title: Newly Recognized Causes of Acute Lung Injury: Transfusion of Blood Products, Severe Acute Respiratory Syndrome, and Avian Influenza

text: Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a clinical syndrome that has an ever-growing list of potential causes. The transfusion of blood products is often a life-saving therapy, but it can be associated with the development of ALI/ARDS. Transfusion-related ALI is now the leading cause of transfusion-associated fatalities in the United States. Two infectious causes of ALI/ARDS, severe acute respiratory syndrome and H5N1 influenza, have recently emerged and have the potential for pandemic spread. This article discusses the clinical importance, pathogenesis, diagnosis, management, and prevention of these newly recognized causes of respiratory failure.


title: Respiratory Viruses

text: Abstract This article is an overview of the most clinically important respiratory viruses including the recently emerged highly pathogenic coronaviruses and other viruses that are transmitted via the respiratory tract. In this article, we highlight a description of the agent, its life cycle, epidemiology, pathogenesis, clinical features, diagnosis and management of the infection. The viruses in this article are respiratory syncytial virus, parainfluenza virus, human metapneumovirus, rhinovirus, seasonal and emerging coronaviruses, adenovirus, bocavirus and other viruses associated with the respiratory tract for their life cycle.


title: Protein-directed ribosomal frameshifting temporally regulates gene expression

text: Programmed −1 ribosomal frameshifting is a mechanism of gene expression, whereby specific signals within messenger RNAs direct a proportion of translating ribosomes to shift −1 nt and continue translating in the new reading frame. Such frameshifting normally occurs at a set ratio and is utilized in the expression of many viral genes and a number of cellular genes. An open question is whether proteins might function as trans-acting switches to turn frameshifting on or off in response to cellular conditions. Here we show that frameshifting in a model RNA virus, encephalomyocarditis virus, is trans-activated by viral protein 2A. As a result, the frameshifting efficiency increases from 0 to 70% (one of the highest known in a mammalian system) over the course of infection, temporally regulating the expression levels of the viral structural and enzymatic proteins.


title: The Pathogenicity of SARS-CoV-2 in hACE2 Transgenic Mice

text: Severe acute respiratory syndrome CoV-2 (SARS-CoV-2) caused the Corona Virus Disease 2019 (COVID-19) cases in China has become a public health emergency of international concern (PHEIC). Based on angiotensin converting enzyme 2 (ACE2) as cell entry receptor of SARS-CoV, we used the hACE2 transgenic mice infected with SARS-CoV-2 to study the pathogenicity of the virus. Weight loss and virus replication in lung were observed in hACE2 mice infected with SARS-CoV-2. The typical histopathology was interstitial pneumonia with infiltration of significant lymphocytes and monocytes in alveolar interstitium, and accumulation of macrophages in alveolar cavities. Viral antigens were observed in the bronchial epithelial cells, alveolar macrophages and alveolar epithelia. The phenomenon was not found in wild type mice with SARS-CoV-2 infection. The pathogenicity of SARS-CoV-2 in hACE2 mice was clarified and the Koch’s postulates were fulfilled as well, and the mouse model may facilitate the development of therapeutics and vaccines against SARS-CoV-2.


title: Acute Uncomplicated Febrile Illness in Children Aged 2-59 months in Zanzibar – Aetiologies, Antibiotic Treatment and Outcome

text: BACKGROUND: Despite the fact that a large proportion of children with fever in Africa present at primary health care facilities, few studies have been designed to specifically study the causes of uncomplicated childhood febrile illness at this level of care, especially in areas like Zanzibar that has recently undergone a dramatic change from high to low malaria transmission. METHODS: We prospectively studied the aetiology of febrile illness in 677 children aged 2–59 months with acute uncomplicated fever managed by IMCI (Integrated Management of Childhood Illness) guidelines in Zanzibar, using point-of-care tests, urine culture, blood-PCR, chest X-ray (CXR) of IMCI-pneumonia classified patients, and multiple quantitative (q)PCR investigations of nasopharyngeal (NPH) (all patients) and rectal (GE) swabs (diarrhoea patients). For comparison, we also performed NPH and GE qPCR analyses in 167 healthy community controls. Final fever diagnoses were retrospectively established based on all clinical and laboratory data. Clinical outcome was assessed during a 14-day follow-up. The utility of IMCI for identifying infections presumed to require antibiotics was evaluated. FINDINGS: NPH-qPCR and GE-qPCR detected ≥1 pathogen in 657/672 (98%) and 153/164 (93%) of patients and 158/166 (95%) and 144/165 (87%) of controls, respectively. Overall, 57% (387/677) had IMCI-pneumonia, but only 12% (42/342) had CXR-confirmed pneumonia. Two patients were positive for Plasmodium falciparum. Respiratory syncytial virus (24.5%), influenza A/B (22.3%), rhinovirus (10.5%) and group-A streptococci (6.4%), CXR-confirmed pneumonia (6.2%), Shigella (4.3%) were the most common viral and bacterial fever diagnoses, respectively. Blood-PCR conducted in a sub-group of patients (n = 83) without defined fever diagnosis was negative for rickettsiae, chikungunya, dengue, Rift Valley fever and West Nile viruses. Antibiotics were prescribed to 500 (74%) patients, but only 152 (22%) had an infection retrospectively considered to require antibiotics. Clinical outcome was generally good. However, two children died. Only 68 (11%) patients remained febrile on day 3 and three of them had verified fever on day 14. An additional 29 (4.5%) children had fever relapse on day 14. Regression analysis determined C-reactive Protein (CRP) as the only independent variable significantly associated with CXR-confirmed pneumonia. CONCLUSIONS: This is the first study on uncomplicated febrile illness in African children that both applied a comprehensive laboratory panel and a healthy control group. A majority of patients had viral respiratory tract infection. Pathogens were frequently detected by qPCR also in asymptomatic children, demonstrating the importance of incorporating controls in fever aetiology studies. The precision of IMCI for identifying infections requiring antibiotics was low.


title: Origin of the human L1 elements: Proposed progenitor genes deduced from a consensus DNA sequence

text: Abstract A consensus sequence for the human long interspersed repeated DNA element, L1H8 (LINE or KpnI sequence), is presented. The sequence contains two open reading frames (ORFs) which are homologous to ORFs in corresponding regions of L1 elements in other species. The L1H8 ORFs are separated by a small evolutionarily nonconserved region. The 5′ end of the consensus contains frequent terminators in all three reading frames and has a relatively high GC content with numerous stretches of weak homology with AluI repeats. The 5′ ORF extends for a minimum of 723 bp (241 codons). The 3′ ORF is 3843 bp (1281 codons) and predicts a protein of 149 kD which has regions of weak homology to the polymerase domain of various reverse transcriptases. The 3′ end of the consensus has a 208-bp nonconserved region followed by an adenine-rich end. The organization of the L1H8 consensus sequence resembles the structure of eukaryotic mRNAs except for the noncoding region between ORFs. However, due to base substitutions or truncation most elements appear incapable of producing mRNA that can be translated. Our observation that individual elements cluster into subfamilies on the basis of the presence or absence of blocks of sequence, or by the linkage of alternative bases at multiple positions, suggests that most L1 sequences were derived from a small number of structural genes. An estimate of the mammalian L1 substitution rate was derived and used to predict the age of individual human elements. From this it follows that the majority of human L1 sequences have been generated within the last 30 million years. The human elements studied here differ from each other, yet overall the L1H8 sequences demonstrate a pattern of species-specificity when compared to the L1 families of other mammals. Possible mechanisms that may account for the origin and evolution of the L1 family are discussed. These include pseudogene formation (retroposition), transposition, gene conversion, and RNA recombination.


title: Laboratory findings of COVID-19: a systematic review and meta-analysis

text: The Coronavirus Disease (COVID-19) pandemic first broke out in December 2019 in Wuhan, China, and has now spread worldwide. Laboratory findings have been only partially described in some observational studies. To date, more comprehensive systematic reviews of laboratory findings on COVID-19 are missing. We performed a systematic review with a meta-analysis to assess laboratory findings in patients with COVID-19. Observational studies from three databases were selected. We calculated pooled proportions and 95% confidence interval (95% CI) using the random-effects model meta-analysis. A total of 1106 articles were identified from PubMed, Web of Science, CNKI (China), and other sources. After screening, 28 and 7 studies were selected for a systematic review and a meta-analysis, respectively. Of the 4,663 patients included, the most prevalent laboratory finding was increased C-reactive protein (CRP; 73.6%, 95% CI 65.0–81.3%), followed by decreased albumin (62.9%, 95% CI 28.3–91.2%), increased erythrocyte sedimentation rate (61.2%, 95% CI 41.3–81.0%), decreased eosinophils (58.4%, 95% CI 46.5–69.8%), increased interleukin-6 (53.1%, 95% CI 36.0–70.0%), lymphopenia (47.9%, 95% CI 41.6–54.9%), and increased lactate dehydrogenase (LDH; 46.2%, 95% CI 37.9–54.7%). A meta-analysis of seven studies with 1905 patients showed that increased CRP (OR 3.0, 95% CI: 2.1–4.4), lymphopenia (OR 4.5, 95% CI: 3.3–6.0), and increased LDH (OR 6.7, 95% CI: 2.4–18.9) were significantly associated with severity. These results demonstrated that more attention is warranted when interpreting laboratory findings in patients with COVID-19. Patients with elevated CRP levels, lymphopenia, or elevated LDH require proper management and, if necessary, transfer to the intensive care unit.


title: Current Experimental Methods for Characterizing Protein–Protein Interactions

text: Protein molecules often interact with other partner protein molecules in order to execute their vital functions in living organisms. Characterization of protein–protein interactions thus plays a central role in understanding the molecular mechanism of relevant protein molecules, elucidating the cellular processes and pathways relevant to health or disease for drug discovery, and charting large‐scale interaction networks in systems biology research. A whole spectrum of methods, based on biophysical, biochemical, or genetic principles, have been developed to detect the time, space, and functional relevance of protein–protein interactions at various degrees of affinity and specificity. This article presents an overview of these experimental methods, outlining the principles, strengths and limitations, and recent developments of each type of method.


title: The effect of COVID-19 and subsequent social distancing on travel behavior

text: Abstract The spread of the COVID-19 virus has resulted in unprecedented measures restricting travel and activity participation in many countries. Social distancing, i.e., reducing interactions between individuals in order to slow down the spread of the virus, has become the new norm. In this viewpoint I will discuss the potential implications of social distancing on daily travel patterns. Avoiding social contact might completely change the number and types of out-of-home activities people perform, and how people reach these activities. It can be expected that the demand for travel will reduce and that people will travel less by public transport. Social distancing might negatively affect subjective well-being and health status, as it might result in social isolation and limited physical activity. As a result, walking and cycling, recreationally or utilitarian, can be important ways to maintain satisfactory levels of health and well-being. Policymakers and planners should consequently try to encourage active travel, while public transport operators should focus on creating ways to safely use public transport.


