title: Pathogen inactivation techniques

text: The desire to rid the blood supply of pathogens of all types has led to the development of many technologies aimed at the same goal—eradication of the pathogen(s) without harming the blood cells or generating toxic chemical agents. This is a very ambitious goal, and one that has yet to be achieved. One approach is to shun the ‘one size fits all’ concept and to target pathogen-reduction agents at the Individual component types. This permits the development of technologies that might be compatible with, for example, plasma products but that would be cytocidal and thus incompatible with platelet concentrates or red blood cell units. The technologies to be discussed include solvent detergent and methylene blue treatments—designed to inactivate plasma components and derivatives; psoralens (S-59—amotosalen) designed to pathogen-reduce units of platelets; and two products aimed at red blood cells, S-303 (a Frale—frangible anchor-linker effector compound) and Inactine (a binary ethyleneimine). A final pathogen-reduction material that might actually allow one material to inactivate all three blood components—riboflavin (vitamin B2)—is also under development. The sites of action of the amotosalen (S-59), the S-303 Frale, Inactine, and riboflavin are all localized in the nucleic acid part of the pathogen. Solvent detergent materials act by dissolving the plasma envelope, thus compromising the integrity of the pathogen membrane and rendering it non-infectious. By disrupting the pathogen's ability to replicate or survive, its infectivity is removed. The degree to which bacteria and viruses are affected by a particular pathogen-reducing technology relates to its Gram-positive or Gram-negative status, to the sporulation characteristics for bacteria, and the presence of lipid or protein envelopes for viruses. Concerns related to photoproducts and other breakdown products of these technologies remain, and the toxicology of pathogen-reduction treatments is a major ongoing area of investigation. Clearly, regulatory agencies have a major role to play in the evaluation of these new technologies. This chapter will cover the several types of pathogen-reduction systems, mechanisms of action, the inactivation efficacy for specific types of pathogens, toxicology of the various systems and the published research and clinical trial data supporting their potential usefulness. Due to the nature of the field, pathogen reduction is a work in progress and this review should be considered as a snapshot in time rather than a clear picture of what the future will bring.


The Global Outbreak Alert and Response Network (GOARN) was established in 2000 as a network of technical institutions, research institutes, universities, international health organisations and technical networks willing to contribute and participate in internationally coordinated responses to infectious disease outbreaks. It reflected a recognition of the need to strengthen and coordinate rapid mobilisation of experts in responding to international outbreaks and to overcome the sometimes chaotic and fragmented operations characterising previous responses. The network partners agreed that the World Health Organization would coordinate the network and provide a secretariat, which would also function as the operational support team. The network has evolved to comprise 153 institutions/technical partners and 37 additional networks, the latter encompassing a further 355 members and has been directly involved in 137 missions to 79 countries, territories or areas. Future challenges will include supporting countries to achieve the capacity to detect and respond to outbreaks of international concern, as required by the International Health Regulations (2005). GOARN's increasing regional focus and expanding geographic composition will be central to meeting these challenges. The paper summarises some of network's achievements over the past 13 years and presents some of the future challenges.


title: Recent insights into pulmonary repair following virus-induced inflammation of the respiratory tract

text: A hallmark of infection by respiratory viruses is productive infection of and the subsequent destruction of the airway epithelium. These viruses can also target other stromal cell types as well as in certain instances, CD45(+) hematopoietic cells either resident in the lungs or part of the inflammatory response to infection. The mechanisms by which the virus produces injury to these cell types include direct infection with cytopathic effects as a consequence of replication. Host mediated damage is also a culprit in pulmonary injury as both innate and adaptive immune cells produce soluble and cell-associated pro-inflammatory mediators. Recently, it has become increasingly clear that in addition to control of excess inflammation and virus elimination, the resolution of infection requires an active repair process, which is necessary to regain normal respiratory function and restore the lungs to homeostasis. The repair response must re-establish the epithelial barrier and regenerate the microarchitecture of the lung. Emerging areas of research have highlighted the importance of innate immune cells, particularly the newly described innate lymphoid cells, as well as alternatively activated macrophages and pulmonary stem cells in the repair process. The mechanisms by which respiratory viruses may impede or alter the repair response will be important areas of research for identifying therapeutic targets aimed at limiting virus and host mediated injury and expediting recovery.


title: Etiology of severe community-acquired pneumonia during the 2013 Hajj—part of the MERS-CoV surveillance program

text: Summary Background Pneumonia is the leading cause of hospital admission during the annual Islamic pilgrimage (Hajj). The etiology of severe pneumonia is complex and includes the newly emerged Middle East respiratory syndrome coronavirus (MERS-CoV). Since 2012, the Saudi Ministry of Health (MoH) has required screening for MERS-CoV for all cases of severe pneumonia requiring hospitalization. We aimed to screen Hajj pilgrims admitted to healthcare facilities in 2013 with severe community-acquired pneumonia (CAP) for MERS-CoV and to determine other etiologies. Methods Sputum samples were collected from all pilgrims admitted to 15 healthcare facilities in the cities of Makkah and Medina, Saudi Arabia, who were diagnosed with severe CAP on admission, presenting with bilateral pneumonia. The medical records were reviewed to collect information on age, gender, nationality, and patient outcome. Samples were screened for MERS-CoV by PCR, and a respiratory multiplex array was used to detect up to 22 other viral and bacterial respiratory pathogens. Results Thirty-eight patients met the inclusion criteria; they were predominantly elderly (mean age 58.6 years, range 25–83 years) and male (68.4%), and all were from developing countries. Fourteen of the 38 patients died (36.8%). MERS-CoV was not detected in any of the samples. Other respiratory pathogens were detected in 26 (68.4%) samples. Of these, bacterial pathogens were detected in 84.6% (22/26) and viruses in 80.7% (21/26). Twenty-one (80.7%) samples were positive for more than one respiratory pathogen and 17 (65.3%) were positive for both bacteria and viruses. The most common respiratory virus was human rhinovirus, detected in 57.7% of the positive samples, followed by influenza A virus (23.1%) and human coronaviruses (19.2%). Haemophilus influenzae and Streptococcus pneumoniae were the predominant bacteria, detected in 57.7% and 53.8%, respectively, of the positive samples, followed by Moraxella catarrhalis (36.4%). Conclusions MERS-CoV was not the cause of severe CAP in any of the hospitalized pilgrims investigated. However we identified a variety of other respiratory pathogens in the sputum of this small number of patients. This indicates that the etiology of severe CAP in Hajj is complex with implications regarding its management.


title: A prospective, community-based study on virologic assessment among elderly people with and without symptoms of acute respiratory infection

text: Abstract Background and objective Community-based elderly studies concerning microbiology of acute respiratory infections are scarce. Data on subclinical infections are even totally absent, although asymptomatic persons might act as a source of respiratory infections. Methods In a 1-year community-based study, we prospectively investigated the possible virologic cause of acute respiratory infections in 107 symptomatic case episodes and 91 symptom-free control periods. Participants, persons ⩾60 years, reported daily the presence of respiratory symptoms in a diary. Virologic assessment was performed by polymerase chain reaction (PCR) and serology. Results In 58% of the case episodes a pathogen was demonstrated, the most common being rhinoviruses (32%), coronaviruses (17%), and influenzaviruses (7%). The odds ratio for demonstrating a virus in cases with symptoms vs. controls without symptoms was 30.0 (95% confidence interval 10.2–87.6). In 4% of the symptom-free control periods a virus was detected. Conclusion This study supports the importance of rhinovirus infections in community-dwelling elderly persons, whereas asymptomatic elderly persons can also harbor pathogens as detected by PCR, and thus might be a source of infection for their environment.


Editorial Commentary: Still Learning From the Earliest Known MERS Outbreak, Zarqa, Jordan, April 2012


title: Chapter 6 Airway Pathology

text: Publisher Summary This chapter examines the anatomy of the human lung and the pathology of both asthma and chronic obstructive pulmonary disease (COPD). The normal human bronchogram shows that the length of pathways from the trachea to the terminal airways differs depending on the pathway followed and it can take as few as 8 or as many as 24 divisions of airway branching to reach the gas-exchanging surface. The small bronchi and bronchioles 2 mm in diameter are spread out from the fourth to the fourteenth generation of airway branching. The pathology of asthma is dominated by widespread plugging of the segmental, subsegmental, and smaller conducting airways that leads to hyperinflation but not destruction of the parenchyma. These airway plugs are a manifestation of the fluid and cellular exudative phase of an inflammatory process based in the airway tissue. The chronic bronchitis of COPD is defined by excess cough with sputum production and is associated with an inflammatory process located in the mucosa, gland ducts, and glands of intermediate-sized bronchi between 2 and 4 mm internal diameter. The airway obstruction in COPD is the result of a similar inflammatory response in the smaller bronchi and bronchioles under 2 mm internal diameter, where the repair process associated with chronic inflammation thickens the airway wall and narrows the lumen to cause fixed airway obstruction.


title: Middle East Respiratory Syndrome-Coronavirus Infection: A Case Report of Serial Computed Tomographic Findings in a Young Male Patient

text: Radiologic findings of Middle East respiratory syndrome (MERS), a novel coronavirus infection, have been rarely reported. We report a 30-year-old male presented with fever, abdominal pain, and diarrhea, who was diagnosed with MERS. A chest computed tomographic scan revealed rapidly developed multifocal nodular consolidations with ground-glass opacity halo and mixed consolidation, mainly in the dependent and peripheral areas. After treatment, follow-up imaging showed that these abnormalities markedly decreased but fibrotic changes developed.


title: Exploring the acceptability of controlled human infection with SARSCoV2—a public consultation

text: Rapid development of an effective vaccine for SARSCoV2 is a global priority. A controlled human infection model (CHIM) would accelerate the efficacy assessment of candidate vaccines. This strategy would require deliberate exposure of volunteers to SARSCoV2 with no currently available treatment and a small but definite risk of serious illness or death. This raises complex questions about the social and ethical acceptability of risk to individuals, given the potential benefit to the wider population, and as such, a study cannot be done without public involvement. We conducted a structured public consultation with 57 individuals aged 20–40 years to understand public attitudes to a CHIM, and pre-requisites for enrolment. The overall response to this strategy was positive, and many would volunteer altruistically. Carefully controlled infection is viewed as safer than natural exposure to wild virus. The prolonged social isolation required for the proposed CHIM is considered an obstacle but not insurmountable, with reasonable compensation and supportive care. Given the significant level of public interest, a CHIM should be done as open science with regular, controlled dissemination of information into the public domain. Importantly, there was a strong view that the final decision whether to conduct a CHIM should be in the hands of qualified and experienced clinician-scientists and the authorities.


