title: Prevalence of Gastrointestinal Symptoms and Fecal Viral Shedding in Patients With Coronavirus Disease 2019: A Systematic Review and Meta-analysis

text: IMPORTANCE: Coronavirus disease 2019 (COVID-19) is a global pandemic and can involve the gastrointestinal (GI) tract, including symptoms like diarrhea and shedding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in feces. OBJECTIVE: To provide a pooled estimate of GI symptoms, liver enzyme levels outside reference ranges, and fecal tests positive for SARS-CoV-2 among patients with COVID-19. DATA SOURCES: An electronic literature search was performed for published (using MEDLINE/PubMed and Embase) and preprint (using bioRxiv and medRxiv) studies of interest conducted from November 1, 2019, to March 30, 2020. Search terms included “COVID-19,” “SARS-Cov-2,” and/or “novel coronavirus.” STUDY SELECTION: Eligible studies were those including patients with SARS-CoV-2 infection who reported GI symptoms. DATA EXTRACTION AND SYNTHESIS: Data on patients with GI symptoms (ie, diarrhea, nausea, or vomiting), liver enzyme level changes, and fecal shedding of virus were extracted. Quality of studies was examined using methodological index for nonrandomized studies. Pooled estimates (%) were reported with 95% CIs with level of heterogeneity (I(2)). MAIN OUTCOMES AND MEASURES: Study and patient characteristics with pooled detection rates for diarrhea, nausea or vomiting, liver enzyme levels outside reference ranges, and SARS-CoV-2 positivity in feces tests were analyzed. RESULTS: Of 1484 records reviewed, 23 published and 6 preprint studies were included in the analysis, with a total of 4805 patients (mean [SD] age, 52.2 [14.8] years; 1598 [33.2%] women) with COVID-19. The pooled rates were 7.4% (95% CI, 4.3%-12.2%) of patients reporting diarrhea and 4.6% (95% CI, 2.6%-8.0%) of patients reporting nausea or vomiting. The pooled rate for aspartate aminotransferase levels outside reference ranges was 20% (95% CI, 15.3%-25.6%) of patients, and the pooled rate for alanine aminotransferase levels outside reference ranges was 14.6% (95% CI, 12.8%-16.6%) of patients. Fecal tests that were positive for SARS-CoV-2 were reported in 8 studies, and viral RNA shedding was detected in feces in 40.5% (95% CI, 27.4%-55.1%) of patients. There was high level of heterogeneity (I(2) = 94%), but no statistically significant publication bias noted. CONCLUSIONS AND RELEVANCE: These findings suggest that that 12% of patients with COVID-19 will manifest GI symptoms; however, SAR-CoV-2 shedding was observed in 40.5% of patients with confirmed SARS-CoV-2 infection. This highlights the need to better understand what measures are needed to prevent further spread of this highly contagious pathogen.


title: Influence of Community and Culture in the Ethical Allocation of Scarce Medical Resources in a Pandemic Situation: Deliberative Democracy Study

text: BACKGROUND: Stark gaps exist between projected health needs in a pandemic situation and the current capacity of health care and medical countermeasure systems. Existing pandemic ethics discussions have advocated to engage the public in scarcity dilemmas and attend the local contexts and cultural perspectives that shape responses to a global health threat. This public engagement study thus considers the role of community and culture in the ethical apportionment of scarce health resources, specifically ventilators, during an influenza pandemic. It builds upon a previous exploration of the values and preferences of Maryland residents regarding how a finite supply of mechanical ventilators ought to be allocated during a severe global outbreak of influenza. An important finding of this earlier research was that local history and place within the state engendered different ways of thinking about scarcity. OBJECTIVE: Given the intrastate variation in the themes expressed by Maryland participants, the project team sought to examine interstate differences by implementing the same protocol elsewhere to answer the following questions. Does variation in ethical frames of reference exist within different regions of the United States? What practical implications does evidence of sameness and difference possess for pandemic planners and policymakers at local and national levels? METHODS: Research using the same deliberative democracy process from the Maryland study was conducted in Central Texas in March 2018 among 30 diverse participants, half of whom identified as Hispanic or Latino. Deliberative democracy provides a moderated process through which community members can learn facts about a public policy matter from experts and explore their own and others’ views. RESULTS: Participants proposed that by evenly distributing supplies of ventilators and applying clear eligibility criteria consistently, health authorities could enable fair allocation of scarce lifesaving equipment. The strong identification, attachment, and obligation of persons toward their nuclear and extended families emerged as a distinctive regional and ethnic core value that has practical implications for the substance, administration, and communication of allocation frameworks. CONCLUSIONS: Maryland and Central Texas residents expressed a common, overriding concern about the fairness of allocation decisions. Central Texas deliberants, however, more readily expounded upon family as a central consideration. In Central Texas, family is a principal, culturally inflected lens through which life and death matters are often viewed. Conveners of other pandemic-related public engagement exercises in the United States have advocated the benefits of transparency and inclusivity in developing an ethical allocation framework; this study demonstrates cultural competence as a further advantage.


title: Development and clinical application of a rapid IgM‐IgG combined antibody test for SARS‐CoV‐2 infection diagnosis

text: The outbreak of the novel coronavirus disease (COVID‐19) quickly spread all over China and to more than 20 other countries. Although the virus (severe acute respiratory syndrome coronavirus [SARS‐Cov‐2]) nucleic acid real‐time polymerase chain reaction (PCR) test has become the standard method for diagnosis of SARS‐CoV‐2 infection, these real‐time PCR test kits have many limitations. In addition, high false‐negative rates were reported. There is an urgent need for an accurate and rapid test method to quickly identify a large number of infected patients and asymptomatic carriers to prevent virus transmission and assure timely treatment of patients. We have developed a rapid and simple point‐of‐care lateral flow immunoassay that can detect immunoglobulin M (IgM) and IgG antibodies simultaneously against SARS‐CoV‐2 virus in human blood within 15 minutes which can detect patients at different infection stages. With this test kit, we carried out clinical studies to validate its clinical efficacy uses. The clinical detection sensitivity and specificity of this test were measured using blood samples collected from 397 PCR confirmed COVID‐19 patients and 128 negative patients at eight different clinical sites. The overall testing sensitivity was 88.66% and specificity was 90.63%. In addition, we evaluated clinical diagnosis results obtained from different types of venous and fingerstick blood samples. The results indicated great detection consistency among samples from fingerstick blood, serum and plasma of venous blood. The IgM‐IgG combined assay has better utility and sensitivity compared with a single IgM or IgG test. It can be used for the rapid screening of SARS‐CoV‐2 carriers, symptomatic or asymptomatic, in hospitals, clinics, and test laboratories.


title: Timing is everything: Fine-tuned molecular machines orchestrate paramyxovirus entry

text: Abstract The Paramyxoviridae include some of the great and ubiquitous disease-causing viruses of humans and animals. In most paramyxoviruses, two viral membrane glycoproteins, fusion protein (F) and receptor binding protein (HN, H or G) mediate a concerted process of recognition of host cell surface molecules followed by fusion of viral and cellular membranes, resulting in viral nucleocapsid entry into the cytoplasm. The interactions between the F and HN, H or G viral glycoproteins and host molecules are critical in determining host range, virulence and spread of these viruses. Recently, atomic structures, together with biochemical and biophysical studies, have provided major insights into how these two viral glycoproteins successfully interact with host receptors on cellular membranes and initiate the membrane fusion process to gain entry into cells. These studies highlight the conserved core mechanisms of paramyxovirus entry that provide the fundamental basis for rational anti-viral drug design and vaccine development.


title: Is DPP4 inhibition a comrade or adversary in COVID-19 Infection

text: Hypertension and Diabetes are the most common comorbid conditions in patients with COVID-19 and has been shown to adversely impact prognosis globally. It has been shown that hyperglycemia is one of the factors that increases the risk of poor outcomes in these patients . These patients are usually on multiple medications and recently a series of discussion on how Dipeptidyl peptidase 4 inhibitors (DPP4i) may be beneficial in these patients has been presented. This commentary presents a nuanced debate on why the DPP4i may not be beneficial in COVID-19 and that caution needs to be addressed in making any judgements until real world data is available.


title: Ischaemic heart disease, influenza and influenza vaccination: a prospective case control study

text: BACKGROUND: Abundant, indirect epidemiological evidence indicates that influenza contributes to all-cause mortality and cardiovascular hospitalisations with studies showing increases in acute myocardial infarction (AMI) and death during the influenza season. OBJECTIVE: To investigate whether influenza is a significant and unrecognised underlying precipitant of AMI. DESIGN: Case-control study. SETTING: Tertiary referral hospital in Sydney, Australia, during 2008 to 2010. PATIENTS: Cases were inpatients with AMI and controls were outpatients without AMI at a hospital in Sydney, Australia. MAIN OUTCOME MEASURES: Primary outcome was laboratory evidence of influenza. Secondary outcome was baseline self-reported acute respiratory tract infection. RESULTS: Of 559 participants, 34/275 (12.4%) cases and 19/284 (6.7%) controls had influenza (OR 1.97, 95% CI 1.09 to 3.54); half were vaccinated. None were recognised as having influenza during their clinical encounter. After adjustment, influenza infection was no longer a significant predictor of recent AMI. However, influenza vaccination was significantly protective (OR 0.55, 95% CI 0.35 to 0.85), with a vaccine effectiveness of 45% (95% CI 15% to 65%). CONCLUSIONS: Recent influenza infection was an unrecognised comorbidity in almost 10% of hospital patients. Influenza did not predict AMI, but vaccination was significantly protective but underused. The potential population health impact of influenza vaccination, particularly in the age group 50–64 years, who are at risk for AMI but not targeted for vaccination, should be further explored. Our data should inform vaccination policy and cardiologists should be aware of missed opportunities to vaccinate individuals with ischaemic heart disease against influenza.


