEM 3D density map, to optimize the model with the best stereochemistry restraints and finally to validate the model with proper protocols. The full process of atomic structure determination from a cryoEM map is described. The tools outlined in this chapter should prove extremely valuable in revealing atomic interactions guided by cryoEM data.


The Move to Online—Getting It Done


title: Emerging respiratory infections threatening public health in the Asia‐Pacific region: A position paper of the Asian Pacific Society of Respirology

text: In past decades, we have seen several epidemics of respiratory infections from newly emerging viruses, most of which originated in animals. These emerging infections, including severe acute respiratory syndrome coronavirus (SARS‐CoV), Middle East respiratory syndrome coronavirus (MERS‐CoV) and the pandemic influenza A(H1N1) and avian influenza (AI) viruses, have seriously threatened global health and the economy. In particular, MERS‐CoV and AI A(H7N9) are still causing infections in several areas, and some clustering of cases of A(H5N1) and A(H7N9) may imply future possible pandemics. Additionally, given the inappropriate use of antibiotics and international travel, the spread of carbapenem‐resistant Gram‐negative bacteria is also a significant concern. These infections with epidemic or pandemic potential present a persistent threat to public health and a huge burden on healthcare services in the Asia‐Pacific region. Therefore, to enable efficient infection prevention and control, more effective international surveillance and collaboration systems, in the context of the ‘One Health’ approach, are necessary.


title: Avian Influenza: Are We Ready?

text: The threat of an H5N1 influenza virus (avian flu) pandemic is substantial, and an effective response is contingent upon effective coordination among state and local public health authorities and individual health care providers. It is imperative that critical care nurses take an active role in the plans to meet the demands that will be placed on the health care system. This can be accomplished by developing an understanding of the etiology and manifestations of the virus, and becoming familiar with recent advances in research that address the demands of a pandemic. Equally important are the ethical considerations our state of preparedness will pose on the health care system, the community, and health care workers, both professionally and personally.


title: Preparation for Quarantine on the Cruise Ship Diamond Princess in Japan due to COVID-19

text: BACKGROUND: Japan implemented a large-scale quarantine on the Diamond Princess cruise ship in an attempt to control the spread of the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in February 2020. OBJECTIVE: We aim to describe the medical activities initiated and difficulties in implementing quarantine on a cruise ship. METHODS: Reverse transcription–polymerase chain reaction (RT-PCR) tests for SARS-CoV-2 were performed for all 3711 people (2666 passengers and 1045 crew) on board. RESULTS: Of those tested, 696 (18.8%) tested positive for coronavirus disease (COVID-19), of which 410 (58.9%) were asymptomatic. We also confirmed that 54% of the asymptomatic patients with a positive RT-PCR result had lung opacities on chest computed tomography. There were many difficulties in implementing quarantine, such as creating a dividing traffic line between infectious and noninfectious passengers, finding hospitals and transportation providers willing to accept these patients, transporting individuals, language barriers, and supporting daily life. As of March 8, 2020, 31 patients (4.5% of patients with positive RT-PCR results) were hospitalized and required ventilator support or intensive care, and 7 patients (1.0% of patients with positive RT-PCR results) had died. CONCLUSIONS: There were several difficulties in implementing large-scale quarantine and obtaining medical support on the cruise ship. In the future, we need to prepare for patients’ transfer and the admitting hospitals when disembarking the passengers. We recommend treating the crew the same way as the passengers to control the infection. We must also draw a plan for the future, to protect travelers and passengers from emerging infectious diseases on cruise ships.


title: Preliminary design of an innovative, simple, and easy-to-build portable ventilator for COVID-19 patients

text: This technical note describes the preliminary design of a simple, easy-to-use, and easy-to-build ventilator with an unique design that can be used for COVID-19 patients in emergencies and to prevent massive loss of life in resource-poor environments. It can be assembled by a nonexpert as a homemade solution, without the need for specific equipment or technology. The proposed system is novel, inexpensive, has a reduced reliance on external power, and is very easy to maintain.