Cyclosporine therapy during the COVID-19 pandemic is not a reason for concern.


title: Proteomics analysis reveals protein expression differences for hypopharyngeal gland activity in the honeybee, Apis mellifera carnica Pollmann

text: BACKGROUND: Most of the proteins contained in royal jelly (RJ) are secreted from the hypopharyngeal glands (HG) of young bees. Although generic protein composition of RJ has been investigated, little is known about how age-dependent changes on HG secretion affect RJ composition and their biological consequences. In this study, we identified differentially expressed proteins (DEPs) during HG development by using the isobaric tag for relative and absolute quantification (iTRAQ) labeling technique. This proteomic method increases the potential for new protein discovery by improving the identification of low quantity proteins. RESULTS: A total of 1282 proteins were identified from five age groups of worker bees, 284 of which were differentially expressed. 43 (15.1%) of the DEPs were identified for the first time. Comparison of samples at day 6, 9, 12, and 16 of development relative to day 3 led to the unambiguous identification of 112, 117, 127, and 127 DEPs, respectively. The majority of these DEPs were up-regulated in the older worker groups, indicating a substantial change in the pattern of proteins expressed after 3 days. DEPs were identified among all the age groups, suggesting that changes in protein expression during HG ontogeny are concomitant with different states of worker development. A total of 649 proteins were mapped to canonical signaling pathways found in the Kyoto Encyclopedia of Genes and Genomes (KEGG), which were preferentially associated with metabolism and biosynthesis of secondary metabolites. More than 10 key high-abundance proteins were involved in signaling pathways related to ribosome function and protein processing in the endoplasmic reticulum. The results were validated by qPCR. CONCLUSION: Our approach demonstrates that HG experienced important changes in protein expression during its ontogenic development, which supports the secretion of proteins involved in diverse functions in adult workers beyond its traditional role in royal jelly production. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1471-2164-15-665) contains supplementary material, which is available to authorized users.


title: Methylene blue degradation by the VUV/UV/persulfate process: Effect of pH on the roles of photolysis and oxidation

text: Abstract This study investigated methylene blue (MB) degradation by the vacuum-ultraviolet/ultraviolet/persulfate (VUV/UV/PS) process using a mini-fluidic VUV/UV photoreaction system. Results show that MB degradation by the VUV/UV/PS process was significantly higher than that of the conventional UV/PS process, as the VUV photolysis of H2O and PS generated more reactive oxygen species (ROSs). HO• and SO4 •−, identified as the main ROSs, were mostly consumed by dissolved organic carbon and Cl‒ in real waters, respectively. Additionally, the impacts of solution pH and the concentrations of PS, humic acid, and inorganic ions (HCO3 ‒, Cl‒, NO3 ‒, SO4 2‒, Fe(II), and Fe(III)) were systematically evaluated. The solution pH significantly affected the photon absorption distributions, as well as the contributions of photolysis and oxidation to MB degradation, resulting in different variations in the degradation rate constant and total organic carbon removal ratio with increasing solution pH. At all tested pH levels (3.0–11.0), particularly under acidic conditions, HO and SO4 − were two predominant contributors to MB degradation, while VUV and UV photolysis contributed more when the solution pH increased. This study provides a highly efficient process for organic pollutant removal, which could be applied in water treatment.


title: Detection of SARS-CoV-2 in Fecal Samples from Patients with Asymptomatic and Mild COVID-19 in Korea

text: Abstract: Background & Aims Although COVID-19 is characterized by fever and respiratory symptoms, some patients have no or mild symptoms. SARS-CoV-2 has been detected in feces of patients. We investigated gastrointestinal symptoms and shedding of virus into feces of patients with asymptomatic or mild COVID-19. Methods We collected data from 46 patients (median age, 26 years; 46% men) with asymptomatic or mild COVID-19 (without fever and pneumonia) and prolonged respiratory shedding of SARS-CoV-2, quarantined from April 4, 2020 through April 24, 2020 in Korea. Respiratory specimens included upper respiratory specimens (nasopharyngeal and oropharyngeal swabs) and lower respiratory specimens (sputum) and were collected twice per week. The median interval between COVID-19 diagnosis to the start of fecal sample collection was 37 days (range, 29–41); 213 stool specimens were collected from 46 patients. We used real-time reverse transcription PCR to detect SARS-CoV-2 in the respiratory and fecal specimens. Results Gastrointestinal manifestations were observed in 16 of the 46 patients (35%); diarrhea was the most common (15%), followed by abdominal pain (11%), dyspepsia (11%), and nausea (2%). Virus RNA was detected in feces from 2 patients without gastrointestinal symptoms (4%). Mean cycle threshold values from the time of quarantine to the time of fecal collection tended to be lower in patients with virus detected in fecal samples than patients without virus in fecal samples (29.91 vs 33.67 in the first week; 29.47 vs 35.71 in the fifth week, respectively). Shedding of virus into feces persisted until day 50 after diagnosis; fecal samples began to test negative before or at approximately the time that respiratory specimens also began to test negative. Conclusions In an analysis of fecal and respiratory specimens from patients with COVID-19 in quarantine in Korea, we found that the gastrointestinal tract could be a route of transmission of SARS-CoV-2 even in patients with asymptomatic or mild disease, with no gastrointestinal symptoms. The viral load of the respiratory specimens appears be related to shedding of the virus into feces in this group of patients.


Retraction: Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19. N Engl J Med. DOI: 10.1056/NEJMoa2007621.


title: The use of debates as an active learning tool in a college of pharmacy healthcare delivery course

text: Abstract Background and purpose To describe the use of debates, and to evaluate student performance and perceptions, when student debates are incorporated as an active learning tool in a required pharmacy healthcare delivery course. Educational activity and setting Student live debates replaced 15% of a traditional lecture-based course. Twelve healthcare controversies were debated by student teams each year. Student perception of debate utility and opinion on topics, pre- and post-debate, were measured via a voluntary survey. Both peer and instructor's assessments of team performances, as well as individual student performance on the debate-based questions on course exams, contributed to course grade. Findings The average survey response rates were 76% (2014) and 86% (2015). Fifteen-54% of student respondents changed their opinion on individual debate topics due to the debates. Although exam performance on debate-based questions was no better than on lecture-based questions, respondents who found the debates useful or very useful in mastering course material increased by 19% post versus pre-debate surveys. Summary Debates are an effective active learning tool for engaging students in controversial subjects. Assessment of student performance should include student and instructor evaluations, and can be incorporated into the course grade.


title: Community quarantine strategy against coronavirus disease 2019 in Anhui: an evaluation based on trauma center patients

text: Abstract Objective The objective of our study was to introduce community quarantine strategy against coronavirus disease 2019(COVID-19) in Anhui and evaluate the effectiveness of community quarantine based on trauma center (TC) patients. Method The structure of community quarantine strategy was illustrated. Distribution of injuries among patients in two TCs between January 24, 2020 and February 24, 2020 was described. Multiple linear regression was used to analyze the correlation between the distribution of Injuries in TCs and the number of COVID-19-associated cases. Results A total of 757 TC patients in the two hospitals were enrolled. The number of traffic injuries and outdoor injuries showed a significant decrease in the early stage and began to increase on February 17. The number of indoor injuries neither decreased nor increased. Multiple linear regression analysis revealed a significant correlation between COVID-19-associated cases and traffic and outdoor injuries Conclusion From the perspective of the injuries in TCs, community quarantine strategy was effectively implemented and significantly slowed the outbreak of COVID-19 in Anhui. However, the implementation and maintenance of the strategy is costly and requires the participation of the entire population.


title: Price Reaction, Volatility Timing and Funds’ Performance during Covid-19

text: In this paper we assess the price reaction, performance and volatility timing of European investment funds during the outbreak of Covid-19. We analyze the time period between January and June 2020 and demonstrate that while most of the investment funds exhibit stressed performance, social entrepreneurship funds endured resilience. This remained robust during various stages of the evolution of this contagion. The social funds also demonstrated volatility timing that was absent for most of their counterparts. We attribute the overall stability of these funds to their niche investments in social enterprises that specialize in providing innovative solutions for social issues.


title: Impact of Regulatory Changes on Pharmacist Delivered Telehealth During the COVID-19 Pandemic

text: Summary: The 2020 COVID-19 pandemic in the United States has created a dramatic need for the rapid implementation of telehealth services in areas of the country where telehealth is limited in scope.1 This implementation would not be possible without significant changes in how the Centers for Medicare and Medicaid Services (CMS) provide reimbursement for these services. In this brief review we intend to evaluate what regulatory changes have occurred, the impact of these changes, and additional opportunities for outpatient pharmacists to receive compensation while providing distant healthcare.


title: A novel neutralizing monoclonal antibody targeting the N-terminal domain of the MERS-CoV spike protein

text: This corrects the article DOI: 10.1038/emi.2017.18.


title: Exploration of the Effectiveness of Social Distancing on Respiratory Pathogen Transmission Implicates Environmental Contributions

text: Background. In both military and civilian settings, transmission of respiratory pathogens may be due to person-to-person and environmental contributions. This possibility was explored in a military training setting, where rates of febrile respiratory illness (FRI) often reach epidemic levels. Methods. Population size and FRI rates were monitored over 10 months in the units of 50–90 individuals. Some units were open to the influx of potentially infectious convalescents (hereafter referred to as “open units,” and some were closed to such an influx (hereafter referred to as “closed units”). Virologic testing and polymerase chain reaction analysis were used to detect adenovirus on surface structures. Results. The odds ratio (OR) associated with FRI in closed units, compared with open units, was 1.13 (95% confidence interval [CI], 0.99–1.28). The OR in units with a population greater than the median size, compared with units with a population lower than the median size was 1.38 (95% CI, 1.23–1.55). Between 5% and 9% of surface samples obtained from selected units harbored viable adenovirus. Conclusions. FRI rates were not reduced in units that were closed to potentially contagious individuals. These findings imply that the primary source of the pathogen is likely environmental rather than human, and they underscore what is known about other virus types. Diligence in identifying the relative roles of different transmission routes is suggested for civilian settings similar to those described in the current study.


title: COVID-19, tuberculosis, and poverty: preventing a perfect storm

text: The COVID-19 pandemic is likely to be the defining global health crisis of our generation. As the United Nations Development Programme highlighted in their recent call to action, the impact of this pandemic will extend beyond the immediate medical consequences to have far-reaching and long-lasting social and economic impacts, threatening to disproportionately affect poorer people in poorer countries [1]. Income losses are anticipated to exceed $220 billion in developing countries, where many people live day-to-day without access to social protection, and food security is precarious [1]. Strikingly, a recent United Nations study suggests that the social and economic consequences of the COVID-19 pandemic could increase the number of people living in poverty by as much as half a billion, with the majority of these newly poor people living in Africa, South-East Asia, and Central and South America [2].