title: COPD in China The Burden and Importance of Proper Management

text: Although, to our knowledge, there has been no exhaustive or credible review of the evidence of the disease burden of COPD in China, COPD has become an increasing public health concern to the Chinese medical community. The purpose of this article is to review the evidence and evaluate and clarify the disease burden of COPD in China with the aim of improving effective management. We reviewed previous studies of COPD in China, which included data on prevalence, mortality, disease burden, risk factors, diagnosis, and management by searching related Web sites, including PubMed, ProQuest, and Thomson Reuters' Web of Knowledge, as well as major Chinese databases and government Web sites. Reported COPD prevalence varied between 5% and 13% in different provinces/cities across China. In 2008, COPD ranked fourth as a leading cause of death in urban areas and third in rural areas. In addition, COPD accounted for 1.6% of all hospital admissions in China in that year. The high prevalence of smoking and biomass fuel use acted as major contributors to the high occurrence of COPD in China. Management of COPD in China should focus on adjusting the distribution of medical resources and on addressing public health policies to facilitate earlier diagnosis in rural areas, aim to reduce smoking prevalence, improve patients' self-management, and keep physicians' knowledge up to date and consistent with current guidelines. COPD is one of the most challenging medical issues facing China because of its influence on both personal and public health and its impact on the economy. Optimal management strategies should be adopted and strengthened immediately.


title: Hong Kong Hospital Authority resource efficiency evaluation: Via a novel DEA-Malmquist model and Tobit regression model

text: The Hospital Authority (HA) is a statutory body managing all the public hospitals and institutes in Hong Kong (HK). In recent decades, Hong Kong Hospital Authority (HKHA) has been making efforts to improve the healthcare services, but there still exist some problems like unfair resource allocation and poor management, as reported by the Hong Kong medical legislative committee. One critical consequence of these problems is low healthcare efficiency of hospitals, leading to low satisfaction among patients. Moreover, HKHA also suffers from the conflict between limited resource and growing demand. An effective evaluation of HA is important for resource planning and healthcare decision making. In this paper, we propose a two-phase method to evaluate HA efficiency for reducing healthcare expenditure and improving healthcare service. Specifically, in Phase I, we measure the HKHA efficiency changes from 2000 to 2013 by applying a novel DEA-Malmquist index with undesirable factors. In Phase II, we further explore the impact of some exogenous factors (e.g., population density) on HKHA efficiency by Tobit regression model. Empirical results show that there are significant differences between the efficiencies of different hospitals and clusters. In particular, it is found that the public hospital serving in a richer district has a relatively lower efficiency. To a certain extent, this reflects the socioeconomic reality in HK that people with better economic condition prefers receiving higher quality service from the private hospitals.


title: Wild canids, domestic dogs and their pathogens in Southeast Brazil: disease threats for canid conservation

text: Wild canids are under many pressures, including habitat loss, fragmentation and disease. The current lack of information on the status of wildlife health may hamper conservation efforts in Brazil. In this paper, we examined the prevalence of canine pathogens in 21 free-ranging wild canids, comprising 12 Cerdocyon thous (crab-eating fox), 7 Chrysocyon brachyurus (maned wolf), 2 Lycalopex vetulus (hoary fox), and 70 non-vaccinated domestic dogs from the Serra do Cipó National Park area, Southeast Brazil. For wild canids, seroprevalence of antibodies to canine parvovirus, canine adenovirus, canine coronavirus and Toxoplasma gondii was 100 (21/21), 33 (7/21), 5 (1/19) and 68 (13/19) percent, respectively. Antibodies against canine distemper virus, Neospora caninum or Babesia spp. were not found. We tested domestic dogs for antibodies to canine parvovirus, canine distemper virus and Babesia spp., and seroprevalences were 59 (41/70), 66 (46/70), and 42 (40/70) percent, respectively, with significantly higher prevalence in domestic dogs for CDV (P < 0.001) and Babesia spp. (P = 0.002), and in wild canids for CPV (P < 0.001). We report for the first time evidence of exposure to canine coronavirus in wild hoary foxes, and Platynossomun sp. infection in wild maned wolves. Maned wolves are more exposed to helminths than crab-eating foxes, with a higher prevalence of Trichuridae and Ancylostomidae in the area. The most common ectoparasites were Amblyomma cajennense, A. tigrinum, and Pulex irritans. Such data is useful information on infectious diseases of Brazilian wild canids, revealing pathogens as a threat to wild canids in the area. Control measures are discussed.


title: Potential Benefits of Tryptophan Metabolism to the Efficacy of Tocilizumab in COVID-19

text: Tocilizumab has been proposed as a means of opposing hyperinflammatory responses in intensive care patients with COVID-19. Here, we briefly discuss the potentially multiple, synergistic mechanisms whereby tocilizumab might exert therapeutic activity, mostly focusing on the production of tryptophan-derived catabolites that would result from blockade of IL-6 signaling, as contextualized to the cytokine storm occurring in COVID-19 patients.


title: Leukocyte adhesion deficiency II syndrome, a generalized defect in fucose metabolism

text: Abstract Leukocyte adhesion deficiency II has been described in only 2 patients; herein we report extensive investigation of another patient. The physical stigmata were detected during prenatal ultrasonographic investigation. Sialyl-Lewis X (sLex) was absent from the surface of polymorphonuclear neutrophils, and cell binding to E- and P-selectin was severely impaired, causing an immunodeficiency. The elevation of peripheral neutrophil counts occurred within several days after birth. A severe hypofucosylation of glycoconjugates bearing fucose in different glycosidic links was present in all cell types investigated, demonstrating that leukocyte adhesion deficiency II is not only a disorder of leukocytes but a generalized inherited metabolic disease affecting the metabolism of fucose. (J Pediatr 1999;134:681-8)


title: X-ray Structural and Biological Evaluation of a Series of Potent and Highly Selective Inhibitors of Human Coronavirus Papain-like Proteases

text: [Image: see text] Structure-guided design was used to generate a series of noncovalent inhibitors with nanomolar potency against the papain-like protease (PLpro) from the SARS coronavirus (CoV). A number of inhibitors exhibit antiviral activity against SARS-CoV infected Vero E6 cells and broadened specificity toward the homologous PLP2 enzyme from the human coronavirus NL63. Selectivity and cytotoxicity studies established a more than 100-fold preference for the coronaviral enzyme over homologous human deubiquitinating enzymes (DUBs), and no significant cytotoxicity in Vero E6 and HEK293 cell lines is observed. X-ray structural analyses of inhibitor-bound crystal structures revealed subtle differences between binding modes of the initial benzodioxolane lead (15g) and the most potent analogues 3k and 3j, featuring a monofluoro substitution at para and meta positions of the benzyl ring, respectively. Finally, the less lipophilic bis(amide) 3e and methoxypyridine 5c exhibit significantly improved metabolic stability and are viable candidates for advancing to in vivo studies.


Double-Edged Spike—Are SARS-CoV-2 Serologic Tests Safe Right Now?


Sospecha de abdomen agudo como manifestación extrapulmonar de infección por Covid-19


title: A Case Series of Stent Thrombosis During the COVID-19 Pandemic

text: Abstract COVID-19 triggers a hypercoagulable state with a high incidence of thrombotic complications. We have noted a higher than expected incidence of stent thrombosis in these patients.


title: The Short-Term Effect of a Single Lapse in Anti-Vascular Endothelial Growth Factor Treatment for Diabetic Macular EdemaWithin Routine Clinical Practice

text: PURPOSE: Diabetic macular edema (DME) is a leading cause of vision loss in diabetics. Anti-vascular endothelial growth factor (VEGF) therapy has been shown to be an effective treatment option for DME, although the injections are costly and require frequent visits which increases the risk for unintended treatment lapses. The aim of this study is to characterize the effects of an unintended treatment lapse in patients with DME undergoing anti-VEGF therapy. DESIGN: Retrospective, comparative case series. METHODS: This retrospective chart review compared patients seen in a multicenter institutional practice with DME exhibiting an un-intended minimum three-month lapse in anti-VEGF treatment, with a control group of DME patients receiving regular anti-VEGF treatment without lapses. The primary outcome was difference in central subfield thickness (CST) between the control group and the treatment lapse group at 6 months following treatment lapse. RESULTS: A total of 164 patients were evaluated, 82 patients in the treatment lapse group and 82 patients in the control group. The average age was 65 years, and the average lapse in treatment was 6.2 ± 3.5 months (range 3-24 months). Comparison of data between the lapse and control groups revealed no significant differences in CST respectively [(359.9±108.3 μm), (335.4±94.6 μM)], p=0.066 or in visual acuity (VA) respectively [(66.5±14.3), (68.9±14.5)], p=0.136. Limitations included a relatively small sample size, retrospective nature, and only a single lapse being evaluated. CONCLUSIONS: An un-intended, single, relatively short-term lapse in anti-VEGF treatment in patients with DME did not appear to result in significant anatomic or visual compromise upon resumption of regular follow-up and treatment.


title: A Case for Palliative Dermatology: COVID-19-related Dermatoses()()

text: The unprecendented COVID-19 pandemic has challenged healthcare systems in different ones. In the United Kingdom, various subspecialties were deployed to the wards to help medical workforce in the frontlines, with dermatologists helping with general medical wards and on-calls. We present a case of COVID-19-related urticaria manifesting in a palliative setting and responding well to systemic antihistamine. This pandemic has highlighted a new subspecialty that should be explored and researched – palliative dermatology – bridging elements of dermatology with the concepts of palliative medicine. As dermatologists, we should be in the position to help with the last stages of a patient's journey.


title: Systems approaches to coronavirus pathogenesis

text: Coronaviruses comprise a large group of emergent human and animal pathogens, including the highly pathogenic SARS-CoV and MERS-CoV strains that cause significant morbidity and mortality in infected individuals, especially the elderly. As emergent viruses may cause episodic outbreaks of disease over time, human samples are limited. Systems biology and genetic technologies maximize opportunities for identifying critical host and viral genetic factors that regulate susceptibility and virus-induced disease severity. These approaches provide discovery platforms that highlight and allow targeted confirmation of critical targets for prophylactics and therapeutics, especially critical in an outbreak setting. Although poorly understood, it has long been recognized that host regulation of virus-associated disease severity is multigenic. The advent of systems genetic and biology resources provide new opportunities for deconvoluting the complex genetic interactions and expression networks that regulate pathogenic or protective host response patterns following virus infection. Using SARS-CoV as a model, dynamic transcriptional network changes and disease-associated phenotypes have been identified in different genetic backgrounds, leading to the promise of population-wide discovery of the underpinnings of Coronavirus pathogenesis.