title: Influenza, influenza‐like symptoms and their association with cardiovascular risks: a systematic review and meta‐analysis of observational studies

text: AIMS: To synthesise the evidence relating influenza and influenza‐like symptoms to the risks of myocardial infarction (MI), heart failure (HF) and stroke. METHODS: We conducted a systematic review and meta‐analysis of the evidence relating influenza and influenza‐like symptoms to the risks of MI, HF and stroke. We systematically searched all MEDLINE and EMBASE entries up to August 2014 for studies of influenza vs. the cardiovascular outcomes above. We conducted random effects meta‐analysis using inverse variance method for pooled odds ratios (OR) and evaluated statistical heterogeneity using the I (2) statistic. RESULTS: We identified 12 studies with a total of 84,003 participants. The pooled OR for risk of MI vs. influenza (serologically confirmed) was 1.27 (95% CI, confidence interval 0.54–2.95), I (2) = 47%, which was significant for the only study that adjusted for confounders (OR 5.50, 95% CI 1.31–23.13). The pooled OR for risk of MI vs. influenza‐like symptoms was 2.17 (95% CI 1.68–2.80), I (2) = 0%, which was significant for both unadjusted (OR 2.23, 95% CI 1.65–3.01, five studies) and adjusted studies (OR 2.01, 95% CI 1.24–3.27, two studies). We found one study that evaluated stroke risk, one study in patients with HF, and one that evaluated mortality from MI – all of these studies suggested increased risks of events with influenza‐like symptoms. CONCLUSIONS: There is an association between influenza‐like illness and cardiovascular events, but the relationship is less clear with serologically diagnosed influenza. We recommend renewed efforts to apply current clinical guidelines and maximise the uptake of annual influenza immunisation among patients with cardiovascular diseases, to decrease their risks of MI and stroke.


title: Molecular and clinical study on prevalence of feline herpesvirus type 1 and calicivirus in correlation with feline leukemia and immunodeficiency viruses

text: Upper respiratory tract diseases (URTD) are common clinical problem in cats worldwide. Feline calicivirus (FCV) and feline herpesvirus type 1 (FHV-1) are the main primary pathogens. Feline immunodeficiency virus (FIV) and Feline leukemia virus (FeLV) are also among the most common infectious diseases of cats which suppress the immunity. Oropharyngeal and conjunctival swabs and blood samples were taken from 16 cats with clinical signs of URTD and 26 clinically healthy cats. PCR and RT-PCR were used to detect FHV/FIV or FCV/FeLV infections, respectively. Feline calicivirus was detected in all cats with URTD and 87.00% and 93.00% of them were positive for FIV and FeLV, respectively. Feline herpesvirus rate of infection was 43.00% in sick cats. In clinically normal cats, prevalence rates of FCV and FHV were about 50.00%, but FIV and FeLV rates (42.00% and 65.00% respectively) were higher compared to other studies. Stomatitis was observed in 50.00% of cats with URTD. The main causative agent of corneal ulcers is FHV-1, but in 50.00% of cats with corneal ulcers, FCV was detected alone. It seems new variants of Caliciviruses are the main causative agents to attack uncommon tissues like cornea, although retroviral infections may be in the background of these various signs. The high retroviral prevalence may be due to existence of large population of stray cats. This is the first molecular study of FeLV and FCV in Iran and seems that FCV and FHV prevalence rates in FIV or FeLV infected cats is more than other non-infected ones.


title: Brain on FIRES: Super Refractory Seizure in a 7 yr Old Boy

text: We present a 7 yr old boy afflicted with super-refractory seizure that responded poorly to antiepileptic drugs and sustained a long course of hospitalization and complications of high doses of medications as well as longstanding stay in hospital. The differential diagnoses were, fever-induced refractory epileptic encephalopathy (FIRES), and infectious and autoimmune encephalitis. However, work-ups had not revealed any evidence of any specific diagnosis, so we assumed that he was afflicted by viral infectious encephalitis as he had, fever, vomiting, and prodromal symptoms of infectious (most probably viral) disease prior to onset of the seizure attacks.


Protecting health worker mental health during COVID-19


title: Migration and health in Southern Africa: 100 years and still circulating

text: Migration has deep historical roots in South and Southern Africa and to this day continues to be highly prevalent and a major factor shaping South African society and health. In this paper we examine the role of migration in the spread of two diseases nearly 100 years apart: tuberculosis following the discovery of gold in 1886 and HIV in the early 1990s. Both cases demonstrate the critical role played by human migration in the transmission and subsequent dissemination of these diseases to rural areas. In both cases, migration acts to assemble in one high-risk environment thousands of young men highly susceptible to new diseases. With poor living and working conditions, these migration destinations act as hot-spots for disease transmission. Migration of workers back to rural areas then serves as a highly efficient means of disseminating these diseases to rural populations. We conclude by raising some more recent questions examining the current role of migration in Southern Africa.


title: Lessening of porcine epidemic diarrhoea virus susceptibility in piglets after editing of the CMP-N-glycolylneuraminic acid hydroxylase gene with CRISPR/Cas9 to nullify N-glycolylneuraminic acid expression

text: The porcine epidemic diarrhoea virus (PEDV) devastates the health of piglets but may not infect piglets whose CMP-N-glycolylneuraminic acid hydroxylase (CMAH) gene is mutated (knockouts, KO) by using CRISPR/Cas9 gene editing techniques. This hypothesis was tested by using KO piglets that were challenged with PEDV. Two single-guide RNAs targeting the CMAH gene and Cas9 mRNA were microinjected into the cytoplasm of newly fertilized eggs. Four live founders generated and proven to be biallelic KO, lacking detectable N-glycolylneuraminic acid (NGNA). The founders were bred, and homozygous offspring were obtained. Two-day-old (in exps. I, n = 6, and III, n = 15) and 3-day-old (in exp. II, n = 9) KO and wild-type (WT, same ages in respective exps.) piglets were inoculated with TCID(50) 1x10(3) PEDV and then fed 20 mL of infant formula (in exps. I and II) or sow’s colostrum (in exp. III) every 4 hours. In exp. III, the colostrum was offered 6 times and was then replaced with Ringer/5% glucose solution. At 72 hours post-PEDV inoculation (hpi), the animals either deceased or euthanized were necropsied and intestines were sampled. In all 3 experiments, the piglets showed apparent outward clinical manifestations suggesting that infection occurred despite the CMAH KO. In exp. I, all 6 WT piglets and only 1 of 6 KO piglets died at 72 hpi. Histopathology and immunofluorescence staining showed that the villus epithelial cells of WT piglets were severely exfoliated, but only moderate exfoliation and enterocyte vacuolization was observed in KO piglets. In exp. II, delayed clinical symptoms appeared, yet the immunofluorescence staining/histopathologic inspection (I/H) scores of the two groups differed little. In exp. III, the animals exhibited clinical and pathological signs after inoculation similar to those in exp. II. These results suggest that porcine CMAH KO with nullified NGNA expression are not immune to PEDV but that this KO may lessen the severity of the infection and delay its occurrence.


title: Predicting the Trajectory of Any COVID19 Epidemic From the Best Straight Line

text: A pipeline involving data acquisition, curation, carefully chosen graphs and mathematical models, allows analysis of COVID-19 outbreaks at 3,546 locations world-wide (all countries plus smaller administrative divisions with data available). Comparison of locations with over 50 deaths shows all outbreaks have a common feature: H(t) defined as loge(X(t)/X(t 1)) decreases linearly on a log scale, where X(t) is the total number of Cases or Deaths on day, t (we use ln for loge). The downward slopes vary by about a factor of three with time constants (1/slope) of between 1 and 3 weeks; this suggests it may be possible to predict when an outbreak will end. Is it possible to go beyond this and perform early prediction of the outcome in terms of the eventual plateau number of total confirmed cases or deaths? We test this hypothesis by showing that the trajectory of cases or deaths in any outbreak can be converted into a straight line. Specifically , is a straight line for the correct plateau value N, which is determined by a new method, Best-Line Fitting (BLF). BLF involves a straight-line facilitation extrapolation needed for prediction; it is blindingly fast and amenable to optimization. We find that in some locations that entire trajectory can be predicted early, whereas others take longer to follow this simple functional form. Fortunately, BLF distinguishes predictions that are likely to be correct in that they show a stable plateau of total cases or death (N value). We apply BLF to locations that seem close to a stable predicted N value and then forecast the outcome at some locations that are still growing wildly. Our accompanying web-site will be updated frequently and provide all graphs and data described here.


Letter to Editor in Response to “COVID-19 and the Correctional Environment: the American Prison as a Focal Point for Public Health”


title: Experiences of American older adults with pre-existing depression during the beginnings of the COVID-19 pandemic: a multi-city, mixed-methods study

text: OBJECTIVE: To determine the effect of the COVID-19 pandemic on the mental health of older adults with pre-existing major depressive disorder (MDD). PARTICIPANTS: Participants were 73 community-living older adults with pre-existing MDD (mean age 69 [SD 6]) in Los Angeles, New York, Pittsburgh, and St Louis. DESIGN AND MEASUREMENTS: During the first two months of the pandemic, we interviewed participants with a semi-structured qualitative interview evaluating access to care, mental health, quality of life, and coping. We also assessed depression, anxiety, and suicidality with validated scales and compared scores before and during the pandemic. RESULTS: Five themes from the interviews highlight the experience of older adults with MDD: (1) They are more concerned about the risk of contracting the virus than the risks of isolation. (2) They exhibit resilience to the stress and isolation of physical distancing. (3) Most are not isolated socially, with virtual contact with friends and family. (4) Their quality of life is lower, and they worry their mental health will suffer with continued physical distancing. (5) They are outraged by an inadequate governmental response to the pandemic. Depression, anxiety, and suicidal ideation symptom scores did not differ from scores before the pandemic. CONCLUSIONS: Most older adults with pre-existing MDD show resilience in the first two months of the COVID-19 pandemic but have concerns about the future. Policies and interventions to provide access to medical services and opportunities for social interaction are needed to help to maintain mental health and quality of life as the pandemic continues.