Extraordinary emergency measures set up by a Breast Unit to prevent COVID‐19: Report of our experience


The WHO programme for virus diseases in relation to recent trends in medical virology


title: SARS‐CoV‐2‐reactive interferon‐γ‐producing CD8+ T cells in patients hospitalized with coronavirus disease 2019

text: There is limited information on severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) T‐cell immune responses in patients with coronavirus disease 2019 (COVID‐19). Both CD4+ and CD8+ T cells may be instrumental in resolution of and protection from SARS‐CoV‐2 infection. Here, we tested 25 hospitalized patients either with microbiologically documented COVID‐19 (n = 19) or highly suspected of having the disease (n = 6) for presence of SARS‐CoV‐2‐reactive CD69+ expressing interferon‐γ (IFN‐γ) producing CD8+ T cells using flow‐cytometry for intracellular cytokine staining assay. Two sets of overlapping peptides encompassing the SARS‐CoV‐2 Spike glycoprotein N‐terminal 1 to 643 amino acid sequence and the entire sequence of SARS‐CoV‐2 M protein were used simultaneously as antigenic stimulus. Ten patients (40%) had detectable responses, displaying frequencies ranging from 0.15 to 2.7% (median of 0.57 cells/µL; range, 0.43‐9.98 cells/µL). The detection rate of SARS‐CoV‐2‐reactive IFN‐γ CD8+ T cells in patients admitted to intensive care was comparable (P = .28) to the rate in patients hospitalized in other medical wards. No correlation was found between SARS‐CoV‐2‐reactive IFN‐γ CD8+ T‐cell counts and SARS‐CoV‐2 S‐specific antibody levels. Likewise, no correlation was observed between either SARS‐CoV‐2‐reactive IFN‐γ CD8+ T cells or S‐specific immunoglobulin G‐antibody titers and blood cell count or levels of inflammatory biomarkers. In summary, in this descriptive, preliminary study we showed that SARS‐CoV‐2‐reactive IFN‐γ CD8+ T cells can be detected in a non‐negligible percentage of patients with moderate to severe forms of COVID‐19. Further studies are warranted to determine whether quantitation of these T‐cell subsets may provide prognostic information on the clinical course of COVID‐19.


title: Role of viruses in asthma

text: Respiratory viral infections are the most important triggers of asthma exacerbations. Rhinovirus (RV), the common cold virus, is clearly the most prevalent pathogen constantly circulating in the community. This virus also stands out from other viral factors due to its large diversity (about 170 genotypes), very effective replication, a tendency to create Th2-biased inflammatory environment and association with specific risk genes in people predisposed to asthma development (CDHR3). Decreased interferon responses, disrupted airway epithelial barrier, environmental exposures (including biased airway microbiome), and nutritional deficiencies (low in vitamin D and fish oil) increase risk to RV and other virus infections. It is intensively debated whether viral illnesses actually cause asthma. Respiratory syncytial virus (RSV) is the leading causative agent of bronchiolitis, whereas RV starts to dominate after 1 year of age. Breathing difficulty induced by either of these viruses is associated with later asthma, but the risk is higher for those who suffer from severe RV-induced wheezing. The asthma development associated with these viruses has unique mechanisms, but in general, RV is a risk factor for later atopic asthma, whereas RSV is more likely associated with later non-atopic asthma. Treatments that inhibit inflammation (corticosteroids, omalizumab) effectively decrease RV-induced wheezing and asthma exacerbations. The anti-RSV monoclonal antibody, palivizumab, decreases the risk of severe RSV illness and subsequent recurrent wheeze. A better understanding of personal and environmental risk factors and inflammatory mechanisms leading to asthma is crucial in developing new strategies for the prevention and treatment of asthma.


title: Risk assessment as a tool for improving external biosecurity at farm level

text: BACKGROUND: Biosecurity routines at herd level may reduce the probability of introduction of disease into the herd, but some measures may be regarded as expensive and cumbersome for the farmers. Custom-made measures based on individual farm characteristics may aid in improving the actual application of on-farm biosecurity. The aim of the study was to provide a tool for calculating the effects of different biosecurity measures and strategies on the individual farm level. A simple model was developed to assess the risk of disease introduction and the need for biosecurity measures in individual farms. To illustrate the general applicability of the tool, it was applied to theoretical examples of Swedish cattle and pig farms and diseases endemic in those animal species in the EU, in two scenarios with different between-farm contact patterns. RESULTS: The model illustrated that the most important factors affecting the risk, and the effect of biosecurity measures such as quarantine routines and protective clothing, were the frequency of between-farm contacts and prevalence of the disease. The risk of introduction as well as the effect of biosecurity measures differed between farm types and disease transmission routes. Adapting contact patterns to mitigate a specific disease risk was as important as biosecurity measures for some farm types, but the largest effect was seen when combining biosecurity measures with more planned contact patterns. CONCLUSIONS: The risk assessment model proved useful for illustrating the risk of introduction of endemic diseases and the mitigating effect of different biosecurity measures on farm level. Model outputs could be used to justify prioritisation of measures or adapting contact patterns. The theoretic exercise of adjusting model inputs and comparing outputs may help veterinary advisors to understand farm-specific risks and motivate farmers to improve biosecurity in their individual farm, as it can be tailored to each farmer’s needs and preferences.


title: Inpatient disposition classification for the creation of hospital surge capacity: a multiphase study

text: Summary Background The ability to provide medical care during sudden increases in patient volume during a disaster or other high-consequence event is a serious concern for health-care systems. Identification of inpatients for safe early discharge (ie, reverse triage) could create additional hospital surge capacity. We sought to develop a disposition classification system that categorises inpatients according to suitability for immediate discharge on the basis of risk tolerance for a subsequent consequential medical event. Methods We did a warfare analysis laboratory exercise using evidence-based techniques, combined with a consensus process of 39 expert panellists. These panellists were asked to define the categories of a disposition classification system, assign risk tolerance of a consequential medical event to each category, identify critical interventions, and rank each (using a scale of 1–10) according to the likelihood of a resultant consequential medical event if a critical intervention is withdrawn or withheld because of discharge. Findings The panellists unanimously agreed on a five-category disposition classification system. The upper limit of risk tolerance for a consequential medical event in the lowest risk group if discharged early was less than 4%. The next categories had upper limits of risk tolerance of about 12% (IQR 8–15%), 33% (25–50%), 60% (45–80%) and 100% (95–100%), respectively. The expert panellists identified 28 critical interventions with a likelihood of association with a consequential medical event if withdrawn, ranging from 3 to 10 on the 10-point scale. Interpretation The disposition classification system allows conceptual classification of patients for suitable disposition, including those deemed safe for early discharge home during surges in demand. Clinical criteria allowing real-time categorisation of patients are awaited.


title: Awareness and concerns among adult Liver Transplant recipients in the current pandemic caused by novel coronavirus (COVID-19): Strategies to safeguard a high-risk population

text: BACKGROUND: The coronavirus disease 2019 (COVID-19) virus is spreading rapidly and there are obvious concerns for the immunocompromised patient population including transplant recipients. Creating awareness and understanding patient concerns will play an important role in protecting this vulnerable group in developing timely and appropriate healthcare interventions. METHODS: A cross-sectional online survey was conducted between 23(rd) March 2020 & 1(st) April 2020 among 154 liver transplant recipients, transplanted between October 2018 and February 2020. An 18-point questionnaire explored their knowledge of COVID-19, awareness of recipient’s high-risk status, interventions to minimize cross-infections and concerns of this patient group regarding the pandemic. RESULTS: There were 112 (73%) respondents, with median age of 53 years (81% males). There was no difference in demographics between those who responded (n=112), to those who did not respond to the survey (n=42). Most of the recipients were aware of the main symptoms of COVID-19, such as fever (92%), breathlessness (86%), dry cough (87%), but less than half were aware of diarrhea (39%) as a symptom. Awareness about spread from asymptomatic individuals was limited (26%). Majority (95%) understood their high-risk status, but worryingly 23% of the respondents felt that there was no risk in visiting the hospital for routine clinic visit and blood tests. Concerns were raised by the recipients mostly regarding the uncertainties of COVID-19 infection and its treatment options, the quality of information on social messaging platforms and lack of access to routine tests/immunosuppression levels due to lockdown/social distancing. CONCLUSIONS: Our liver transplant recipients have a reasonable awareness regarding COVID-19. Problems in accessing the healthcare system during prolonged periods of lockdown was a major concern. It is important for each transplant unit to educate, support and remain accessible to this vulnerable patient cohort as the pandemic continues to progress worldwide.


title: The Impact of COVID‐19 on Share Prices in the UK(1)

text: The spread of COVID‐19, and international measures to contain it, are having a major impact on economic activity in the UK. In this paper we describe how this impact has varied across industries using data on share prices of firms listed on the London Stock Exchange, and how well targeted government support for workers and companies is in light of this. This article is protected by copyright. All rights reserved