title: Les pneumopathies communautaires

text: Community acquired pneumonia Acute infectious pneumonia is a serious public health problem because it is a major cause of morbidity and mortality in adults. The clinical and radiographic data are usually sufficient to diagnose infectious pneumonia. On the contrary, the etiological diagnosis is more difficult to establish because many pathogens are known, but with non-specific reactions of the lung parenchyma. Outside exceptional cases, the radiological lesions have low specificity. Understanding the physiological mechanisms can explain some radiological aspects. Similarly, knowledge of the radiological and pathological mechanisms involved can enable adequate recognition of three main radiographic features. Epidemiology and immunology depend on the causal agent.


title: Hydroxychloroquine as antiviral prophylaxis for exposed caregivers to Covid-19: an urgent appraisal is needed

text: Abstract Background Since the onset of the new coronavirus pandemic, the world is facing a public health emergency. Repositioning hydroxychloroquine (HQ) seems to be a promising option. Many emerging evidences have converged on the effectiveness of HQ in the treatment of Covid-19 infection. In a recent paper, Gautret et al. suggested that further works are needed to determine if HQ antiviral prophylaxis is useful, especially for healthcare workers. Methods The purpose of this paper is to assess the Covid-19 exposure and risks level among caregivers. For this, we performed research on internet and PubMed by crossing the following keywords: healthcare givers, healthcare workers, doctors, nurses, coronavirus, Covid-19, mortality, infection rate, chloroquine, hydroxychloroquine. Results Data on healthcare worker's infection and mortality by Covid-19 are partial and are not systematically published. However, it seems that the infection rate varies between 3.8% and 9% depending on the country. Moreover, the mean age of this population is relatively old, especially in the OECD area. Conclusions Anti-Covid-19 HQ prophylaxis should be urgently accessed, especially for healthcare workers. It is to be hoped that HQ prophylaxis reduces the morbidity and mortality from Covid-19 infection among this population which is particularly exposed and relatively old.


docid: eaaxkreu

title: Deutlich weniger akute STEMI-Interventionen während der COVID-19-Pandemie


title: The value of clinical parameters in predicting the severity of COVID‐19

text: To study the relationship between clinical indexes and the severity of coronavirus disease 2019 (COVID‐19), and to explore its role in predicting the severity of COVID‐19. Clinical data of 443 patients with COVID‐19 admitted to our hospital were retrospectively analyzed, which were divided into nonsevere group (n = 304) and severe group (n = 139) according to their condition. Clinical indicators were compared between different groups. The differences in sex, age, the proportion of patients with combined heart disease, leukocyte, neutrophil‐to‐lymphocyte ratio (NLR), neutrophil, lymphocyte, platelet, D‐dimer, C‐reactive protein (CRP), procalcitonin, lactate dehydrogenase, and albumin on admission between the two groups were statistically significant (P < .05). Multivariate logistic regression analysis showed NLR and CRP were independent risk factors for severe COVID‐19. Platelets were independent protective factors for severe COVID‐19. The receiver operating characteristic (ROC) curve analysis demonstrated area under the curve of NLR, platelet, CRP, and combination was 0.737, 0.634, 0.734, and 0.774, respectively. NLR, CRP, and platelets can effectively assess the severity of COVID‐19, among which NLR is the best predictor of severe COVID‐19, and the combination of three clinical indicators can further predict severe COVID‐19.


title: Hospital accreditation and the surgeon: The Canadian experience

text: Accreditation is an internationally recognised process through which healthcare organisations are able to improve the safety and quality of services delivered to patients. The focus of accreditation is to help organisations understand what they are doing well and what opportunities are available for improvement. The Canadian approach to accreditation is a rigorous peer review process comprised of a self-assessment against a set of standards, an on-site survey and follow-up action on recommendations that arise from the survey. The accreditation standards can be used effectively to guide the surgical teams in the transformation of the specialty. The 17 standards that are used to evaluate surgical teams relate to the activities that represent the continuum of clinical care as well as aspects related to learning. Within the subsections and standards are opportunities for surgeons and surgical teams to use the standards to effectively deliver services and to continuously improve patient care. In 38 recent Canadian Accreditation AIM surveys, that included at least one surgical team, there were a total of 75 recommendations made to the teams. Most recommendations related to process as opposed to outcome issues, implying that surgeons need to become more proactive in the functioning of the surgical team and to participate more effectively in management issues related to surgical care. Attention to these details will position surgical programmes to effectively deal with the rapid pace of change that is inherent in a modern surgical practice


docid: ndjbrtrv

title: Frameshift mutations in infectious cDNA clones of Citrus tristeza virus: a strategy to minimize the toxicity of viral sequences to Escherichia coli

text: Abstract The advent of reverse genetics revolutionized the study of positive-stranded RNA viruses that were amenable for cloning as cDNAs into high-copy-number plasmids of Escherichia coli. However, some viruses are inherently refractory to cloning in high-copy-number plasmids due to toxicity of viral sequences to E. coli. We report a strategy that is a compromise between infectivity of the RNA transcripts and toxicity to E. coli effected by introducing frameshift mutations into “slippery sequences” near the viral “toxicity sequences” in the viral cDNA. Citrus tristeza virus (CTV) has cDNA sequences that are toxic to E. coli. The original full-length infectious cDNA of CTV and a derivative replicon, CTV-ΔCla, cloned into pUC119, resulted in unusually limited E. coli growth. However, upon sequencing of these cDNAs, an additional uridinylate (U) was found in a stretch of U’s between nts 3726 and 3731 that resulted in a change to a reading frame with a stop codon at nt 3734. Yet, in vitro produced RNA transcripts from these clones infected protoplasts, and the resulting progeny virus was repaired. Correction of the frameshift mutation in the CTV cDNA constructs resulted in increased infectivity of in vitro produced RNA transcripts, but also caused a substantial increase of toxicity to E. coli, now requiring 3 days to develop visible colonies. Frameshift mutations created in sequences not suspected to facilitate reading frame shifting and silent mutations introduced into oligo(U) regions resulted in complete loss of infectivity, suggesting that the oligo(U) region facilitated the repair of the frameshift mutation. Additional frameshift mutations introduced into other oligo(U) regions also resulted in transcripts with reduced infectivity similarly to the original clones with the +1 insertion. However, only the frameshift mutations introduced into oligo(U) regions that were near and before the toxicity region improved growth and stability in E. coli. These data demonstrate that, when hosts are sufficiently susceptible for infection by transcripts of reduced specific infectivity, introduction of frameshift mutations at “slippery sequences” near toxic regions of viral cDNAs can be used as an additional strategy to clone recalcitrant viral sequences in high-copy-number plasmids for reverse genetics.


title: Lack of detection of Middle East respiratory syndrome coronavirus in mild and severe respiratory infections in Catalonia, northeastern Spain

text: Surveillance of Middle East respiratory syndrome coronavirus (MERS-CoV) was conducted to explore the possible introduction and circulation of this novel virus in Catalonia, northeastern Spain. Five hundred and sixty-three samples from mild and severe respiratory infections collected between January 2012 and April 2013 were screened using real-time RT-PCR. All samples were negative, suggesting that MERS-CoV is not circulating silently in Catalonia.


title: Early nutritional supplementation in non-critically ill patients hospitalized for the 2019 novel coronavirus disease (COVID-19): Rationale and feasibility of a shared pragmatic protocol

text: Abstract Objectives Beginning in December 2019, the 2019 novel coronavirus disease (COVID-19) has caused a pneumonia epidemic that began in Wuhan, China, and is rapidly spreading throughout the whole world. Italy is the hardest hit country after China. Considering the deleterious consequences of malnutrition, which certainly can affect patients with COVID-19, the aim of this article is to present a pragmatic protocol for early nutritional supplementation of non-critically ill patients hospitalized for COVID-19 disease. It is based on the observation that most patients present at admission with severe inflammation and anorexia leading to a drastic reduction of food intake, and that a substantial percentage develops respiratory failure requiring non-invasive ventilation or even continuous positive airway pressure. Methods High-calorie dense diets in a variety of different consistencies with highly digestible foods and snacks are available for all patients. Oral supplementation of whey proteins as well as intravenous infusion of multivitamin, multimineral trace elements solutions are implemented at admission. In the presence of 25-hydroxyvitamin D deficit, cholecalciferol is promptly supplied. If nutritional risk is detected, two to three bottles of protein-calorie oral nutritional supplements (ONS) are provided. If <2 bottles/d of ONS are consumed for 2 consecutive days and/or respiratory conditions are worsening, supplemental/total parenteral nutrition is prescribed. Conclusion We are aware that our straight approach may be debatable. However, to cope with the current emergency crisis, its aim is to promptly and pragmatically implement nutritional care in patients with COVID-19, which might be overlooked despite being potentially beneficial to clinical outcomes and effective in preventing the consequences of malnutrition in this patient population.