title: Investigation of the viral and bacterial microbiota in intestinal samples from mink (Neovison vison) with pre-weaning diarrhea syndrome using next generation sequencing

text: Pre-weaning diarrhea (PWD) in mink kits is a common multifactorial syndrome on commercial mink farms. Several potential pathogens such as astroviruses, caliciviruses, Escherichia coli and Staphylococcus delphini have been studied, but the etiology of the syndrome seems complex. In pooled samples from 38 diarrheic and 42 non-diarrheic litters, each comprising of intestinal contents from 2–3 mink kits from the same litter, the bacterial populations were studied using Illumina Next Generation Sequencing technology and targeted 16S amplicon sequencing. In addition, we used deep sequencing to determine and compare the viral intestinal content in 31 healthy non-diarrheic and 30 diarrheic pooled samples (2–3 mink kits from the same litter per pool). The results showed high variations in composition of the bacterial species between the pools. Enterococci, staphylococci and streptococci dominated in both diarrheic and non-diarrheic pools. However, enterococci accounted for 70% of the reads in the diarrheic group compared to 50% in the non-diarrheic group and this increase was at the expense of staphylococci and streptococci which together accounted for 45% and 17% of the reads in the non-diarrheic and diarrheic group, respectively. Moreover, in the diarrheic pools there were more reads assigned to Clostridia, Escherichia-Shigella and Enterobacter compared to the non-diarrheic pools. The taxonomically categorized sequences from the virome showed that the most prevalent viruses in all pools were caliciviruses and mamastroviruses (almost exclusively type 10). However, the numbers of reads assigned to caliciviruses were almost 3 times higher in the diarrheic pools compared the non-diarrheic pools and Sapporo-like caliciviruses were more abundant than the Norwalk-like caliciviruses. The results from this study have contributed to the insight into the changes in the intestinal microbiota associated with the PWD syndrome of mink.


title: Fatal adenovirus type 7b infection in a child with Smith‐Lemli‐Opitz syndrome

text: Adenovirus type 7 causes worldwide respiratory tract infections, mainly in children. Severe systemic infections can occur, especially in immunocompromised patients and in patients with underlying chronic diseases. This report describes the first case of a fatal disseminated adenovirus type 7 infection in a child with Smith‐Lemli‐Opitz syndrome, a rare autosomal recessive disorder due to a primary enzymatic defect in cholesterol metabolism. Nasopharyngeal secretions and autopsy specimens including liver, lung, pleural fluid, and rectum were collected for viral culture. Adenovirus serotype 7 strains were obtained from all anatomic sites, except the liver. All these clinical isolates were analyzed using restriction endonuclease digestion of the genome, identifying them as genome type 7b, a virulent type. In this case, the fatal evolution could have been accelerated by the presence of an immunodeficiency although immunodeficiency is not included in the definition of Smith‐Lemli‐Opitz syndrome. The frequent recurrent banal infections in Smith‐Lemli‐Opitz syndrome could be prevented by a cholesterol supplementation regimen. Finally, this report emphasizes the need for efficient therapy for disseminated adenovirus infections, especially for virulent genome types. J. Med. Virol. 65:66–69, 2001. © 2001 Wiley‐Liss, Inc.


title: Social Distancing as a Health Behavior: County-Level Movement in the United States During the COVID-19 Pandemic Is Associated with Conventional Health Behaviors

text: BACKGROUND: Social distancing—when people limit close contact with others outside their household—is a primary intervention available to combat the COVID-19 pandemic. The importance of social distancing is unlikely to change until effective treatments or vaccines become widely available. However, relatively little is known about how best to promote social distancing. Applying knowledge from social and behavioral research on conventional health behaviors (e.g., smoking, physical activity) to support public health efforts and research on social distancing is promising, but empirical evidence supporting this approach is needed. PURPOSE: We examined whether one type of social distancing behavior—reduced movement outside the home—was associated with conventional health behaviors. METHOD: We examined the association between GPS-derived movement behavior in 2,858 counties in USA from March 1 to April 7, 2020 and the prevalence of county-level indicators influenced by residents’ conventional health behaviors. RESULTS: Changes in movement were associated with conventional health behaviors, and the magnitude of these associations were similar to the associations among the conventional health behaviors. Counties with healthier behaviors—particularly less obesity and greater physical activity—evidenced greater reduction in movement outside the home during the initial phases of the pandemic in the USA. CONCLUSIONS: Social distancing, in the form of reduced movement outside the home, is associated with conventional health behaviors. Existing scientific literature on health behavior and health behavior change can be more confidently used to promote social distancing behaviors during the COVID-19 pandemic.


title: Human metapneumovirus in paediatric intensive care unit (PICU) admissions in the United Kingdom (UK) 2006–2014

text: Abstract Background Human metapneumovirus (HMPV) is a pneumovirus known to cause respiratory disease in children. It was identified as a pathogen in 2001 and its healthcare burden and associated costs are not fully understood. Objectives This study aimed to assess the clinical characteristics of children with HMPV infection admitted to paediatric intensive care units (PICUs) across the United Kingdom (UK) over a nine-year period and to estimate the associated costs of care. Study design Data were collected from the UK paediatric intensive care audit network (PICANet) and costs calculated using the National Health Service (NHS) reference costing scheme. Results There were 114 admissions in which HMPV was detected. The number of admissions associated with a code of HMPV rose steadily over the study period (three in 2006 to 28 in 2014) and showed significant seasonal variability, with the peak season being from November to May. Children required varying levels of intensive care support from minimal to complex support including invasive ventilation, inotropes, renal replacement therapy and extracorporeal membrane oxygenation (ECMO). HMPV was associated with five deaths during the study period. The associated costs of PICU admissions were estimated to be between £2,256,823 and £3,997,823 over the study period, with estimated annual costs rising over the study period due to increasing HMPV admissions. Conclusions HMPV is associated with a significant healthcare burden and associated cost of care in PICUs in the UK.


title: Case report: Detection of the Middle East respiratory syndrome corona virus (MERS-CoV) in nasal secretions of a dead human

text: The Middle East respiratory syndrome coronavirus (MERS-CoV) has been recognized as a highly pathogenic virus that infects the human respiratory tract and has high morbidity and mortality. The MERS-CoV is a huge burden on Saudi Arabian health-care facilities, causing approximately 40% mortality. The transmission mechanism of the virus is still not well understood. Therefore, the prevention of any route of transmission is the best measure to arrest the spread of this disease. Using the real time polymerase chain reaction (RT-PCR), MERS-CoV was detected in the nasal secretions of a human cadaver. Full precautions should be applied and carefully followed to prevent the transmission of the virus, especially among health care workers.


title: Rising Strengths Hong Kong SAR in Bioinformatics

text: Hong Kong’s bioinformatics sector is attaining new heights in combination with its economic boom and the predominance of the working-age group in its population. Factors such as a knowledge-based and free-market economy have contributed towards a prominent position on the world map of bioinformatics. In this review, we have considered the educational measures, landmark research activities and the achievements of bioinformatics companies and the role of the Hong Kong government in the establishment of bioinformatics as strength. However, several hurdles remain. New government policies will assist computational biologists to overcome these hurdles and further raise the profile of the field. There is a high expectation that bioinformatics in Hong Kong will be a promising area for the next generation.


title: Global food crisis looms

text: The covid-19 pandemic could lead to extreme poverty that leaves many struggling to afford food, reports Adam Vaughan


title: A 24-Month Follow-Up of a Custom-Made Suture-Button Assembly for Syndesmotic Injuries of the Ankle

text: Abstract In the present retrospective analysis, we introduce a custom suture-button fixation device for acute ankle syndesmotic injuries that allows for early weightbearing without another planned operation for hardware removal. We evaluated 87 consecutive ankles in 87 patients (49 males [56.32%] and 38 females [43.68%]). Of the 87 patients, 15 (17.24%) withdrew or were lost to follow-up, leaving 72 patients (82.76%) in the present study. Their mean age was 35.2 (range 17 to 67) years. Nineteen patients (26.39%) presented with a pure syndesmotic disruption, and 53 (73.61%) had associated malleolar fractures. The American Orthopaedic Foot and Ankle Society scale score improved significantly from 31.2 ± 4.2 preoperatively to 88.5 ± 5.3 at an average of 24 months postoperatively (p < .0043). Revision was undertaken because of implant failure in 4 ankles (5.56%). Two revisions (2.78%) were performed in 2 ankles because of early weightbearing in the first 2 weeks after surgery. The third patient (1.39%) underwent revision at 5 weeks postoperatively. This syndesmotic reduction failure was attributed to failure of the threads, which was noted at the second surgery. The fourth patient (1.39%), a 66-year-old male, underwent revision at 5 months postoperatively because of persistent infection. An 18-month postoperative radiograph was available for all patients. The medial clear space had significantly decreased, from 8.2 ± 3.1 mm preoperatively to 3.5 ± 2.2 mm at 18 months postoperatively (p < .0344). Likewise, the tibiofibular clear space had decreased significantly, from a mean of 8.8 ± 3.7 mm preoperatively to a mean of 3.7 ± 2.2 mm at 18 months postoperatively (p < .0322). In conclusion, suture-button fixation described in the present report delivered satisfactory functional outcomes and anatomic reduction at minimum of 18 months after surgery.


title: “Estrategias para la práctica de la otorrinolaringología y cirugía de cabeza y cuello durante la fase de control de la COVID-19”

text: ABSTRACT The appearance of a new coronavirus disease called COVID-19 at the end of 2019 and its pandemic expansion in the world has changed the usual practice of the specialty of Otorhinolaryngology (ENT). After a phase of exponential growth of infections, it has been possible to enter a phase of control of the spread of the disease in which the possibility of infection persists, and the appearance of new cases is considered acceptable by the health system. The aim of this document is to review the available evidence and propose strategies and recommendations for the medical-surgical practice of otorhinolaryngology and head and neck surgery, which allow establishing the usual activity, adapting the safety and efficacy standards to the current situation. Therefore, it is required to identify and classify patients according to criteria of infectious-immunological status, and to establish recommendations for protection in consultations, hospitalization and the operating room, which avoid the transmission of the disease to other users and healthcare personnel, in the specific context of the development of our specialty. This document is the result of the collaboration of all the scientific commissions and the SEORLCCC COVID-19 committee.