Battling 21st-Century Scourges with a 14th-Century Toolbox


title: GRP78: A cell's response to stress

text: Abstract Background Glucose-Regulated Protein 78 (GRP78) is a chaperone heat shock protein that has been intensely studied in the last two decades. GRP78 is the master of the unfolded protein response (UBR) in the Endoplasmic Reticulum (ER) in normal cells. GRP78 force the unfolded proteins to refold or degrade using cellular degradation mechanisms. Scope Under stress, the overexpression of GRP78 on the cell membrane mediates the vast amount of disordered proteins. Unfortunately, this makes it a tool for pathogens (bacterial, fungal and viral) to enter the cell and to start different pathways leading to pathogenesis. Additionally, GRP78 is overexpressed on the membranes of various cancer cells and increase the aggressiveness of the disease. Major conclusions The current review summarizes structure, function, and different mechanisms GRP78 mediate in response to normal or stress conditions. General significance GRP78 targeting and possible inhibition mechanisms are also covered in the present review aiming to prevent the virulence of pathogens and cancer.


title: Clinical trials (and tribulations): the immediate effects of COVID-19 on IBD clinical research activity in the United Kingdom

text: There have been immediate and profound impacts of SARS-CoV-2 and COVID-19 on healthcare services worldwide with major consequences for non-COVID-19 related healthcare. Alongside efforts to reconfigure services and enable continued delivery of safe clinical care for patients with IBD, consideration must also be given to management of IBD research activity. In many centres there has been an effective shutdown of IBD clinical trial activity as research sites have switched focus to either COVID-19 related research or clinical care only. As a result, the early termination of trial programmes and loss of potentially effective therapeutic options for IBD, has become a real and worrying prospect. Moreover, in many countries research activity has become embedded into clinical care – with clinical trials often providing access to new therapies or strategies - which would otherwise not have been available in standard clinical pathways. This pandemic has significant implications for the design, conduct, analysis and reporting of clinical trials in IBD. In this Viewpoint, we share our experiences from a clinical and academic perspective in the United Kingdom, highlighting the early challenges encountered and consider implications for patients and staff at research sites, sponsors, research ethics committees, funders and regulators. We also offer potential solutions both for now and for when we enter a recovery phase from the pandemic.


Drug repurposing in cardiology


title: Chapter 3 Applications of Molecular Tools to Infectious Disease Epidemiology

text: Publisher Summary Molecular tools enhance outbreak investigation and surveillance, facilitate description of the transmission system, and increase understanding of the epidemiology. Molecular tools enhance case definitions, increasing specificity and reducing misclassification, and are now a standard tool in outbreak investigations. Although it is assumed during an outbreak that a single microbe is causing the clinical symptoms, it is possible that a microbe of the same genus and species but different strain is causing disease during the same time period. Molecular typing can distinguish between outbreak and nonoutbreak strains. Molecular tools also facilitate estimating parameters key to understanding the transmission system, including the incidence, prevalence, transmission probability, duration of carriage, effective dose, and probability of effective contact. Molecular tools enable one to trace the dissemination of a particular subtype across time and space and thus develop theories of transmission and dissemination, determine the origin of an epidemic and test theories about reservoirs and evolution of a particular pathogen, follow the emergence of new infections as they cross species, testing the hypotheses about the apparent transmissibility and rate of evolution, and follow mobile genetic elements conferring antimicrobial resistance or virulence between strains within a species or between species, and so develop theories about evolution and transmission within the populations of pathogens.


title: Upper respiratory infection during pregnancy and neurodevelopmental outcomes among offspring

text: Abstract Objective Maternal infection during pregnancy is associated with psychiatric disorders among offspring. The aim of this study was to investigate associations between upper respiratory infection (URI) in pregnancy and measures of cognitive and behavioral outcomes in child offspring. Materials and methods A longitudinal study of 534 mother-child pairs with information regarding prenatal exposures collected through an interview conducted on average one year after delivery and subsequent participation in a childhood cognitive and psychosocial assessment between the ages 5–12years. Childhood cognition was measured using the Peabody Picture Vocabulary Test (PPVT-III) and the Beery-Buktenica Test of Visual Motor Integration-Fifth Edition (VMI-5) and behavioral function measured using the Child Behavior Checklist (CBCL) and teacher-report using the Teacher Report Form (TRF). Adjusted mean differences (adjMD) in outcome measures were calculated between mothers reporting the presence or absence of a URI during pregnancy. Results URI during pregnancy was not associated with the two measures of cognition given to offspring, but was associated with modest increases in total behavioral problems reported by mothers (adjMD: 3.72; CI: 1.91–5.54) and teachers (adjMD: 2.74; CI: 0.97–4.50). We observed differences in CBCL and TRF scores based on timing of URI: infections in mid-pregnancy (lunar months 4–5) were associated with poorer scores than were infections in early pregnancy (lunar months 2–3). Conclusions In general, URI in pregnancy was not associated with decrements in childhood cognition, but may be associated with behavior problems.


title: Sacubitril/Valsartan in Advanced Heart Failure with Reduced Ejection Fraction: Rationale/Design of the LIFE Trial

text: Abstract The PARADIGM-HF trial reported that sacubitril/valsartan (S/V), an angiotensin receptor-neprilysin inhibitor, significantly reduced mortality and heart failure (HF) hospitalization in HF patients with a reduced ejection fraction (HFrEF). However, fewer than 1% of patients in PARADIGM-HF had NYHA class IV symptomology; accordingly, data that informs the use of S/V among patients with advanced HF are limited. The LIFE (LCZ696 In Hospitalized Advanced Heart FailurE) study is a 24-week prospective, multicenter, double-blinded, double-dummy, active-comparator trial to assess the safety, efficacy and tolerability of S/V compared with V in patients with advanced HFrEF. The trial planned to randomize 400 patients age ≥18 years with advanced HF, defined as an EF ≤35%, NYHA functional class IV symptoms, elevated natriuretic peptide concentration (B-type natriuretic peptide [BNP] ≥250 pg/mL or N-terminal-pro-B-type natriuretic peptide [NT-proBNP] ≥800 pg/mL), and ≥1 objective finding(s) of advanced HF. Following a 3-7 day open-label run-in period with S/V 24/26 mg twice daily, patients are randomized 1:1 to S/V titrated to 97/103 mg twice daily versus 160 mg V twice daily. The primary endpoint is the proportional change from baseline in the area under the curve for NT-proBNP levels measured through week 24. Secondary and tertiary endpoints include clinical outcomes, as well as safety and tolerability. Because of the COVID-19 pandemic enrollment in the LIFE trial was stopped prematurely to ensure patient safety and data integrity. The primary analysis will consist of the first 335 randomized patients, whose clinical follow-up was not severely impacted by COVID-19.


title: Signal amplification and quantification on lateral flow assays by laser excitation of plasmonic nanomaterials

text: Lateral flow assay (LFA) has become one of the most widely used point-of-care diagnostic methods due to its simplicity and low cost. While easy to use, LFA suffers from its low sensitivity and poor quantification, which largely limits its applications for early disease diagnosis and requires further testing to eliminate false-negative results. Over the past decade, signal enhancement strategies that took advantage of the laser excitation of plasmonic nanomaterials have pushed down the detection limit and enabled quantification of analytes. Significantly, these methods amplify the signal based on the current LFA design without modification. This review highlights these strategies of signal enhancement for LFA including surface enhanced Raman scattering (SERS), photothermal and photoacoustic methods. Perspectives on the rational design of the reader systems are provided. Future translation of the research toward clinical applications is also discussed.


A pandemic of Body, Mind, and Spirit: The Burden of “Social Distancing” in Rural Communities During an Era of Heightened Suicide Risk


title: Bioinformatic analysis and identification of single-stranded RNA sequences recognized by TLR7/8 in the SARS-CoV-2, SARS-CoV, and MERS-CoV genomes

text: Abstract During virus infection, host toll-like receptors (TLRs) can recognize different pathogen-associated molecular patterns and trigger the innate immune response. TLR7/8 can identify the single-stranded RNA (ssRNA) of the virus. This study aimed to search ssRNA sequences recognized by TLR7/8 from the SARS-CoV-2, SARS-CoV, and MERS-CoV whole genomes by a bioinformatic technique. The immunoinformatic approach showed that the SARS-CoV-2 genome has more ssRNA fragments that could be recognized by TLR7/8 than the SARS-CoV genome. These findings suggest innate immune hyperactivation by SARS-CoV-2. This activity is possibly able to provoke a robust proinflammatory response via TLR7/8 recognition and cause acute lung injury.


Compassionate use of others’ immunity — understanding gut microbiome in Covid-19


title: Can literature analysis identify innovation drivers in drug discovery?

text: Drug discovery must be guided not only by medical need and commercial potential, but also by the areas in which new science is creating therapeutic opportunities, such as target identification and the understanding of disease mechanisms. To systematically identify such areas of high scientific activity, we use bibliometrics and related data-mining methods to analyse over half a terabyte of data, including PubMed abstracts, literature citation data and patent filings. These analyses reveal trends in scientific activity related to disease studied at varying levels, down to individual genes and pathways, and provide methods to monitor areas in which scientific advances are likely to create new therapeutic opportunities. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/nrd2973) contains supplementary material, which is available to authorized users.


title: A Circulating miRNA Signature for Stratification of Breast Lesions among Women with Abnormal Screening Mammograms

text: Although mammography is the gold standard for breast cancer screening, the high rates of false-positive mammograms remain a concern. Thus, there is an unmet clinical need for a non-invasive and reliable test to differentiate between malignant and benign breast lesions in order to avoid subjecting patients with abnormal mammograms to unnecessary follow-up diagnostic procedures. Serum samples from 116 malignant breast lesions and 64 benign breast lesions were comprehensively profiled for 2,083 microRNAs (miRNAs) using next-generation sequencing. Of the 180 samples profiled, three outliers were removed based on the principal component analysis (PCA), and the remaining samples were divided into training (n = 125) and test (n = 52) sets at a 70:30 ratio for further analysis. In the training set, significantly differentially expressed miRNAs (adjusted p < 0.01) were identified after correcting for multiple testing using a false discovery rate. Subsequently, a predictive classification model using an eight-miRNA signature and a Bayesian logistic regression algorithm was developed. Based on the receiver operating characteristic (ROC) curve analysis in the test set, the model could achieve an area under the curve (AUC) of 0.9542. Together, this study demonstrates the potential use of circulating miRNAs as an adjunct test to stratify breast lesions in patients with abnormal screening mammograms.