title: Characterization of a novel bat-HKU2-like swine enteric alphacoronavirus (SeACoV) infection in cultured cells and development of a SeACoV infectious clone

text: Abstract Swine enteric alphacoronavirus (SeACoV), also known as swine acute diarrhea syndrome coronavirus (SADS-CoV), belongs to the species Rhinolophus bat coronavirus HKU2. Herein, we report on the primary characterization of SeACoV in vitro. Four antibodies against the SeACoV spike, membrane, nucleocapsid and nonstructural protein 3 capable of reacting with viral antigens in SeACoV-infected Vero cells were generated. We established a DNA-launched SeACoV infectious clone based on the cell adapted passage-10 virus and rescued the recombinant virus with a unique genetic marker in cultured cells. Six subgenomic mRNAs containing the leader-body junction sites, including a bicistronic mRNA encoding the accessory NS7a and NS7b genes, were experimentally identified in SeACoV-infected cells. Cellular ultrastructural changes induced by SeACoV infection were visualized by electron microscopy. The availability of the SeACoV infectious clone and a panel of antibodies against different viral proteins will facilitate further studies on understanding the molecular mechanisms of SeACoV replication and pathogenesis.


title: Serologic responses of 42 MERS-coronavirus-infected patients according to the disease severity

text: Abstract We evaluated serologic response of 42 Middle East respiratory syndrome coronavirus (MERS-CoV)-infected patients according to 4 severity groups: asymptomatic infection (Group 0), symptomatic infection without pneumonia (Group 1), pneumonia without respiratory failure (Group 2), and pneumonia progressing to respiratory failure (Group 3). None of the Group 0 patients showed seroconversion, while the seroconversion rate gradually increased with increasing disease severity (0.0%, 60.0%, 93.8%, and 100% in Group 0, 1, 2, 3, respectively; P = 0.001). Group 3 patients showed delayed increment of antibody titers during the fourth week, while Group 2 patients showed robust increment of antibody titer during the third week. Among patients having pneumonia, 75% of deceased patients did not show seroconversion by the third week, while 100% of the survived patients were seroconverted (P = 0.003).


title: ORF8-Related Genetic Evidence for Chinese Horseshoe Bats as the Source of Human Severe Acute Respiratory Syndrome Coronavirus

text: Several lineage B betacoronaviruses termed severe acute respiratory syndrome (SARS)–like CoVs (SL-CoVs) were identified from Rhinolophus bats in China. These viruses are characterized by a set of unique accessory open reading frames (ORFs) that are located between the M and N genes. Among unique accessory ORFs, ORF8 is most hypervariable. In this study, the ORF8s of all SL-CoVs were classified into 3 types, and, for the first time, it was found that very few SL-CoVs from Rhinolophus sinicus have ORF8s that are identical to that of human SARS-CoV. This finding provides new genetic evidence for Chinese horseshoe bats as the source of human SARS-CoV.


title: Challenges of evaluating lung function as part of cancer care during the COVID-19 pandemic

text: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a newly identified agent foisted upon humanity and responsible for the contagious affliction, coronavirus disease 2019 (COVID-19) [1] that has rapidly evolved into a pandemic testing to their limits, and sometimes beyond, the capacity to respond of healthcare systems across the world [2]. Management is purely supportive and social isolation crucial to containment [3]. Enforced reallocation of hospital resources and personnel to cope with the increasing numbers requiring hospital admission and intensive care [4] in the most trying of conditions has been at the expense of many hospital departments, among them those offering diagnostic and support services for lung cancer [5–7].


title: Production of immunogenic VP6 protein of bovine group A rotavirus in transgenic potato plants

text: We report here the production of transgenic potato plants expressing the major capsid protein VP6 of bovine group A rotavirus (GAR). Transgenic plants under the control of a cauliflower mosaic virus 35S promoter, or a modified promoter linked to the tobacco mosaic virus 5′-untranslated sequence were positive for GAR antigens by ELISA. The expressed protein was consistent in size with VP6 of GAR by Western blot assay. The presence of the VP6 gene and its transcript was detected by PCR and RT-PCR. Adult BALB/c mice were immunized intraperitoneally with concentrated transgenic potato extracts emulsified in Freund’s adjuvant. Sera collected after immunization showed the anti-VP6 response in ELISA and Western blot assay. These results suggest that the immunogenic VP6 protein expressed in plants could be useful for the preparation of diagnostic reagents.