title: Crystal Structure of the C-Terminal Cytoplasmic Domain of Non-Structural Protein 4 from Mouse Hepatitis Virus A59

text: BACKGROUND: The replication of coronaviruses takes place on cytoplasmic double membrane vesicles (DMVs) originating in the endoplasmic reticulum (ER). Three trans-membrane non-structural proteins, nsp3, nsp4 and nsp6, are understood to be membrane anchors of the coronavirus replication complex. Nsp4 is localized to the ER membrane when expressed alone but is recruited into the replication complex in infected cells. It is revealed to contain four trans-membrane regions and its N- and C-termini are exposed to the cytosol. METHODOLOGY/PRINCIPAL FINDINGS: We have determined the crystal structures of the C-terminal hydrophilic domain of nsp4 (nsp4C) from MHV strain A59 and a C425S site-directed mutant. The highly conserved 89 amino acid region from T408 to Q496 is shown to possess a new fold. The wild-type (WT) structure features two monomers linked by a Cys425-Cys425 disulfide bond in one asymmetric unit. The monomers are arranged with their N- and C-termini in opposite orientations to form an “open” conformation. Mutation of Cys425 to Ser did not affect the monomer structure, although the mutant dimer adopts strikingly different conformations by crystal packing, with the cross-linked C-termini and parallel N-termini of two monomers forming a “closed” conformation. The WT nsp4C exists as a dimer in solution and can dissociate easily into monomers in a reducing environment. CONCLUSIONS/SIGNIFICANCE: As nsp4C is exposed in the reducing cytosol, the monomer of nsp4C should be physiological. This structure may serve as a basis for further functional studies of nsp4.


title: Coronavirus Disease 2019 (COVID-19) pandemic, lessons to be learned!

text: Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been reported as a worldwide emergency. Due to the extensiveness of spread and death, it has been declared as a pandemic. This review focused on the current pandemic situation and understanding the prevention and control strategies of COVID-19. Data presented here was by April 3, 2020. A total of 1,016,399 cases of COVID-19 with 53,238 deaths was reported from 204 countries and territories including two international conveyances over the world. After China, most of the new cases were from Europe, particularly Italy acting as the source of importation to many of the other countries around the world. China has obtained success by ascribing control strategies against COVID-19. The implementation of China’s strategy, as well as the development of a vaccine, may control the pandemic of COVID-19. Further robust studies are required for a clear understanding of transmission parameters, prevention, and control strategies of SARS-CoV-2. This review paper describes the nature of COVID-19 and the possible ways for the effective controlling of the COVID-19 or similar viral diseases that may come in the future.


Nursing home physician with normal chest X‐ray and probable COVID‐19 based on 18F‐FDG PET/CT imaging


title: Viral Bacterial Artificial Chromosomes: Generation, Mutagenesis, and Removal of Mini-F Sequences

text: Maintenance and manipulation of large DNA and RNA virus genomes had presented an obstacle for virological research. BAC vectors provided a solution to both problems as they can harbor large DNA sequences and can efficiently be modified using well-established mutagenesis techniques in Escherichia coli. Numerous DNA virus genomes of herpesvirus and pox virus were cloned into mini-F vectors. In addition, several reverse genetic systems for RNA viruses such as members of Coronaviridae and Flaviviridae could be established based on BAC constructs. Transfection into susceptible eukaryotic cells of virus DNA cloned as a BAC allows reconstitution of recombinant viruses. In this paper, we provide an overview on the strategies that can be used for the generation of virus BAC vectors and also on systems that are currently available for various virus species. Furthermore, we address common mutagenesis techniques that allow modification of BACs from single-nucleotide substitutions to deletion of viral genes or insertion of foreign sequences. Finally, we review the reconstitution of viruses from BAC vectors and the removal of the bacterial sequences from the virus genome during this process.


title: Limits to Forecasting Precision for Outbreaks of Directly Transmitted Diseases

text: BACKGROUND: Early warning systems for outbreaks of infectious diseases are an important application of the ecological theory of epidemics. A key variable predicted by early warning systems is the final outbreak size. However, for directly transmitted diseases, the stochastic contact process by which outbreaks develop entails fundamental limits to the precision with which the final size can be predicted. METHODS AND FINDINGS: I studied how the expected final outbreak size and the coefficient of variation in the final size of outbreaks scale with control effectiveness and the rate of infectious contacts in the simple stochastic epidemic. As examples, I parameterized this model with data on observed ranges for the basic reproductive ratio (R (0)) of nine directly transmitted diseases. I also present results from a new model, the simple stochastic epidemic with delayed-onset intervention, in which an initially supercritical outbreak (R (0) > 1) is brought under control after a delay. CONCLUSION: The coefficient of variation of final outbreak size in the subcritical case (R (0) < 1) will be greater than one for any outbreak in which the removal rate is less than approximately 2.41 times the rate of infectious contacts, implying that for many transmissible diseases precise forecasts of the final outbreak size will be unattainable. In the delayed-onset model, the coefficient of variation (CV) was generally large (CV > 1) and increased with the delay between the start of the epidemic and intervention, and with the average outbreak size. These results suggest that early warning systems for infectious diseases should not focus exclusively on predicting outbreak size but should consider other characteristics of outbreaks such as the timing of disease emergence.


title: Regulation of viral persistence in human glioblastoma and rhabdomyosarcoma cells infected with coronavirus OC43

text: Abstract Cultures of human rhabdomyosarcoma (RD) and human glioblastoma (U87-MG) were compared for their ability to sustain a persistent infection with coronavirus OC43. Within 28 days, infectious virus and hemagglutinin were being produced at high levels in both types of cells. Temperature sensitive plaque variants were recovered at 31 °C. In both cell types, the virus caused increased antigen synthesis and cell death, if the temperature was lowered to 31 °C. Infectious virus was lost if cells were treated with antiserum to whole virus or if the temperature was raised to 39.5 °C. Probing the cured cells with OC43-specific 32P-cDNA showed that cured cells contained no detectable viral RNA. The relative ease of establishment and cure of these persistent infectious makes them attractive as models to study coronavirus regulatory processes.


title: Childhood multiple sclerosis: A review

text: Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system (CNS) that is increasingly recognized as a disease that affects children. Similar to adult‐onset MS, children present with visual and sensory complaints, as well as weakness, spasticity, and ataxia. A lumbar puncture can be helpful in diagnosing MS when CSF immunoglobulins and oligoclonal bands are present. White matter demyelinating lesions on MRI are required for the diagnosis; however, children typically have fewer lesions than adults. Many criteria have been proposed to diagnose MS that have been applied to children, mostly above 10 years of age. The recent revisions to the McDonald criteria allow for earlier diagnosis, such as after a clinically isolated event. However, children are more likely than adults to have monosymptomatic illnesses. None of the approved disease‐modifying therapies used in adult‐onset MS have been approved for pediatrics; however, a few studies have verified their safety and tolerability in children. Although children and adults with MS have similar neurological symptoms, laboratory (cerebrospinal fluid) data, and neuroimaging findings, the clinical course, pathogenesis, and treatment of childhood onset MS require further investigation. MRDD Research Reviews 2006;12:147–156. © 2006 Wiley‐Liss, Inc.


title: Management of Breast Cancer during the COVID-19 Pandemic

text: The novel coronavirus disease (COVID-19) arises from the virus SARS-CoV-2 which is similar to the original SARS virus. The most common symptoms of the COVID-19 infection are fever, coughing and shortness of breath. According to the current data, the primary mode of transmission for the COVID-19 virus is between people through respiratory droplets and contact routes. The virus may lead to worse respiratory complications, including pneumonia, especially in older patients and patients with pre-existing illnesses, such as cancer. Cancer patients are at a significantly higher risk of getting infected with COVID-19 since their immune system can be compromised and that reality has to do with both that they have cancer and that they are on therapy for their cancer. COVID-19 crisis has impacted every aspect of the practice, including outpatient, elective, wards, emergency care, conferences, teaching and research. We should make sure cancer patients on active treatment are treated appropriately. In this review, we tried to explain how to prevent the negative effects of the COVID-19 pandemic on the diagnosis and treatment of breast cancer patients.


title: Effect of antisecretory drugs on experimentally induced weanling diarrhoea in piglets

text: In 45 newly-weaned 3 to 4-week-old piglets, diarrhoea was induced by a combined infection with transmissible gastroenteritis (TGE) virus and enterotoxigenic E. coli (ETEC) strains. In untreated control animals this dual inoculation resulted in profuse diarrhoea, vomiting, hypovolaemic shock and death of 77% of the animals within five days of TGE virus inoculation. Antisecretory drugs were administered intramuscularly for three consecutive days after experimental infection. The neurolepticum chlorpromazine, at 2 mg/kg/24 h, resulted in a significant inhibition of diarrhoea and vomiting, and in an increase in weight gain and survival. Sedation and hypothermia, however, were serious side-effects. The α(2) agonist clonidine, at 80 μg/kg/12 h, induced a significant antidiarrhoeal effect and a reduction in mortality. The drug, however, provoked decreased activity of α(2)-adrenergic excitation and incoordination. The β-adrenergic antagonist propranolol, at 0.33 mg/kg/8 h, and the calcium channel blocker verapamil, at 2 mg/kg/8 h, had no beneficial effect on the experimentally induced diarrhoea.


title: Head and neck cancer radiotherapy amid COVID‐19 pandemic: Report from Milan, Italy

text: BACKGROUND: Management of head and neck cancers (HNC) in radiation oncology in the coronavirus disease 2019 (COVID‐19) era is challenging. Aim of our work is to report organization strategies at a radiation therapy (RT) department in the first European area experiencing the COVID‐19 pandemic. METHODS: We focused on (a) dedicated procedures for HNC, (b) RT scheduling, and (c) health care professionals' protection applied during the COVID‐19 breakdown (from March 1, 2020 to April 30, 2020). RESULTS: Applied procedures are reported and discussed. Forty‐three patients were treated. Image‐guided, intensity modulated RT was performed in all cases. Median overall treatment time was 50 (interquartile range: 47‐54.25) days. RT was interrupted/delayed in seven patients (16%) for suspected COVID‐19 infection. Two health professionals managing HNC patients were proven as COVID‐19 positive. CONCLUSION: Adequate and well‐timed organization allowed for the optimization of HNC patients balancing at the best of our possibilities patients' care and personnel's safety.


