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Pain and Evil: From Local Nociception to Misery Following Social Harm

Experiencing pain, especially when chronic, is an excruciating condition that should be regarded as a syndrome, if not a disease. People suffering from chronic pain tend to develop psychological discomfort mostly due to lack of acceptance, disbelief, blame. The complexity of pain pathophysiology, plus a wide range of negative psychosocial factors, leads to a more complex suffering that deserves attention and multidisciplinary treatments. The possibility that chronic pain may occur following physical aggression, torture, or persecution raises the issue of evil as a major contributor to pain in its worst representation – when individuals or groups are attacked based on racial, social, gender, religious, political, or other grounds. To explore the complex issue of chronic pain following physical or psychological harm, and to underscore the need for a multidisciplinary approach to reduce the burden of chronic pain, we discuss the biological mechanisms underlying pain state. We seek to clarify those factors leading to pain chronification, as well as personal and social attitudes that confound patients with chronic pain. The importance of family and social environment is also investigated, as well as personality traits of chronic pain patients that may further hamper successful treatment. The presence of chronic pain, modulated by, for example, acceptance of being a victim of premeditated physical and social violence, makes the issue more difficult to comprehend.

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Lentiviral Vector Design for Multiple shRNA Expression and Durable HIV-1 Inhibition

Human immunodeficiency virus type 1 (HIV-1) replication in T cells can be inhibited by RNA interference (RNAi) through short hairpin RNA (shRNA) expression from a lentiviral vector. However, for the development of a durable RNAi-based gene therapy against HIV-1, multiple shRNAs need to be expressed simultaneously in order to avoid viral escape. In this study, we tested a multiple shRNA expression strategy for different shRNAs using repeated promoters in a lentiviral vector. Although highly effective in co-transfection experiments, a markedly reduced activity of each expressed shRNA was observed in transduced cells. We found that this reduced activity was due to recombination of the expression cassette repeat sequences during the transduction of the lentiviral vector, which resulted in deletions of one or multiple cassettes. To avoid recombination, we tested different promoters for multiple shRNA expression. We compared the activity of the human polymerase III promoters U6, H1, and 7SK and the polymerase II U1 promoter. Activities of these promoters were similar, irrespective of which shRNA was expressed. We showed that these four expression cassettes can be combined in a single lentiviral vector without causing recombination. Moreover, whereas HIV-1 could escape from a single shRNA, we now show that HIV-1 escape can be prevented when four shRNAs are simultaneously expressed in a cell.

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Spike protein recognition of mammalian ACE2 predicts the host range and an optimized ACE2 for SARS-CoV-2 infection

Abstract SARS-CoV-2 causes the recent global COVID-19 public health emergency. ACE2 is the receptor for both SARS-CoV-2 and SARS-CoV. To predict the potential host range of SARS-CoV-2, we analyzed the key residues of ACE2 for recognizing S protein. We found that most of the selected mammals including pets (dog and cat), pangolin and Circetidae mammals remained the most of key residues for association with S protein from SARS-CoV and SARS-CoV-2. The interaction interface between cat/dog/pangolin/Chinese hamster ACE2 and SARS-CoV/SARS-CoV-2 S protein was simulated through homology modeling. We identified that N82 in ACE2 showed a closer contact with SARS-CoV-2 S protein than M82 in human ACE2. Our finding will provide important insights into the host range of SARS-CoV-2 and a new strategy to design an optimized ACE2 for SARS-CoV-2 infection.

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Cytokine Storm Induced by SARS-CoV-2

A novel coronavirus disease 2019 (COVID-19) triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently spreading globally, causing severe pneumonia and acute lung injury in many patients. Even worse, severe respiratory may develop into acute respiratory distress syndrome and multiple organ dysfunction syndrome in COVID-19. The cytokine storm caused by immune over-activation due to virus infection may be an important cause of death in the late period of progress, but the pathogenesis of cytokine storm is still unclear. This article reviews the mechanisms of SARS-CoV-2-induced cytokine storm in detail based on the current discovered researches, and put forward some valuable medication ideas for the targeted cytokines drug researches and treatment. The goal of this work will be helpful for reducing excessive immune response.

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Analysis and Numerical Simulations of a Stochastic SEIQR Epidemic System with Quarantine-Adjusted Incidence and Imperfect Vaccination

This paper considers a high-dimensional stochastic SEIQR (susceptible-exposed-infected-quarantined-recovered) epidemic model with quarantine-adjusted incidence and the imperfect vaccination. The main aim of this study is to investigate stochastic effects on the SEIQR epidemic model and obtain its thresholds. We first obtain the sufficient condition for extinction of the disease of the stochastic system. Then, by using the theory of Hasminskii and the Lyapunov analysis methods, we show there is a unique stationary distribution of the stochastic system and it has an ergodic property, which means the infectious disease is prevalent. This implies that the stochastic disturbance is conducive to epidemic diseases control. At last, computer numerical simulations are carried out to illustrate our theoretical results.

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The authors’ response: Propofol and sedation in patients with coronavirus disease 2019

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Respiratory viral infections are not uncommon in neonatal intensive care units

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Viral evasion and subversion of pattern-recognition receptor signalling

The expression of pattern-recognition receptors (PRRs) by immune and tissue cells provides the host with the ability to detect and respond to infection by viruses and other microorganisms. Significant progress has been made from studying this area, including the identification of PRRs, such as Toll-like receptors and RIG-I-like receptors, and the description of the molecular basis of their signalling pathways, which lead to the production of interferons and other cytokines. In parallel, common mechanisms used by viruses to evade PRR-mediated responses or to actively subvert these pathways for their own benefit are emerging. Accumulating evidence on how viral infection and PRR signalling pathways intersect is providing further insights into the function of the pathways involved, their constituent proteins and ways in which they could be manipulated therapeutically.

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Short hairpin RNAs targeting M and N genes reduce replication of porcine deltacoronavirus in ST cells

Porcine deltacoronavirus (PDCoV) is a recently identified coronavirus that causes intestinal diseases in neonatal piglets with diarrhea, vomiting, dehydration, and post-infection mortality of 50–100%. Currently, there are no effective treatments or vaccines available to control PDCoV. To study the potential of RNA interference (RNAi) as a strategy against PDCoV infection, two short hairpin RNA (shRNA)-expressing plasmids (pGenesil-M and pGenesil-N) that targeted the M and N genes of PDCoV were constructed and transfected separately into swine testicular (ST) cells, which were then infected with PDCoV strain HB-BD. The potential of the plasmids to inhibit PDCoV replication was evaluated by cytopathic effect, virus titers, and real-time quantitative RT-PCR assay. The cytopathogenicity assays demonstrated that pGenesil-M and pGenesil-N protected ST cells against pathological changes with high specificity and efficacy. The 50% tissue culture infective dose showed that the PDCoV titers in ST cells treated with pGenesil-M and pGenesil-N were reduced 13.2- and 32.4-fold, respectively. Real-time quantitative RT-PCR also confirmed that the amount of viral RNA in cell cultures pre-transfected with pGenesil-M and pGenesil-N was reduced by 45.8 and 56.1%, respectively. This is believed to be the first report to show that shRNAs targeting the M and N genes of PDCoV exert antiviral effects in vitro, which suggests that RNAi is a promising new strategy against PDCoV infection.

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Infectious disease antibodies for biomedical applications: A mini review of immune antibody phage library repertoire

Antibody phage display is regarded as a critical tool for the development of monoclonal antibodies for infectious diseases. The different classes of antibody libraries are classified based on the source of repertoire used to generate the libraries. Immune antibody libraries are generated from disease infected host or immunization against an infectious agent. Antibodies derived from immune libraries are distinct from those derived from naïve libraries as the host's in vivo immune mechanisms shape the antibody repertoire to yield high affinity antibodies. As the immune system is constantly evolving in accordance to the health state of an individual, immune libraries can offer more than just infection-specific antibodies but also antibodies derived from the memory B-cells much like naïve libraries. The combinatorial nature of the gene cloning process would give rise to a combination of natural and un-natural antibody gene pairings in the immune library. These factors have a profound impact on the coverage of immune antibody libraries to target both disease-specific and non-disease specific antigens. This review looks at the diverse nature of antibody responses for immune library generation and discusses the extended potential of a disease-specified immune library in the context of phage display.

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Social mixing patterns in rural and urban areas of southern China

A dense population, global connectivity and frequent human–animal interaction give southern China an important role in the spread and emergence of infectious disease. However, patterns of person-to-person contact relevant to the spread of directly transmitted infections such as influenza remain poorly quantified in the region. We conducted a household-based survey of travel and contact patterns among urban and rural populations of Guangdong, China. We measured the character and distance from home of social encounters made by 1821 individuals. Most individuals reported 5–10 h of contact with around 10 individuals each day; however, both distributions have long tails. The distribution of distance from home at which contacts were made is similar: most were within a kilometre of the participant's home, while some occurred further than 500 km away. Compared with younger individuals, older individuals made fewer contacts which tended to be closer to home. There was strong assortativity in age-based contact rates. We found no difference between the total number or duration of contacts between urban and rural participants, but urban participants tended to make contacts closer to home. These results can improve mathematical models of infectious disease emergence, spread and control in southern China and throughout the region.

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Extrapolating Antibiotic Sales to Number of Treated Animals: Treatments in Pigs and Calves in Switzerland, 2011–2015

To evaluate the contribution of antimicrobial use in human and veterinary medicine to the emergence and spread of resistant bacteria, the use of these substances has to be accurately monitored in each setting. Currently, various initiatives collect sales data of veterinary antimicrobials, thereby providing an overview of quantities on the market. However, sales data collected at the level of wholesalers or marketing authorization holders are of limited use to associate with the prevalence of bacterial resistances at species level. We converted sales data to the number of potential treatments of calves and pigs in Switzerland for the years 2011 to 2015 using animal course doses (ACD). For each authorized product, the number of potential therapies was derived from the sales at wholesaler's level and the ACD in mg per kg. For products registered for use in multiple species, a percentage of the sales was attributed to each authorized species according to their biomass distribution. We estimated a total of 5,914,349 therapies for pigs and 1,407,450 for calves in 2015. Using the number of slaughtered animals for that year as denominator, we calculated a treatment intensity of 2.15 therapies per pig and 5.96 per calf. Between 2011 and 2015, sales of veterinary antimicrobials decreased by 30%. The calculated number of potential therapies decreased by 30% for pigs and 15% for calves. An analysis of treatment intensity at antimicrobial class level showed a decrease of 64% for colistin used in pigs, and of 7% for macrolides used in both pigs and calves. Whereas the use of 3rd and 4th generation cephalosporins in calves decreased by 15.8%, usage of fluoroquinolones increased by 10.8% in the same period. Corresponding values for pigs were −16.4 and +0.7%. This is the first extrapolation of antimicrobial usage at product level for pigs and calves in Switzerland. It shows that calves were more frequently treated than pigs with a decreasing trend for both number of therapies and use of colistin, macrolides and cephalosporins 3rd and 4th generations. Nonetheless, we calculated an increase in the usage of fluoroquinolones. Altogether, this study's outcomes allow for trend analysis and can be used to assess the relationship between antimicrobial use and resistance at the national level.