title: Governing Towards ‘One Health’: Establishing Knowledge Integration in Global Health Security Governance

text: Recent global threats (e.g. Ebola, avian influenza, the Zika virus) have demonstrated the need for policy makers to focus on the detection of risks at the animal‐human interface. Yet epistemic knowledge across these domains is not sufficiently joined‐up. The article argues that, despite some progress, in order for the policy agenda for global health security to develop towards a ‘One Health’ model there is a need for integration across public and animal health domains. This article sets out an evaluation framework for establishing knowledge integration across these sectors. The article concludes that although ‘One Health may seem utopian, given there are key challenges when it comes to reaching integration, there are important steps that can be taken the short to medium‐term. These include reforms to education and training programmes and interdisciplinary research collaborations. A key determinant of whether One Health becomes a paradigm which frames public policy, and leads to policy and institutional changes to enable public value creation and sustainability, is the presence of an ‘epistemic community’ that bridges health networks.


title: Delays in Service for Non-Emergent Patients Due to Arrival of Emergent Patients in the Emergency Department: A Case Study in Hong Kong

text: Abstract Background In Hong Kong Emergency Departments (EDs), the timeliness of providing high-quality services has been compromised by the increasing attendance of non-emergent patients in addition to the unpredictable arrival of emergency patients. Objectives We sought to quantify the impact of the presence of emergent patients and other related factors on the delay in service for non-emergent patients. Methods We conducted a retrospective study in patients who visited the ED of a large hospital in Hong Kong from July 1, 2009 to June 30, 2010. We estimated waiting and length of stay (LOS) for individual non-emergent patients registered during day and evening shifts. Using multiple linear regression, we estimated waiting time and LOS as a function of the presence of emergent patients and other related factors such as patient demographics and clinical factors. In particular, we evaluated the influence of the arrival or presence of emergent patients on the odds of violating the 120-min waiting time target for semi-urgent patients. Results The arrival of a new emergent patient prolonged the waiting time and LOS of a non-emergent patient by 14.9% (95% confidence interval [CI] 14.2–15.5) and 10.8% (95% CI 10.6–11.0), respectively. An additional patient-hour needed for an emergent patient increased the probability of violating the waiting time target for non-emergent patients (odds ratio 2.3, 95% CI 2.2–2.4). Conclusions The arrival of an emergent patient significantly prolonged the waiting time and LOS for non-emergent patients. Discouraging non-urgent ED utilization and building a real-time decision-support system are critical methods needed to relieve staff pressure and guide contingent resource reallocation when emergent patients arrive.


title: Respiratory Syncytial Virus Infects Regulatory B Cells in Human Neonates via Chemokine Receptor CX3CR1 and Promotes Lung Disease Severity

text: Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infections in infants and is characterized by pulmonary infiltration of B cells in fatal cases. We analyzed the B cell compartment in human newborns and identified a population of neonatal regulatory B lymphocytes (nBreg cells) that produced interleukin 10 (IL-10) in response to RSV infection. The polyreactive B cell receptor of nBreg cells interacted with RSV protein F and induced upregulation of chemokine receptor CX3CR1. CX3CR1 interacted with RSV glycoprotein G, leading to nBreg cell infection and IL-10 production that dampened T helper 1 (Th1) cytokine production. In the respiratory tract of neonates with severe RSV-induced acute bronchiolitis, RSV-infected nBreg cell frequencies correlated with increased viral load and decreased blood memory Th1 cell frequencies. Thus, the frequency of nBreg cells is predictive of the severity of acute bronchiolitis disease and nBreg cell activity may constitute an early-life host response that favors microbial pathogenesis.


title: Regulation of the p38 mitogen-activated protein kinase and dual-specificity phosphatase 1 feedback loop modulates the induction of interleukin 6 and 8 in cells infected with coronavirus infectious bronchitis virus

text: Abstract Induction of pro-inflammatory response is a crucial cellular process that detects and controls the invading viruses at early stages of the infection. Along with other innate immunity, this nonspecific response would either clear the invading viruses or allow the adaptive immune system to establish an effective antiviral response at late stages of the infection. The objective of this study was to characterize cellular mechanisms exploited by coronavirus infectious bronchitis virus (IBV) to regulate the induction of two pro-inflammatory cytokines, interleukin (IL)-6 and IL-8, at the transcriptional level. The results showed that IBV infection of cultured human and animal cells activated the p38 mitogen-activated protein kinase (MAPK) pathway and induced the expression of IL-6 and IL-8. Meanwhile, IBV has developed a strategy to counteract the induction of IL-6 and IL-8 by inducing the expression of dual-specificity phosphatase 1 (DUSP1), a negative regulator of the p38 MAPK, in order to limit the production of an excessive amount of IL-6 and IL-8 in the infected cells. As activation of the p38 MAPK pathway and induction of IL-6 and IL-8 may have multiple pathogenic effects on the whole host as well as on individual infected cells, regulation of the p38 MAPK and DUSP1 feedback loop by IBV may modulate the pathogenesis of the virus.