O manejo do absorvedor de CO2 durante o uso do aparelho de anestesia como respirador mecânico em pacientes com COVID-19


title: Evaluation of the efficacy and safety of intravenous remdesivir in adult patients with severe COVID-19: study protocol for a phase 3 randomized, double-blind, placebo-controlled, multicentre trial

text: BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by a novel corinavirus (later named SARS-CoV-2 virus), was fistly reported in Wuhan, Hubei Province, China towards the end of 2019. Large-scale spread within China and internationally led the World Health Organization to declare a Public Health Emergency of International Concern on 30(th) January 2020. The clinical manifestations of COVID-19 virus infection include asymptomatic infection, mild upper respiratory symptoms, severe viral pneumonia with respiratory failure, and even death. There are no antivirals of proven clinical efficacy in coronavirus infections. Remdesivir (GS-5734), a nucleoside analogue, has inhibitory effects on animal and human highly pathogenic coronaviruses, including MERS-CoV and SARS-CoV, in in vitro and in vivo experiments. It is also inhibitory against the COVID-19 virus in vitro. The aim of this study is to assess the efficacy and safety of remdesivir in adult patients with severe COVID-19. METHODS: The protocol is prepared in accordance with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines. This is a phase 3, randomized, double-blind, placebo-controlled, multicentre trial. Adults (≥ 18 years) with laboratory-confirmed COVID-19 virus infection, severe pneumonia signs or symptoms, and radiologically confirmed severe pneumonia are randomly assigned in a 2:1 ratio to intravenously administered remdesivir or placebo for 10 days. The primary endpoint is time to clinical improvement (censored at day 28), defined as the time (in days) from randomization of study treatment (remdesivir or placebo) until a decline of two categories on a six-category ordinal scale of clinical status (1 = discharged; 6 = death) or live discharge from hospital. One interim analysis for efficacy and futility will be conducted once half of the total number of events required has been observed. DISCUSSION: This is the first randomized, placebo-controlled trial in COVID-19. Enrolment began in sites in Wuhan, Hubei Province, China on 6(th) February 2020. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04257656. Registered on 6 February 2020.


title: Safety of dupilumab in severe atopic dermatitis and infection of Covid‐19: two case reports

text: Dupilumab is a fully human monoclonal antibody against the alfa subunit of interleukin (IL)‐4 receptor that blocks signalling from both IL‐4 and IL‐13, which are key type 2 cytokines in the pathophysiology of atopic dermatitis (AD). It shows good efficacy with a rapid response and good safety with few side effects. In a paper of Deleuran et al. the authors showed long term safety and efficacy of dupilumab; they reported viral upper respiratory tract infection, cough and influenza in about 2% of patients.


title: Is periodontal disease a risk factor for severe COVID-19 illness?

text: Periodontal disease (PD) comprises a group of diseases involving inflammatory aspects of the host and dysbiotic events that affect periodontal tissues and could have systemic implications. Diverse factors and comorbidities have been closely associated with PD such as diabetes, obesity, aging, hypertension, and so on; although, underlying mechanisms or causal associations have not established completely. Interestingly, these same factors have widely associated with progression or severe coronavirus disease 2019 (COVID-19), an illness caused by coronavirus named SARS-CoV-2. Since inflammatory and dysbiotic factors as well as comorbidities affect systemic health, it is possible that periodontal status indicates the risk of complication of COVID-19. However, assessment of oral health history including periodontal status in COVID-19 patients has not been reported. Knowing PD is associated with severe COVID-19 could help identify risk groups and establish pertinent recommendations.


title: Building Telemedicine Capacity for Trainees During the Novel Coronavirus Outbreak: a Case Study and Lessons Learned

text: INTRODUCTION: Hospital and ambulatory care systems are rapidly building their virtual care capacity in response to the novel coronavirus (COVID-19) pandemic. The use of resident trainees in telemedicine is one area of potential development and expansion. To date, however, training opportunities in this field have been limited, and residents may not be adequately prepared to provide high-quality telemedicine care. AIM: This study evaluates the impact of an adapted telemedicine Objective Structured Clinical Examination (OSCE) on telemedicine-specific training competencies of residents. SETTING: Primary Care Internal Medicine residents at a large urban academic hospital. PROGRAM DESCRIPTION: In March 2020, the New York University Grossman School of Medicine Primary Care program adapted its annual comprehensive OSCE to a telemedicine-based platform, to comply with distance learning and social distancing policies during the COVID-19 pandemic. A previously deployed in-person OSCE on the subject of a medical error was adapted to a telemedicine environment and deployed to 23 primary care residents. Both case-specific and core learning competencies were assessed, and additional observations were conducted on the impact of the telemedicine context on the encounter. PROGRAM EVALUATION: Three areas of telemedicine competency need were identified in the OSCE case: technical proficiency; virtual information gathering, including history, collateral information collection, and physical exam; and interpersonal communication skills, both verbal and nonverbal. Residents expressed enthusiasm for telemedicine training, but had concerns about their preparedness for telemedicine practice and the need for further competency and curricular development. DISCUSSION: Programs interested in building capacity among residents to perform telemedicine, particularly during the COVID-19 pandemic, can make significant impact in their trainees’ comfort and preparedness by addressing key issues in technical proficiency, history and exam skills, and communication. Further research and curricular development in digital professionalism and digital empathy for trainees may also be beneficial. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11606-020-05979-9) contains supplementary material, which is available to authorized users.


title: Comparative serum proteome expression of the steroid-induced femoral head osteonecrosis in adults

text: Steroid-induced osteonecrosis of the femoral head (SONFH) is a disabling, aseptic and ischemic disease that develops following steroid therapy. The pathogenesis of SONFH is unclear, so the early diagnosis and treatment for this disease is yet to be established. The purpose of the present study was to identify potential biomarkers for SONFH. The differential expression of serum proteins from patients with SONFH and healthy volunteers was analyzed by the proteomics method. The protein samples were labeled and subjected to isoelectric focusing and two-dimensional gel electrophoresis. The resultant protein spots were matched and quantified by an imaging analysis system. The differentially-expressed protein spots were subjected to in-gel trypsin digestion followed by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Significantly lower levels of complement component 3 (C3), C4, inter-α-trypsin inhibitor heavy chain H4 and α-2-macroglobulin were found in the serum of patients with SONFH. These proteins are reported to be actively involved in intravascular coagulation, apoptosis and reactive oxygen species imbalance, indicating that multiple pathological reactions occur in SONFH and these proteins may serve as potential biomarkers for the diagnosis of SONFH.


title: Structural Insights into the Interaction of Coronavirus Papain-Like Proteases and Interferon-Stimulated Gene Product 15 from Different Species

text: Abstract Severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) encode multifunctional papain-like proteases (PLPs) that have the ability to process the viral polyprotein to facilitate RNA replication and antagonize the host innate immune response. The latter function involves reversing the post-translational modification of cellular proteins conjugated with either ubiquitin (Ub) or Ub-like interferon-stimulated gene product 15 (ISG15). Ub is known to be highly conserved among eukaryotes, but surprisingly, ISG15 is highly divergent among animals. The ramifications of this sequence divergence to the recognition of ISG15 by coronavirus PLPs at a structural and biochemical level are poorly understood. Therefore, the activity of PLPs from SARS-CoV, MERS‐CoV, and mouse hepatitis virus was evaluated against seven ISG15s originating from an assortment of animal species susceptible, and not, to certain coronavirus infections. Excitingly, our kinetic, thermodynamic, and structural analysis revealed an array of different preferences among PLPs. Included in these studies is the first insight into a coronavirus PLP’s interface with ISG15 via SARS-CoV PLpro in complex with the principle binding domain of human ISG15 (hISG15) and mouse ISG15s (mISG15s). The first X-ray structure of the full-length mISG15 protein is also reported and highlights a unique, twisted hinge region of ISG15 that is not conserved in hISG15, suggesting a potential role in differential recognition. Taken together, this new information provides a structural and biochemical understanding of the distinct specificities among coronavirus PLPs observed and addresses a critical gap of how PLPs can interact with ISG15s from a wide variety of species.


title: Clinical Characteristics and Outcomes of Community- and Hospital-Acquired Acute Kidney Injury with COVID-19 in a US Inner City Hospital System

text: INTRODUCTION: Emerging data have described poor clinical outcomes from infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2) among African American patients and those from underserved socioeconomic groups. We sought to describe the clinical characteristics and outcomes of acute kidney injury (AKI) in this special population. METHODS: This is a retrospective study conducted in an underserved area with a predominance of African American patients with coronavirus disease 2019 (COVID-19). Descriptive statistics were used to characterize the sample population. The onset of AKI and relation to clinical outcomes were determined. Multivariate logistic regression was used to determine factors associated with AKI. RESULTS: Nearly half (49.3%) of the patients with COVID-19 had AKI. Patients with AKI had a significantly lower baseline estimated glomerular filtration rate (eGFR) and higher FiO2 requirement and D-dimer levels on admission. More subnephrotic proteinuria and microhematuria was seen in these patients, and the majority had a pre-renal urine electrolyte profile. Patients with hospital-acquired AKI (HA-AKI) as opposed to those with community-acquired AKI (CA-AKI) had higher rates of in-hospital death (52 vs. 23%, p = 0.005), need for vasopressors (42 vs. 25%, p = 0.024), and need for intubation (55 vs. 25%, p = 0.006). A history of heart failure was significantly associated with AKI after adjusting for baseline eGFR (OR 3.382, 95% CI 1.121–13.231, p = 0.032). CONCLUSION: We report a high burden of AKI among underserved COVID-19 patients with multiple comorbidities. Those who had HA-AKI had worse clinical outcomes compared to those who with CA-AKI. A history of heart failure is an independent predictor of AKI in patients with COVID-19.


title: From Corona Virus to Corona Crisis: The Value of An Analytical and Geographical Understanding of Crisis

text: The term ‘crisis’ is omnipresent. The current corona virus pandemic is perceived as the most recent example. However, the notion of crisis is increasingly deployed as a signifier of relevance, rather than as an analytical concept. Moreover, human geography has so far little contributed to the interdisciplinary crisis research field which is fixated on the temporal aspects of crisis but neglects its spatiality. Against this background, the first aim of the paper is to demonstrate the value of thinking about crisis analytically. Therefore, we introduce theoretical knowledge developed within a recently emerging literature on crisis management. Second, we demonstrate the relevance of including geographical thinking into crisis research more systematically. Based on the TPSN‐framework by Jessop et al., we illustrate spatial dimensions of the ‘corona crisis’, its perception and handling in Germany. The empirical references are based on media reports.