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The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak – an update on the status

An acute respiratory disease, caused by a novel coronavirus (SARS-CoV-2, previously known as 2019-nCoV), the coronavirus disease 2019 (COVID-19) has spread throughout China and received worldwide attention. On 30 January 2020, World Health Organization (WHO) officially declared the COVID-19 epidemic as a public health emergency of international concern. The emergence of SARS-CoV-2, since the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, marked the third introduction of a highly pathogenic and large-scale epidemic coronavirus into the human population in the twenty-first century. As of 1 March 2020, a total of 87,137 confirmed cases globally, 79,968 confirmed in China and 7169 outside of China, with 2977 deaths (3.4%) had been reported by WHO. Meanwhile, several independent research groups have identified that SARS-CoV-2 belongs to β-coronavirus, with highly identical genome to bat coronavirus, pointing to bat as the natural host. The novel coronavirus uses the same receptor, angiotensin-converting enzyme 2 (ACE2) as that for SARS-CoV, and mainly spreads through the respiratory tract. Importantly, increasingly evidence showed sustained human-to-human transmission, along with many exported cases across the globe. The clinical symptoms of COVID-19 patients include fever, cough, fatigue and a small population of patients appeared gastrointestinal infection symptoms. The elderly and people with underlying diseases are susceptible to infection and prone to serious outcomes, which may be associated with acute respiratory distress syndrome (ARDS) and cytokine storm. Currently, there are few specific antiviral strategies, but several potent candidates of antivirals and repurposed drugs are under urgent investigation. In this review, we summarized the latest research progress of the epidemiology, pathogenesis, and clinical characteristics of COVID-19, and discussed the current treatment and scientific advancements to combat the epidemic novel coronavirus.

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Alphaherpesvirus infection of mice primes PNS neurons to an inflammatory state regulated by TLR2 and type I IFN signaling

Pseudorabies virus (PRV), an alphaherpesvirus closely related to Varicella-Zoster virus (VZV) and Herpes simplex type 1 (HSV1) infects mucosa epithelia and the peripheral nervous system (PNS) of its host. We previously demonstrated that PRV infection induces a specific and lethal inflammatory response, contributing to severe neuropathy in mice. So far, the mechanisms that initiate this neuroinflammation remain unknown. Using a mouse footpad inoculation model, we found that PRV infection rapidly and simultaneously induces high G-CSF and IL-6 levels in several mouse tissues, including the footpad, PNS and central nervous system (CNS) tissues. Interestingly, this global increase occurred before PRV had replicated in dorsal root ganglia (DRGs) neurons and also was independent of systemic inflammation. These high G-CSF and IL-6 levels were not caused by neutrophil infiltration in PRV infected tissues, as we did not detect any neutrophils. Efficient PRV replication and spread in the footpad was sufficient to activate DRGs to produce cytokines. Finally, by using knockout mice, we demonstrated that TLR2 and IFN type I play crucial roles in modulating the early neuroinflammatory response and clinical outcome of PRV infection in mice. Overall, these results give new insights into the initiation of virus-induced neuroinflammation during herpesvirus infections.

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The effectiveness of quarantine and isolation determine the trend of the COVID-19 epidemic in the final phase of the current outbreak in China

OBJECTIVES: Since January 23rd, 2020, stringent measures for controlling the novel coronavirus epidemic have been gradually enforced and strengthened in mainland China. The detection and diagnosis have been improved, as well. However, the daily reported cases remaining at a high level make the epidemic trend prediction difficult. METHODS: Since the traditional SEIR model does not evaluate the effectiveness of control strategies, a novel model in line with the current epidemic's process and control measures was proposed, utilizing multisource datasets including the cumulative number of reported, deceased, quarantined and suspected cases. RESULTS: Results show that the trend of the epidemic mainly depends on quarantined and suspected cases. The predicted cumulative numbers of quarantined and suspected cases nearly reached static states, and their inflection points have already been achieved, with the epidemic's peak coming soon. The estimated effective reproduction numbers using model-free and model-based methods are decreasing, as well as new infections, while newly reported cases are increasing. Most infected cases have been quarantined or put in the suspected class, which has been ignored in existing models. CONCLUSIONS: The uncertainty analyses reveal that the epidemic is still uncertain, and it is important to continue enhancing the quarantine and isolation strategy and improving the detection rate in mainland China.

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Analysis of Newcastle disease virus quasispecies and factors affecting the emergence of virulent virus

Genome sequence analysis of a number of avirulent field isolates of Newcastle disease virus revealed the presence of viruses (within their quasispecies) that contained virulent F0 sequences. Detection of these virulent sequences below the ~1% level, using standard cloning and sequence analysis, proved difficult, and thus a more sensitive reverse-transcription real-time PCR procedure was developed to detect both virulent and avirulent NDV F0 sequences. Reverse-transcription real-time PCR analysis of the quasispecies of a number of Newcastle disease virus field isolates, revealed variable ratios (approximately 1:4–1:4,000) of virulent to avirulent viral F0 sequences. Since the ratios of these sequences generally remained constant in the quasispecies population during replication, factors that could affect the balance of virulent to avirulent sequences during viral infection of birds were investigated. It was shown both in vitro and in vivo that virulent virus present in the quasispecies did not emerge from the “avirulent background” unless a direct selection pressure was placed on the quasispecies, either by growth conditions or by transient immunosuppression. The effect of a prior infection of the host by infectious bronchitis virus or infectious bursal disease virus on the subsequent emergence of virulent Newcastle disease virus was examined.

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Incidence of pulmonary embolism in non-critically ill COVID-19 patients. Predicting factors for a challenging diagnosis

Recent studies suggest that thrombotic complications are a common phenomenon in the novel SARS-CoV-2 infection. The main objective of our study is to assess cumulative incidence of pulmonary embolism (PE) in non critically ill COVID-19 patients and to identify its predicting factors associated to the diagnosis of pulmonary embolism. We retrospectevely reviewed 452 electronic medical records of patients admitted to Internal Medicine Department of a secondary hospital in Madrid during Covid 19 pandemic outbreak. We included 91 patients who underwent a multidetector Computed Tomography pulmonary angiography(CTPA) during conventional hospitalization. The cumulative incidence of PE was assessed ant the clinical, analytical and radiological characteristics were compared between patients with and without PE. PE incidence was 6.4% (29/452 patients). Most patients with a confirmed diagnosed with PE recieved low molecular weight heparin (LMWH): 79.3% (23/29). D-dimer peak was significatly elevated in PE vs non PE patients (14,480 vs 7230 mcg/dL, p = 0.03). In multivariate analysis of patients who underwent a CTPA we found that plasma D-dimer peak was an independen predictor of PE with a best cut off point of > 5000 µg/dl (OR 3.77; IC95% (1.18–12.16), p = 0.03). We found ninefold increased risk of PE patients not suffering from dyslipidemia (OR 9.06; IC95% (1.88–43.60). Predictive value of AUC for ROC is 75.5%. We found a high incidence of PE in non critically ill hospitalized COVID 19 patients despite standard thromboprophylaxis. An increase in D-dimer levels is an independent predictor for PE, with a best cut-off point of > 5000 µg/ dl.

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CLEC5A: A Promiscuous Pattern Recognition Receptor to Microbes and Beyond

CLEC5A is a spleen tyrosine kinase (Syk)-coupled C-type lectin that is highly expressed by monocytes, macrophages, neutrophils, and dendritic cells and interacts with virions directly, via terminal fucose and mannose moieties of viral glycans. CLEC5A also binds to N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc) disaccharides of bacterial cell walls. Compared to other C-type lectins (DC-SIGN and DC-SIGNR) and TLRs, CLEC5A binds its ligands with relatively low affinities. However, CLEC5A forms a multivalent hetero-complex with DC-SIGN and other C-type lectins upon engagement with ligands, and thereby mediates microbe-induced inflammatory responses via activation of Syk. For example, in vivo studies in mouse models have demonstrated that CLEC5A is responsible for flaviviruses-induced hemorrhagic shock and neuroinflammation, and a CLEC5A polymorphism in humans is associated with disease severity following infection with dengue virus. In addition, CLEC5A is co-activated with TLR2 by Listeria and Staphylococcus. Furthermore, CLEC5A-postive myeloid cells are responsible for Concanavilin A-induced aseptic inflammatory reactions. Thus, CLEC5A is a promiscuous pattern recognition receptor in myeloid cells and is a potential therapeutic target for attenuation of both septic and aseptic inflammatory reactions.

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Anno 1529 – der „Englische Schweiß“ in Wien, die Türken um Wien

After the battle of Bosworth in 1485 London was frightened by a severe epidemic of Sweating Disease. Until 1551 four more followed of which only the 1525 epidemic invaded Central and Northern Europe harassing Vienna during its “First Turkish Siege”. People abruptly fell ill with headache, tachycardia, fever and secretion of stinking sweat. They were afflicted with anxiety, deliria and somnolence. The illness mostly lasted for 24 h, but death although could occur earlier. At the beginning of epidemics the lethality was particularly high. The treatment with distinct medicaments had to be started instantly. The patients must be kept warm and sleepless (“Dutch Regiment”). The thus caused high lethality was lowered by omitting the hyperthermia (“English Regiment”). I suppose that the Sweating Disease was an “Emerging Disease” of the 15th/16th century, as nowadays AIDS, Ebola, SARS, MERS and influenza variants are.

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Targeting phospholipase D in cancer, infection and neurodegenerative disorders

Lipid second messengers have essential roles in cellular function and contribute to the molecular mechanisms that underlie inflammation, malignant transformation, invasiveness, neurodegenerative disorders, and infectious and other pathophysiological processes. The phospholipase D (PLD) isoenzymes PLD1 and PLD2 are one of the major sources of signal-activated phosphatidic acid (PtdOH) generation downstream of a variety of cell-surface receptors, including G protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTKs) and integrins. Recent advances in the development of isoenzyme-selective PLD inhibitors and in molecular genetics have suggested that PLD isoenzymes in mammalian cells and pathogenic organisms may be valuable targets for the treatment of several human diseases. Isoenzyme-selective inhibitors have revealed complex inter-relationships between PtdOH biosynthetic pathways and the role of PtdOH in pathophysiology. PLD enzymes were once thought to be undruggable owing to the ubiquitous nature of PtdOH in cell signalling and concerns that inhibitors would be too toxic for use in humans. However, recent promising discoveries suggest that small-molecule isoenzyme-selective inhibitors may provide novel compounds for a unique approach to the treatment of cancers, neurodegenerative disorders and other afflictions of the central nervous system, and potentially serve as broad-spectrum antiviral and antimicrobial therapeutics.

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Identification and Characterization of Severe Acute Respiratory Syndrome Coronavirus Subgenomic RNAs

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Influenza and other respiratory viruses: standardizing disease severity in surveillance and clinical trials

Introduction: Influenza-Like Illness is a leading cause of hospitalization in children. Disease burden due to influenza and other respiratory viral infections is reported on a population level, but clinical scores measuring individual changes in disease severity are urgently needed. Areas covered: We present a composite clinical score allowing individual patient data analyses of disease severity based on systematic literature review and WHO-criteria for uncomplicated and complicated disease. The 22-item ViVI Disease Severity Score showed a normal distribution in a pediatric cohort of 6073 children aged 0–18 years (mean age 3.13; S.D. 3.89; range: 0 to 18.79). Expert commentary: The ViVI Score was correlated with risk of antibiotic use as well as need for hospitalization and intensive care. The ViVI Score was used to track children with influenza, respiratory syncytial virus, human metapneumovirus, human rhinovirus, and adenovirus infections and is fully compliant with regulatory data standards. The ViVI Disease Severity Score mobile application allows physicians to measure disease severity at the point-of care thereby taking clinical trials to the next level.