Advancing Leadership Opportunities for Women: The China and Hong Kong Scenario


docid: prqeufwg

title: Cryo-EM Structure of the 2019-nCoV Spike in the Prefusion Conformation

text: The outbreak of a novel betacoronavirus (2019-nCov) represents a pandemic threat that has been declared a public health emergency of international concern. The CoV spike (S) glycoprotein is a key target for urgently needed vaccines, therapeutic antibodies, and diagnostics. To facilitate medical countermeasure (MCM) development we determined a 3.5 Å-resolution cryo-EM structure of the 2019-nCoV S trimer in the prefusion conformation. The predominant state of the trimer has one of the three receptor-binding domains (RBDs) rotated up in a receptor-accessible conformation. We also show biophysical and structural evidence that the 2019-nCoV S binds ACE2 with higher affinity than SARS-CoV S. Additionally we tested several published SARS-CoV RBD-specific monoclonal antibodies and found that they do not have appreciable binding to nCoV-2019 S, suggesting antibody cross-reactivity may be limited between the two virus RBDs. The atomic-resolution structure of 2019-nCoV S should enable rapid development and evaluation of MCMs to address the ongoing public health crisis.


title: The outcomes and controversies of transplant tourism—Lessons of an 11-year retrospective cohort study from Taiwan

text: BACKGROUND: Transplant tourism has increased rapidly in the past two decades, accounting for about 10% of world organ transplants. However it is ethically controversial and discouraged by professional guidelines. We conducted this study to investigate the outcomes and trends of overseas kidney and liver transplantation in Taiwan to provide a sound basis for ethical reflection. METHODS AND FINDINGS: The Taiwanese National Health Insurance Research Database was used to identify 2381 domestic and 2518 overseas kidney transplant (KT) recipients from 1998 to 2009 and 1758 domestic and 540 overseas liver transplantation (LT) recipients from 1999 to 2009. Cox proportional hazards models were used to assess the risks of mortality and graft failure. The numbers of overseas transplantation increased after 2000, reached a peak in 2005 and decreased after 2007. Compared to their domestic counterparts, the overseas KT recipients were older, male predominant, with shorter pre-op dialysis period and more comorbidities. Similarly, the overseas LT recipients were older, male predominant and had more hepatocellular carcinoma cases. The 1-, 5-, and 10-year patient survival rates were 96.9%, 91.7% and 83.0% respectively for domestic KT and 95.8%, 87.8% and 73.1% for overseas KT (p<0.001). The 1-, 5-, and 10-year patient survival rates were 89.2%, 79.5%, 75.2% for domestic LT and 79.8%, 54.7%, 49.9% for overseas LT (p<0.001). CONCLUSION: The poorer outcomes of the overseas groups may be due to more older patients, more comorbidities (KT), or more hepatocellular carcinoma recurrences (LT). After domestic reform and international ethical challenges, the numbers of organ tourism decreased but the practice still persisted surreptitiously. Compulsory registration policies for overseas transplantation with international conventions to sanction organ trafficking and transplant tourism should be considered to stop these controversial practices.


title: Cancer Patients’ Perceived Difficulties Filling Opioid Prescriptions After Receiving Outpatient Supportive Care

text: CONTEXT: Limited access to opioids for cancer patients has been reported as a potential unintended consequence of recent regulations restricting opioid use and prescribing practices. To our knowledge, there are a limited number of peer-reviewed studies that evaluate cancer patients’ perceived difficulties when filling their opioid prescription. To understand these difficulties, we surveyed patients receiving opioids in our outpatient Supportive Care Center (SCC). OBJECTIVES: The primary objective of this study was to evaluate cancer patients’ perceptions of overall difficulties when filling their opioid prescription. Secondary objectives included determining associations between patient characteristics and difficulty, and comparing difficulty between filling opioid and non-opioid prescriptions. METHODS: Cancer patients receiving opioids that had been seen two times or more at our SCC were asked to complete a survey. The information collected included patient demographics, clinical characteristics, and patients’ experiences filling their opioid prescription. RESULTS: The patients’ median age was 60 years; 54% were female and 69% were white. Forty-four patients (32%) reported that they have experienced difficulty filling their opioid prescription. More than 25% of those 44 patients perceived difficulty from interactions with the pharmacy/pharmacist. Forty-six patients (33%) reported more difficulty filling their opioid prescriptions than filling their non-opioid prescriptions. CONCLUSIONS: This study provides evidence that patients with cancer visiting our SCC perceived difficulties obtaining their opioid prescriptions. The results suggest that negative interactions with the pharmacy/pharmacist contributes to their perceived difficulty. Additional research is needed to further characterize the contributors of the difficulties cancer patients face in filling their opioid prescriptions.


title: The SARS-CoV-2 receptor ACE2 expression of maternal-fetal interface and fetal organs by single cell transcriptome study

text: The new type of pneumonia caused by the SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) has been declared as a global public health concern by WHO. Thousands of human infections have been diagnosed in China along with many other countries, which exhibited apparent person-to-person transmission characteristics of this virus. The capacity of vertical transmission in SARS-CoV-2 remains controversial recently. Angiotensin-converting enzyme 2 (ACE2) is now confirmed as the receptor of SARS-CoV-2 and plays essential roles in human infection and transmission. In present study, we collected the online available single-cell RNA sequencing (scRNA-seq) data to evaluate the cell specific expression of ACE2 in maternal-fetal interface as well as in multiple fetal organs. Our results revealed that ACE2 was highly expressed in maternal-fetal interface cells including stromal cells and perivascular cells of decidua, and cytotrophoblast and syncytiotrophoblast in placenta. Meanwhile, ACE2 was also expressed in specific cell types of human fetal heart, liver and lung, but not in kidney. And in a study containing series fetal and post-natal mouse lung, we observed ACE2 was dynamically changed over the time, and ACE2 was extremely high in neonatal mice at post-natal day 1~3. In summary, this study revealed that the SARS-CoV-2 receptor ACE2 was widely spread in specific cell types of maternal-fetal interface and fetal organs. Although previous clinical studies have not observed vertical transmission of SARS-COV-2 among limited cases, this phenomenon still needs to be further carefully investigated in clinical practice.


title: Limitations and lessons in the use of X-ray structural information in drug design

text: The use of X-ray crystal structure models continues to provide a strong stimulus to drug discovery, through the direct visualisation of ligand–receptor interactions. There is sometimes a limited appreciation of the uncertainties introduced during the process of deriving an atomic model from the experimentally observed electron density. Here, some of these uncertainties are highlighted with recent examples from the literature, together with snippets of advice for the medicinal chemist embarking on using X-ray crystal structure information in a drug discovery programme.


title: Porcine CD8α(dim/-)NKp46(high) NK cells are in a highly activated state

text: Natural Killer (NK) cells play a crucial role in the early phase of immune responses against various pathogens. In swine so far only little information about this lymphocyte population exists. Phenotypical analyses with newly developed monoclonal antibodies (mAbs) against porcine NKp46 recently revealed that in blood NKp46(-) and NKp46(+) cells with NK phenotype exist with comparable cytotoxic properties. In spleen a third NKp46-defined population with NK phenotype was observed that was characterised by a low to negative CD8α and increased NKp46 expression. In the current study it is shown that this NKp46(high) phenotype was correlated with an increased expression of CD16 and CD27 compared to the CD8α(+)NKp46(-) and NKp46(+) NK-cell subsets in spleen and blood. Additionally NKp46(high) NK cells expressed elevated levels of the chemokine receptor CXCR3 on mRNA level. Functional analyses revealed that splenic NKp46(high) NK cells produced much higher levels of Interferon-γ and Tumor Necrosis Factor-α upon stimulation with cytokines or phorbol-12-myristate-13-acetate/Ionomycin compared to the other two subsets. Furthermore, cross-linking of NKp46 by NKp46-specific mAbs led to a superior CD107a expression in the NKp46(high) NK cells, thus indicating a higher cytolytic capacity of this subset. Therefore porcine splenic NKp46(high) NK cells represent a highly activated subset of NK cells and may play a profound role in the immune surveillance of this organ.


title: Ivermectin: repurposing a multipurpose drug for Venezuela's humanitarian crisis

text: Abstract For decades, Ivermectin (IVM) has been recognized as a robust antiparasitic drug with excellent tolerance and safety profiles. Historically it has been used as the drug of choice for onchocerciasis and lymphatic filariasis global elimination programs. IVM is also a standard treatment against intestinal helminths and ectoparasites given its action as an oral insecticide. The current humanitarian crisis in Venezuela is a regional public health threat that requires immediate action. Venezuela's public health system has now crumbled due to a 70% shortage of medicines in public hospitals, low vaccination campaigns, and the massive exodus of medical personnel. Herein we discuss the repurposing of IVM to attenuate the burden imposed by the most prevalent neglected tropical diseases (NTDs) in Venezuela including soil-transmitted helminths, ectoparasites and, possibly, vector-borne diseases such as malaria. Additionally, novel experimental evidence has shown that IVM is active and efficacious against Chagas disease, Leishmaniases, arboviruses, and SARS-CoV-2 in vitro. In crisis-hit Venezuela, all of the aforementioned infectious diseases are public health emergencies that have been long ignored and that also require immediate attention. IVM's versatile nature could serve as a powerful tool to tackle the multiple overlapping endemic and emergent diseases that affect Venezuela today. The repurposing of this multipurpose drug would be without a doubt a timely therapeutical approach to help mitigate the tremendous burden of NTDs nationwide.


Regulating laboratory-developed tests


title: Caring for Patients with Advanced Stage Cancer at the Time of COVID‐19

text: This letter to the editor alerts oncologists to the importance of accurately defining benefit‐risk ratio during the COVID‐19 pandemic for patients with advanced‐stage cancer treated with chemotherapy after failure of first‐line and second‐line therapy.


title: Urinary Tract Infection with Atypical Mycobacteria

text: Abstract We present a case of disseminated atypical mycobacterial (Mycobacterium intracellularis) infection of the urinary tract. The patient had anhydrous ectodermal dysplasia and an unrelated defect in cell-mediated immunity. The infection resulted in a lengthy ureteral stricture with resultant hydronephrosis and diminished kidney function. A review of the literature revealed only 13 previous cases of atypical mycobacterial infection of the urinary tract. It is important to distinguish between simple colonization by these organisms and actual infection. Differentiation between atypical mycobacterial infection and urinary tuberculosis is important in determining the therapeutic regimen.


title: Different Epidemic Curves for Severe Acute Respiratory Syndrome Reveal Similar Impacts of Control Measures

text: Severe acute respiratory syndrome (SARS) has been the first severe contagious disease to emerge in the 21st century. The available epidemic curves for SARS show marked differences between the affected regions with respect to the total number of cases and epidemic duration, even for those regions in which outbreaks started almost simultaneously and similar control measures were implemented at the same time. The authors developed a likelihood-based estimation procedure that infers the temporal pattern of effective reproduction numbers from an observed epidemic curve. Precise estimates for the effective reproduction numbers were obtained by applying this estimation procedure to available data for SARS outbreaks that occurred in Hong Kong, Vietnam, Singapore, and Canada in 2003. The effective reproduction numbers revealed that epidemics in the various affected regions were characterized by markedly similar disease transmission potentials and similar levels of effectiveness of control measures. In controlling SARS outbreaks, timely alerts have been essential: Delaying the institution of control measures by 1 week would have nearly tripled the epidemic size and would have increased the expected epidemic duration by 4 weeks.