title: Tuberculosis, COVID-19 and migrants: preliminary analysis of deaths occurring in 69 patients from two cohorts

text: Abstract Little is known about the relationship between the COVID-19 and tuberculosis (TB). The aim of this study is to describe a group of patients who died with TB (active disease or sequelae) and COVID-19 in two cohorts. Data from 49 consecutive cases in 8 countries (cohort A) and 20 hospitalized patients with TB and COVID-19 (cohort B) were analysed and patients who died were described. Demographic and clinical variables were retrospectively collected, including co-morbidities and risk factors for TB and COVID-19 mortality. Overall, 8 out of 69 (11.6%) patients died, 7 from cohort A (14.3%) and one from cohort B (5%). Out of 69 patients 43 were migrants, 26/49 (53.1%) in cohort A and 17/20 (85.0%) in cohort B. Migrants: 1) were younger than natives; in cohort A the median (IQR) age was 40 (27-49) VS. 66 (46-70) years, whereas in cohort B 37 (27-46) VS. 48 (47-60) years; 2) had a lower mortality rate than natives (1/43, 2.3% versus 7/26, 26.9%; p-value: 0.002); 3) had fewer co-morbidities than natives (23/43, 53.5 % versus 5/26- 19.2%) natives; p-value: 0.005). The study findings show that: 1) mortality is likely to occur in elderly patients with co-morbidities; 2) TB might not be a major determinant of mortality and 3) migrants had lower mortality, probably because of their younger age and lower number of co-morbidities. However, in settings where advanced forms of TB frequently occur and are caused by drug-resistant strains of M. tuberculosis, higher mortality rates can be expected in young individuals.


title: Annotation of long non-coding RNAs expressed in Collaborative Cross founder mice in response to respiratory virus infection reveals a new class of interferon-stimulated transcripts

text: The outcome of respiratory virus infection is determined by a complex interplay of viral and host factors. Some potentially important host factors for the antiviral response, whose functions remain largely unexplored, are long non-coding RNAs (lncRNAs). Here we systematically inferred the regulatory functions of host lncRNAs in response to influenza A virus and severe acute respiratory syndrome coronavirus (SARS-CoV) based on their similarity in expression with genes of known function. We performed total RNA-Seq on viral-infected lungs from eight mouse strains, yielding a large data set of transcriptional responses. Overall 5,329 lncRNAs were differentially expressed after infection. Most of the lncRNAs were co-expressed with coding genes in modules enriched in genes associated with lung homeostasis pathways or immune response processes. Each lncRNA was further individually annotated using a rank-based method, enabling us to associate 5,295 lncRNAs to at least one gene set and to predict their potential cis effects. We validated the lncRNAs predicted to be interferon-stimulated by profiling mouse responses after interferon-α treatment. Altogether, these results provide a broad categorization of potential lncRNA functions and identify subsets of lncRNAs with likely key roles in respiratory virus pathogenesis. These data are fully accessible through the MOuse NOn-Code Lung interactive database (MONOCLdb).


title: Therapeutic effect of an anti-human-TNF-alpha antibody and itraconazole on feline infectious peritonitis

text: Feline infectious peritonitis (FIP) is a fatal disease in wild and domestic cat species. Although several drugs are expected to be useful as treatments for FIP, no drugs are available in clinical practice. In this study, we evaluated the therapeutic effect of combined use of adalimumab (an anti-human-TNF-alpha monoclonal antibody, ADA) and itraconazole (ICZ), which are presently available to veterinarians. The neutralizing activity of ADA against fTNF-alpha-induced cytotoxicity was measured in WEHI-164 cells. Ten specific pathogen-free (SPF) cats were inoculated intraperitoneally with type I FIPV KU-2. To the cats that developed FIP, ADA (10 mg/animal) was administered twice between day 0 and day 4 after the start of treatment. ICZ (50 mg/head, SID) was orally administered daily from day 0 after the start of treatment. ADA demonstrated dose-dependent neutralizing activity against rfTNF-alpha. In an animal experiment, 2 of 3 cats showed improvements in FIP clinical symptoms and blood chemistry test results, an increase in the peripheral blood lymphocyte count, and a decrease in the plasma alpha 1-AGP level were observed after the beginning of treatment. One of the cats failed to respond to treatment and was euthanized, although the viral gene level in ascites temporarily decreased after the start of treatment. ADA was found to have neutralizing activity against rfTNF-alpha. The combined use of ADA and ICZ showed a therapeutic effect for experimentally induced FIP. We consider these drugs to be a treatment option until effective anti-FIPV drugs become available.


title: Viral pathogens associated with acute respiratory illness in hospitalized adults and elderly from Zagreb, Croatia, 2016 to 2018

text: AIMS: To investigate the viral etiology of acute respiratory infection (ARI) in hospitalized adults and elderly patients in Croatia, compare the prevalence of detected viruses, and to determine clinical characteristics and seasonal occurrence of investigated infections. METHODS: From January 2016 to June 2018, a total of 182 adult patients presented with symptoms of ARI and admitted to the hospital were tested for 15 respiratory viruses by multiplex reverse‐transcription polymerase chain reaction. Clinical data were collected by retrospective analysis of the patient's chart. RESULTS: A virus was identified in 106 (58.5%) of the patients. The most commonly detected virus was influenza virus (41.5%), followed by respiratory syncytial virus (13.8%), human metapneumovirus (13.0%), parainfluenza viruses (12.2%), rhinoviruses (11.4%), adenovirus and coronaviruses with equal frequencies (3.3%), and enterovirus (1.6%). The serum level of C‐reactive protein and white blood cell count were significantly lower in patients with respiratory viruses identified when compared with those in whom no virus was detected (P < 0.001 and P = 0.007, respectively). There were no differences in clinical symptoms according to the type of the detected virus, except for more frequent illness exposure recall for influenza infection ( P = 0.010). Influenza, parainfluenza, and pneumoviruses were detected mostly in winter months, while rhinoviruses in autumn and spring. CONCLUSIONS: In addition to influenza, pneumoviruses, rhinoviruses, and parainfluenza viruses play an important role in etiology of ARIs in adults. Fast and accurate laboratory diagnosis for respiratory viruses in routine practice is needed for clinicians optimally manage patients with ARI and potentially avoid the unnecessary use of antimicrobial drugs.


title: Conséquences de l'épidémie de SRAS sur le système hospitalier de l'Ontario

text: Résumé L'épidémie de syndrome respiratoire aigu sévère (SRAS), qui a duré de mars à juillet 2003, a profondément modifié le système de soins de la région de Toronto. Les caractéristiques de cet agent infectieux, en particulier son caractère extrêmement contagieux expliquant la contamination précoce du personnel hospitalier, et la sévérité de la maladie qu'il induit ont contribué à désorganiser profondément le système de soins, en particulier les services de réanimation et d'urgences. La réponse rapide des acteurs du système a permis d'élaborer dans l'urgence une stratégie hospitalière et de contrôler cette épidémie grâce à une mobilisation générale. Lors de la seconde phase de l'épidémie en avril, une réponse coordonnée a été élaborée, par la création d'un réseau de soins d'hôpitaux dédiés à la lutte contre le SRAS, doté de moyens de communication et de transfert adaptés. À la fin de l'épidémie, les leçons tirées par les professionnels de Santé ont entraîné une complète transformation du système de soins de l'Ontario, avec la création de réseaux de soins régionaux, la mise en place d'une stratégie de coordination des services d'urgence et de réanimation, dont on a augmenté les capacités. Ces réflexions ont aussi permis de créer des groupes de travail, au niveau provincial et régional, pour préparer la réponse à d'autres désastres infectieux éventuels, comme une pandémie de grippe aviaire. Abstract In March 2003 the healthcare system of Toronto had to respond to an outbreak of severe acute respiratory syndrome. This infectious disease due to a novel coronavirus spread rapidly because this infectious agent was highly contagious and contaminated many caregivers. The increase in the demand in critical care beds with concomitantly a decrease in the number of caregivers sick or in quarantine, deeply disorganized the emergency and critical care system. Lack of preparedness, absence of coordination and leadership, poor communication were identified as factors amplifying the impact of this outbreak. Rapidly, however a disaster plan was implemented allowing for better organizing the response of hospitals, allowing the control of the outbreak. During the second phase of the outbreak in April 2003, a coordinated network of hospital is designed to isolate the patients and provide best evidenced care with optimal protection of the caregivers. Several recommendations resulted from the retrospective analysis of these events. These were used to develop a transformation of the healthcare system in Ontario, with creation of local health integrated networks, reorganization of the acute care system with increased capacity, development of infectious disease control. In preparation of a new outbreak, provincial and local task forces have been implemented to provide recommendations in collaboration with the newly created Public Health Agency of Canada.


title: Middle East respiratory syndrome coronavirus disease is rare in children: An update from Saudi Arabia

text: AIM: To summarize the reported Middle East respiratory syndrome-coronavirus (MERS-CoV) cases, the associated clinical presentations and the outcomes. METHODS: We searched the Saudi Ministry of Health website, the World Health Organization website, and the Flutracker website. We also searched MEDLINE and PubMed for the keywords: Middle East respiratory syndrome-coronavirus, MERS-CoV in combination with pediatric, children, childhood, infancy and pregnancy from the initial discovery of the virus in 2012 to 2016. The retrieved articles were also read to further find other articles. Relevant data were placed into an excel sheet and analyzed accordingly. Descriptive analytic statistics were used in the final analysis as deemed necessary. RESULTS: From June 2012 to April 19, 2016, there were a total of 31 pediatric MERS-CoV cases. Of these cases 13 (42%) were asymptomatic and the male to female ratio was 1.7:1. The mean age of patients was 9.8 ± 5.4 years. Twenty-five (80.6%) of the cases were reported from the Kingdom of Saudi Arabia. The most common source of infection was household contact (10 of 15 with reported source) and 5 patients acquired infection within a health care facility. Using real time reverse transcriptase polymerase chain reaction of pediatric patients revealed that 9 out of 552 (1.6%) was positive in the Kingdom of Saudi Arabia. CONCLUSION: Utilizing serology for MERS-CoV infection in Jordan and Saudi Arabia did not reveal any positive patients. Thus, the number of the pediatric MERS-CoV is low; the exact reason for the low prevalence of the disease in children is not known.