title: Simple barrier device to minimize facial exposure of endoscopists during COVID‐19 pandemic

text: Watch a video of this article


Mes patients me manquent


title: Natural products may interfere with SARS-CoV-2 attachment to the host cell

text: SARS-CoV-2 has been emerged in December 2019 in China, causing deadly (5% mortality) pandemic pneumonia, termed COVID-19. More than one host-cell receptor is reported to be recognized by the viral spike protein, among them is the cell-surface Heat Shock Protein A5 (HSPA5), also termed GRP78 or BiP. Upon viral infection, HSPA5 is upregulated, then translocating to the cell membrane where it is subjected to be recognized by the SARS-CoV-2 spike. In this study, some natural product compounds are tested against the HSPA5 substrate-binding domain β (SBDβ), which reported to be the recognition site for the SARS-CoV-2 spike. Molecular docking and molecular dynamics simulations are used to test some natural compounds binding to HSPA5 SBDβ. The results show high to a moderate binding affinity for the phytoestrogens (Diadiazin, Genistein, Formontein, and Biochanin A), chlorogenic acid, linolenic acid, palmitic acid, caffeic acid, caffeic acid phenethyl ester, hydroxytyrosol, cis-p-Coumaric acid, cinnamaldehyde, thymoquinone, and some physiological hormones such as estrogens, progesterone, testosterone, and cholesterol to the HSPA5 SBDβ. Based on its binding affinities, the phytoestrogens and estrogens are the best in binding HSPA5, hence may interfere with SARS-CoV-2 attachment to the stressed cells. These compounds can be successful as anti-COVID-19 agents for people with a high risk of cell stress like elders, cancer patients, and front-line medical staff. Communicated by Ramaswamy H. Sarma


title: The impact of COPD and smoking history on the severity of COVID‐19: A systemic review and meta‐analysis

text: Comorbidities are associated with the severity of coronavirus disease 2019 (COVID‐19). This meta‐analysis aimed to explore the risk of severe COVID‐19 in patients with pre‐existing chronic obstructive pulmonary disease (COPD) and ongoing smoking history. A comprehensive systematic literature search was carried out to find studies published from December 2019 to 22 March 2020 from five databases. The languages of literature included English and Chinese. The point prevalence of severe COVID‐19 in patients with pre‐existing COPD and those with ongoing smoking was evaluated with this meta‐analysis. Overall 11 case series, published either in Chinese or English language with a total of 2002 cases, were included in this study. The pooled OR of COPD and the development of severe COVID‐19 was 4.38 (fixed‐effects model; 95% CI: 2.34‐8.20), while the OR of ongoing smoking was 1.98 (fixed‐effects model; 95% CI: 1.29‐3.05). There was no publication bias as examined by the funnel plot and Egger's test (P = not significant). The heterogeneity of included studies was moderate for both COPD and ongoing smoking history on the severity of COVID‐19. COPD and ongoing smoking history attribute to the worse progression and outcome of COVID‐19.


title: Approach to Adult Patients with Acute Dyspnea

text: Undifferentiated patients in respiratory distress require immediate attention in the emergency department. Using a thorough history and clinical examination, clinicians can determine the most likely causes of dyspnea. Understanding the pathophysiology of the most common diseases contributing to dyspnea guides rational testing and informed, expedited treatment decisions.


title: Viruses and dendritic cells: enemy mine

text: Dendritic cells (DCs) act not only as sentinels for detection of, but also as target cells for viruses, and this can be important for viral transport and spread. All subsets of DCs are equipped with a battery of receptors recognizing virus‐associated molecular signatures, and recognition of those launches a maturation programme that results in substantial alterations of morphology, motility and the DCs' interactive properties with the extracellular matrix and scanning T cells. In addition to being sensed, viruses are internalized into DCs and, for the major proportion, processed into peptides that are subsequently presented by major histocompatibility complex (MHC) molecules. Transmission of virus to T cells can occur after completion of their replication cycle if the intracellular milieu of the DC permits that. Alternatively, viruses can remain protected from degradation following entrapment by pattern recognition receptors in intracellular compartments, also referred to as virosomes, which translocate towards the DC/T cell interface. Most likely, transfer of virus to T cells occurs in these junctions, referred to as infectious synapses. In addition to promoting DC maturation, many viruses are able to downmodulate DC development and functions in order to evade immune recognition or to induce a generalized immunosuppression.


title: Transmissible gastroenteritis virus infection induces cell cycle arrest at S and G2/M phases via p53-dependent pathway

text: Abstract p53 signaling pathway plays an important role in the regulation of cell cycle. Our previous studies have demonstrated that TGEV infection induces the activation of p53 signaling pathway. In this study we investigated the effects of TGEV infection on the cell cycle of host cells and the roles of p53 activation in this process. The results showed that TGEV infection induced cell cycle arrest at S and G2/M phases in both asynchronous and synchronized PK-15 and ST cells, while UV-inactivated TGEV lost the ability of induction of cell cycle arrest. TGEV infection promoted p21 accumulation, down-regulated cell cycle-regulatory proteins cyclins B1, cdc2, cdk2 and PCNA. Further studies showed that inhibition of p53 signaling could attenuate the TGEV-induced S- and G2/M-phase arrest by reversing the expression of p21 and corresponding cyclin/cdk. In addition, TGEV infection of the cells synchronized in various stages of cell cycle showed that viral genomic RNA and subgenomic RNA, and virus titer were higher in the cells released from S-phase- or G2/M phase-synchronized cells than that in the cells released from the G0/G1 phase-synchronized or asynchronous cells after 18h p.i. Taken together, our data suggested that TGEV infection induced S and G2/M phase arrest in host cells, which might provide a favorable condition for viral replication.


Schädigt COVID-19 das Herz auch dauerhaft?


High dose chemotherapy in a patient with COVID-19


title: Efficacy and safety of aerosolized intra-tracheal dornase alfa administration in patients with SARS-CoV-2-induced acute respiratory distress syndrome (ARDS): a structured summary of a study protocol for a randomised controlled trial

text: OBJECTIVES: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) may trigger severe pneumonia in coronavirus disease of 2019 (COVID-19) patients through release of damage-associated molecular patterns (DAMPs) and recruitment of neutrophils in the lungs. Activated neutrophils induce inflammation and severe alveolar injury by releasing neutrophil extracellular traps (NETs). The backbones of many DAMPs and NETs are made of extracellular, cell-free DNA decorated with highly toxic compounds such as elastase, myeloperoxidase and citrullinated histones. Dornase alfa is a FDA-approved recombinant human DNAse 1 for the treatment of cystic fibrosis, which cleaves extracellular DNA and may break up cell-free DNA, loosening sticky mucus in the distal airways and reducing NETs-induced toxicity on alveolar pneumocytes. The COVIDornase trial intends to define the impact of aerosolized intra-tracheal dornase alfa administration on the severity and progression of acute respiratory distress syndrome (ARDS) in COVID-19 patients. This drug might make lung mucus thinner and looser, promoting improved clearance of secretions and reduce extracellular double-stranded DNA-induced hyperinflammation in alveoli, preventing further damage to the lungs. TRIAL DESIGN: COVIDornase is a prospective, randomized, controlled, 2-arm (1:1 ratio), multicentric, open-label clinical trial. PARTICIPANTS: The study will recruit mechanically ventilated patients hospitalized in the intensive care unit (ICU) in the recruiting centres (at the time of writing: The Rothschild foundation hospital in Paris, the Strasbourg university hospitals, and Metz-Thionville hospital) who have been diagnosed with COVID-19 and meet ARDS criteria. INCLUSION CRITERIA: - Adult patient (age ≥ 18 years old); - Hospitalized in ICU; - With severe COVID-19 pneumonia and ARDS according to Berlin criteria (PaO(2)/FiO(2) < 300 and PEEP > 5 cmH(2)O); - Intubated for less than 8 days; - With an anticipated duration of mechanical ventilation > 48 hours; - Carrier of an arterial catheter; - For whom 4 PaO(2)/FiO(2) values over the preceding 24 hours are available; NON-INCLUSION CRITERIA: - Known hypersensitivity to dornase alfa or any of its excipients; - Pregnant or breastfeeding status; - Patient under legal protection. INTERVENTION AND COMPARATOR: Intervention 1, Study group Dornase alfa (Pulmozyme®, Roche, Switzerland) will be administered by aerosol, at a dose of 2500 IU twice daily, 12 hours apart, for 7 consecutive days, using a vibrating mesh nebulizer (Aerogen Solo®, Aerogen, Ireland). The remainder of the management will be performed in accordance with good clinical practice, including mechanical ventilation (protective ventilation, PEEP > 5 cmH(2)O, tracheal balloon pressure check every 4 hours or automatic device, 30° head of the bed elevation, tidal volume 6-8mL/kg, plateau pressure < 30 cmH(2)O), neuromuscular blockers if necessary, prone position if PaO(2)/FiO(2) < 150, early enteral nutrition, glycemic control and a sedation protocol based on the RASS score. Intervention 2, Comparator Patients will receive usual care in accordance with good practice (as detailed above), without aerosols. MAIN OUTCOMES: The primary outcome is the occurrence of at least one grade improvement between D(0) (inclusion) and D(7) in the ARDS scale severity (Berlin criteria). For instance from “severe” to “moderate” or from “moderate” to “mild”. RANDOMISATION: All consecutive patients meeting the inclusion criteria will be randomised 1:1 using an eCRF-based, computer-generated randomisation table, either to the dornase alfa arm or to the control arm. An interim analysis will be performed after inclusion of 20 patients. Inclusions may be stopped at the interim analysis per data safety and monitoring board (DSMB) advice, if statistical analyses conclude on the futility or efficacy of the intervention or by other DSMB decision. BLINDING (MASKING): The participants and caregivers will not be blinded to study group assignment. Those assessing the outcomes will be blinded to study group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Fifty patients will be randomized to each group, 100 patients in total. TRIAL STATUS: Protocol version number 2, April 29(th), 2020. Recruitment is ongoing. The trial started recruitment on the 21(st) April 2020. We estimate recruitment will finish August 21(st) 2020. TRIAL REGISTRATION: The trial was registered in ClinicalTrials.gov on 21 April 2020, updated on 8 May 2020. Trial registration number is NCT04355364. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated. This Letter serves as a summary of the key elements of the full protocol.