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Idea File

Consider online commencement ceremonies Eloy Oakley, Chancellor of the California Community College System, announced that in response to COVID‐19, the system would prepare for isolation measures to be in place through June, and would either delay or move all commencement ceremonies online, according to EdSource The CCCS moved to online instruction in early March Oakley also announced that California's two‐year colleges should be ready for remote instruction to continue through June, and to make plans for the upcoming academic year Review relaxed online international education guidelines U S Immigration and Customs Enforcement's Student and Exchange Visitor Program announced it would be flexible with the restrictions formerly imposed on the number of international students who can enroll in online classes, due to disruptions in higher education from COVID‐19 The SEVP notes that this guidance is specific to international students who are currently enrolled in a program of study, and not new students located outside the United States Understand concerns about future enrollment Admissions officers are increasingly concerned about the impact of COVID‐19 on enrollment, according to survey results released by EAB in mid‐March Using a scale, more than 40% of survey respondents ranked the worst possible outcomes as the likely potential impact on their future enrollment yield, and 32% marked the second‐worst possible outcomes The survey also found that 87% of respondents expressed concern that future visits to campuses by potential students will decline in the wake of COVID‐19 However, respondents also showed that many campuses are beefing up their virtual initiatives, with 54% reporting an increase in promoting virtual tours of campus Read more at http://bit ly/396CoBg Stay up to date on admissions fraud case David Sidoo, a Canadian businessman and former professional football player, has pled guilty to one count of conspiracy to commit mail and wire fraud for twice paying a man $100,000 to take the SAT for each of his sons According to CTV News, Sidoo agreed to a 90‐day jail sentence and a $250,000 fine

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Working Parties

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Management and Treatment of COVID-19: The Chinese Experience

Abstract With over 1,800,000 cases and 110,000 deaths globally, COVID-19 is one of worst infectious disease outbreaks in history. The objective of this paper is to critically review the available evidence regarding the lessons learned from the Chinese experience regarding COVID-19 prevention and management. The steps that have led to a near disappearance of new cases in China included rapid sequencing of the virus to establish testing kits which allowed tracking of infected persons in and out of Wuhan. In addition, aggressive quarantine measures included the complete isolation of Wuhan and then later Hebei and the rest of the country, as well as closure of all schools and non-essential businesses. Other measures included the rapid construction of two new hospitals and the establishment of Fangcang shelter hospitals. In the absence of a vaccine, the management of COVID-19 included antivirals, high flow oxygen, mechanical ventilation, corticosteroids, hydroxychloroquine, tocilizumab, interferons, intravenous immunoglobulin and convalescent plasma infusions. These measures appeared to provide only moderate success. While some measures have been supported by weak descriptive data, their effectiveness is still unclear pending well-controlled clinical trials. In the end, it was the enforcement of drastic quarantine measures that stopped SARS-CoV-2 from spreading. The earlier the implementation, the less likely resources will be depleted. The most critical factors in stopping a pandemic are early recognition of infected individuals, carriers and contacts, and early implementation of quarantine measures with an organized, proactive and unified strategy at a national level. Delays result in significantly higher death tolls.

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Comparative pathology of rhesus macaque and common marmoset animal models with Middle East respiratory syndrome coronavirus

Middle East respiratory syndrome (MERS), which is caused by a newly discovered coronavirus (CoV), has recently emerged. It causes severe viral pneumonia and is associated with a high fatality rate. However, the pathogenesis, comparative pathology and inflammatory cell response of rhesus macaques and common marmosets experimentally infected with MERS-CoV are unknown. We describe the histopathological, immunohistochemical, and ultrastructural findings from rhesus macaque and common marmoset animal models of MERS-CoV infection. The main histopathological findings in the lungs of rhesus macaques and common marmosets were varying degrees of pulmonary lesions, including pneumonia, pulmonary oedema, haemorrhage, degeneration and necrosis of the pneumocytes and bronchial epithelial cells, and inflammatory cell infiltration. The characteristic inflammatory cells in the lungs of rhesus macaques and common marmosets were eosinophils and neutrophils, respectively. Based on these observations, the lungs of rhesus macaques and common marmosets appeared to develop chronic and acute pneumonia, respectively. MERS-CoV antigens and viral RNA were identified in type I and II pneumocytes, alveolar macrophages and bronchial epithelial cells, and ultrastructural observations showed that viral protein was found in type II pneumocytes and inflammatory cells in both species. Correspondingly, the entry receptor DDP4 was found in type I and II pneumocytes, bronchial epithelial cells, and alveolar macrophages. The rhesus macaque and common marmoset animal models of MERS-CoV can be used as a tool to mimic the oncome of MERS-CoV infections in humans. These models can help to provide a better understanding of the pathogenic process of this virus and to develop effective medications and prophylactic treatments.

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Changes in Gambling Behavior during the COVID-19 Pandemic—A Web Survey Study in Sweden

The COVID-19 pandemic has dramatically changed everyday life, and policy makers have raised concerns about possible changes in gambling patterns during the pandemic. This study aimed to examine whether self-reported gambling has increased during the pandemic, and to examine potential correlates of such a change. This general population survey study in Sweden collected self-report data from 2016 web survey members (51 percent men, nine percent moderate-risk/problem gamblers). Correlates of increased gambling and increased gambling specifically due to COVID-19-related cancellation of sports were calculated. Four percent reported an overall gambling increase during the pandemic. The proportion of individuals reporting an increase, compared to individuals reporting a decrease, was markedly higher for online casinos (0.62), online horse betting (0.76) and online lotteries (0.73), and lower for sports betting (0.11). Overall, gambling increases were independently associated with gambling problems and increased alcohol consumption. In the sub-group, where there was an increase in specific gambling types in response to cancelled sports betting events, rates of gambling problems were high. In conclusion, only a minority report increased gambling in response to the pandemic, but this group has markedly higher gambling problems and changes in alcohol consumption, and may represent a sub-group with a particularly high vulnerability. This calls for preventive action in people with higher gambling risks in response to the pandemic.

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Chapter 8 Innate Immunity in Simian Immunodeficiency Virus Infection

Abstract The past decade has seen the emergence of innate immunity as a mature field. The study of innate immunity has had a significant impact on the concepts of HIV immunity, pathogenesis, and vaccines. In this chapter, basic concepts of innate immunity at the anatomical, cellular, and molecular levels will be introduced from the perspective of their interplay with HIV and simian immunodeficiency virus (SIV). An emphasis will be placed on studies using SIV/non-human primate (NHP) models that shape current models of HIV pathogenesis. Finally, studies modulating the innate system in vivo in NHPs will be discussed.

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Can hyperimmune anti-CMV globuline substitute for convalescent plasma for treatment of COVID-19?

Information on treatment of COVID-19 infection in renal transplant recipients is scarce, especially in symptomatic patients and patients with recent major clinical events. This group of patients suffers from different opportunistic infections which may coexist with COVID-19. Currently available expert opinions suggest reduction of immunosuppression therapy for renal transplant recipients with symptomatic COVID-19 infection with either antiviral drugs, hydroxychloroquine and/or azithromycin. Inspired by our experience in treatment of CMV pneumonia and literature data on the potential benefit of convalescent plasma for treatment of different viral diseases we suggest use of the hyperimmune anti-CMV gamma globulins in addition to other available therapies. Besides the immunosuppression reduction which is supposed to be beneficial, immunoglobulins with their immunomodulatory effects and possible antiviral role, may increase a possibility for favorable outcome.

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Short-term immunoglobulin A B-cell memory resides in intestinal lymphoid tissues but not in bone marrow of gnotobiotic pigs inoculated with Wa human rotavirus

Immunological memory is important for protecting the host from reinfection. To investigate the development and sites of residence of intestinal memory B cells, and their role in protective immunity to reinfection with an enteric virus, we assessed the association between memory B cell and antibody-secreting cell (ASC) responses and protection using a gnotobiotic pig model for human rotavirus (HRV) infection and diarrhoea. The isotypes, quantities and tissue distribution of rotavirus-specific memory B cells and ASC were evaluated prechallenge (28 and 83 postinoculation days [PID]) and postchallenge (7 postchallenge days [PCD]), using enzyme-linked immunospot (ELISPOT) assay, in gnotobiotic pigs inoculated once with virulent or three times with attenuated HRV and challenged at PID 28 with the corresponding virulent HRV. Complete protection against HRV shedding and diarrhoea was associated with significantly higher numbers of immunoglobulin A (IgA) and immunoglobulin G (IgG) memory B cells and ASC in the ileum of virulent HRV-inoculated pigs at challenge. In contrast, pigs inoculated with attenuated HRV had lower numbers of IgA and IgG memory B cells and ASC in intestinal lymphoid tissues, but higher numbers in the spleen. The bone marrow had the lowest mean numbers of IgA and IgG memory B cells and ASC prechallenge in both groups of HRV-inoculated pigs. Therefore, bone marrow was not a site for IgA and IgG rotavirus-specific antibody production or for memory B cells after inoculation with live rotavirus, from 28 PID up to at least 83 PID. The effect of in vitro antigen dose was examined and it was determined to play an important role in the development of ASC from memory B cells for the different tissues examined.

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Chapter 6 Exacerbations of chronic respiratory diseases

Abstract Respiratory viral infections including human rhinovirus (RV) infection have been identified as the most important environmental trigger of exacerbations of chronic lung diseases. While well established as the most common viral infections associated with exacerbations of asthma and chronic obstructive pulmonary disease, RVs and other respiratory viruses are also now thought to be important in triggering exacerbations of cystic fibrosis and the interstitial lung diseases. Here, we summarize the epidemiological evidence the supports respiratory viruses including RV as triggers of exacerbations of chronic lung diseases. We propose that certain characteristics of RVs may explain why they are the most common trigger of exacerbations of chronic lung diseases. We further highlight the latest mechanistic evidence supporting how and why common respiratory viral infections may enhance and promote disease triggering exacerbation events, through their interactions with the host immune system, and may be affected by ongoing treatments. We also provide a commentary on how new treatments may better manage the disease burden associated with respiratory viral infections and the exacerbation events that they trigger.

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Toroviruses (Coronaviridae)

Abstract Toroviruses are single-stranded RNA peplomer-bearing enveloped viruses producing enteric disease in animals and humans. They have a unique extracellular C-shape or open torus morphology. There are four species in the genus Torovirus (family Coronaviridae, order Nidovirales): Equine torovirus (EToV), Bovine torovirus (BToV), Human torovirus (HToV), and Porcine torovirus (PToV), which have been reported worldwide. Their genome contains six ORFs, which are transcribed as a 3’-coterminal nested set of four mRNAs. ORF1a and 1b encode the replicase, and ORFs 2–5 encode the spike (S), membrane (M), hemagglutinin-esterase (HE), and nucleocapsid (N) proteins, respectively. Only EToVs and BToV Aichi/2004 propagate in cell culture.

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Inhibitors of the Influenza A Virus M2 Proton Channel Discovered Using a High-Throughput Yeast Growth Restoration Assay

The M2 proton channel of the influenza A virus is the target of the anti-influenza drugs amantadine and rimantadine. The effectiveness of these drugs has been dramatically limited by the rapid spread of drug resistant mutations, mainly at sites S31N, V27A and L26F in the pore of the channel. Despite progress in designing inhibitors of V27A and L26F M2, there are currently no drugs targeting these mutated channels in clinical trials. Progress in developing new drugs has been hampered by the lack of a robust assay with sufficient throughput for discovery of new active chemotypes among chemical libraries and sufficient sensitivity to provide the SAR data essential for their improvement and development as drugs. In this study we adapted a yeast growth restoration assay, in which expression of the M2 channel inhibits yeast growth and exposure to an M2 channel inhibitor restores growth, into a robust and sensitive high-throughput screen for M2 channel inhibitors. A screen of over 250,000 pure chemicals and semi-purified fractions from natural extracts identified 21 active compounds comprising amantadine, rimantadine, 13 related adamantanes and 6 non-adamantanes. Of the non-adamantanes, hexamethylene amiloride and a triazine derivative represented new M2 inhibitory chemotypes that also showed antiviral activity in a plaque reduction assay. Of particular interest is the fact that the triazine derivative was not sufficiently potent for detection as an inhibitor in the traditional two electrode voltage clamp assay for M2 channel activity, but its discovery in the yeast assay led to testing of analogues of which one was as potent as amantadine.