Responses to emerging and re-emerging infectious diseases: One world, One health


title: Discovery of functional genomic motifs in viruses with ViReMa–a Virus Recombination Mapper–for analysis of next-generation sequencing data

text: We developed an algorithm named ViReMa (Viral-Recombination-Mapper) to provide a versatile platform for rapid, sensitive and nucleotide-resolution detection of recombination junctions in viral genomes using next-generation sequencing data. Rather than mapping read segments of pre-defined lengths and positions, ViReMa dynamically generates moving read segments. ViReMa initially attempts to align the 5′ end of a read to the reference genome(s) with the Bowtie seed-based alignment. A new read segment is then made by either extracting any unaligned nucleotides at the 3′ end of the read or by trimming the first nucleotide from the read. This continues iteratively until all portions of the read are either mapped or trimmed. With multiple reference genomes, it is possible to detect virus-to-host or inter-virus recombination. ViReMa is also capable of detecting insertion and substitution events and multiple recombination junctions within a single read. By mapping the distribution of recombination events in the genome of flock house virus, we demonstrate that this information can be used to discover de novo functional motifs located in conserved regions of the viral genome.


title: Difficulties of Managing Submassive and Massive Pulmonary Embolism in the era of COVID-19

text: Abstract: Acute pulmonary embolism (PE) is a potentially life-threatening manifestation of venous thromboembolic disease. SARS-COV2, a novel coronavirus that causes COVID-19, has been associated with increased risk of thrombosis. We describe the therapeutic challenges of three patients presenting with PE and suspected or confirmed COVID-19.


title: Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

text: BACKGROUND: A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. METHODS: All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. FINDINGS: By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. INTERPRETATION: The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. FUNDING: Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.


docid: tcnzdose

title: Foraging Behaviour and Landscape Utilisation by the Endangered Golden-Crowned Flying Fox (Acerodon jubatus), The Philippines

text: Species of Old World fruit-bats (family Pteropodidae) have been identified as the natural hosts of a number of novel and highly pathogenic viruses threatening livestock and human health. We used GPS data loggers to record the nocturnal foraging movements of Acerodon jubatus, the Golden-crowned flying fox in the Philippines to better understand the landscape utilisation of this iconic species, with the dual objectives of pre-empting disease emergence and supporting conservation management. Data loggers were deployed on eight of 54 A. jubatus (two males and six females) captured near Subic Bay on the Philippine island of Luzon between 22 November and 2 December 2010. Bodyweight ranged from 730 g to 1002 g, translating to a weight burden of 3–4% of bodyweight. Six of the eight loggers yielded useful data over 2–10 days, showing variability in the nature and range of individual bat movements. The majority of foraging locations were in closed forest and most were remote from evident human activity. Forty-six discrete foraging locations and five previously unrecorded roost locations were identified. Our findings indicate that foraging is not a random event, with the majority of bats exhibiting repetitious foraging movements night-to-night, that apparently intact forest provides the primary foraging resource, and that known roost locations substantially underestimate the true number (and location) of roosts. Our initial findings support policy and decision-making across perspectives including landscape management, species conservation, and potentially disease emergence.


What does androgenetic alopecia have to do with COVID‐19? An insight into a potential new therapy


title: Understanding Spatial Heterogeneity of COVID-19 Pandemic Using Shape Analysis of Growth Rate Curves

text: The growth rates of COVID-19 across different geographical regions (e.g., states in a nation, countries in a continent) follow different shapes and patterns. The overall summaries at coarser spatial scales that are obtained by simply averaging individual curves (across regions) obscure nuanced variability and blurs the spatial heterogeneity at finer spatial scales. We employ statistical methods to analyze shapes of local COVID-19 growth rate curves and statistically group them into distinct clusters, according to their shapes. Using this information, we derive the so-called elastic averages of curves within these clusters, which correspond to the dominant incidence patterns. We apply this methodology to the analysis of the daily incidence trajectory of the COVID-pandemic at two spatial scales: A state-level analysis within the USA and a country-level analysis within Europe during mid-February to mid-May, 2020. Our analyses reveal a few dominant incidence trajectories that characterize transmission dynamics across states in the USA and across countries in Europe. This approach results in broad classifications of spatial areas into different trajectories and adds to the methodological toolkit for guiding public health decision making at different spatial scales.


title: RNA interference: From gene silencing to gene-specific therapeutics

text: Abstract In the past 4 years, RNA interference (RNAi) has become widely used as an experimental tool to analyse the function of mammalian genes, both in vitro and in vivo. By harnessing an evolutionary conserved endogenous biological pathway, first identified in plants and lower organisms, double-stranded RNA (dsRNA) reagents are used to bind to and promote the degradation of target RNAs, resulting in knockdown of the expression of specific genes. RNAi can be induced in mammalian cells by the introduction of synthetic double-stranded small interfering RNAs (siRNAs) 21–23 base pairs (bp) in length or by plasmid and viral vector systems that express double-stranded short hairpin RNAs (shRNAs) that are subsequently processed to siRNAs by the cellular machinery. RNAi has been widely used in mammalian cells to define the functional roles of individual genes, particularly in disease. In addition, siRNA and shRNA libraries have been developed to allow the systematic analysis of genes required for disease processes such as cancer using high throughput RNAi screens. RNAi has been used for the knockdown of gene expression in experimental animals, with the development of shRNA systems that allow tissue-specific and inducible knockdown of genes promising to provide a quicker and cheaper way to generate transgenic animals than conventional approaches. Finally, because of the ability of RNAi to silence disease-associated genes in tissue culture and animal models, the development of RNAi-based reagents for clinical applications is gathering pace, as technological enhancements that improve siRNA stability and delivery in vivo, while minimising off-target and nonspecific effects, are developed.


title: Prevalence of diabetes mellitus in 2019 novel coronavirus: a Meta-analysis

text: Abstract Background Since December 2019, a new strain ofcoronavirus named 2019 novel coronavirus (2019-nCoV) has been discovered in Wuhan. The prevalence of diabetes mellitus, which is a great public health issue leading to immunity inhibition and anincreased incidenceofinfections, has been increasing over the past ten years. The aim of this research was to systematically assess the prevalence of diabetes mellitus among 2019-nCoV. Methods We searched PubMed, Embase, Web of Science and Medline for observational studies up to February 25, 2020. A random effects model or fixed-effects model was applied to evaluate the pooled prevalence of diabetes mellitus and odds ratio (OR) with 95% confidence interval (CI). Findings In total, nine papers met the eligibility criteria. The pooled prevalence of DM was 9% (95% CI 6%–12%). There was obvious heterogeneity (I2 65%, p=0.004) in the prevalence of DM in these studies. The prevalence of DM in moderate patients with 2019-nCoV was 7% (95% CI 4%–10%). The prevalence of DM in severe patients with 2019-nCoV was 17% (95% CI 13%–21%). The prevalence of DM in severe patients with 2019-nCoV was significantly higher than that in moderate patients with 2019-nCoV (OR 2.49, 95% CI 1.70 to 3.64). Interpretation To our knowledge, this work is the first report showing the prevalence of diabetes mellitus in patients with 2019-nCoV, which is beneficial to prevent the spread of 2019-nCoV in the future.


Response to Gould et al. and Vincelli et al.


docid: jhzbsdel

title: Amesh Adalja: taking pandemic preparation seriously

text: Amesh Adalja talks to Gary Humphreys about pandemic preparedness and the challenges posed by COVID-19.


title: Prophylactic and therapeutic efficacy of mAb treatment against MERS-CoV in common marmosets

text: Abstract The high case-fatality rate of confirmed MERS-CoV infections underlines the urgent need for an effective treatment to reduce the disease severity and mortality. REGN3051 and REGN3048 are two fully human neutralizing monoclonal antibodies (mAb) against MERS-CoV that reduced virus replication in mice expressing human DPP4 upon prophylactic and therapeutic treatment. Here, we evaluated the prophylactic and therapeutic efficacy of REGN3048 and REGN3051 in the common marmoset model of MERS-CoV infection. Intravenous administration of mAb resulted in high levels of MERS-CoV-neutralizing activity in circulating blood. When animals were treated with mAbs one day before challenge, respiratory disease was less severe and, in animals treated with both REGN3048 and REGN3051, viral loads in the lungs were reduced. However, therapeutic treatment on day one after challenge was less efficacious as it did not prevent the development of severe respiratory disease and all treated animals developed bronchointerstitial pneumonia of similar severity as the control animals. Thus, mAb administration may be more effective in a prophylactic treatment regimen rather than treatment of MERS.


title: Otorhinolaryngology/maxillofacial disorders

text: ●. Upper respiratory infections are ubiquitous; ●. Voice changes may herald laryngeal cancer.


title: Coronavirus Infection in Cats

text: Cats are susceptible to natural infection with several strains of feline coronavirus that result in either effusive and noneffusive feline infectious peritonitis or enteritis. Excretion of coronavirus by infected cats into the environment occurs by way of feces, oronasal secretions, and possibly urine. Clinical diagnosis of coronavirus infection is made by evaluating the case history, physical findings, laboratory results, and coronavirus antibody titers as well as ruling out analogous diseases. An intranasal temperature-sensitive feline infectious peritonitis coronavirus vaccine is available for use in healthy cats 16 weeks of age or older.


title: Regioselective synthesis of 6-substituted-2-amino-5-bromo-4(3H)-pyrimidinones and evaluation of their antiviral activity

text: Abstract A series of 2-amino-5-bromo-4(3H)-pyrimidinone derivatives bearing different substituents at the C-6 position were synthesized using a highly regioselective lithiation–substitution protocol, and the effect of structural variation at the C-6 position on their antiviral activity in cell culture was evaluated. Although some of the derivatives were found to be active against various virus strains, they were effective only close to their toxicity threshold.


title: Coronavirus Disease (COVID-19–SARS-CoV-2) and Nutrition: Is Infection in Italy Suggesting a Connection?

text: Novel coronavirus disease (COVID-19) was declared a global pandemic on March 11, 2020. The outbreak first occurred in Wuhan, Hubei, China, in December 2019 and hit Italy heavily in February 2020. Several countries are adopting complete or partial lockdown to contain the growth of COVID-19 infection. These measures may affect people's mental health and well-being but are necessary to avoid spreading the pandemic. There has been a gradual increase in studies exploring prevention and control measures, and we recommend paying close attention to nutrition, which may contribute to modulating some important consequences of COVID-19 infection, as such pro-inflammatory cytokine storm.