title: Inhibition of enterovirus 71 infection by antisense octaguanidinium dendrimer-conjugated morpholino oligomers

text: Abstract Enterovirus 71 (EV-71) infections are generally manifested as mild hand, foot and mouth disease, but have been reported to cause severe neurological complications with high mortality rates. Treatment options remain limited due to the lack of antivirals. Octaguanidinium-conjugated morpholino oligomers (vivo-MOs) are single-stranded DNA-like antisense agents that can readily penetrate cells and reduce gene expression by steric blocking of complementary RNA sequences. In this study, inhibitory effects of three vivo-MOs that are complementary to the EV-71 internal ribosome entry site (IRES) and the RNA-dependent RNA polymerase (RdRP) were tested in RD cells. Vivo-MO-1 and vivo-MO-2 targeting the EV-71 IRES showed significant viral plaque reductions of 2.5 and 3.5 log10PFU/ml, respectively. Both vivo-MOs reduced viral RNA copies and viral capsid expression in RD cells in a dose-dependent manner. In contrast, vivo-MO-3 targeting the EV-71 RdRP exhibited less antiviral activity. Both vivo-MO-1 and 2 remained active when administered either 4h before or within 6h after EV-71 infection. Vivo-MO-2 exhibited antiviral activities against poliovirus (PV) and coxsackievirus A16 but vivo-MO-1 showed no antiviral activities against PV. Both the IRES-targeting vivo-MO-1 and vivo-MO-2 inhibit EV-71 RNA translation. Resistant mutants arose after serial passages in the presence of vivo-MO-1, but none were isolated against vivo-MO-2. A single T to C substitution at nucleotide position 533 was sufficient to confer resistance to vivo-MO-1. Our findings suggest that IRES-targeting vivo-MOs are good antiviral candidates for treating early EV-71 infection, and vivo-MO-2 is a more favorable candidate with broader antiviral spectrum against enteroviruses and are refractory to antiviral resistance.


title: Crisis Communication and Public Perception of COVID-19 Risk in the Era of Social Media

text: A number of important principles in effective risk communication established in the late 20th century can provide important scientific insight into patient response to the risks posed by COVID-19 [1-3]. Early risk communication scholars studied public perceptions of risk in response to environmental disasters, or infectious disease outbreaks. They found acceptability of risk, and any limitations and acceptability of response by experts was shaped by two key components: hazard and outrage. The number of people who are exposed, infected and fall ill can be considered the hazard. How the public and patients perceive the risk and respond to messages regarding risk mitigation relates to outrage. Social and cultural factors, immediacy, uncertainty, familiarity, personal control, scientific uncertainty and trust in institutions and media all shape acceptability of response. These outrage factors influence the ever-changing public understanding of COVID-19 risk, as well as the public’s acceptance of personal and societal mitigation strategies. Risk perceptions and acceptability of mitigation strategies are also largely shaped in the context of culture and society. In concert, hazard and outrage along with cultural and economic context shape adherence to, and overall acceptance of, personal mitigation strategies including wearing facemasks, and social distancing among the general public. The spread of misinformation on social media in the context of crisis communication provides both challenges and opportunities for experts and officials to effectively communicate and influence these outrage factors. Social media offers an opportunity for experts to quickly convey true information about hazards, but offers others the opportunity to counter this with the spread of misinformation and exacerbate outrage. We propose strategies for infectious diseases clinicians to apply risk communication principles and frameworks to improve patient care and public message development in response to COVID-19.


title: Base protocol for real time active random surveillance of coronavirus disease (COVID-19) – Adapting veterinary methodology to public health

text: The pandemic of new coronavirus disease COVID-19 is threatening our health, economy and life style. Collaborations across countries and sectors as a One Health World could be a milestone. We propose a general protocol, for setting timely active random surveillance of COVID-19, at the human community level, with systematic repeated detection efforts. Strengths and limitations are discussed. If considered applicable by public health, the protocol could evaluate the status of COVID-19 epidemics consistently and objectively.


title: Evolutionary and bioinformatic analysis of the spike glycoprotein gene of H120 vaccine strain protectotype of infectious bronchitis virus from India

text: The infectious bronchitis virus is a causative agent of avian infectious bronchitis (AIB), and is is an important disease that produces severe economic losses to the poultry industry worldwide. Recent AIB outbreaks in India have been associated with poor growth in broilers, drop in egg production, and thin egg shells in layers. The complete spike gene of Indian AIB vaccine strain was amplified and sequenced using a conventional reverse transcription polymerase chain reaction and is submitted to the GenBank (accession no KF188436). Phylogenetic analysis revealed that the vaccine strain currently used belongs to H120 genotype, an attenuated strain of Massachusetts (Mass) serotype. Nucleotide and amino acid sequence comparisons have shown that the reported spike gene from Indian isolates have 71.8%–99% and 71.4%–96.9% genetic similarity with the sequenced H120 strain. The study identifies live attenuated IBV vaccine strain, which is routinely used for vaccination, for the first time. Based on nucleotide and amino acid relatedness studies of the vaccine strain with reported IBV sequences from India, it is shown that the current vaccine strain is efficient in controlling the IBV infection. Continuous monitoring of IBV outbreaks by sequencing for genotyping and in vivo cross protection studies for serotyping is not only important for epidemiological investigation but also for evaluation of efficacy of the current vaccine.


title: Chaperone-Mediated Autophagy in the Liver: Good or Bad?

text: Hepatitis C virus (HCV) infection triggers autophagy processes, which help clear out the dysfunctional viral and cellular components that would otherwise inhibit the virus replication. Increased cellular autophagy may kill the infected cell and terminate the infection without proper regulation. The mechanism of autophagy regulation during liver disease progression in HCV infection is unclear. The autophagy research has gained a lot of attention recently since autophagy impairment is associated with the development of hepatocellular carcinoma (HCC). Macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA) are three autophagy processes involved in the lysosomal degradation and extracellular release of cytosolic cargoes under excessive stress. Autophagy processes compensate for each other during extreme endoplasmic reticulum (ER) stress to promote host and microbe survival as well as HCC development in the highly stressed microenvironment of the cirrhotic liver. This review describes the molecular details of how excessive cellular stress generated during HCV infection activates CMA to improve cell survival. The pathological implications of stress-related CMA activation resulting in the loss of hepatic innate immunity and tumor suppressors, which are most often observed among cirrhotic patients with HCC, are discussed. The oncogenic cell programming through autophagy regulation initiated by a cytoplasmic virus may facilitate our understanding of HCC mechanisms related to non-viral etiologies and metabolic conditions such as uncontrolled type II diabetes. We propose that a better understanding of how excessive cellular stress leads to cancer through autophagy modulation may allow therapeutic development and early detection of HCC.


title: Beyond Coronativism: The Need For Agape

text: In this contribution we focus on togetherness, as one of the key notions in the current COVID‐19 crisis. Globally, it is seen as vital to stand and act together to combat the virus, and avoid a tragedy of the commons, in which actors are acting out of self‐interest and counterproductively to the general interest. In this essay we analyse the current geographical dissonant developments that the required human togetherness across the globe is facing. We find that the main conflicting tendencies, that we summarise as utilitarian locking up, nationalistic locking in and exclusionary locking out, are all employing a notion of togetherness which is largely based on an in‐group solidarity based on either age, gender, ethnicity, nationality or fitness. We argue that such narrow definition of togetherness falls short in dealing with the crisis in an effective as well as non‐discriminatory manner, and potentially could even lengthen or worsen the corona crisis. We end with a plea for a different conceptualisation of solidarity in the combat of the crisis, a radical non‐dividing form of togetherness: agape.


title: COVID‐19 and toxicity from potential treatments: Panacea or poison

text: Since December 2019, coronavirus disease (COVID‐19) has been increasingly spreading from its origin in Wuhan, China to many countries around the world eventuating in morbidity and mortality affecting millions of people. This pandemic has proven to be a challenge given that there is no immediate cure, no vaccine is currently available and medications or treatments being used are still undergoing clinical trials. There have already been examples of self‐medication and overdose. Clearly, there is a need to further define the efficacy of treatments used in the management of COVID‐19. This evidence needs to be backed by large randomised‐controlled clinical trials. In the meantime, there will no doubt be further off‐label use of these medications by patients and practitioners and possibly related toxicity.


title: Parallel Synthesis of Peptide-Like Macrocycles Containing Imidazole-4,5-dicarboxylic Acid

text: We prepared a series of peptide-like 14-membered macrocycles containing an imidazole-4,5-dicarboxylic acid scaffold by using known coupling reagents and protecting group strategies. Yields of the purified macrocycles were poor on average, yet seemingly independent of amino acid substitution or stereochemistry. The macrocycles retain some level of conformational variability as observed by both molecular modeling and X-ray crystallography. These macrocycles represent a new class of structures for further development and for future application in high-throughput screening against a variety of biological targets.


title: Feline immunodeficiency. ABCD guidelines on prevention and management

text: Abstract Overview Feline immunodeficiency virus (FIV) is a retrovirus closely related to human immunodeficiency virus. Most felids are susceptible to FIV, but humans are not. Feline immunodeficiency virus is endemic in domestic cat populations worldwide. The virus loses infectivity quickly outside the host and is susceptible to all disinfectants. Infection Feline immunodeficiency virus is transmitted via bites. The risk of transmission is low in households with socially well-adapted cats. Transmission from mother to kittens may occur, especially if the queen is undergoing an acute infection. Cats with FIV are persistently infected in spite of their ability to mount antibody and cell-mediated immune responses. Disease signs Infected cats generally remain free of clinical signs for several years, and some cats never develop disease, depending on the infecting isolate. Most clinical signs are the consequence of immunodeficiency and secondary infection. Typical manifestations are chronic gingivostomatitis, chronic rhinitis, lymphadenopathy, weight loss and immune-mediated glomerulonephritis. Diagnosis Positive in-practice ELISA results obtained in a low-prevalence or low-risk population should always be confirmed by a laboratory. Western blot is the ‘gold standard’ laboratory test for FIV serology. PCR-based assays vary in performance. Disease management Cats should never be euthanased solely on the basis of an FIV-positive test result. Cats infected with FIV may live as long as uninfected cats, with appropriate management. Asymptomatic FIV-infected cats should be neutered to avoid fighting and virus transmission. Infected cats should receive regular veterinary health checks. They can be housed in the same ward as other patients, but should be kept in individual cages. Vaccination recommendations At present, there is no FIV vaccine commercially available in Europe. Potential benefits and risks of vaccinating FIV-infected cats should be assessed on an individual cat basis. Needles and surgical instruments used on FIV-positive cats may transmit the virus to other cats, so strict hygiene is essential.


title: Husbandry and Medical Care of Callitrichids

text: Abstract Callitrichids, marmosets and tamarins are small Central and South American nonhuman primates. All are considered threatened in the wild and many are on the endangered species list (Convention on International Trade in Endangered Species of Wild Fauna and Flora: Appendix 1). Because of their small size and anthropomorphic appeal, people are interested in owning callitrichids as pets. Hand-raised bottle-fed babies are quite charming until sexual maturity, at which time they often become aggressive and unpredictable to humans, including their owners. Consequently, people should be discouraged from keeping callitrichids as pets. If a veterinarian is consulted about callitrichids by a potential owner before purchase, it may be possible to offer encouragement toward a more suitable pet (e.g., ferret and sugar glider).