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Histopathological and immunohistochemical findings in lymphoid tissues of the endangered Iberian lynx (Lynx pardinus)

Abstract The Iberian lynx (Lynx pardinus) is the most threatened wild feline in the world. Little is known about the diseases and pathology that affect this animal. The aim of this study was to evaluate the histopathological status of the peripheral lymphoid tissues and thymus of Iberian lynxes necropsied between 1998 and 2003. Seventeen animals including females (n=8) and males (n=9), age range of 10 months to 16 years, with different causes of death were histopathologically and immunohistochemically (anti-CD3, CD79, MAC387, CD68) studied. Feline immunosuppressive virus laboratorial tests were negative. Five individuals presented neoplasia and/or tuberculosis. All animals presented some degree of both B and T cells depletion in peripheral lymphoid tissues and follicular hyalinosis in the center of depleted follicles. A viral origin of the lymphoid depletion is postulated although other causes (inbreeding, stress, toxic) are not ruled out. The loss of the effectiveness of the immune system increases the vulnerability of the critically endangered Iberian lynx to pathogens.

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Author index and Subject index

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The S2 Subunit of QX-type Infectious Bronchitis Coronavirus Spike Protein Is an Essential Determinant of Neurotropism

Some coronaviruses (CoVs) have an extra furin cleavage site (RRKR/S, furin-S2′ site) upstream of the fusion peptide in the spike protein, which plays roles in virion adsorption and fusion. Mutation of the S2′ site of QX genotype (QX-type) infectious bronchitis virus (IBV) spike protein (S) in a recombinant virus background results in higher pathogenicity, pronounced neural symptoms and neurotropism when compared with conditions in wild-type IBV (WT-IBV) infected chickens. In this study, we present evidence suggesting that recombinant IBV with a mutant S2′ site (furin-S2′ site) leads to higher mortality. Infection with mutant IBV induces severe encephalitis and breaks the blood–brain barrier. The results of a neutralization test and immunoprotection experiment show that an original serum and vaccine can still provide effective protection in vivo and in vitro. This is the first demonstration of IBV-induced neural symptoms in chickens with encephalitis and the furin-S2′ site as a determinant of neurotropism.

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Isolation and molecular characterization of type I and type II feline coronavirus in Malaysia

BACKGROUND: Feline infectious peritonitis virus (FIPV) and feline enteric coronavirus (FECV) are two important coronaviruses of domestic cat worldwide. Although FCoV is prevalent among cats; the fastidious nature of type I FCoV to grow on cell culture has limited further studies on tissue tropism and pathogenesis of FCoV. While several studies reported serological evidence for FCoV in Malaysia, neither the circulating FCoV isolated nor its biotypes determined. This study for the first time, describes the isolation and biotypes determination of type I and type II FCoV from naturally infected cats in Malaysia. FINDINGS: Of the total number of cats sampled, 95% (40/42) were RT-PCR positive for FCoV. Inoculation of clinical samples into Crandell feline kidney cells (CrFK), and Feline catus whole fetus-4 cells (Fcwf-4), show cytopathic effect (CPE) characterized by syncytial cells formation and later cell detachment. Differentiation of FCoV biotypes using RT-PCR assay revealed that, 97.5% and 2.5% of local isolates were type I and type II FCoV, respectively. These isolates had high sequence homology and phylogenetic similarity with several FCoV isolates from Europe, South East Asia and USA. CONCLUSIONS: This study reported the successful isolation of local type I and type II FCoV evident with formation of cytopathic effects in two types of cell cultures namely the CrFK and Fcwf-4 , where the later cells being more permissive. However, the RT-PCR assay is more sensitive in detecting the antigen in suspected samples as compared to virus isolation in cell culture. The present study indicated that type I FCoV is more prevalent among cats in Malaysia.

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Clinical recommendations on lung cancer management during the COVID‐19 pandemic

Coronavirus disease 2019 (COVID‐19) is spreading worldwide, and has been declared as an international public health concern. Patients with lung cancer are highly susceptible to infection compared to healthy individuals because of systemic immunosuppression induced by malignancy and anticancer therapy. Furthermore, patients with cancer demonstrate poorer outcomes following infection. Hence, patients with lung cancer should be considered a priority group for COVID‐19 prevention. Furthermore, the routine treatment of patients with cancer has been affected during the COVID‐19 pandemic, and patients may not have been able to undergo timely and effective antitumor treatment, thereby indicating a poor prognosis. Here, we provide some suggestions for early identification of COVID‐19 and differential diagnosis in patients with lung cancer who have fever and respiratory symptoms. Our medical team also provide clinical recommendations on lung cancer management during the COVID‐19 pandemic, for carrying out meticulous and individualized clinical management of lung cancer patients and maximum protection to effectively prevent COVID‐19. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: This article provides suggestions for early identification of COVID‐19 and differential diagnosis in patients with lung cancer with fever and respiratory symptoms. WHAT THIS STUDY ADDS: This article makes clinical recommendations on lung cancer management during the COVID‐19 pandemic.

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Severe acute respiratory syndrome and the liver

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A LAD-based method for selecting short oligo probes for genotyping applications

Specializing a general framework of logical analysis of data for efficiently handling large-scale genomic data, we develop in this paper a probe design method for selecting short oligo probes for genotyping applications. When tested on genomic sequences obtained from the National Center of Biotechnology Information in various monospecific and polyspecific in silico experiments, the proposed probe design method was able to select a small number of oligo probes of length 7 or 8 nucleotides that perfectly classified all unseen testing sequences. These results demonstrate the efficacy of the proposed probe design method and illustrate the usefulness and potential a well-designed optimization-based probe selection method has in genotyping applications.

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Elucidation of the mechanism of anti-herpes action of two novel semisynthetic cardenolide derivatives

Human herpesviruses are among the most prevalent pathogens worldwide and have become an important public health issue. Recurrent infections and the emergence of resistant viral strains reinforce the need of searching new drugs to treat herpes virus infections. Cardiac glycosides are used clinically to treat cardiovascular disturbances, such as congestive heart failure and atrial arrhythmias. In recent years, they have sparked new interest in their potential anti-herpes action. It has been previously reported by our research group that two new semisynthetic cardenolides, namely C10 (3β-[(N-(2-hydroxyethyl)aminoacetyl]amino-3-deoxydigitoxigenin) and C11 (3β-(hydroxyacetyl)amino-3-deoxydigitoxigenin), exhibited potential anti-HSV-1 and anti-HSV-2 with selectivity index values > 1,000, comparable with those of acyclovir. This work reports the mechanism investigation of anti-herpes action of these derivatives. The results demonstrated that C10 and C11 interfere with the intermediate and final steps of HSV replication, but not with the early stages, since they completely abolished the expression of the UL42 (β) and gD (γ) proteins and partially reduced that of ICP27 (α). Additionally, they were not virucidal and had no prophylactic effects. Both compounds inhibited HSV replication at nanomolar concentrations, but cardenolide C10 was more active than C11 and can be considered as an anti-herpes drug candidate including against acyclovir-resistant HSV-1 strains.

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COVID‐19 epidemic: Skin protection for health care workers must not be ignored

Since first reported in 2019, pneumonia associated with 2019 novel coronavirus disease (COVID‐19) has rapidly developed into an outbreak across the world.(1) Number of the patients of all age groups has increased significantly.(2) In order to curb the spread of the epidemic, thousands of health care workers (HCWs) have joined the front line of the fight against this highly contagious disease.(3) When taking care of patients with COVID‐19 pneumonia, HCWs must first protect themselves by performing adequate hand hygiene and using protective equipment including medical mask, goggles/face shield, gown and gloves.(4) However, the wearing of these personal protective equipment (PPE) on a daily basis and the frequent use of hand disinfectants often cause skin problems which could reduce their enthusiasm for overloaded work and make them anxious at all stages of the pandemic.

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When preserving life becomes imperative, quality of life is eclipsed! COVID‐19 outbreak impacting patients with pelvic floor disorders undergoing pelvic floor rehabilitation

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Measuring Grip Strength in COVID-19: A Simple Way to Predict Overall Frailty/Impairment

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Experimental investigation of integrated air purifying technology for bioaerosol removal and inactivation in central air-conditioning system

In this research, high voltage static electricity and ultraviolet technologies were integrated to an air purifying device which can be used to trap and kill airborne bacteria and viruses in central air-conditioning systems. An experimental platform was built to mimic the central air system, in which the efficacy of the newly built device was examined. In addition to the standard physical and chemical tests, bacteriophages were used to simulate airborne viruses in the experimental system. The bacteriophage suspension was aerosolized into the air with ultrasonic wave atomization. The result showed that more than 86% removal efficiency of micro-particles (<10 micron in diameter) were removed after the device was in operation in a building and more than 95% of bacteriophages in the experimental system. It is concluded that the integrated air purifier is suitable for controlling air quality and preventing virus transmission through the central air system.

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An Outlook on the Global Development of Renewable and Sustainable Energy at the Time of Covid-19

The outbreak of the novel COVID-19 has dominated the world stage, and its consequences, both direct and indirect, are expected to prove to be even more pervasive over time. The COVID-19 pandemic has struck the renewable energy manufacturing facilities, supply chains, and companies and slowed down the transition to the sustainable energy world. The global decline in economy-driven demand could damage the positive trend of green and low-carbon energy progress. Although it is too early to judge how profound the negative effects of the pandemic on the global renewable and sustainable energy systems will be, a significant short-run contraction to the development of renewables is inevitable. Therefore, the energy and climate policies may require to be restructured based on the new circumstances. In this context, several beneficial stimuluses should be offered by the governments to persuade the private sectors and society to invest on renewables. Undoubtedly, intelligent policies could convert the menaces of COVID-19 to the great opportunities for renewables and ultimately the world’s sustainable energy scenario could return to its long-term trajectory toward green power generation and utilization over the next few years.

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Effects of 5‐alpha reductase inhibitors on lung function: A reason for discontinuation during COVID‐19 pandemic?

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Potential transmission of SARS-CoV-2 on a flight from Singapore to Hanghzou, China: An epidemiological investigation

BACKGROUND: Between January 24, 2020 and February 15, 2020, an outbreak of COVID-19 occurred among 335 passengers on a flight from Singapore to Hangzhou in China. This study aimed to investigate the source of the outbreak and assess the risk of transmission of COVID-19 during the flight. METHOD: Using a standardized questionnaire, we collected information on the travelers’ demographic characteristics and illness before, during, and after the flight. We also collected data on factors potentially associated with COVID-19 transmission during the flight. RESULTS: A total of 16 COVID-19 patients were diagnosed among all passengers; the overall attack rate was 4.8%. The attack rate among passengers who had departed from Wuhan was significantly higher than that among those who had departed from other places. One passenger without an epidemiological history of exposure before boarding developed COVID-19. During the flight, he was seated near four infected passengers from Wuhan for approximately an hour and did not wear his facemask correctly during the flight. CONCLUSIONS: COVID-19 transmission may have occurred during the flight. However, the majority of the cases in the flight-associated outbreak could not be attributed to transmission on the flight but were associated with exposure to the virus in Wuhan or to infected members in a single tour group.