The resumption of surgical activities: A health emergency and a contribution to the economic recovery


title: Coronavirus and PARP expression dysregulate the NAD Metabolome: a potentially actionable component of innate immunity

text: SARS-CoV-2 is a coronavirus (CoV) and cause of COVID-19, which is much more lethal in older people and those with comorbid conditions for unknown reasons. Innate immune responses to CoVs are initiated by recognition of double-stranded RNA and induction of interferon, which turns on a gene expression program that inhibits viral replication. Here we show that SARS-CoV-2 infection of cells, ferrets and a person strikingly dysregulates the NAD gene set by inducing a set of PARP family members that includes enzymes required for the innate immune response to CoVs. CoV infection also induces a severe attack on host cell NAD. Overexpression of one induced enzyme, PARP10, is sufficient to depress host NAD. Gene expression and pharmacological data suggest that boosting NAD through the nicotinamide and nicotinamide riboside kinase pathways may restore antiviral PARP functions to support innate immunity to CoVs, whereas PARP1,2 inhibition does not restore PARP10 activity.


Precautions in ophthalmic practice in a hospital with the risk of COVID‐19: experience from China


title: Cellular Cullin RING Ubiquitin Ligases: Druggable Host Dependency Factors of Cytomegaloviruses

text: Human cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus that frequently causes morbidity and mortality in individuals with insufficient immunity, such as transplant recipients, AIDS patients, and congenitally infected newborns. Several antiviral drugs are approved to treat HCMV infections. However, resistant HCMV mutants can arise in patients receiving long-term therapy. Additionally, side effects and the risk to cause birth defects limit the use of currently approved antivirals against HCMV. Therefore, the identification of new drug targets is of clinical relevance. Recent work identified DNA-damage binding protein 1 (DDB1) and the family of the cellular cullin (Cul) RING ubiquitin (Ub) ligases (CRLs) as host-derived factors that are relevant for the replication of human and mouse cytomegaloviruses. The first-in-class CRL inhibitory compound Pevonedistat (also called MLN4924) is currently under investigation as an anti-tumor drug in several clinical trials. Cytomegaloviruses exploit CRLs to regulate the abundance of viral proteins, and to induce the proteasomal degradation of host restriction factors involved in innate and intrinsic immunity. Accordingly, pharmacological blockade of CRL activity diminishes viral replication in cell culture. In this review, we summarize the current knowledge concerning the relevance of DDB1 and CRLs during cytomegalovirus replication and discuss chances and drawbacks of CRL inhibitory drugs as potential antiviral treatment against HCMV.


title: Detection of subgenomic mRNA of feline coronavirus by real-time polymerase chain reaction based on primer-probe energy transfer (P-sg-QPCR)

text: Abstract Feline infectious peritonitis is one of the most severe devastating diseases of the Felidae. Upon the appearance of clinical signs, a cure for the infected animal is impossible. Therefore rapid and proper diagnosis for both the presence of the causative agent, feline coronavirus (FCoV) and the manifestation of feline infectious peritonitis is of paramount importance. In the present work, a novel real-time RT-PCR method is described which is able to detect FCoV and to determine simultaneously the quantity of the viral RNA. The new assay combines the M gene subgenomic messenger RNA (sg-mRNA) detection and the quantitation of the genome copies of FCoV. In order to detect the broadest spectrum of potential FCoV variants and to achieve the most accurate results in the detection ability the new assay is applying the primer-probe energy transfer (PriProET) principle. This technology was chosen since PriProET is very robust to tolerate the nucleotide substitutions in the target area. Therefore, this technology provides a very broad-range system, which is able to detect simultaneously many variants of the virus(es) even if the target genomic regions show large scale of variations. The detection specificity of the new assay was proven by positive amplification from a set of nine different FCoV strains and negative from the tested non-coronaviral targets. Examination of faecal samples of healthy young cats, organ samples of perished animals, which suffered from feline infectious peritonitis, and cat leukocytes from uncertain clinical cases were also subjected to the assay. The sensitivity of the P-sg-QPCR method was high, since as few as 10 genome copies of FCoV were detected. The quantitative sg-mRNA detection method revealed more than 10–50,000 times increase of the M gene sg-mRNA in organ materials of feline infectious peritonitis cases, compared to those of the enteric FCoV variants present in the faeces of normal, healthy cats. These results indicate the applicability of the new P-sg-QPCR test as a powerful novel tool for the better detection and quantitation of FCoV and for the improved diagnosis of feline infectious peritonitis, this important disease of the Felidae, causing serious losses in the cat populations at a global scale.