title: P450s and UGTs: Key Players in the Structural Diversity of Triterpenoid Saponins

text: The recent spread of next-generation sequencing techniques has facilitated transcriptome analyses of non-model plants. As a result, many of the genes encoding enzymes related to the production of specialized metabolites have been identified. Compounds derived from 2,3-oxidosqualene (the common precursor of sterols, steroids and triterpenoids), a linear compound of 30 carbon atoms produced through the mevalonate pathway, are called triterpenes. These include essential sterols, which are structural components of biomembranes; steroids such as the plant hormones, brassinolides and the toxin in potatoes, solanine; as well as the structurally diverse triterpenoids. Triterpenoids containing one or more sugar moieties attached to triterpenoid aglycones are called triterpenoid saponins. Triterpenoid saponins have been shown to have various medicinal properties, such as anti-inflammatory, anticancerogenic and antiviral effects. This review summarizes the recent progress in gene discovery and elucidates the biochemical functions of biosynthetic enzymes in triterpenoid saponin biosynthesis. Special focus is placed on key players in generating the structural diversity of triterpenoid saponins, cytochrome P450 monooxygenases (P450s) and the UDP-dependent glycosyltransferases (UGTs). Perspectives on further gene discovery and the use of biosynthetic genes for the microbial production of plant-derived triterpenoid saponins are also discussed.


title: Proteomic Profiling of the Amniotic Fluid to Detect Inflammation, Infection, and Neonatal Sepsis

text: BACKGROUND: Proteomic analysis of amniotic fluid shows the presence of biomarkers characteristic of intrauterine inflammation. We sought to validate prospectively the clinical utility of one such proteomic profile, the Mass Restricted (MR) score. METHODS AND FINDINGS: We enrolled 169 consecutive women with singleton pregnancies admitted with preterm labor or preterm premature rupture of membranes. All women had a clinically indicated amniocentesis to rule out intra-amniotic infection. A proteomic fingerprint (MR score) was generated from fresh samples of amniotic fluid using surface-enhanced laser desorption ionization (SELDI) mass spectrometry. Presence or absence of the biomarkers of the MR score was interpreted in relationship to the amniocentesis-to-delivery interval, placental inflammation, and early-onset neonatal sepsis for all neonates admitted to the Newborn Special Care Unit (n = 104). Women with “severe” amniotic fluid inflammation (MR score of 3 or 4) had shorter amniocentesis-to-delivery intervals than women with “no” (MR score of 0) inflammation or even “minimal” (MR score of 1 or 2) inflammation (median [range] MR 3–4: 0.4 d [0.0–49.6 d] versus MR 1–2: 3.8 d [0.0–151.2 d] versus MR 0: 17.0 d [0.1–94.3 d], p < 0.001). Nonetheless, a “minimal” degree of inflammation was also associated with preterm birth regardless of membrane status. There was a significant association between the MR score and severity of histological chorioamnionitis (r = 0.599, p < 0.001). Furthermore, neonatal hematological indices and early-onset sepsis significantly correlated with the MR score even after adjusting for gestational age at birth (OR for MR 3–4: 3.3 [95% CI, 1.1 to 9.2], p = 0.03). When compared with other laboratory tests routinely used to diagnose amniotic fluid inflammation and infection, the MR score had the highest accuracy to detect inflammation (white blood cell count > 100 cells/mm(3)), whereas the combination of Gram stain and MR score was best for rapid prediction of intra-amniotic infection (positive amniotic fluid culture). CONCLUSIONS: High MR scores are associated with preterm delivery, histological chorioamnionitis, and early-onset neonatal sepsis. In this study, proteomic analysis of amniotic fluid was shown to be the most accurate test for diagnosis of intra-amniotic inflammation, whereas addition of the MR score to the Gram stain provides the best combination of tests to rapidly predict infection.


title: Necrotizing Enteritis Caused by Pharyngostomum cordatum Infection in a Stray Cat

text: A stray female cat of unknown age, presenting bright red watery diarrhea, was submitted to the Animal and Plant Quarantine Agency for diagnosis. In the small intestines extracted from the necropsied cat, numerous white oval-shaped organisms were firmly embedded in the mucosa and there was thickening of intestinal wall. Histopathological analysis revealed severe necrotizing enteritis, together with atrophied intestinal villi, exfoliated enterocytes, and parasitic worms. Recovered worms were identified as Pharyngostomum cordatum by morphological observation and genetic analysis. Although P. cordatum is known to occur widely in Korea, this is the first clinical description of an infection by P. cordatum causing severe feline enteritis.


title: Maladie de Kawasaki

text: Résumé La maladie de Kawasaki, bien connue des pédiatres, est une vascularite multisystémique aiguë touchant les vaisseaux de moyens calibres avec une prédilection pour les artères coronaires. Dans les pays développés, cette maladie est la première cause de cardiopathie acquise chez l’enfant. La physiopathologie de cette maladie est actuellement toujours inconnue, mais il est communément admis qu’un ou plusieurs agents infectieux induisent une réponse inflammatoire inappropriée chez un sujet génétiquement prédisposé. Le diagnostic est clinique et doit être évoqué chez des enfants présentant une fièvre prolongée de plus de cinq jours avec un syndrome inflammatoire biologique. Des critères cliniques d’inflammation cutanéomuqueuse ont été définis par l’American Heart Association en 2004 afin d’établir le diagnostic. Cependant, certains enfants peuvent présenter des formes incomplètes de la maladie surtout lorsque la maladie apparaît à un âge inhabituel. Les symptômes sont proches de certaines pathologies infectieuses de l’enfant comme la scarlatine ou une infection virale rendant le diagnostic difficile. Par ailleurs, un retard au diagnostic ou l’absence de traitement majore le risque de développer des anévrismes coronaires. Les immunoglobulines polyvalentes constituent le traitement de première ligne, avec un taux de succès de l’ordre de 80 %. En cas de non-réponse à cette première ligne de traitement, le recours aux corticoïdes peut être proposé, en association à une deuxième cure d’immunoglobulines, surtout dans les formes de mauvais pronostic. D’autres thérapeutiques comme les anti-tumor necrosis factor alpha ou certains immunosuppresseurs peuvent aussi être employées en cas de résistance aux immunoglobulines, mais doivent être discutées avec une équipe spécialisée.


title: Type I Interferon Reaction to Viral Infection in Interferon-Competent, Immortalized Cell Lines from the African Fruit Bat Eidolon helvum

text: Bats harbor several highly pathogenic zoonotic viruses including Rabies, Marburg, and henipaviruses, without overt clinical symptoms in the animals. It has been suspected that bats might have evolved particularly effective mechanisms to suppress viral replication. Here, we investigated interferon (IFN) response, -induction, -secretion and -signaling in epithelial-like cells of the relevant and abundant African fruit bat species, Eidolon helvum (E. helvum). Immortalized cell lines were generated; their potential to induce and react on IFN was confirmed, and biological assays were adapted to application in bat cell cultures, enabling comparison of landmark IFN properties with that of common mammalian cell lines. E. helvum cells were fully capable of reacting to viral and artificial IFN stimuli. E. helvum cells showed highest IFN mRNA induction, highly productive IFN protein secretion, and evidence of efficient IFN stimulated gene induction. In an Alphavirus infection model, O'nyong-nyong virus exhibited strong IFN induction but evaded the IFN response by translational rather than transcriptional shutoff, similar to other Alphavirus infections. These novel IFN-competent cell lines will allow comparative research on zoonotic, bat-borne viruses in order to model mechanisms of viral maintenance and emergence in bat reservoirs.


title: Chapter 6.2 Bacteria, Virus, Fungi, and Infectious Diseases

text: Abstract Bacterial, fungus, and viral infections can be aggressive life-threatening infections or nonhostile relatively mild short-term infections. In response to all infectious agents, the body generates antibodies or generates resistance to infection agents. In all cases, bacteria, fungi, and viruses infect one cell or one tissue and then start to spread around the body infecting multiple other cells or tissues, in some cases killing humans. One common symptom of most bacterial, fungal, and virus infections is fever.


title: Knowledge‐based structural models of SARS‐CoV‐2 proteins and their complexes with potential drugs

text: The World Health Organization (WHO) has declared the coronavirus disease 2019 (COVID‐19) caused by the novel coronavirus SARS‐CoV‐2 a pandemic. There is, however, no confirmed anti‐COVID‐19 therapeutic currently. In order to assist structure‐based discovery efforts for repurposing drugs against this disease, we constructed knowledge‐based models of SARS‐CoV‐2 proteins and compared the ligand molecules in the template structures with approved/experimental drugs and components of natural medicines. Our theoretical models suggest several drugs, such as carfilzomib, sinefungin, tecadenoson, and trabodenoson, that could be further investigated for their potential for treating COVID‐19.


title: Hospital-based Influenza Morbidity and Mortality (HIMM) Surveillance for A/H7N9 Influenza Virus Infection in Returning Travelers

text: Since 2013, the Hospital-based Influenza Morbidity and Mortality (HIMM) surveillance system began a H7N9 influenza surveillance scheme for returning travelers in addition to pre-existing emergency room (ER)-based influenza-like illness (ILI) surveillance and severe acute respiratory infection (SARI) surveillance. Although limited to eastern China, avian A/H7N9 influenza virus is considered to have the highest pandemic potential among currently circulating influenza viruses. During the study period between October 1st, 2013 and April 30th, 2016, 11 cases presented with ILI within seven days of travel return. These patients visited China, Hong Kong, or neighboring Southeast Asian countries, but none of them visited a livestock market. Seasonal influenza virus (54.5%, 6 among 11) was the most common cause of ILI among returning travelers, and avian A/H7N9 influenza virus was not detected during the study period.


title: Recovery opportunities for metals and energy from sewage sludges

text: Abstract Limitations on current wastewater treatment plant (WWTP) biological processes and solids disposal options present opportunities to implement novel technologies that convert WWTPs into resource recovery facilities. This review considered replacing or augmenting extensive dewatering, anaerobic digestion, and off-site disposal with new thermo-chemical and liquid extraction processes. These technologies may better recover energy and metals while inactivating pathogens and destroying organic pollutants. Because limited direct comparisons between different sludge types exist in the literature for hydrothermal liquefaction, this study augments the findings with experimental data. These experiments demonstrated 50% reduction in sludge mass, with 30% of liquefaction products converted to bio-oil and most metals sequestered within a small mass of solid bio-char residue. Finally, each technology’s contribution to the three sustainability pillars is investigated. Although limiting hazardous materials reintroduction to the environment may increase economic cost of sludge treatment, it is balanced by cleaner environment and valuable resource benefits for society.