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COVID‐19: A review of therapeutics under investigation

The COVID‐19 outbreak has disrupted global health care networks and caused thousands of deaths and an international economic downturn. Multiple drugs are being used on patients with COVID‐19 based on theoretical and in vitro therapeutic targets. Several of these therapies have been studied, but many have limited evidence behind their use, and clinical trials to evaluate their efficacy are either ongoing or have not yet begun. This review summarizes the existing evidence for medications currently under investigation for treatment of COVID‐19, including remdesivir, chloroquine/hydroxychlorquine, convalescent plasma, lopinavir/ritonavir, IL‐6 inhibitors, corticosteroids, and angiotensin‐converting enzyme inhibitors.

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Advancing a multivalent ‘Pan-anthelmintic’ vaccine against soil-transmitted nematode infections

ASCARIS LUMBRICOIDES: The Sabin Vaccine Institute Product Development Partnership is developing a Pan-anthelmintic vaccine that simultaneously targets the major soil-transmitted nematode infections, in other words, ascariasis, trichuriasis and hookworm infection. The approach builds off the current bivalent Human Hookworm Vaccine now in clinical development and would ultimately add both a larval Ascaris lumbricoides antigen and an adult-stage Trichuris trichiura antigen from the parasite stichosome. Each selected antigen would partially reproduce the protective immunity afforded by UV-attenuated Ascaris eggs and Trichuris stichosome extracts, respectively. Final antigen selection will apply a ranking system that includes the evaluation of expression yields and solubility, feasibility of process development and the absence of circulating antigen-specific IgE among populations living in helminth-endemic regions. Here we describe a five year roadmap for the antigen discovery, feasibility and antigen selection, which will ultimately lead to the scale-up expression, process development, manufacture, good laboratory practices toxicology and preclinical evaluation, ultimately leading to Phase 1 clinical testing.

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Pathogen-Tested Planting Material

Abstract Certification programs have been developed to provide plant material that meets a predetermined level of plant health. The primary objectives of these programs are to limit pathogen incidence in plant material in order to minimize losses by growers and prevent movement of harmful pests and pathogens that may harm the environment. For many fruit and nut crops, orchards are expected to remain productive for years or decades; thus, starting with plants of high health status is essential. The components of certification programs in terms of plant health will be outlined, along with the benefits of harmonizing these programs where possible to facilitate plant movement without increasing trade in plant pathogens.

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Potential Impact of Antiviral Drug Use during Influenza Pandemic

The recent spread of highly pathogenic strains of avian influenza has highlighted the threat posed by pandemic influenza. In the early phases of a pandemic, the only treatment available would be neuraminidase inhibitors, which many countries are considering stockpiling for pandemic use. We estimate the effect on hospitalization rates of using different antiviral stockpile sizes to treat infection. We estimate that stockpiles that cover 20%–25% of the population would be sufficient to treat most of the clinical cases and could lead to 50% to 77% reductions in hospitalizations. Substantial reductions in hospitalization could be achieved with smaller antiviral stockpiles if drugs are reserved for persons at high risk.

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Regarding COVID‐19 and the Otolaryngologist: Preliminary Evidence‐Based Review

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In vitro evaluation of antiviral activity of single and combined repurposable drugs against SARS-CoV-2

In response to the current pandemic caused by the novel SARS-CoV-2, identifying and validating effective therapeutic strategies is more than ever necessary. We evaluated the in vitro antiviral activities of a shortlist of compounds, known for their cellular broad-spectrum activities, together with drugs that are currently under evaluation in clinical trials for COVID-19 patients. We report the antiviral effect of remdesivir, lopinavir, chloroquine, umifenovir, berberine and cyclosporine A in Vero E6 cells model of SARS-CoV-2 infection, with estimated 50% inhibitory concentrations of 0.99, 5.2, 1.38, 3.5, 10.6 and 3 μM, respectively. Virus-directed plus host-directed drug combinations were also investigated. We report a strong antagonism between remdesivir and berberine, in contrast with remdesivir/diltiazem, for which we describe high levels of synergy, with mean Loewe synergy scores of 12 and peak values above 50. Combination of host-directed drugs with direct acting antivirals underscore further validation in more physiological models, yet they open up interesting avenues for the treatment of COVID-19.

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Fully Human Immunoglobulin G From Transchromosomic Bovines Treats Nonhuman Primates Infected With Ebola Virus Makona Isolate

Transchromosomic bovines (Tc-bovines) adaptively produce fully human polyclonal immunoglobulin (Ig)G antibodies after exposure to immunogenic antigen(s). The National Interagency Confederation for Biological Research and collaborators rapidly produced and then evaluated anti-Ebola virus IgG immunoglobulins (collectively termed SAB-139) purified from Tc-bovine plasma after sequential hyperimmunization with an Ebola virus Makona isolate glycoprotein nanoparticle vaccine. SAB-139 was characterized by several in vitro production, research, and clinical level assays using wild-type Makona-C05 or recombinant virus/antigens from different Ebola virus variants. SAB-139 potently activates natural killer cells, monocytes, and peripheral blood mononuclear cells and has high-binding avidity demonstrated by surface plasmon resonance. SAB-139 has similar concentrations of galactose-α-1,3-galactose carbohydrates compared with human-derived intravenous Ig, and the IgG1 subclass antibody is predominant. All rhesus macaques infected with Ebola virus/H.sapiens-tc/GIN/2014/Makona-C05 and treated with sufficient SAB-139 at 1 day (n = 6) or 3 days (n = 6) postinfection survived versus 0% of controls. This study demonstrates that Tc-bovines can produce pathogen-specific human Ig to prevent and/or treat patients when an emerging infectious disease either threatens to or becomes an epidemic.

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Development of Small-Molecule MERS-CoV Inhibitors

Middle East respiratory syndrome coronavirus (MERS-CoV) with potential to cause global pandemics remains a threat to the public health, security, and economy. In this review, we focus on advances in the research and development of small-molecule MERS-CoV inhibitors targeting different stages of the MERS-CoV life cycle, aiming to prevent or treat MERS-CoV infection.

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Convalescent plasma for COVID-19 in pregnancy: a case report and review

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COVID-19: Lessons for the climate change emergency

The ongoing COVID-19 outbreak pandemic is now a global crisis. It has caused 9+ million confirmed cases and 400,000+ deaths at the time of writing and triggered unprecedented preventative measures that have confined a substantial portion of the global population and established ‘social distancing’ as a new global behavioral norm. The COVID-19 crisis has affected all aspects of everyday life and work, and heavily impacted the global economy. This crisis also offers unprecedented insights into how the global climate crisis may be managed, as there are many parallels between the COVID-19 crisis and what we expect from the imminent global climate emergency. Reflecting upon the challenges of today's crisis may help us better prepare for the future. Here we compile a list, by no means comprehensive, of the similarities and differences between the two crises, and the lessons we can learn from them: (i) High momentum trends, (ii) Irreversible changes, (iii) Social and spatial inequality, (iv) Weakening of international solidarity, and (v) Less costly to prevent than to cure.

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Detection of HIV-1 RNA/DNA and CD4 mRNA in feces and urine from chronic HIV-1 infected subjects with and without anti-retroviral therapy

HIV-1 infects gut associated lymphoid tissues (GALT) very early after transmission by multiple routes. The infected GALT consequently serves as the major reservoir for HIV-1 infection and could constantly shed HIV-1 and CD4(+ )T cells into the intestinal lumen. To examine this hypothesis, we monitored HIV-1 RNA/DNA and CD4 mRNA in fecal samples of chronically infected subjects with and without antiretroviral therapy (ART). We compared this to levels of HIV-1 RNA/DNA in urine and blood from the same subjects. Our results show that HIV-1 DNA, RNA and CD4 mRNA were detected in 8%, 19% and 31% respectively, of feces samples from infected subjects with detectable plasma viral load, and were not detected in any of subjects on ART with undetectable plasma viral load. In urine samples, HIV-1 DNA was detected in 24% of infected subjects with detectable plasma viral load and 23% of subjects on ART with undetectable plasma viral load. Phylogenetic analysis of the envelope sequences of HIV-1 revealed distinct virus populations in concurrently collected serum, feces and urine samples from one subject. In addition, our study demonstrated for the first time the presence of CD4 mRNA in fecal specimens of HIV-1 infected subjects, which could be used to assess GALT pathogenesis in HIV-1 infection.

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COVID-19 and Acute Pancreatitis: What Do Surgeons Need to Know?

Coronavirus disease 2019 (COVID-19) typically presents with pulmonary symptoms. Extra-pulmonary symptomatology of COVID-19 has drawn significant attention. However, information about the incidence, course and outcomes of acute pancreatitis in these patients is still limited.

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Identification by functional proteomics of a deubiquitinating/deNeddylating enzyme in Plasmodium falciparum

Ubiquitination is a post‐translational modification implicated in a variety of cellular functions, including transcriptional regulation, protein degradation and membrane protein trafficking. Ubiquitin and the enzymes that act on it, although conserved and essential in eukaryotes, have not been well studied in parasites, despite sequencing of several parasite genomes. Several putative ubiquitin hydrolases have been identified in Plasmodium falciparum based on sequence homology alone, with no evidence of expression or function. Here we identify the first deubiquitinating enzyme in P. falciparum, PfUCH54, by its activity. We show that PfUCH54 also has deNeddylating activity, as assayed by a mammalian Nedd8‐based probe. This activity is absent from mammalian homologues of PfUCH54. Given the importance of parasitic membrane protein trafficking as well as protein degradation in the virulence of this parasite, this family of enzymes may represent a target for pharmacological intervention with this disease.

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ASE Statement on the Reintroduction of Echocardiography Services During the COVID-19 Pandemic

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Hospital Emergency Management Plan During the COVID‐19 Epidemic

The confirmed and suspected cases of the 2019 novel coronavirus disease (COVID-19) have increased not only in Wuhan, Hubei Province but also China and the world. Enormous demand for handling the COVID-19 outbreak challenged both the healthcare personnel and medical supply system. In West China Hospital, Emergency Department (ED) undertook the mission of clinical reception, primary diagnosis, and interim treatment for the suspected cases of COVID-19.

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Air Pollution and temperature are associated with increased COVID-19 incidence: a time series study

OBJECTIVES: Although the COVID-19 is known to cause by human-to-human transmission, it remains largely unclear whether ambient air pollutants and meteorological parameters could promote its transmission. METHODS: A retrospective study is conducted to study whether air quality index (AQI), four ambient air pollutants (PM(2.5), PM(10), NO(2) and CO) and five meteorological variables (daily temperature, highest temperature, lowest temperature, temperature difference and sunshine duration) could increase COVID-19 incidence in Wuhan and XiaoGan between Jan 26(th) to Feb 29(th) in 2020. RESULTS: First, a significant correlation was found between COVID-19 incidence and AQI in both Wuhan (R(2) = 0.13, p < 0.05) and XiaoGan (R(2) = 0.223, p < 0.01). Specifically, among four pollutants, COVID-19 incidence was prominently correlated with PM(2.5) and NO(2) in both cities. In Wuhan, the tightest correlation was observed between NO(2) and COVID-19 incidence (R(2) = 0.329, p < 0.01). In XiaoGan, in addition to the PM(2.5) (R(2) = 0.117, p < 0.01) and NO(2) (R(2) = 0.015, p < 0.05), a notable correlation was also observed between the PM(10) and COVID-19 incidence (R(2) = 0.105, p < 0.05). Moreover, temperature is the only meteorological parameter that constantly correlated well with COVID-19 incidence in both Wuhan and XiaoGan, but in an inverse correlation (p < 0.05). CONCLUSIONS: AQI, PM(2.5), NO(2), and temperature are four variables that could promote the sustained transmission of COVID-19.