title: Advancements in Host-Based Interventions for Influenza Treatment

text: Influenza is a major acute respiratory infection that causes mortality and morbidity worldwide. Two classes of conventional antivirals, M2 ion channel blockers and neuraminidase inhibitors, are mainstays in managing influenza disease to lessen symptoms while minimizing hospitalization and death in patients with severe influenza. However, the development of viral resistance to both drug classes has become a major public health concern. Vaccines are prophylaxis mainstays but are limited in efficacy due to the difficulty in matching predicted dominant viral strains to circulating strains. As such, other potential interventions are being explored. Since viruses rely on host cellular functions to replicate, recent therapeutic developments focus on targeting host factors involved in virus replication. Besides controlling virus replication, potential targets for drug development include controlling virus-induced host immune responses such as the recently suggested involvement of innate lymphoid cells and NADPH oxidases in influenza virus pathogenesis and immune cell metabolism. In this review, we will discuss the advancements in novel host-based interventions for treating influenza disease.


title: Bacteria–autophagy interplay: a battle for survival

text: Autophagy is a cellular process that targets proteins, lipids and organelles to lysosomes for degradation, but it has also been shown to combat infection with various pathogenic bacteria. In turn, bacteria have developed diverse strategies to avoid autophagy by interfering with autophagy signalling or the autophagy machinery and, in some cases, they even exploit autophagy for their growth. In this Review, we discuss canonical and non-canonical autophagy pathways and our current knowledge of antibacterial autophagy, with a focus on the interplay between bacterial factors and autophagy components. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/nrmicro3160) contains supplementary material, which is available to authorized users.


Amid COVID-19 drug shortages: proposed plan for reprocessing and reusing salbutamol pressurized metered dose inhalers (pMDIs) for shared use


title: Impact of Historic Migrations and Evolutionary Processes on Human Immunity

text: The evolution of mankind has constantly been influenced by the pathogens encountered. The various populations of modern humans that ventured out of Africa adapted to different environments and faced a large variety of infectious agents, resulting in local adaptations of the immune system for these populations. The functional variation of immune genes as a result of evolution is relevant in the responses against infection, as well as in the emergence of autoimmune and inflammatory diseases observed in modern populations. Understanding how host–pathogen interactions have influenced the human immune system from an evolutionary perspective might contribute to unveiling the causes behind different immune-mediated disorders and promote the development of new strategies to detect and control such diseases.


title: ‘’Treatment adherence in psoriatic patients during COVID‐19 pandemic: Real‐world data from a tertiary hospital in Greece’’

text: COVID‐19 pandemic raised questions both in dermatologists and in patients about the use of immunosuppressive medications. Although dermatologic societies recommend the continuing of psoriatic systemic therapies and biologics, little is known about treatment adherence in psoriatic patients during COVID‐19 outbreak. Medication self‐management may feel burdensome to patients with psoriasis due to the nature of treatments and many of them face additional challenges as they may suffer from comorbidities. Under these already difficult conditions, COVID‐19 disease puts extra pressure on individuals and may undermine adherence. Acknowledging treatment non‐adherence as a consequence of conflicting goals may help to find the reasons for but, most important, solutions to non‐adherence especially during public health crises. The objective of our study was to evaluate the adherence of psoriatic patients in traditional systemic treatment as well as biologics and identify possible influencing factors of drug interruption during COVID‐10 pandemic.


title: Diversity of avian Pasteurella multocida strains based on capsular PCR typing and variation of the OmpA and OmpH outer membrane proteins

text: Abstract One hundred avian Pasteurella multocida isolates recovered from cases of fowl cholera and related infections in England and Wales over a 13-year period were characterised by capsular PCR typing and analysis of outer membrane protein (OMP) profiles. Sixty-eight percent of the strains were of capsular type A, 14% were type F, 5% were type D, 4% were type B and 9% were untypable. Nineteen distinct OMP profiles (OMP-types) were identified based mainly on molecular mass heterogeneity of the heat-modifiable (OmpA) and porin (OmpH) proteins. Fifty-six percent of the isolates were represented by 15 OMP-types, whereas 44% of the isolates were associated with four OMP-types. The extensive molecular mass heterogeneity of the OmpA and OmpH proteins supports previous findings that avian P. multocida strains are very diverse. Furthermore, the isolates studied were associated with different clinical symptoms and were recovered from a wide range of lesions and tissues. The high degree of strain diversity together with the wide variety of clinical symptoms suggest that certain avian strains of P. multocida are opportunistic pathogens of relatively low virulence. Strains of capsular types B, D and F, as well as the untypable isolates, were associated exclusively with specific OMP-types and represent distinct and widely disseminated clonal groups. These observations support the view that avian strains of P. multocida have a clonal population structure. Based on previous studies, the molecular mass heterogeneity of the OmpA and OmpH proteins might provide a selective advantage to P. multocida by generating antigenic variation.


title: Regulation of the ER Stress Response by the Ion Channel Activity of the Infectious Bronchitis Coronavirus Envelope Protein Modulates Virion Release, Apoptosis, Viral Fitness, and Pathogenesis

text: Coronavirus (CoV) envelope (E) protein is a small structural protein critical for virion morphogenesis and release. The recently characterized E protein ion channel activity (EIC) has also been implicated in modulating viral pathogenesis. In this study, we used infectious bronchitis coronavirus (IBV) as a model to study EIC. Two recombinant IBVs (rIBVs) harboring EIC-inactivating mutations – rT16A and rA26F – were serially passaged, and several compensatory mutations were identified in the transmembrane domain (TMD). Two rIBVs harboring these putative EIC-reverting mutations – rT16A/A26V and rA26F/F14N – were recovered. Compared with the parental rIBV-p65 control, all four EIC mutants exhibited comparable levels of intracellular RNA synthesis, structural protein production, and virion assembly. Our results showed that the IBV EIC contributed to the induction of ER stress response, as up-regulation of ER stress-related genes was markedly reduced in cells infected with the EIC-defective mutants. EIC-defective mutants also formed smaller plaques, released significantly less infectious virions into the culture supernatant, and had lower levels of viral fitness in cell culture. Significantly, all these defective phenotypes were restored in cells infected with the putative EIC revertants. EIC mutations were also implicated in regulating IBV-induced apoptosis, induction of pro-inflammatory cytokines, and viral pathogenicity in vivo. Taken together, this study highlights the importance of CoV EIC in modulating virion release and various aspects of CoV – host interaction.


Reply: A Dermatologic Manifestation of COVID-19: Transient Livedo Reticularis


title: Therapeutic uses of antioxidant liposomes

text: This review will focus on the therapeutic uses of antioxidant liposomes. Antioxidant liposomes have a unique ability to deliver both lipid- and water-soluble antioxidants to tissues. This review will detail the varieties of antioxidants which have been incorporated into liposomes, their modes of administration, and the clinical conditions in which antioxidant liposomes could play an important therapeutic role. Antioxidant liposomes should be particularly useful for treating diseases or conditions in which oxidative stress plays a significant pathophysiological role because this technology has been shown to suppress oxidative stress. These diseases and conditions include cancer, trauma, irradiation, retinotherapy or prematurity, respiratory distress syndrome, chemical weapon exposure, and pulmonary infections.


title: Tannic acid facilitates expression of the polypyrimidine tract binding protein and alleviates deleterious inclusion of CHRNA1 exon P3A due to an hnRNP H-disrupting mutation in congenital myasthenic syndrome

text: We recently reported that the intronic splice-site mutation IVS3-8G>A of CHRNA1 that encodes the muscle nicotinic acetylcholine receptor α subunit disrupts binding of a splicing repressor, hnRNP H. This, in turn, results in exclusive inclusion of the downstream exon P3A. The P3A(+) transcript encodes a non-functional α subunit that comprises 50% of the transcripts in normal human skeletal muscle, but its functional significance remains undetermined. In an effort to search for a potential therapy, we screened off-label effects of 960 bioactive chemical compounds and found that tannic acid ameliorates the aberrant splicing due to IVS3-8G>A but without altering the expression of hnRNP H. Therefore, we searched for another splicing trans-factor. We found that the polypyrimidine tract binding protein (PTB) binds close to the 3′ end of CHRNA1 intron 3, that PTB induces skipping of exon P3A and that tannic acid increases the expression of PTB in a dose-dependent manner. Deletion assays of the PTB promoter region revealed that the tannic acid-responsive element is between positions −232 and −74 from the translation initiation site. These observations open the door to the discovery of novel therapies based on PTB overexpression and to detecting possible untoward effects of the overexpression.


Offline: COVID-19—a reckoning


title: Law, Structural Racism, and the COVID-19 Pandemic

text: Racial and ethnic minorities have always been the most impacted by pandemics because of: disparities in exposure to the virus; disparities in susceptibility to contracting the virus; and disparities in treatment. This article explains how structural racism, the ways in which laws are used to advantage the majority and disadvantage racial and ethnic minorities, has caused these disparities. Specifically, this article focuses on how employment, housing, health care, and COVID-19 relief laws have been manipulated to disadvantage racial and ethnic minorities, making minorities more susceptible to COVID-19 infection and death. This article uses Blumenshine’s 2008 framework to outline how structural racism causes racial and ethnic minorities’ disparities in exposure to viruses, in susceptibility to contracting viruses, in treatment of viruses, and in infection and death rates. This article discusses how historical and current practices of structural racism in existing employment, housing, and health care laws and the Coronavirus Aid, Relief, and Economic Security Act (CARES Act) cause disparities in COVID-19 infections and deaths. This article suggests legal solutions to address structural racism as well as public health solutions to help mitigate the racialized effects of the disease.


title: Alignment-free method for DNA sequence clustering using Fuzzy integral similarity

text: A larger amount of sequence data in private and public databases produced by next-generation sequencing put new challenges due to limitation associated with the alignment-based method for sequence comparison. So, there is a high need for faster sequence analysis algorithms. In this study, we developed an alignment-free algorithm for faster sequence analysis. The novelty of our approach is the inclusion of fuzzy integral with Markov chain for sequence analysis in the alignment-free model. The method estimate the parameters of a Markov chain by considering the frequencies of occurrence of all possible nucleotide pairs from each DNA sequence. These estimated Markov chain parameters were used to calculate similarity among all pairwise combinations of DNA sequences based on a fuzzy integral algorithm. This matrix is used as an input for the neighbor program in the PHYLIP package for phylogenetic tree construction. Our method was tested on eight benchmark datasets and on in-house generated datasets (18 s rDNA sequences from 11 arbuscular mycorrhizal fungi (AMF) and 16 s rDNA sequences of 40 bacterial isolates from plant interior). The results indicate that the fuzzy integral algorithm is an efficient and feasible alignment-free method for sequence analysis on the genomic scale.