title: Do children need a longer time to shed SARS-CoV-2 in stool than adults?

text: Abstract SARS-CoV-2 can be shed in the stool of patients in the recovery phase. Children show a longer shedding time than adults. We analyzed the possible causes of this finding and recommend that a negative stool sample be included in a patient's discharge criteria.


title: Intensive care admissions of children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in the UK: a multicentre observational study

text: BACKGROUND: In April, 2020, clinicians in the UK observed a cluster of children with unexplained inflammation requiring admission to paediatric intensive care units (PICUs). We aimed to describe the clinical characteristics, course, management, and outcomes of patients admitted to PICUs with this condition, which is now known as paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS). METHODS: We did a multicentre observational study of children (aged <18 years), admitted to PICUs in the UK between April 1 and May 10, 2020, fulfilling the case definition of PIMS-TS published by the Royal College of Paediatrics and Child Health. We analysed routinely collected, de-identified data, including demographic details, presenting clinical features, underlying comorbidities, laboratory markers, echocardiographic findings, interventions, treatments, and outcomes; serology information was collected if available. PICU admission rates of PIMS-TS were compared with historical trends of PICU admissions for four similar inflammatory conditions (Kawasaki disease, toxic shock syndrome, haemophagocytic lymphohistiocytosis, and macrophage activation syndrome). FINDINGS: 78 cases of PIMS-TS were reported by 21 of 23 PICUs in the UK. Historical data for similar inflammatory conditions showed a mean of one (95% CI 0·85–1·22) admission per week, compared to an average of 14 admissions per week for PIMS-TS and a peak of 32 admissions per week during the study period. The median age of patients was 11 years (IQR 8–14). Male patients (52 [67%] of 78) and those from ethnic minority backgrounds (61 [78%] of 78) were over-represented. Fever (78 [100%] patients), shock (68 [87%]), abdominal pain (48 [62%]), vomiting (49 [63%]), and diarrhoea (50 [64%]) were common presenting features. Longitudinal data over the first 4 days of admission showed a serial reduction in C-reactive protein (from a median of 264 mg/L on day 1 to 96 mg/L on day 4), D-dimer (4030 μg/L to 1659 μg/L), and ferritin (1042 μg/L to 757 μg/L), whereas the lymphocyte count increased to more than 1·0 × 10(9) cells per L by day 3 and troponin increased over the 4 days (from a median of 157 ng/mL to 358 ng/mL). 36 (46%) of 78 patients were invasively ventilated and 65 (83%) needed vasoactive infusions; 57 (73%) received steroids, 59 (76%) received intravenous immunoglobulin, and 17 (22%) received biologic therapies. 28 (36%) had evidence of coronary artery abnormalities (18 aneurysms and ten echogenicity). Three children needed extracorporeal membrane oxygenation, and two children died. INTERPRETATION: During the study period, the rate of PICU admissions for PIMS-TS was at least 11-fold higher than historical trends for similar inflammatory conditions. Clinical presentations and treatments varied. Coronary artery aneurysms appear to be an important complication. Although immediate survival is high, the long-term outcomes of children with PIMS-TS are unknown. FUNDING: None.


title: Crystallographic analysis of the N-terminal domain of Middle East respiratory syndrome coronavirus nucleocapsid protein

text: The N-terminal domain of the nucleocapsid protein from Middle East respiratory syndrome coronavirus (MERS-CoV NP-NTD) contains many positively charged residues and has been identified to be responsible for RNA binding during ribonucleocapsid formation by the virus. In this study, the crystallization and crystallographic analysis of MERS-CoV NP-NTD (amino acids 39–165), with a molecular weight of 14.7 kDa, are reported. MERS-CoV NP-NTD was crystallized at 293 K using PEG 3350 as a precipitant and a 94.5% complete native data set was collected from a cooled crystal at 77 K to 2.63 Å resolution with an overall R (merge) of 9.6%. The crystals were monoclinic and belonged to space group P2(1), with unit-cell parameters a = 35.60, b = 109.64, c = 91.99 Å, β = 101.22°. The asymmetric unit contained four MERS-CoV NP-NTD molecules.


title: Middle East Respiratory Syndrome Coronavirus and Pulmonary Tuberculosis Coinfection: Implications for Infection Control

text: Coinfection of Middle East respiratory syndrome coronavirus (MERS-CoV) with tuberculosis (TB) has not been previously reported. Here, we present 2 cases with both MERS-CoV and pulmonary TB. The first case was a 13-year-old patient who was admitted with a 2-month history of fever, weight loss, night sweats, and cough. The second patient was a 30-year-old female who had a 4-week history of cough associated with shortness of breath and weight loss of 2 kg. The 2 patients were diagnosed with pulmonary TB and had positive MERS-CoV. Both patients were discharged to complete their therapy for TB at home. It is likely that both patients had pulmonary TB initially as they had prolonged symptoms and they subsequently developed MERS-CoV infection. It is important to carefully evaluate suspected MERS-CoV patients for the presence of other infectious diseases, such as TB, especially if cohorting is done for suspected MERS-CoV to avoid nosocomial transmission.


title: Impact of COVID-19 pandemic on patients with ST-segment elevation myocardial infarction: Insights from a British cardiac center

text: Abstract The current study aimed to examine the impact of COVID-19 pandemic on patient-related delay with ST-segment elevation myocardial infarction (STEMI) at a tertiary center in the United Kingdom. The study demonstrated a significant delay in symptom-to-first medical contact and a higher cardiac troponin-I level on admission in patients with STEMI during the COVID-19 pandemic versus the pre-COVID era.


title: Mental Health and Psychosocial Challenges in the COVID-19 Pandemic: Food for Thought for Cardiovascular Health Care Professionals

text: Background The coronavirus disease (COVID-19) pandemic has produced substantial health challenges from the perspective of both its direct health complications and the disruption to delivery of standard care for individuals with a range of acute and chronic health issues. In parallel, the widespread application of social isolation initiatives in most countries raises the potential for significant mental health consequences and psychosocial impacts. This has major implications for cardiovascular health care professionals and the management of their patients. Challenges The COVID-19 pandemic and associated physical isolation practices are likely to result in a range of mental health and psychosocial challenges. In addition to an increasing incidence of anxiety, depression, suicidal ideation and post-traumatic stress, the pandemic may also witness an increase in substance abuse, domestic violence and relationship discord. The consequences of these complications will be further magnified, when considering their potential effect on cardiovascular disease and its management. Purpose This statement aims to summarise some of the potential mental health and psychosocial challenges that may arise in the setting of the COVID-19 pandemic.


title: Long-term protection from SARS coronavirus infection conferred by a single immunization with an attenuated VSV-based vaccine

text: Abstract Although the recent SARS coronavirus (SARS-CoV) that appeared in 2002 has now been contained, the possibility of re-emergence of SARS-CoV remains. Due to the threat of re-emergence, the overall fatality rate of ∼10%, and the rapid dispersion of the virus via international travel, viable vaccine candidates providing protection from SARS are clearly needed. We developed an attenuated VSV recombinant (VSV-S) expressing the SARS coronavirus (SARS-CoV) spike (S) protein. In cells infected with this recombinant, S protein was synthesized, glycosylated at approximately 17 Asn residues, and transported via the Golgi to the cell surface. Mice vaccinated with VSV-S developed SARS-neutralizing antibody and were able to control a challenge with SARS-CoV performed at 1 month or 4 months after a single vaccination. We also demonstrated, by passive antibody transfer, that the antibody response induced by the vaccine was sufficient for controlling SARS-CoV infection. A VSV-vectored SARS vaccine could have significant advantages over other SARS vaccine candidates described to date.


title: The Utility of Acute‐Phase Proteins in the Assessment of Treatment Response in Dogs With Bacterial Pneumonia

text: BACKGROUND: Acute‐phase proteins (APPs) are sensitive markers of inflammation, and serum C‐reactive protein (CRP) recently has been shown to be a useful diagnostic marker in dogs with bacterial pneumonia (BP). In humans with community‐acquired pneumonia, APPs also have great utility as follow‐up markers aiding in the assessment of treatment response. OBJECTIVES: The aim of our study was to investigate the applicability of APPs as markers of treatment response in dogs with BP. ANIMALS: Nineteen dogs diagnosed with BP and 64 healthy dogs. METHODS: The study was conducted as a prospective longitudinal observational study. Serum CRP, serum amyloid A (SAA), and haptoglobin concentrations were followed during a natural course of BP. Normalization of serum CRP was used to guide the duration of antibiotic treatment (treatment was stopped 5–7 days after CRP normalized) in 8 of 17 dogs surviving to discharge; 9 of 17 dogs were treated according to conventional recommendations. RESULTS: All measured APPs initially were significantly increased, but the magnitude of increase was not correlated to disease severity. C‐reactive protein and SAA concentrations decreased rapidly after initiation of antimicrobial treatment. When normalization of serum CRP was used to guide the duration of antibiotic treatment, treatment duration was significantly (P = .015) decreased without increasing the number of relapses. CONCLUSIONS AND CLINICAL IMPORTANCE: Serum CRP and SAA reflected the recovery process well and therefore may be used as markers of treatment response. According to the results, the normalization of serum CRP may be used to guide the duration of antibiotic treatment in dogs with BP.


title: Use and Interpretation of a Rapid Respiratory Syncytial Virus Antigen Detection Test Among Infants Hospitalized in a Neonatal Intensive Care Unit — Wisconsin, March 2015

text: On March 25, 2015, the Wisconsin Division of Public Health was notified of a possible respiratory syncytial virus (RSV) infection outbreak among infants hospitalized in a neonatal intensive care unit (NICU). On March 23, the index patient (neonate A), aged 3 days, had feeding intolerance and apnea. A nasopharyngeal swab specimen collected from neonate A was tested using a single-manufacturer rapid RSV antigen detection test (RRADT) at the hospital laboratory; the result was positive. The following day, because of concern about the possibility of more widespread RSV infection, RRADT was used to test nasopharyngeal swab specimens from neonate B, aged 1 month, who had resided in a different hospital room in the NICU and had developed an increased oxygen requirement, apnea, and poor feeding that day, as well as from two asymptomatic neonates who were hospitalized in the same room with neonate A; all three were positive. Later that day, nasopharyngeal swab specimens from the remaining 16 asymptomatic NICU patients were tested using the same RRADT; seven tests were positive, making a total of 11 positives. All 20 RRADTs were performed at the hospital laboratory.