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Bioaerosols and Transmission, a Diverse and Growing Community of Practice

The transmission of infectious microbes via bioaerosols is of significant concern for both human and animal health. However, gaps in our understanding of respiratory pathogen transmission and methodological heterogeneity persist. New developments have enabled progress in this domain, and one of the major turning points has been the recognition that cross-disciplinary collaborations across spheres of human and animal health, microbiology, biophysics, engineering, aerobiology, infection control, public health, occupational health, and industrial hygiene are essential. Collaborative initiatives support advances in topics such as bioaerosol behavior, dispersion models, risk assessment, risk/exposure effects, and mitigation strategies in clinical, experimental, agricultural, and other field settings. There is a need to enhance the knowledge translation for researchers, stakeholders, and private partners to support a growing network of individuals and agencies to achieve common goals to mitigate inter- and intra-species pathogen transmission via bioaerosols.

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Rhabdomyolysis in a Patient With Coronavirus Disease 2019

Coronavirus disease 2019 has rapidly enveloped the world in a pandemic after emerging in Wuhan, China, in December 2019. We describe a 49-year-old man presenting with fever, cough, dyspnea, and myalgia diagnosed with coronavirus disease 2019 along with rhabdomyolysis and acute kidney injury. The creatine phosphokinase was elevated to 23,800 U/L before trending down to normal levels. Rapid identification and treatment with aggressive intravenous hydration and correction of electrolyte abnormalities remain key to successful management. In a pandemic, often atypical presentations of this new disease have to be considered as differentials for early diagnosis and treatment of life-threatening conditions.

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Obstructive Sleep Apnea, Obesity, and Noninvasive Ventilation: Considerations During the Coronavirus Disease 2019 Pandemic

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A clinical approach to the threat of emerging influenza viruses in the Asia‐Pacific region

Seasonal influenza epidemics and periodic pandemics are important causes of morbidity and mortality. Patients with chronic co‐morbid illness, those at the extremes of age and pregnant women are at higher risks of complications requiring hospitalization, whereas young adults and obese individuals were also at increased risk during the A(H1N1) pandemic in 2009. Avian influenza A(H5N1) and A(H7N9) viruses have continued to circulate widely in some poultry populations and infect humans sporadically since 1997 and 2013, respectively. The recent upsurge in human cases of A(H7N9) infections in Mainland China is of great concern. Sporadic human cases of avian A(H5N6), A(H10N8) and A(H6N1) have also emerged in recent years while there are also widespread poultry outbreaks due to A(H5N8) in many countries. Observational studies have shown that treatment with a neuraminidase inhibitor (NAI) for adults hospitalized with severe influenza is associated with lower mortality and better clinical outcomes, especially when administered early in the course of illness. Whether higher than standard doses of NAI would provide greater antiviral effects in such patients will require further investigation. High‐dose systemic corticosteroids were associated with worse outcomes in patients with severe influenza. There is an urgent need for developing more effective antiviral therapies for treatment of influenza infections.

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Structural parameterization and functional prediction of antigenic polypeptome sequences with biological activity through quantitative sequence-activity models (QSAM) by molecular electronegativity edge-distance vector (VMED)

Only from the primary structures of peptides, a new set of descriptors called the molecular electronegativity edge-distance vector (VMED) was proposed and applied to describing and characterizing the molecular structures of oligopeptides and polypeptides, based on the electronegativity of each atom or electronic charge index (ECI) of atomic clusters and the bonding distance between atom-pairs. Here, the molecular structures of antigenic polypeptides were well expressed in order to propose the automated technique for the computerized identification of helper T lymphocyte (Th) epitopes. Furthermore, a modified MED vector was proposed from the primary structures of polypeptides, based on the ECI and the relative bonding distance of the fundamental skeleton groups. The side-chains of each amino acid were here treated as a pseudo-atom. The developed VMED was easy to calculate and able to work. Some quantitative model was established for 28 immunogenic or antigenic polypeptides (AGPP) with 14 (1–14) A(d) and 14 other restricted activities assigned as “1”(+) and “0”(−), respectively. The latter comprised 6 A(b)(15–20), 3 A(k)(21–23), 2 E(k)(24–26), 2 H-2(k)(27 and 28) restricted sequences. Good results were obtained with 90% correct classification (only 2 wrong ones for 20 training samples) and 100% correct prediction (none wrong for 8 testing samples); while contrastively 100% correct classification (none wrong for 20 training samples) and 88% correct classification (1 wrong for 8 testing samples). Both stochastic samplings and cross validations were performed to demonstrate good performance. The described method may also be suitable for estimation and prediction of classes I and II for major histocompatibility antigen (MHC) epitope of human. It will be useful in immune identification and recognition of proteins and genes and in the design and development of subunit vaccines. Several quantitative structure activity relationship (QSAR) models were developed for various oligopeptides and polypeptides including 58 dipeptides and 31 pentapeptides with angiotensin converting enzyme (ACE) inhibition by multiple linear regression (MLR) method. In order to explain the ability to characterize molecular structure of polypeptides, a molecular modeling investigation on QSAR was performed for functional prediction of polypeptide sequences with antigenic activity and heptapeptide sequences with tachykinin activity through quantitative sequence-activity models (QSAMs) by the molecular electronegativity edge-distance vector (VMED). The results showed that VMED exhibited both excellent structural selectivity and good activity prediction. Moreover, the results showed that VMED behaved quite well for both QSAR and QSAM of poly-and oligopeptides, which exhibited both good estimation ability and prediction power, equal to or better than those reported in the previous references. Finally, a preliminary conclusion was drwan: both classical and modified MED vectors were very useful structural descriptors. Some suggestions were proposed for further studies on QSAR/QSAM of proteins in various fields.

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Telecommuting: A viable option for medical physicists amid the COVID‐19 outbreak and beyond

The impact of recent outbreak of novel coronavirus disease, COVID-19, to the global healthcare systems is unprecedently enormous. Like many other clinical disciplines, medical physics has encountered unique challenges during this special period in wider aspects from clinical practice, research, administration to education. As hospitals implement various preventive and control measures to contain the virus, medical physicists are asked to perform non-essential activities by telecommuting or work-from-home (WFH) in many places.

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Human adenovirus load in respiratory tract secretions are predictors for disease severity in children with human adenovirus pneumonia

BACKGROUND: Pneumonia is a serious public health issue and is concerned around the world. This study is to investigate the association between viral load in children with human adenovirus (HAdV) pneumonia and disease severity. METHODS: A total of 1313 cases of children hospitalized in Hunan Provincial People’s Hospital due to community acquired pneumonia (CAP) from April 2011 to May 2014 were enrolled in this study. Samples of nasopharyngeal aspirate were collected for the cohort. WHO criteria for CAP grading was emerged for pneumonia severity classification. Real-time fluorescence quantitative PCR (qRT-PCR) was used to detect 12 kinds of respiratory viruses. HAdV types were identified by nested PCR. The relationship between HAdV load and severity of disease was there by analyzed. RESULTS: Finally, 174 cases (174/1313, 13.3%) were positive for HAdV, and HAdV type 7 (HAdV-7) was the main serotype (76/174, 43.7%). Among the 174 cases, 70 cases were with HAdV infection alone and 104 cases were accompanied by other viruses. The patients were divided into mild pneumonia group (n = 108 cases) and severe pneumonia group (n = 66 cases). HAdV load of children in severe pneumonia group was higher than that in mild pneumonia group. Similar result was obtained in the 70 cases with HAdV infection alone after subgrouping. Relevant factors analysis results showed that severe pneumonia children presented lower onset age, more prone to fever, longer fever time, and longer hospital stay compared with that of mild pneumonia children. Children with HAdV-7 infection developed more frequently severe pneumonia. Multivariate regression analysis showed that HAdV load, age, and fever time were risk factors for pneumonia severity. CONCLUSION: The severity of HAdV infection is significantly correlated with viral load and serotype.

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Nasal virome of dogs with respiratory infection signs include novel taupapillomaviruses

Using viral metagenomics, we characterized the mammalian virome of nasal swabs from 57 dogs with unexplained signs of respiratory infection showing mostly negative results using the IDEXX Canine Respiratory Disease RealPCR™ Panel. We identified canine parainfluenza virus 5, canine respiratory coronavirus, carnivore bocaparvovirus 3, canine circovirus and canine papillomavirus 9. Novel canine taupapillomaviruses (CPV21-23) were also identified in 3 dogs and their complete genome sequenced showing L1 nucleotide identity ranging from 68.4 to 70.3% to their closest taupapillomavirus relative. Taupapillomavirus were the only mammalian viral nucleic acids detected in two affected dogs, while a third dog was coinfected with low levels of canine parainfluenza 5. A role for these taupapillomavirues in canine respiratory disease remains to be determined. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11262-019-01634-6) contains supplementary material, which is available to authorized users.

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Response to Emergence of Middle East Respiratory Syndrome Coronavirus, Abu Dhabi, United Arab Emirates, 2013–2014

In January 2013, several months after Middle East respiratory syndrome coronavirus (MERS-CoV) was first identified in Saudi Arabia, Abu Dhabi, United Arab Emirates, began surveillance for MERS-CoV. We analyzed medical chart and laboratory data collected by the Health Authority–Abu Dhabi during January 2013–May 2014. Using real-time reverse transcription PCR, we tested respiratory tract samples for MERS-CoV and identified 65 case-patients. Of these patients, 23 (35%) were asymptomatic at the time of testing, and 4 (6%) showed positive test results for >3 weeks (1 had severe symptoms and 3 had mild symptoms). We also identified 6 clusters of MERS-CoV cases. This report highlights the potential for virus shedding by mildly ill and asymptomatic case-patients. These findings will be useful for MERS-CoV management and infection prevention strategies.

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Inhibition of PIKfyve kinase prevents infection by Zaire ebolavirus and SARS-CoV-2

Virus entry is a multistep process. It initiates when the virus attaches to the host cell and ends when the viral contents reach the cytosol. Genetically unrelated viruses can subvert analogous subcellular mechanisms and use similar trafficking pathways for successful entry. Antiviral strategies targeting early steps of infection are therefore appealing, particularly when the probability for successful interference through a common step is highest. We describe here potent inhibitory effects on content release and infection by chimeric VSV containing the envelope proteins of Zaire ebolavirus (VSV-ZEBOV) or SARS-CoV-2 (VSV-SARS-CoV-2) elicited by Apilimod and Vacuolin-1, small molecule inhibitors of the main endosomal Phosphatidylinositol-3-Phosphate/Phosphatidylinositol 5-Kinase, PIKfyve. We also describe potent inhibition of SARS-CoV-2 strain 2019-nCoV/USA-WA1/2020 by Apilimod. These results define new tools for studying the intracellular trafficking of pathogens elicited by inhibition of PIKfyve kinase and suggest the potential for targeting this kinase in developing small-molecule antivirals against SARS-CoV-2.

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Autoimmune and inflammatory diseases following COVID-19

Emerging reports show that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection precedes the appearance of various autoimmune and autoinflammatory diseases, including paediatric inflammatory multisystemic syndrome (PIMS) or multisystem inflammatory syndrome in children (MIS-C), thus adding to the growing mystery of this virus and raising questions about the nature of its link with autoimmune and autoinflammatory sequelae.