title: Ancient Evolution of Mammarenaviruses: Adaptation via Changes in the L Protein and No Evidence for Host–Virus Codivergence

text: The Mammarenavirus genus includes several pathogenic species of rodent-borne viruses. Old World (OW) mammarenaviruses infect rodents in the Murinae subfamily and are mainly transmitted in Africa and Asia; New World (NW) mammarenaviruses are found in rodents of the Cricetidae subfamily in the Americas. We applied a selection-informed method to estimate that OW and NW mammarenaviruses diverged less than ∼45,000 years ago (ya). By incorporating phylogeographic inference, we show that NW mammarenaviruses emerged in the Latin America-Caribbean region ∼41,400–3,300 ya, whereas OW mammarenaviruses originated ∼23,100–1,880 ya, most likely in Southern Africa. Cophylogenetic analysis indicated that cospeciation did not contribute significantly to mammarenavirus–host associations. Finally, we show that extremely strong selective pressure on the viral polymerase accompanied the speciation of NW viruses. These data suggest that the evolutionary history of mammarenaviruses was not driven by codivergence with their hosts. The viral polymerase should be regarded as a major determinant of mammarenavirus adaptation.


title: Comparative analysis of routes of immunization of a live porcine reproductive and respiratory syndrome virus (PRRSV) vaccine in a heterologous virus challenge study

text: Porcine reproductive and respiratory syndrome (PRRS) is caused by PRRS virus (PRRSV), which infects primarily the respiratory tract of pigs. Thus intranasal (IN) delivery of a potent vaccine-adjuvant formulation is promising. In this study, PRRS-MLV (VR2332) was coadministered ± an adjuvant Mycobacterium vaccae whole cell lysate or CpG ODN through intramuscular (IM) or IN route as a mist, and challenged with a heterologous PRRSV 1-4-4 IN at 42 days post-vaccination (dpv). At 14 and 26 dpv, vaccine viral RNA copies were one log greater in the plasma of PRRS-MLV IM compared to IN vaccinated pigs, and the infectious replicating vaccine virus was detected only in the IM group. In PRRS-MLV ± adjuvant IM vaccinated pigs, reduced viral RNA load and absence of the replicating challenged virus was observed at 7, 10 and 14 days post-challenge (dpc). At 14 dpc, in BAL fluid ≥5 log viral RNA copies were detected in all the pig groups, but the replicating challenged virus was undetectable only in IM groups. Immunologically, virus neutralizing antibody titers in the plasma of IM (but not IN) vaccine groups was ≥8 against the vaccine and challenged viruses. At 26 dpv, PRRS-MLV IM (without adjuvant) received pigs had significantly increased population of CD4 and CD8 T cells in PBMC. At 14 dpc, relatively increased population of IFN-γ(+) total lymphocytes, NK, CD4, CD8 and γδ T cells were observed in the MLV-IM group. In conclusion, PRRS-MLV IM vaccination induced the virus specific T cell response in pigs, but still it is required to improve its cross-protective efficacy.


title: Effective treatment of severe COVID-19 patients with tocilizumab

text: After analyzing the immune characteristics of patients with severe coronavirus disease 2019 (COVID-19), we have identified that pathogenic T cells and inflammatory monocytes with large amount of interleukin 6 secreting may incite the inflammatory storm, which may potentially be curbed through monoclonal antibody that targets the IL-6 pathways. Here, we aimed to assess the efficacy of tocilizumab in severe patients with COVID-19 and seek a therapeutic strategy. The patients diagnosed as severe or critical COVID-19 in The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital) and Anhui Fuyang Second People’s Hospital were given tocilizumab in addition to routine therapy between 5 and 14 February 2020. The changes of clinical manifestations, computerized tomography (CT) scan image, and laboratory examinations were retrospectively analyzed. Fever returned to normal on the first day, and other symptoms improved remarkably within a few days. Within 5 d after tocilizumab, 15 of the 20 patients (75.0%) had lowered their oxygen intake, and 1 patient needed no oxygen therapy. CT scans manifested that the lung lesion opacity absorbed in 19 patients (90.5%). The percentage of lymphocytes in peripheral blood, which decreased in 85.0% of patients (17/20) before treatment (mean, 15.52 ± 8.89%), returned to normal in 52.6% of patients (10/19) on the fifth day after treatment. Abnormally elevated C-reactive protein decreased significantly in 84.2% of patients (16/19). No obvious adverse reactions were observed. All patients have been discharged on average 15.1 d after giving tocilizumab. Preliminary data show that tocilizumab, which improved the clinical outcome immediately in severe and critical COVID-19 patients, is an effective treatment to reduce mortality.


title: Structural and Evolutionary Analysis Indicate That the SARS-CoV-2 Mpro Is a Challenging Target for Small-Molecule Inhibitor Design

text: The novel coronavirus whose outbreak took place in December 2019 continues to spread at a rapid rate worldwide. In the absence of an effective vaccine, inhibitor repurposing or de novo drug design may offer a longer-term strategy to combat this and future infections due to similar viruses. Here, we report on detailed classical and mixed-solvent molecular dynamics simulations of the main protease (Mpro) enriched by evolutionary and stability analysis of the protein. The results were compared with those for a highly similar severe acute respiratory syndrome (SARS) Mpro protein. In spite of a high level of sequence similarity, the active sites in both proteins showed major differences in both shape and size, indicating that repurposing SARS drugs for COVID-19 may be futile. Furthermore, analysis of the binding site’s conformational changes during the simulation time indicated its flexibility and plasticity, which dashes hopes for rapid and reliable drug design. Conversely, structural stability of the protein with respect to flexible loop mutations indicated that the virus’ mutability will pose a further challenge to the rational design of small-molecule inhibitors. However, few residues contribute significantly to the protein stability and thus can be considered as key anchoring residues for Mpro inhibitor design.


Surviving the first COVID‐19 wave and learning lessons for the second


Reply to “Relation among right ventricular dysfunction, lung damage and mortality in patients with COVID-19” and “Right ventricular longitudinal strain: a new prognostic tool for COVID-19?”


title: Detection and phylogenetic characterization of arbovirus dual-infections among persons during a chikungunya fever outbreak, Haiti 2014

text: In the context of recent arbovirus epidemics, questions about the frequency of simultaneous infection of patients with different arbovirus species have been raised. In 2014, a major Chikungunya virus (CHIKV) epidemic impacted the Caribbean and South America. As part of ongoing screening of schoolchildren presenting with acute undifferentiated febrile illness in rural Haiti, we used RT-PCR to identify CHIKV infections in 82 of 100 children with this diagnosis during May—August 2014. Among these, eight were infected with a second arbovirus: six with Zika virus (ZIKV), one with Dengue virus serotype 2, and one with Mayaro virus (MAYV). These dual infections were only detected following culture of the specimen, suggesting low viral loads of the co-infecting species. Phylogenetic analyses indicated that the ZIKV and MAYV strains differ from those detected later in 2014 and 2015, respectively. Moreover, CHIKV and ZIKV strains from co-infected patients clustered monophyletically in their respective phylogeny, and clock calibration traced back the common ancestor of each clade to an overlapping timeframe of introduction of these arboviruses onto the island.


title: Mouse Hepatitis Virus Infection Induces an Early, Transient Calcium Influx in Mouse Astrocytoma Cells

text: Abstract Mouse hepatitis virus (MHV), a murine coronavirus, utilizes murine carcinoembryonic antigens as receptors. The events that follow virus–receptor binding and eventually lead to virus entry are poorly understood. We studied the possible effects of MHV infection on intracellular calcium in a mouse astrocytoma cell line. Using the calcium-sensitive dye fluo-3 and confocal laser scanning microscopy, we found that MHV strain JHM induced an immediate (within 20 s) and transient (lasting no longer than 2 min) calcium increase in about 5% of the infected cells. The calcium increase was blocked by antibodies against the viral spike protein, suggesting that it was specifically triggered by the interaction of the viral spikes with cells. It was also inhibited by L-type calcium channel blockers and was not detected in calcium-free medium, suggesting that the calcium increase was caused by calcium influx from the extracellular medium. Studies of the kinetics of viral replication by immunofluorescence staining of the viral nucleocapsid protein revealed that at 3 h postinfection there was roughly the same percentage of cells (5%) that produced the viral protein as the percentage of cells that had responded with a calcium signal. This finding and the virus dilution studies together suggest that calcium responders may represent cells that had been infected with multiple viruses and undergone rapid viral replication. Furthermore, calcium channel blockers, including verapamil and cadmium chloride, and the calcium chelator EGTA inhibited virus infection. Therefore, the transient intracellular calcium increase reported here may be an early signaling event associated with virus infection.


title: Supporting children and families through the pandemic, and after: The case for a US child allowance

text: Abstract The COVID-19 pandemic has precipitated a contraction in economic activity that is unprecedented in both its nature and speed. In doing so, it has exposed who is protected and supported by modern welfare states, and who is not. While the US has a relatively robust set of social insurance and assistance programs for older Americans and working-age Americans who become unemployed or disabled, it lacks – in contrast to many other wealthy nations – a comparably strong universal or wide-reaching mechanism to support families with children. The US emergency relief packages enacted to date will undoubtedly mitigate the economic effects of the current crisis for many families, but because this legislation relies on the existing social policy infrastructure, its intended cash relief reinforces current inequalities and underserves families with children, with a particular impact on immigrant families and families of color. To protect all families with children through the immediate crisis and beyond, existing gaps and inequities in the US social safety net must be addressed. The creation of a national US child allowance offers a concrete and evidence-based way in which to do so. This analysis outlines key shortcomings in the existing system of US public support for families with children, the ways in which these shortcomings have been exacerbated in the COVID-19 economic response package to date, and how a national child allowance can provide the immediate relief families need during the pandemic and the unfolding economic downturn, as well as lay the foundation for positive health and development for all children in the years to follow.