High population densities catalyze the spread of COVID-19


title: Modelling the volatility of international visitor arrivals to New Zealand

text: Abstract International visitor arrivals are considered to be a major source of foreign exchange, tourism-related employment and other tourism-related activities. This study used SARIMAX/(E)GARCH volatility models to forecast visitor arrivals by air transport to New Zealand from its eight key tourist source markets (Australia, Canada, China, Japan, South Korea, Germany, the United Kingdom (UK) and the United States (US)) and control macroeconomic factors together with global and regional structural changes. The empirical models reveal that the macroeconomic factors contributed at various levels to different markets, and the models we provided made accurate and reliable forecasts for visitor arrivals by air transport from all studied markets. The results from the markets for Germany, Japan, South Korea and the UK showed that significantly negative tourism demand shocks increased the volatility of tourism arrivals, more than positive tourism demand shocks of equal magnitude. Accordingly, the findings of this study will allow policy-makers in the New Zealand tourism sector and other stakeholders (e.g. airline management) to better understand the impacts on the volatility of visitor arrivals to New Zealand.


docid: ihinqmig

title: The Structure and Functions of Coronavirus Genomic 3’ and 5’ Ends

text: Coronaviruses (CoVs) are an important cause of illness in humans and animals. Most human coronaviruses commonly cause relatively mild respiratory illnesses; however two zoonotic coronaviruses, SARS-CoV and MERS-CoV, can cause severe illness and death. Investigations over the past thirty-five years have illuminated many aspects of coronavirus replication. The focus of this review is the functional analysis of conserved RNA secondary structures in the 5’ and 3’ of the betacoronavirus genomes. The 5’ 350 nucleotides folds into a set of RNA secondary structures which are well conserved, and reverse genetic studies indicate that these structures play an important role in the discontinuous synthesis of subgenomic RNAs in the betacoronaviruses. These cis-acting elements extend 3’ of the 5’UTR into ORF1a. The 3’UTR is similarly conserved and contains all of the cis-acting sequences necessary for viral replication. Two competing conformations near the 5’ end of the 3’UTR have been shown to make up a potential molecular switch. There is some evidence that an association between the 3’ and 5’UTRs is necessary for subgenomic RNA synthesis, but the basis for this association is not yet clear. A number of host RNA proteins have been shown to bind to the 5’ and 3’ cis-acting regions, but the significance of these in viral replication is not clear. Two viral proteins have been identified as binding to the 5’ cis-acting region, nsp1 and N protein. A genetic interaction between nsp8 and nsp9 and the region of the 3’UTR that contains the putative molecular switch suggests that these two proteins bind to this region.


title: Rechtsfragen der Ressourcenzuteilung in der COVID-19-Pandemie – Zwischen Utilitarismus und Lebenswertindifferenz

text: The COVID-19 pandemic poses unprecedented challenges for the German health care system. What is already the case in some other countries, may occur in Germany in the near future also: Faced with limited ICU resources, doctors will be forced to decide which patients to treat and which to let die. This paper examines the legal implications of such decisions. It takes up arguments from the general discussion on prioritization in medicine. A constitutional hurdle for the application of utilitarian criteria (in particular patients' age or social role) comes from the principle that every human life is of equal value and must not be traded off against others ("life value indifference"). However, the limits that the Grundgesetz (German Basic Law) sets for state actions do not apply directly to doctors. According to the Musterberufsordnung (professional code of conduct), doctors act based on their conscience and the requirements of medical ethics and humanity. The implications of this normative standard for the prioritizing in an exceptional situation as the COVID 19 pandemic have not been sufficiently clarified. This uncertainty leads to emotional and moral burdens for doctors. The authors conclude that the German law grants a limited freedom of choice that allows physicians to apply utilitarian criteria in addition to purely medical decision algorithms.


title: The emerging novel Middle East respiratory syndrome coronavirus: The “knowns” and “unknowns”

text: A novel lineage C betacoronavirus, originally named human coronavirus EMC/2012 (HCoV-EMC) and recently renamed Middle East respiratory syndrome coronavirus (MERS-CoV), that is phylogenetically closely related to Tylonycteris bat coronavirus HKU4 and Pipistrellus bat coronavirus HKU5, which we discovered in 2007 from bats in Hong Kong, has recently emerged in the Middle East to cause a severe acute respiratory syndrome (SARS)-like infection in humans. The first laboratory-confirmed case, which involved a 60-year-old man from Bisha, the Kingdom of Saudi Arabia (KSA), who died of rapidly progressive community-acquired pneumonia and acute renal failure, was announced by the World Health Organization (WHO) on September 23, 2012. Since then, a total of 70 cases, including 39 fatalities, have been reported in the Middle East and Europe. Recent clusters involving epidemiologically-linked household contacts and hospital contacts in the Middle East, Europe, and Africa strongly suggested possible human-to-human transmission. Clinical and laboratory research data generated in the past few months have provided new insights into the possible animal reservoirs, transmissibility, and virulence of MERS-CoV, and the optimal laboratory diagnostic options and potential antiviral targets for MERS-CoV-associated infection.


title: The “forgotten zone”: Acquired disorders of the trachea in adults

text: Summary The upper airway is generally defined as the air passage segment that extends between the naso- or oropharynx and the carina. The longest segment of the upper airway—the trachea—begins at the inferior portion of the larynx and extends to the branch point of the main carina. The trachea has the potential to be a “forgotten zone” in differential diagnoses, as pathological processes involving this portion may not receive prominent clinical consideration in disorders presenting with respiratory symptoms and signs. Unlike the oropharynx, this anatomical area is beyond visualization on routine inspection; unlike the mediastinum and lung fields, it is a potential “blind spot” on initial, plain radiographic examination of the chest. Nonetheless, the adult trachea is affected by a number of primary disorders and is also a target organ of a variety of systemic diseases. This review will focus on both primary and systemic diseases involving the adult trachea with specific attention to their clinical manifestations and diagnostic hallmarks.


title: Psychological Stress among Health Care Professionals during the 2019 Novel Coronavirus Disease Outbreak: Cases from Online Consulting Customers

text: BACKGROUND: During the 2019 novel coronavirus disease (COVID-19) outbreak, online consulting has been widely used to address mental health problems, including health care professionals (HCPs) caring for COVID-19 patients who experienced substantial psychological distress. AIM: To explore the severity of perceived stress and potential correlates among the HCPs seeking online mental health services during the COVID-19 outbreak. METHODS: A descriptive study was conducted among 34 HCPs to assess levels of psychological distress using the Perceived Stress Scale (PSS-10), Patient Health Questionnaire (PHQ-9), and Generalized Anxiety Disorder (GAD-7) questionnaire. The HCPs working in different departments were compared using χ(2)-test for categorized variables and t-test for continuous ones, followed by the analysis of covariate (ANCOVA) to compare the perceived stress. Linear regression for the PSS-10 score was performed to identify potential correlates of stress. RESULTS: The sample overall (n=34) showed a relatively moderate level of perceived stress (PSS mean=15.71±4.02) with 38% identified as depressed (PHQ-9≥5) and 24% as suffering from anxiety (GAD-7≥5). Those working at intensive care units (ICUs) or in departments of respiratory medicine (RM) demonstrated significantly higher perceived stress than those at other departments (adjusted mean: 17.48±.96 vs. 13.06±1.25, p=.018, partial η(2)=.173). High perceived stress was most strongly associated with being depressed (beta=.486, p=.002) and working at ICUs/RM (beta=.345, p=.023). CONCLUSIONS: The psychological health status of frontline health care professionals during the 2019 novel coronavirus outbreak warrants clinical attention. Online mental health services has played a major role although its effectiveness and barriers to its utilization require further evaluation.


title: Immunoregulation through membrane proteins modified by reducing conditions induced by immune reactions

text: Selected disulfide bonds in membrane proteins are labile and are thus susceptible to changes in redox potential and/or the presence of thiol isomerase enzymes. Modification of these disulfide bonds can lead to conformational changes of the protein that in turn may alter protein activity and function. This occurs in the entry of several enveloped viruses into their host cells, e.g. HIV, hepatitis C virus and Newcastle disease virus. Labile disulfide bonds are also important in platelet activation, cytokine signalling and in a variety of diseases including cancer and arthritis. In this review we will concentrate on recent advances in understanding the conditions that lead to disulfide bond reduction in membrane proteins and their effects in regulating immune function.


title: Synthesis of 5-isoxazol-5-yl-2′-deoxyuridines exhibiting antiviral activity against HSV and several RNA viruses

text: Abstract This paper describes a simple method for synthesizing a small library of 5-isoxazol-5-yl-2′-deoxyuridines from 5-iodo-2′-deoxyuridine. Nitrile oxides were generated in situ from oximes using a commercial bleaching agent; their cycloaddition with 5-ethynyl-2′-deoxyuridine yielded isoxazoles possessing activity against herpes simplex viruses 1 and 2, Encephalomyocarditis virus, Coxsackie B3, and vesicular stomatitis virus; these isoxazoles were, however, inactive against corona virus, influenza virus, and HIV.


title: Predicting COVID-19 Incidence Using Anosmia and Other COVID-19 Symptomatology: Preliminary Analysis Using Google and Twitter

text: OBJECTIVE: To determine the relative correlations of Twitter and Google Search user trends concerning smell loss with daily coronavirus disease 2019 (COVID-19) incidence in the United States, compared to other severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) symptoms. To describe the effect of mass media communications on Twitter and Google Search user trends. STUDY DESIGN: Retrospective observational study. SETTING: United States. SUBJECTS AND METHODS: Google Search and “tweet” frequency concerning COVID-19, smell, and nonsmell symptoms of COVID-19 generated between January 1 and April 8, 2020, were collected using Google Trends and Crimson Hexagon, respectively. Spearman coefficients linking each of these user trends to COVID-19 incidence were compared. Correlations obtained after excluding a short timeframe (March 22 to March 24) corresponding to the publication of a widely read lay media publication reporting anosmia as a symptom of infection was performed for comparative analysis. RESULTS: Google searches and tweets concerning all nonsmell symptoms (0.744 and 0.761, respectively) and COVID-19 (0.899 and 0.848) are more strongly correlated with disease incidence than smell loss (0.564 and 0.539). Twitter users tweeting about smell loss during the study period were more likely to be female (52%) than users tweeting about COVID-19 more generally (47%). Tweet and Google Search frequency pertaining to smell loss increased significantly (>2.5 standard deviations) following a widely read media publication linking smell loss and SARS-CoV-2 infection. CONCLUSIONS: Google Search and tweet frequency regarding fever and shortness of breath are more robust indicators of COVID-19 incidence than anosmia. Mass media communications represent important confounders that should be considered in future analyses.