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Current knowledge, attitude and behaviour of hand and food hygiene in a developed residential community of Singapore: a cross-sectional survey

BACKGROUND: Diarrhoea incidence has been increasing progressively over the past years in developed countries, including Singapore, despite the accessibility and availability to clean water, well-established sanitation infrastructures and regular hygiene promotion. The aim of this study is to determine the current knowledge, attitude and behaviour of hand and food hygiene, and the potential risk factors of diarrhoea in a residential community of Singapore. METHODS: A cross-sectional study was conducted within a residential area in the west of Singapore from June to August 2013. A total of 1,156 household units were randomly sampled and invited to participate in an interviewer-assisted survey using standardised questionnaires. Descriptive, univariate and multivariate analyses were performed using descriptive statistics, Fisher’s Exact test and multivariate logistic regression modelling, respectively. R program was used for all statistical analysis. All tests were conducted at 5 % level of significance with 95 % confidence intervals (CI) reported where applicable. RESULTS: A total of 240 units (20.8 %) consented and responded to the survey invitation. About 77 % of the expected knowledge and attitude were observed in at least 80 % of the participants, compared to only about 31 % of the expected behaviours and practises. Being single [adjusted odds ratio (AOR) = 2.29; 95 % CI = 1.16-4.48], having flu in the past six month (AOR = 3.24; 95 % CI = 1.74-6.06), preferred self-medication (AOR = 2.07; 95 % CI = 1.06–4.12) were risk factors of diarrhoea. Washing hands with water before attending to children or sick persons (AOR = 0.30; 95 % CI = 0.11–0.82), washing hands with water (AOR = 0.16; 95 % CI = 0.05–0.45) and water with soap (AOR = 0.29; 95 % CI = 0.12–0.72) after attending to children or sick persons, and hand washing between 30 s to a minute (AOR = 0.44; 95 % CI = 0.20-0.90) were protective factors against diarrhoea. CONCLUSIONS: Good knowledge and attitude of the participants did not positively translate into high compliance and motivation to perform good hygiene practices. This observation may have resulted in a significant extent on the increasing diarrhoea incidences. Current interventions may be improved with more active community partnership among the residents, schools and the relevant social organizations, to raise awareness on the importance of compliance to good hygiene practices, and the risk factors of diarrhoea. A large case–control study would be required to validate these findings in future. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12889-015-1910-3) contains supplementary material, which is available to authorized users.

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MMPs and ADAMs in neurological infectious diseases and multiple sclerosis

Metalloproteinases—such as matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinases (ADAMs)—are involved in various diseases of the nervous system but also contribute to nervous system development, synaptic plasticity and neuroregeneration upon injury. MMPs and ADAMs proteolytically cleave many substrates including extracellular matrix components but also signaling molecules and receptors. During neuroinfectious disease with associated neuroinflammation, MMPs and ADAMs regulate blood–brain barrier breakdown, bacterial invasion, neutrophil infiltration and cytokine signaling. Specific and broad-spectrum inhibitors for MMPs and ADAMs have experimentally been shown to decrease neuroinflammation and brain damage in diseases with excessive neuroinflammation as a common denominator, such as pneumococcal meningitis and multiple sclerosis, thereby improving the disease outcome. Timing of metalloproteinase inhibition appears to be critical to effectively target the cascade of pathophysiological processes leading to brain damage without inhibiting the neuroregenerative effects of metalloproteinases. As the critical role of metalloproteinases in neuronal repair mechanisms and regeneration was only lately recognized, the original idea of chronic MMP inhibition needs to be conceptually revised. Recently accumulated research urges for a second chance of metalloproteinase inhibitors, which—when correctly applied and dosed—harbor the potential to improve the outcome of different neuroinflammatory diseases.

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Rôle des infections rhino-sinusiennes dans le déclenchement des pathologies allergiques et inflammatoires

Summary Much controversy still exists about the role of viruses, bacteria and fungi in nasal sinus diseases. Viral rhinitis alone does not seem to be able to elicit clinical acute sinusitis. Bacteria determine the clinical picture and outcome of sinusitis. S. pneumoniae, H. influenzae and M. catarrhalis are the bacteria most frequently involved. Much more conflicting reports are published about normal sinus flora, the role of anaerobes and the microbiology of chronic sinusitis. The relationship between infectious and allergic diseases ise more difficult to explain. It is shown that, in particular viruses can induce the release of inflammatory mediators and modify the inflammatory process. Their role in epithelial damage, excitation of nerve fibers, sensitization of inflammatory cells, and therefore, in general hyperreactivity has also been reported. Finally, with regard to sinusitis, different hypothesis have been proposed to explain the possible links with bronchial hyperreactivity.

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Life at the Editorial “COVID Frontline”. The American Thoracic Society Journal Family

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Gastrointestinal and Liver Manifestations of COVID-19

The worldwide pandemic of COVID-19, caused by the virus SARS-CoV,-2 has continued to progress, and increasing information is becoming available about the incidence of digestive symptoms as well as abnormal liver-associated enzymes in patients who are infected. These are postulated to be related to the virus's use of ACE-2 receptors located on certain intestinal cells, cholangiocytes, and hepatocytes. This brief review summarizes the available limited data on digestive manifestations of COVID-19. A significant proportion of COVID-19 patients can present initially with only digestive complaints. The most common digestive symptoms are anorexia, nausea, vomiting, and diarrhea. Liver-related transaminases are elevated in a substantial proportion of patients, although generally only mildly elevated. Currently there is no firm evidence to suggest that severity of digestive symptoms corresponds to severity of COVID-19 clinical course, however, more severe alterations in liver enzymes may correlate with worse clinical course. Given use of antiviral and antibacterial agents in sicker patients, drug-induced liver injury cannot be ruled out either in these cases. Although viral RNA can be detected in stool, it is unclear whether fecal-oral transmission can be achieved by the virus. As further data becomes available, our understanding of the digestive manifestations of COVID-19 will continue to evolve.

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Evaluating a multicomponent program to improve hypertension control in Guatemala: study protocol for an effectiveness-implementation cluster randomized trial

BACKGROUND: Hypertension is a major risk factor for cardiovascular disease (CVD). Despite advances in hypertension prevention and treatment, the proportion of patients who are aware, treated and controlled is low, particularly in low-income and middle-income countries (LMICs). We will evaluate an adapted version of a multilevel and multicomponent hypertension control program in Guatemala, previously proven effective and feasible in Argentina. The program components are: protocol-based hypertension treatment using a standardized algorithm; team-based collaborative care; health provider education; health coaching sessions; home blood pressure monitoring; blood pressure audit; and feedback. METHODS: Using a hybrid type 2 effectiveness-implementation design, we will evaluate clinical and implementation outcomes of the multicomponent program in Guatemala over an 18-month period. Through a cluster randomized trial, we will randomly assign 18 health districts to the intervention arm and 18 to enhanced usual care across five departments, enrolling 44 participants per health district and 1584 participants in total. The clinical outcomes are (1) the difference in the proportion of patients with controlled hypertension (< 130/80 mmHg) between the intervention and control groups at 18 months and (2) the net change in systolic and diastolic blood pressure from baseline to 18 months. The context-enhanced Reach, Efficacy, Adoption, Implementation, Maintenance (RE-AIM)/Practical Robust Implementation and Sustainability Model (PRISM) framework will guide the evaluation of the implementation at the level of the patient, provider, and health system. Using a mixed-methods approach, we will evaluate the following implementation outcomes: acceptability, adoption, feasibility, fidelity, adaptation, reach, sustainability, and cost-effectiveness. DISCUSSION: We will disseminate the study findings, and promote scale up and scale out of the program, if proven effective. This study will generate urgently needed data on effective, adoptable, and sustainable interventions and implementation strategies to improve hypertension control in Guatemala and other LMICs. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03504124. Registered on 20 April 2018.

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Isolation of a thermostable trypsin inhibitor with exploitable potential

A novel trypsin inhibitor with considerable thermal and pH stability, designated Glytine, was isolated from seeds of the Chinese black soybean Glycine max (L.) Merr. The purification procedure involved ammonium sulfate precipitation, ion-exchange chromatography on CM-Sephadex C-50, gel filtration chromatography on Sephacryl S-200HR, and gel filtration chromatography on POROS HS-20. The 20 N-terminal amino acid sequences were determined to be DEYSKPCCDLCMCTRRCPPQ, demonstrating close homology with the sequences of leguminous trypsin inhibitors. The molecular mass and isoelectric point of the inhibitor were estimated by SDS-PAGE and isoelectric focusing to be 19.9 kDa and 6.2, respectively. Trypsin could be completely inhibited by Glytine when the weight ratio was 1.5. The inhibitory activity of Glytine was unaffected by exposure to temperatures up to 100 °C, or within the pH range 2–12. Besides trypsin–chymotrypsin inhibition activity, Glytine demonstrated other biological activities including antiproliferative activity against tumor cells including human liver hepatoma cells Bel-7402 and neuroblastoma cells SHSY5Y. In addition, the inhibitor showed antifungal activity against Pythium aphanidermatum, Fusarium oxysporum, Alternaria alternata (Fr.) Keiss, Fusarium solani, and Botrytis cinerea. This study extended research on leguminous trypsin–chymotrypsin inhibitor and suggested exploitable potential.

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Hepatitis E Virus ORF2 Protein Activates the Pro-Apoptotic Gene CHOP and Anti-Apoptotic Heat Shock Proteins

BACKGROUND: Hepatitis E virus (HEV) is a non-enveloped plus-strand RNA virus that causes acute hepatitis. The capsid protein open reading frame 2 (ORF2) is known to induce endoplasmic reticulum stress in ORF2 expressing cells. METHODOLOGY/PRINCIPAL FINDINGS: In this study we found that HEV ORF2 activates the expression of the pro-apoptotic gene C/EBP homologous protein (CHOP). ORF2 stimulates the CHOP promoter mainly through AARE (amino acid response elements) and to a minor extent the ERSE (endoplasmic reticulum stress response elements). Activating transcription factor 4 (ATF4) protein binds and activates the AARE regulatory sites of the CHOP promoter. ORF2 expression also leads to increased phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α) that in turn initiates the translation of ATF4 mRNA. The pro-apoptotic gene CHOP is an important trigger to initiate endoplasmic reticulum stress induced apoptosis. However, the activation of CHOP by ORF2 in this study did not induce apoptosis, nor did BCL2-associated X protein (Bax) translocate to mitochondria. Microarray analysis revealed an ORF2 specific increased expression of chaperones Hsp72, Hsp70B', and co-chaperone Hsp40. Co-immunoprecipitation (Co-IP) and in silico molecular docking analysis suggests that HEV ORF2 interacts with Hsp72. In addition, Hsp72 shows nuclear accumulation in ORF2 expressing cells. CONCLUSIONS/SIGNIFICANCE: These data provide new insight into simultaneously occurring counter-acting effects of HEV ORF2 that may be part of a strategy to prevent host suicide before completion of the viral replication cycle.

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Titration of Human Coronaviruses, HCoV-229E and HCoV-OC43, by an Indirect Immunoperoxidase Assay

Calculation of infectious viral titers represents a basic and essential experimental approach for virologists. Classical plaque assays cannot be used for viruses that do not cause significant cytopathic effects, which is the case for strains 229E and OC43 of human coronavirus (HCoV). An alternative indirect immunoperoxidase assay (IPA) is herein described for the detection and titration of these viruses. Susceptible cells are inoculated with serial logarithmic dilutions of samples in a 96-well plate. After viral growth, viral detection by IPA yields the infectious virus titer, expressed as “tissue culture infectious dose” (TCID(50)). This represents the dilution of a virus-containing sample at which half of a series of laboratory wells contain replicating virus. This technique is a reliable method for the titration of HCoV in biological samples (cells, tissues, or fluids).

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The spike protein of SARS-CoV — a target for vaccine and therapeutic development

Severe acute respiratory syndrome (SARS) is a newly emerging infectious disease caused by a novel coronavirus, SARS-coronavirus (SARS-CoV). The SARS-CoV spike (S) protein is composed of two subunits; the S1 subunit contains a receptor-binding domain that engages with the host cell receptor angiotensin-converting enzyme 2 and the S2 subunit mediates fusion between the viral and host cell membranes. The S protein plays key parts in the induction of neutralizing-antibody and T-cell responses, as well as protective immunity, during infection with SARS-CoV. In this Review, we highlight recent advances in the development of vaccines and therapeutics based on the S protein.