title: The effect of porcine reproductive and respiratory syndrome virus and porcine epidemic diarrhea virus challenge on growing pigs I: Growth performance and digestibility

text: Porcine reproductive and respiratory syndrome (PRRS) and porcine epidemic diarrhea (PED) are two diseases costly to the U.S. swine industry. The objective of this study was to determine the impact of PRRS virus and PED virus, alone or in combination, on growth performance, feed efficiency, and digestibility in grower pigs. Forty-two gilts (16 ± 0.98 kg BW) naïve for PRRS and PED were selected and allocated to 1 of 4 treatments. Treatments included 1) a control, 2) PRRS virus infected, 3) PED virus infected, and 4) PRRS+PED coinfection (PRP). Pigs in treatments 2 and 4 were inoculated with a live field strain of PRRS virus via intramuscular and intranasal routes at 0 d after inoculation (dpi). Treatments 3 and 4 were orally inoculated with a cloned PED virus at 15 dpi. Infection with PRRS virus was confirmed by quantitative PCR and seroconversion. Infection with PED virus was confirmed with PCR. Control pigs remained PRRS and PED virus negative throughout the study. All pigs were offered, ad libitum, a standard diet with free access to water. During the test period, PRRS reduced ADG and ADFI by 30 and 26%, respectively (P < 0.05), compared with control pigs, whereas PRP decreased ADG, ADFI, and G:F by 45, 30, and 23%, respectively (P < 0.05). Additional reductions in ADG and G:F were detected in PRP pigs compared with singular PED or PRRS treatments (33 and 16%, respectively). The impact of PED, alone or in combination, on performance (15–21 dpi) reduced ADG (0.66 vs. 0.35 vs. 0.20 kg/d; P < 0.01), ADFI (1.22 vs. 0.88 vs. 0.67 kg/d; P = 0.003), and G:F (0.54 vs. 0.39 vs. 0.31; P = 0.001) compared with control pigs. Compared with control pigs, PRRS infection did not reduce apparent total tract digestibility (ATTD) of nutrients and energy. However, PED infection, alone or in combination, decreased ATTD of DM and energy by 8 and 12%, respectively (P < 0.05). Compared with control pigs, PRP reduced N and OM ATTD by 13 and 3%, respectively (P < 0.05). No significant differences in apparent ileal digestibility (AID) were detected between virus challenges. However, Lys AID tended to be reduced in both PED treatments compared with the control (10 and 12%; P = 0.095). Altogether, PRRS reduced growth but did not alter digestibility. Pigs challenged with PED and, to a greater extent, the coinfection of PED and PRRS viruses had reduced ADG, ADFI, G:F, and ATTD of nutrients and energy.


title: The novel amidocarbamate derivatives of ketoprofen: synthesis and biological activity

text: A series of novel ketoprofen derivatives 4a–j bearing both amide and carbamate functionalities were prepared using the benzotriazole method of carboxylic and hydroxy group activation. Selective reduction of ketoprofen produced hydroxy derivative 2, which in the reaction with one or two moles of 1-benzotriazole carboxylic acid chloride (1) gave benzotriazole derivatives 3a and 3b, respectively. Compounds 3a and 3b with various amines afforded amidocarbamates 4a–j. Antioxidative screenings revealed that the prepared compounds 3b and 4a–j possess excellent lipid peroxidation inhibition at 0.1 mM concentration, higher than 95% for the derivatives bearing aromatic, cycloalkyl or heterocyclic substituents. Two of the compounds, 3b and 4g, also show high soybean lipoxygenase inhibition activity (95 and 83.5%, respectively). On the other hand, the amidocarbamate derivatives of ketoprofen show only weak reducing activity against 1,1-diphenyl-2-picrylhydrazyl radicals. No selective antiviral effects were noted for the tested compounds against a broad variety of DNA and RNA viruses. Most compounds were endowed with a moderate (IC(50): 10–25 μM) cytostatic activity.