title: Chapter 9 Global Regulatory Guidelines for Vaccines

text: Abstract Because in the past vaccines were considered inherently safe, only limited nonclinical testing used to be required. However, from about 2003 more stringent nonclinical testing guidelines were introduced for novel vaccines (and, in some cases, marketed vaccines attempting registration in new markets) given that vaccines are typically administered to healthy individuals, often infants. These safety considerations become even more important as technologies allowing the development of novel vaccine types are developed, such as DNA vaccines and those delivered in vector systems such as adenoviral vectors. The use of adjuvants other than the standard aluminum-based ones and novel delivery systems such as electrostimulation have also led to additional testing requirements. This chapter describes the current regulatory expectations for the preclinical development of vaccines.


title: Towards the first multi-epitope recombinant vaccine against Crimean-Congo hemorrhagic fever virus: A computer-aided vaccine design approach

text: Abstract Crimean-Congo hemorrhagic fever (CCHF) is considered one of the major public health concerns with case fatality rates of up to 80%. Currently, there is no effective approved vaccine for CCHF. In this study, we used a computer-aided vaccine design approach to develop the first multi-epitope recombinant vaccine for CCHF. For this purpose, linear B-cell and T-cell binding epitopes from two structural glycoproteins of CCHF virus including Gc and Gn were predicted. The epitopes were further studied regarding their antigenicity, allergenicity, hydrophobicity, stability, toxicity and population coverage. A total number of seven epitopes including five T-cell and two B-cell epitopes were screened for the final vaccine construct. Final vaccine construct composed of 382 amino acid residues which were organized in four domains including linear B-cell, T-cell epitopes and cholera toxin B-subunit (CTxB) along with heat labile enterotoxin IIc B subunit (LT-IIc) as adjuvants. All the segments were joined using appropriate linkers. The physicochemical properties as well as the presence of IFN-γ inducing epitopes in the proposed vaccine, was also checked to determining the vaccine stability, solubility and its ability to induce cell-mediated immune responses. The 3D structure of proposed vaccine was subjected to the prediction of computational B-cell epitopes and molecular docking studies with MHC-I and II molecules. Furthermore, molecular dynamics stimulations were performed to study the vaccine-MHCs complexes stability during stimulation time. The results suggest that our proposed vaccine was stable, well soluble in water and potentially antigenic. Results also demonstrated that the vaccine can induce both humoral and cell-mediated immune responses and could serve as a promising anti-CCHF vaccine candidate.


title: Seroprevalence of MERS-CoV in healthy adults in western Saudi Arabia, 2011–2016

text: Abstract Background The Middle East respiratory syndrome coronavirus (MERS-CoV) is a newly recognized zoonotic coronavirus. Current evidence confirms the role of dromedaries in primary human infections but does not explain the sporadic community cases. However, asymptomatic or subclinical cases could represent a possible source of infection in the community. Methods Archived human sera (7461) collected between 2011 and 2016 from healthy adult blood donors from 50 different nationalities in the western part of Saudi Arabia were obtained for MERS-CoV seroprevalence investigation. Samples were tested for MERS-CoV S1-specific antibodies (Abs) by ELISA and confirmed by testing for neutralizing Abs (nAbs) using both pseudotyped and live virus neutralization assays. Results Out of 7461 samples, 174 sera from individuals with 18 different nationalities were ELISA positive (2.3%, 95% CI 2.0–2.7). Presence of nAbs was confirmed in 17 samples (0.23%, 95% CI 0.1–0.4) of which one sample exhibited positivity in both neutralization assays. Confirmed seropositivity was identified in young (15–44 years) men and women from Saudi Arabia, Egypt, Yemen, Pakistan, Palestine, Sudan, and India without significant preference. Conclusions An increasing trend of MERS-CoV seroprevalence was observed in the general population in western Saudi Arabia, suggesting that asymptomatic or mild infections might exist and act as an unrecognized source of infection. Seropositivity of individuals from different nationalities underscores the potential MERS exportation outside of the Arabian Peninsula. Thus, enhanced and continuous surveillance is highly warranted.


docid: hynbtwlb

title: Abnormal regulation of TSG101 in mice with spongiform neurodegeneration

text: Spongiform neurodegeneration is characterized by the appearance of vacuoles throughout the central nervous system. It has many potential causes, but the underlying cellular mechanisms are not well understood. Mice lacking the E3 ubiquitin ligase Mahogunin Ring Finger-1 (MGRN1) develop age-dependent spongiform encephalopathy. We identified an interaction between a “PSAP” motif in MGRN1 and the ubiquitin E2 variant (UEV) domain of TSG101, a component of the endosomal sorting complex required for transport I (ESCRT-I), and demonstrate that MGRN1 multimonoubiquitinates TSG101. We examined the in vivo consequences of loss of MGRN1 on TSG101 expression and function in the mouse brain. The pattern of TSG101 ubiquitination differed in the brains of wild-type mice and Mgrn1 null mutant mice: at 1 month of age, null mutant mice had less ubiquitinated TSG101, while in adults, mutant mice had more ubiquitinated, insoluble TSG101 than wild-type mice. There was an associated increase in epidermal growth factor receptor (EGFR) levels in mutant brains. These results suggest that loss of MGRN1 promotes ubiquitination of TSG101 by other E3s and may prevent its disassociation from endosomal membranes or cause it to form insoluble aggregates. Our data implicate loss of normal TSG101 function in endo-lysosomal trafficking in the pathogenesis of spongiform neurodegeneration in Mgrn1 null mutant mice.


title: Why we march! Feminist activism in critical times: Lessons from the women's march on Washington

text: Abstract As professors, we have witnessed, anecdotally, a shift in doing social justice advocacy teaching. We have witnessed within some of our classrooms a more empowered hostility and intolerance to conversations pertaining to social justice. We agree that this phenomenon is pedagogical because this language usage not only teaches, but also legitimizes hate speech. We have witnessed the illogical extension of this hate speech with an increase in hate crimes across the country since the 2016 election, Without peaceful protest and grassroots feminist activism, we fear that this speech, this pedagogy, will spread even more violent forms of hate. This research was conducted in and around the first Women's March of 2017. We wanted to know: What were marchers' prior histories of political activism prior to the election? If this was their first time participating in such a manner, how did the election and its early political fallout inspire marchers to attend? 2) What plans did marchers have for political activism after the march? 3) What can be learned from these participants about the current state of political activism in our current era? A total of 788 individuals had taken part in the online survey. Among the participants, 45% marched on Washington, and 55% participated in the march in their local cities. We found that issues of gender equality were of great concern to many of the marchers. In particular, issues related to economic and social equity, including salary. These findings are interesting as they speak to the broader implications of gender equality. And, as the past few years have demonstrated, these issues continue to be of concern.


Acute coronary syndromes during COVID-19: A simple short guide from Italy to assist in the management of ACS during the COVID-19 pandemic is presented


title: Development of rapid guidelines: 1. Systematic survey of current practices and methods

text: BACKGROUND: Guidelines in the healthcare field generally should contain evidence-based recommendations to inform healthcare decisions. Guidelines often require 2 years or more to develop, but certain circumstances necessitate the development of rapid guidelines (RGs) in a short period of time. Upholding methodological rigor while meeting the reduced development timeframe presents a challenge for developing RGs. Our objective was to review current practices and standards for the development of RGs. This is the first of a series of three articles addressing methodological issues around RGs. METHODS: We conducted a systematic survey of methods manuals and published RGs to identify reasons for the development of RGs. Data sources included existing guideline manuals, published RGs, Trip Medical Database, MEDLINE, EMBASE and communication with guideline developers until February 2018. RESULTS: We identified 46 guidelines that used a shortened timeframe for their development. Nomenclature describing RGs varied across organisations, wherein the United States Centers for Disease Control and Prevention produced ‘Interim Guidelines’, the National Institute for Health and Care Excellence in the United Kingdom developed ‘Short Clinical Guidelines’, and WHO provided ‘Rapid Advice’. The rationale for RGs included response to emergencies, rapid increases in cases of a condition or disease severity, or new evidence regarding treatment. In general, the methods to assess the quality of evidence, the consensus process and the management of the conflict of interest were not always clear. While we identified another 11 RGs from other institutions, there was no reference to timeframe and reasons for conducting a RG. The three organisations mentioned above provide guidance for the development of RGs. CONCLUSIONS: There is a lack of standardised nomenclature and definitions regarding RGs and there is inconsistency in the methods described in manuals and in RG. It is therefore important that all RGs provide a detailed and transparent description of their methods in order for readers and end-users to be able to assess their quality and validate their findings. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12961-018-0327-8) contains supplementary material, which is available to authorized users.


title: Alcohol use in times of the COVID 19: Implications for monitoring and policy

text: Based on a literature search undertaken to determine the impacts of past public health crises, and a systematic review of the effects of past economic crises on alcohol consumption, two main scenarios—with opposite predictions regarding the impact of the current COVID‐19 pandemic on the level and patterns of alcohol consumption—are introduced. The first scenario predicts an increase in consumption for some populations, particularly men, due to distress experienced as a result of the pandemic. A second scenario predicts the opposite outcome, a lowered level of consumption, based on the decreased physical and financial availability of alcohol. With the current restrictions on alcohol availability, it is postulated that, for the immediate future, the predominant scenario will likely be the second, while the distress experienced in the first may become more relevant in the medium‐ and longer‐term future. Monitoring consumption levels both during and after the COVID‐19 pandemic will be necessary to better understand the effects of COVID‐19 on different groups, as well as to distinguish them from those arising from existing alcohol control policies.