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Scaling up testing for COVID-19 in Africa: Responding to the pandemic in ways that strengthen health systems

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Tobacco use and vaping in the COVID‐19 era

Health crises have become a popular topic of discussion. In the wave of the ongoing pandemic, experts have suggested the role of vaping and other tobacco product use exemplifying the vulnerability of the population to contract the COVID‐19. We discuss some of the events that led up to these conclusions and also offer a unique insight into another form of tobacco use that is potentially propagating its spread especially in the South Asian region—chewed tobacco. Both of these have been a perennial issue that head and neck cancer surgeons have been dealing with. Governments and head and neck cancer care providers now have an opportunity to deal with a common enemy in the midst of this pandemic.

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COVID-19, insurer board utility, and capital regulation

This paper develops a down-and-out call option model by introducing a structural break in volatility to capture the coronavirus (COVID-19) outbreak. The life insurer's equity and its board's utility are evaluated at the optimal guaranteed rate in the equity maximization. Results suggest that the seriousness degree of the COVID-19 outbreak and capital regulation enhance the optimal guaranteed rate and the board's utility. Increased the board's utility by increasing liabilities costs insurer profitability. Conflicts of incentives can arise during the COVID-19 outbreak.

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COVID-19 and the Ophthalmology Match

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Impacto de la pandemia COVID-19 en el servicio de urología de un centro de referencia en la Comunidad de Madrid

Abstract The COVID-19 pandemic caused by the SARS-CoV-2 virus has caused tens of thousands of deaths in Spain and has managed to breakdown the healthcare system hospitals in the Community of Madrid, largely due to its tendency to cause severe pneumonia, requiring ventilatory support. This fact has caused our center to collapse, with 130% of its beds occupied by COVID-19 patients, thus causing the absolute cessation of activity of the urology service, the practical disappearance of resident training programs, and the incorporation of a good part of the urology staff into the group of medical personnel attending these patients. In order to recover from this extraordinary level of suspended activity, we will be obliged to prioritize pathologies based on purely clinical criteria, for which tables including the relevance of each pathology within each area of urology are being proposed. Technology tools such as online training courses or surgical simulators may be convenient for the necessary reestablishment of resident education.

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Etiology and Risk Factors for Mortality in an Adult Community-acquired Pneumonia Cohort in Malawi

Rationale: In the context of rapid antiretroviral therapy rollout and an increasing burden of noncommunicable diseases, there are few contemporary data describing the etiology and outcome of community-acquired pneumonia (CAP) in sub-Saharan Africa. Objectives: To describe the current etiology of CAP in Malawi and identify risk factors for mortality. Methods: We conducted a prospective observational study of adults hospitalized with CAP to a teaching hospital in Blantyre, Malawi. Etiology was defined by blood culture, Streptococcus pneumoniae urinary antigen detection, sputum mycobacterial culture and Xpert MTB/RIF, and nasopharyngeal aspirate multiplex PCR. Measurements and Main Results: In 459 patients (285 [62.1%] males; median age, 34.7 [interquartile range, 29.4–41.9] yr), 30-day mortality was 14.6% (64/439) and associated with male sex (adjusted odds ratio, 2.60 [95% confidence interval, 1.17–5.78]), symptom duration greater than 7 days (2.78 [1.40–5.54]), tachycardia (2.99 [1.48–6.06]), hypoxemia (4.40 [2.03–9.51]), and inability to stand (3.59 [1.72–7.50]). HIV was common (355/453; 78.4%), frequently newly diagnosed (124/355; 34.9%), but not associated with mortality. S. pneumoniae (98/458; 21.4%) and Mycobacterium tuberculosis (75/326; 23.0%) were the most frequently identified pathogens. Viral infection occurred in 32.6% (148/454) with influenza (40/454; 8.8%) most common. Bacterial–viral coinfection occurred in 9.1% (28/307). Detection of M. tuberculosis was associated with mortality (adjusted odds ratio, 2.44 [1.19–5.01]). Conclusions: In the antiretroviral therapy era, CAP in Malawi remains predominantly HIV associated, with a large proportion attributable to potentially vaccine-preventable pathogens. Strategies to increase early detection and treatment of tuberculosis and improve supportive care, in particular the correction of hypoxemia, should be evaluated in clinical trials to address CAP-associated mortality.

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Clinical characteristics and therapeutic procedure for a critical case of novel coronavirus pneumonia treated with glucocorticoids and non-invasive ventilator treatment

The novel coronavirus pneumonia (NCP) outbreak occurred in Wuhan, China at the end of 2019. Here, we report the clinical characteristics and therapeutic procedure for a case of severe NCP. The patient was started on glucocorticoids and non-invasive ventilator treatment. After treatment, the patient’s symptoms improved, and the status was confirmed as NCP negative. Our results may provide clues for the treatment of NCP.

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COVID‐19: From pathogenesis models to the first drug trials

The number of people infected with SARS‐CoV‐2, and sadly dying from COVID‐19, has exploded, and so the amount of literature on the novel coronavirus and the disease it causes has increased proportionately. The case numbers in some countries are beyond the epidemic peak, but the uncertainty about a second wave keeps politicians and societies under pressure. Appropriate decision‐making and winning support from the population depends on precise scientific information rather than leaving the field to scaremongers of all proveniences. This mini‐review is an update of earlier reports (Brüssow, Microb Biotechnol 2020a;13:607; Brüssow, Microb Biotechnol 2020b; https://doi.org/10.1111/1751-7915.13592).

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Severe maternal morbidity and mortality associated with COVID‐19: The risk should not be down‐played

Nordic countries have a long tradition of collecting health related population data meticulously and reporting them transparently. Such data provide firm grounds for making good decisions and as a result the public health institutions in Scandinavia enjoy the trust of society. The Covid‐19 pandemic has, however, resulted in a completely new situation as we are now exploring in uncharted waters. Based on reports from China,(1,2,3) Italy,(4) USA(5) and perhaps with the good intention of reducing anxiety among this vulnerable population group, it has been widely publicized that pregnant women are not at increased risk of susceptibility, infectivity and severity of COVID‐19 compared to the general population or non‐pregnant women, although a systematic review of 108 cases of laboratory confirmed pregnancies with COVID‐19 has reported the possibility of increased risk of severe disease among pregnant women.(6)

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Association between dopamine and cerebral autoregulation in preterm neonates

BACKGROUND: To test the hypothesis that dopamine is associated with impaired cerebral autoregulation (ICA) in a dose-dependent fashion. METHODS: Non a priori designed secondary analysis of a prospectively enrolled cohort study subjects <12 h of life between 24(0) and 29(6) weeks gestation. Cerebral saturations (rScO2) and mean arterial blood pressure (MAP) were continuously monitored every 30 s for 96 h. ICA was defined by a 10 min epoch rScO2-MAP correlation coefficient of >0.5. RESULTS: Twenty-three of 61 subjects (38%) required dopamine. Time spent with ICA was 23% in dopamine-exposed subjects vs. 14% in those not exposed (p = 0.0001). On the epoch level, time spent with ICA was 15%, 29%, 34%, 37%, and 23% in epochs with dopamine titration of 0, 1–5, 6–10, 11–15, and 16–20 μg/kg/min, respectively. Using mixed-effect modeling, ICA for each dopamine titration was significantly higher than unexposed times when controlling for gestation, presence of a patent ductus arteriosus, day of life, MAP less than gestational age, and illness severity score (p < 0.02). CONCLUSIONS: Dopamine exposure during the first 96 h was associated with ICA. Time periods with ICA increased with dopamine exposure in a dose-dependent fashion peaking at a concentration of 11–15 μg/kg/min.

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Informing Emergency Care for all patients: The Registry for Emergency Care (REC) Project Protocol

OBJECTIVES: In Australia, the current emergency department (ED) burden related to COVID‐19 is from ‘suspected’ rather than ‘confirmed’ cases. The initial aim of the Registry for Emergency Care (REC) Project is to determine the impact of isolation processes on the emergency care of all patients. METHODS: The REC Project builds on the COVID‐19 Emergency Department Quality Improvement Project (COVED). Outcomes measured include times to critical assessment and management. RESULTS: Clinical tools will be generated to inform emergency care, both during and beyond the COVID‐19 pandemic. CONCLUSIONS: The REC Project will support ED clinicians in the emergency care of all patients. This article is protected by copyright. All rights reserved.

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Lessons learned from HIV can inform our approach to COVID‐19 stigma

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Outcome of phacoemulsification in 71 cats: A multicenter retrospective study (2006‐2017)

PURPOSE: To assess outcome of phacoemulsification in cats. METHODS: Records of 71 cats (82 eyes) from five referral centers were reviewed. Groups were divided by cause of cataract (congenital/juvenile [n = 32], traumatic [n = 33], and secondary to uveitis [n = 6]), and group comparisons were performed for the most common complications: postoperative ocular hypertension (POH), uveitis, corneal ulceration, synechia/dyscoria, and posterior capsular opacity (PCO) in three different time periods: immediately postoperatively, at 1‐90 days, and at >90 days. RESULTS: Median follow‐up was 198 days (interquartile range 64‐518 days). The overall visual success rate of the cats with a 12‐month follow‐up was 92.6% (25/27 eyes). POH occurred in 35/82 (42.6%) eyes. Immediately postoperatively, uveitis was the most common complication in 28/82 eyes (34.1%) followed by corneal ulceration in 22/82 eyes (26.8%). At 1‐90 days, uveitis in 41/81 eyes (50.6%) remained the most common complication, followed by synechia/dyscoria in 21/81 eyes (25.9%), corneal ulceration in 16/81 eyes (19.7%), and PCO in 15/81 eyes (18.5%). At >90 days, PCO in 17/47 eyes (36.1%), followed by synechia/dyscoria in 16/47 eyes (34%), was the most common complications. The number of eyes with synechia/dyscoria in the trauma group was higher (13/33 [39.3%]) than in the congenital/juvenile group (5/31 [16.1%]) at 1‐90 days (P = .039). No statistical difference was found for the other group comparisons. Three eyes in total were enucleated owing to endophthalmitis, post‐traumatic ocular sarcoma, and secondary glaucoma. CONCLUSION: Uveitis in the short‐term and PCO and synechia/dyscoria in the long‐term were the most common complications following phacoemulsification in cats.

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The history and epidemiology of Middle East respiratory syndrome corona virus

Corona viruses cause common cold, and infections caused by corona viruses are generally self-resolving. During the last 4 years, corona viruses have become the most important viruses worldwide because of the occurrence of several recent deaths caused by corona viruses in Saudi Arabia. Spread of the infection occurred worldwide; however, most cases of mortality have occurred in the Middle East. Owing to the predominance of outbreaks in the Middle Eastern countries, the virus was renamed a Middle East respiratory syndrome corona virus (MERS-CoV) by the Corona virus Study Group. The Center for Diseases Control and Prevention and World Health Organization maintain a website that is updated frequently with new cases of MERS-CoV infection. In this review, we describe the history and epidemiology of this novel virus. Studies of the genetics and molecular mechanisms of this virus are expected to facilitate the development of vaccines in the future.

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Infectious MERS-CoV Isolated From a Mildly Ill Patient, Saudi Arabia

Middle East respiratory syndrome coronavirus (MERS-CoV) is associated with a wide range of clinical presentations, from asymptomatic or mildly ill to severe respiratory illness including death. We describe isolation of infectious MERS-CoV from the upper respiratory tract of a mildly ill 27-year-old female in Saudi Arabia 15 days after illness onset.