title: Coronavirus fallout threatens financial stability

text: ▪ The coronavirus is set to sharply cut global growth and also risks sparking substantial levels of financial distress among both businesses and households, potentially cascading into the banking sector. The challenges this poses for policymakers is formidable. ▪ Financial vulnerabilities were evident in the corporate sector in many economies even before the virus struck, with rising debt, declining credit quality and worsening liquidity positions. Consumer‐facing sectors especially at risk from the impact of the virus tend to have weaker financial positions. ▪ There are also household fragilities. A large fraction of households ‐ often 40%–50% ‐ have limited liquid assets to tide them over if they cannot work. Access to sickness and unemployment benefits varies widely across economies. ▪ High levels of bad loans in some banking systems, most notably in Italy, could be exacerbated by the virus impact, threatening financial stability. High dollar debts in many economies outside the US are another risk factor. ▪ As well as containing the virus, policymakers need to consider imaginative approaches to prevent financial distress worsening the economic downturn, potentially including a need to rapidly backstop banks, firms, and households.


title: Inhibition of Enterovirus 71 by Selenium Nanoparticles Loaded with siRNA through Bax Signaling Pathways

text: [Image: see text] Enterovirus 71 (EV71) is the principal pathogen leading to severe cases of hand, foot, and mouth disease (HFMD). Specific drugs for EV71 are not discovered currently. Small interfering RNA (siRNA) provides a promising antiviral treatment pathway, but it is difficult to cross cell membranes and is easy to degrade. Nanoparticles are promising for their carrying capacity currently. In this study, the siRNA targeting EV71 VP1 gene was loaded with selenium nanoparticles (SeNPs) and surface decorated with polyethylenimine (PEI) (Se@PEI@siRNA). Se@PEI@siRNA showed a remarkable interference efficiency in the nerve cell line SK-N-SH and prevented the cells to be infected. The mechanism study revealed that Se@PEI@siRNA could lighten the extent of SK-N-SH cells for staying in the sub-G1 phase. Activation of Bax apoptosis signaling was restrained either. Taken together, this study demonstrated that Se@PEI@siRNA is a promising drug against EV71 virus.


title: Marketing ecosystem: An outside-in view for sustainable advantage

text: Abstract In the modern business environment, consumers are increasingly influenced by megatrends involving marketplace, technology, socioeconomics, geopolitics, and natural environment. Simultaneously, the data and insights that can inform consumer attitudes and behaviors often reside outside of firms' direct control. Consciously incorporating these interdependent factors into firms' decision-making is essential for adaptability and sustainable profitability. Building on the “outside-in” perspective, we propose that firm strategies should be informed through the lens of the marketing ecosystem that considers the interrelated and dynamic megatrends. By leveraging advances in data and technology, firms can sense-make the marketplace by extracting insights from massive amounts of diverse consumer data with modern-day analytics. By mapping out the megatrends with marketing analytics, firms can 1) more accurately predict consumers' changing preferences and formulate appropriate strategies to engage with them; and 2) become more market-adaptable and competitive in the present and the future. To deliver sustainably compelling value to customers, firms should adopt an ecosystem mindset and cooperate with various stakeholders. A broad-thinking, agile, and humble firm culture can enable the development of more robust outside-in capabilities. We elaborate on the megatrends in the interconnected world of the marketing ecosystem, and propose emerging research directions in each area.


Considerations in Upper Limb Rehabilitation during COVID-19 Crisis


title: Sequential Adaptive Mutations Enhance Efficient Vector Switching by Chikungunya Virus and Its Epidemic Emergence

text: The adaptation of Chikungunya virus (CHIKV) to a new vector, the Aedes albopictus mosquito, is a major factor contributing to its ongoing re-emergence in a series of large-scale epidemics of arthritic disease in many parts of the world since 2004. Although the initial step of CHIKV adaptation to A. albopictus was determined to involve an A226V amino acid substitution in the E1 envelope glycoprotein that first arose in 2005, little attention has been paid to subsequent CHIKV evolution after this adaptive mutation was convergently selected in several geographic locations. To determine whether selection of second-step adaptive mutations in CHIKV or other arthropod-borne viruses occurs in nature, we tested the effect of an additional envelope glycoprotein amino acid change identified in Kerala, India in 2009. This substitution, E2-L210Q, caused a significant increase in the ability of CHIKV to develop a disseminated infection in A. albopictus, but had no effect on CHIKV fitness in the alternative mosquito vector, A. aegypti, or in vertebrate cell lines. Using infectious viruses or virus-like replicon particles expressing the E2-210Q and E2-210L residues, we determined that E2-L210Q acts primarily at the level of infection of A. albopictus midgut epithelial cells. In addition, we observed that the initial adaptive substitution, E1-A226V, had a significantly stronger effect on CHIKV fitness in A. albopictus than E2-L210Q, thus explaining the observed time differences required for selective sweeps of these mutations in nature. These results indicate that the continuous CHIKV circulation in an A. albopictus-human cycle since 2005 has resulted in the selection of an additional, second-step mutation that may facilitate even more efficient virus circulation and persistence in endemic areas, further increasing the risk of more severe and expanded CHIK epidemics.


title: Capture the abrupt changes in Asian residential property markets

text: In this paper, studies on the real estate markets mainly focused on the relationship between abrupt change points and corresponding political issues and economic collapse. Within the past statistical framework, change-point detection technique was widely considered based on large and long data sets. Few studies considered the situation where a limited size of time-series data sets is available in the real estate markets. To fill in this gap, the wavelet analysis with minimax threshold is introduced in this paper. By comparing Daubechies LA(8), wavelet analysis with minimax threshold is a versatile and powerful approach to the analysis of residential data as they are flexible in their function form and provide a robust computational method even with a small sample size. The detected change points reflect some significant political issues and economic collapses. It can be shown from the empirical result that a “diffusion relationship” happened from one location to another.


title: Response to: Medical students’ preference for returning to the clinical setting during the COVID‐19 pandemic

text: As fourth‐year medical students in the UK who have had to adapt to working from home amidst nationwide cancellation of clinical placements, we read with interest Compton et al.’s survey assessing the prevalence of medical students’ preference for re‐entering clinical environments during the COVID‐19 pandemic(1).


title: After Less Than 2 Months, the Simulations That Drove the World to Strict Lockdown Appear to be Wrong, the Same of the Policies They Generated

text: Here, we review modeling predictions for Covid-19 mortality based on recent data. The Imperial College model trusted by the British Government predicted peak mortalities above 170 deaths per million in the United States, and above 215 deaths per million in Great Britain, after more than 2 months from the outbreak, and a length for the outbreak well above 4 months. These predictions drove the world to adopt harsh distancing measures and forget the concept of herd immunity. China had peak mortalities of less than 0.1 deaths per million after 40 days since first deaths, and an 80-day-long outbreak. Italy, Belgium, the Netherlands, Sweden, or Great Britain flattened the curve at 13.6, 28.6, 9.0, 10.6, and 13.9 deaths per million after 40, 39, 33, 44, and 39 days from first deaths, or 31, 29, 24, 38, and 29 days since the daily confirmed deaths reached 0.1 per million people, respectively. The declining curve is much slower for Italy, the Netherlands, or Great Britain than Belgium or Sweden. Opposite to Great Britain, Italy, or Belgium that enforced a complete lockdown, the Netherlands only adopted an “intelligent” lockdown, and Sweden did not adopt any lockdown. However, they achieved better results. Coupled to new evidence for minimal impact of Covid-19 on the healthy population, with the most part not infected even if challenged, or only mild or asymptomatic if infected, there are many good reasons to question the validity of the specific epidemiological model simulations and the policies they produced. Fewer restrictions on the healthy while better protecting the vulnerable would have been a much better option, permitting more sustainable protection of countries otherwise at risk of second waves as soon as the strict measures are lifted.


title: rOv-ASP-1, a recombinant secreted protein of the helminth Onchocercavolvulus, is a potent adjuvant for inducing antibodies to ovalbumin, HIV-1 polypeptide and SARS-CoV peptide antigens

text: We studied the adjuvanticity of recombinant Onchocerca volvulus activation associated protein-1 (rOv-ASP-1) for ovalbumin (OVA) in mice. After a single immunization and one boost, rOv-ASP-1 exceeded the efficacy of alum or MPL + TDM adjuvants in terms of end-point total IgG or IgG1 and IgG2a anti-OVA titres. Using the helminth-derived adjuvant, IgG isotype responses to OVA were of a mixed Th1/Th2 profile and spleen cell cytokines exclusively Th1-type. The potent adjuvanticity of rOv-ASP-1 was confirmed in mice vaccinated with a 37-mer peptide from the S protein of SARS-CoV and an HIV-1 gp120-CD4 chimeric polypeptide antigen. Unusually for a helminth product, the rOv-ASP-1 adjuvant augmented not only Th2 but also Th1 responses, the latter property being of potential utility in stimulating anti-viral immune responses.


title: Postexposure Protection of Guinea Pigs against a Lethal Ebola Virus Challenge Is Conferred by RNA Interference

text: BackgroundEbola virus (EBOV) infection causes a frequently fatal hemorrhagic fever (HF) that is refractory to treatment with currently available antiviral therapeutics. RNA interference represents a powerful, naturally occurring biological strategy for the inhibition of gene expression and has demonstrated utility in the inhibition of viral replication. Here, we describe the development of a potential therapy for EBOV infection that is based on small interfering RNAs (siRNAs) MethodsFour siRNAs targeting the polymerase (L) gene of the Zaire species of EBOV (ZEBOV) were either complexed with polyethylenimine (PEI) or formulated in stable nucleic acid–lipid particles (SNALPs). Guinea pigs were treated with these siRNAs either before or after lethal ZEBOV challenge ResultsTreatment of guinea pigs with a pool of the L gene–specific siRNAs delivered by PEI polyplexes reduced plasma viremia levels and partially protected the animals from death when administered shortly before the ZEBOV challenge. Evaluation of the same pool of siRNAs delivered using SNALPs proved that this system was more efficacious, as it completely protected guinea pigs against viremia and death when administered shortly after the ZEBOV challenge. Additional experiments showed that 1 of the 4 siRNAs alone could completely protect guinea pigs from a lethal ZEBOV challenge ConclusionsFurther development of this technology has the potential to yield effective treatments for EBOV HF as well as for diseases caused by other agents that are considered to be biological threats