title: Protective Role of Toll-like Receptor 3-Induced Type I Interferon in Murine Coronavirus Infection of Macrophages

text: Toll-like Receptors (TLRs) sense viral infections and induce production of type I interferons (IFNs), other cytokines, and chemokines. Viral recognition by TLRs and other pattern recognition receptors (PRRs) has been proven to be cell-type specific. Triggering of TLRs with selected ligands can be beneficial against some viral infections. Macrophages are antigen-presenting cells that express TLRs and have a key role in the innate and adaptive immunity against viruses. Coronaviruses (CoVs) are single-stranded, positive-sense RNA viruses that cause acute and chronic infections and can productively infect macrophages. Investigation of the interplay between CoVs and PRRs is in its infancy. We assessed the effect of triggering TLR2, TLR3, TLR4, and TLR7 with selected ligands on the susceptibility of the J774A.1 macrophage cell line to infection with murine coronavirus (mouse hepatitis virus, [MHV]). Stimulation of TLR2, TLR4, or TLR7 did not affect MHV production. In contrast, pre-stimulation of TLR3 with polyinosinic-polycytidylic acid (poly I:C) hindered MHV infection through induction of IFN-β in macrophages. We demonstrate that activation of TLR3 with the synthetic ligand poly I:C mediates antiviral immunity that diminishes (MHV-A59) or suppresses (MHV-JHM, MHV-3) virus production in macrophages.


title: Concurrent chilblains and retinal vasculitis in a child with COVID‐19

text: Reports on COVID‐19 in children are limited. Despite new data emerging, and understanding of the disease improves rapidly, there are as yet several features and complications related to the disease that remain unknown. Herein, we report the first case of a child with chilblains and retinal vasculitis related to COVID‐19.


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title: Establishing a clinical decision rule of severe acute respiratory syndrome at the emergency department()

text: STUDY OBJECTIVE: In the absence of reliable rapid confirmatory tests during severe acute respiratory syndrome (SARS) endemics, we designed a 2-phase cohort study to establish a scoring system for SARS and to evaluate whether it could improve the sensitivity and specificity of the World Health Organization (WHO) criteria. METHODS: According to the clinical characteristics and initial laboratory findings of 175 suspected cases defined by the WHO criteria (20 confirmed as cases of SARS) in 3 university teaching hospitals in Taipei between March 1 and April 20, 2003, the scoring system for SARS was designed by multivariate analysis and stepwise logistic regression as the simple arithmetic sum of point values assigned to 7 parameters. We thereafter applied the scoring system for SARS to the consecutive 232 patients (the validation group) who met the WHO criteria of suspected cases from April 21 to May 22, 2003. Final diagnosis of SARS was determined by the results of real-time polymerase chain reaction and paired serum. RESULTS: The scoring system for SARS was defined as radiographic findings of multilobar or bilateral infiltrates (3 points), sputum monocyte predominance (3 points), lymphocytopenia (2 points), history of exposure (1 point), lactate dehydrogenase more than 450 U/L (1 point), C-reactive protein more than 5.0 mg/dL (1 point), and activated partial prothrombin time more than 40 seconds (1 point). Of the validation group, 60 patients (group A) were confirmed as having cases of SARS, and the other 172 (group B) patients tested negative for SARS. The total points of the scoring system for SARS at initial presentation were significantly higher in the SARS group (median 9; range 6 to 11) than in the non-SARS group (median 4; range 3 to 7; P<.001). At the cutoff value of 6 points, the sensitivity and specificity of the scoring system for SARS in diagnosing SARS were 100% and 93%, respectively. The positive and negative predictive values of the scoring system for SARS were 83% and 100%, respectively. CONCLUSION: The scoring system for SARS can provide a rapid and reliable clinical decision to help emergency physicians detect cases of SARS more accurately in the endemic area.


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title: Designing a Psychological Preparedness Toolkit for Healthcare Workers in the wake of COVID-19: A Singapore perspective

text: • The COVID-19 pandemic is a tensile stress test of the robustness of healthcare emergency preparedness measures. • Fear of the unknown, uncertainty, and anxiety are risk factors for burnout and trauma in healthcare workers in the wake of a pandemic. • A reliable and accurate psychological preparedness toolkit for healthcare workers is important in reducing stress and anxiety. • A psychological preparedness toolkit for COVID-19 frontline healthcare workers may incorporate pragmatic interventions, mental health education, organizational theories and principles of health professions education.


The Silver Linings Journal: Gratitude During a Pandemic


Contagion 2.0


Ribosome gymnastics—Degree of difficulty 9.5, style 10.0


Epidemia covid-19: ¿debe el oftalmólogo estar alerta ante las paresias oculomotoras?


title: Epidemiology of Infectious Diarrhea

text: Diarrhea is a very frequent symptom. A great variety of chemical agents, microorganisms, and biotoxins can cause diarrhea, acute or persistent, slight or serious. From the epidemiological point of view, the cases can be sporadic or epidemic, and identification of the infection source and transmission mechanism is important for prevention and control. Knowledge of the etiology is a great help. The entrance route to the human body is usually through the digestive system. From some source in an individual's surroundings, the causal agent somehow reaches the mouth of the susceptible person. The hands play a fundamental role in many situations. This article revises the most important epidemiological characteristics of the agents that produce diarrhea as a main symptom, placing an emphasis on epidemiological point of view and environmental transmission mechanisms. Some aspects regarding individual susceptibility (genetic or other types) are also mentioned. Because the long-term consequences of infectious gastroenteritis are less well known, a small section dedicated to the long-term consequences of infectious gastroenteritis has been included. With suitable prevention, not only the acute consequences but also the aftereffects of these diseases can be avoided.


title: Potential for the International Spread of Middle East Respiratory Syndrome in Association with Mass Gatherings in Saudi Arabia

text: Background: A novel coronavirus (MERS-CoV) causing severe, life-threatening respiratory disease has emerged in the Middle East at a time when two international mass gatherings in Saudi Arabia are imminent. While MERS-CoV has already spread to and within other countries, these mass gatherings could further amplify and/or accelerate its international dissemination, especially since the origins and geographic source of the virus remain poorly understood. Methods: We analyzed 2012 worldwide flight itinerary data and historic Hajj pilgrim data to predict population movements out of Saudi Arabia and the broader Middle East to help cities and countries assess their potential for MERS-CoV importation. We compared the magnitude of travel to countries with their World Bank economic status and per capita healthcare expenditures as surrogate markers of their capacity for timely detection of imported MERS-CoV and their ability to mount an effective public health response. Results: 16.8 million travelers flew on commercial flights out of Saudi Arabia, Jordan, Qatar, and the United Arab Emirates between June and November 2012, of which 51.6% were destined for India (16.3%), Egypt (10.4%), Pakistan (7.8%), the United Kingdom (4.3%), Kuwait (3.6%), Bangladesh (3.1%), Iran (3.1%) and Bahrain (2.9%). Among the 1.74 million foreign pilgrims who performed the Hajj last year, an estimated 65.1% originated from low and lower-middle income countries. Conclusion: MERS-CoV is an emerging pathogen with pandemic potential with its apparent epicenter in Saudi Arabia, where millions of pilgrims will imminently congregate for two international mass gatherings. Understanding global population movements out of the Middle East through the end of this year's Hajj could help direct anticipatory MERS-CoV surveillance and public health preparedness to mitigate its potential global health and economic impacts.


title: Thiopyrano[2,3-d]Thiazoles as New Efficient Scaffolds in Medicinal Chemistry

text: This review presents the up to date development of fused thiopyranothiazoles that comprise one of the thiazolidine derivatives classes. Thiazolidine and thiazolidinone-related compounds belong to the widely studied heterocycles from a medicinal chemistry perspective. From the chemical point of view, they are perfect heterodienes to undergo hetero-Diels–Alder reaction with a variety of dienophiles, yielding regio- and diastereoselectively thiopyranothiazole scaffolds. The annealing of thiazole and thiopyran cycles in condensed heterosystem is a precondition for the “centers conservative” creation of the ligand-target binding complex and can promote a potential selectivity to biotargets. The review covers possible therapeutic applications of thiopyrano[2,3-d]thiazoles, such as anti-inflammatory, antibacterial, anticancer as well as aniparasitic activities. Thus, thiopyrano[2,3-d]thiazoles may be used as powerful tools in the development of biologically active agents and drug-like molecules.