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The second COVID-19 wave is sweeping the globe as restrictions are lifted. Malta, the ‘poster child of Europe’s COVID-19 first wave success’ also fell victim shortly after it welcomed the first tourists on 1st of July 2020. Only four positive cases were reported over the successive 15 days. Stability was disrupted when two major mass events were organized despite various health professional warnings. In a matter of few just days, daily cases rose to two-digit figures, with high community transmission, a drastic rise in active cases, and a rate per hundred thousand in Europe second only to Spain. Frontliners were swamped with swabbing requests while trying to sustain robust case management, contact tracing and follow-up. Indeed, the number of hospitalizations and the need for intensive ventilation increased. Despite the initial cases were among young adults, within weeks a small spill off on the more elderly population was observed. Restrictions were re-introduced including mandatory mask wearing in specific locations and capping of the total number of people in a single gathering. Malta is an island and the potential for containment would have been relatively simple and effective and permitting mass gatherings was unwise. Protecting the health of the population should take centre stage while carrying out extensive testing, contact tracing and surveillance. Containment and mitigation along with public cooperation is the key to curbing resurgences especially with the influenza season around the corner.
In response to the coronavirus disease 2019 (COVID-19) outbreak, caused by SARS-CoV-2, multiple diagnostic tests are required for acute disease diagnosis, contact tracing, monitoring asymptomatic infection rates and assessing herd immunity. While PCR remains the frontline test of choice in the acute diagnostic setting, serological tests are urgently needed. Unlike PCR tests which are highly specific, cross-reactivity is a major challenge for COVID-19 antibody tests considering there are six other coronaviruses known to infect humans. SARS-CoV is genetically related to SARS-CoV-2 sharing approximately 80% sequence identity and both belong to the species SARS related coronavirus in the genus Betacoronavirus of family Coronaviridae. We developed and compared the performance of four different serological tests to comprehensively assess the cross-reactivity between COVID-19 and SARS patient sera. There is significant cross-reactivity when N protein of either virus is used. The S1 or RBD regions from the spike (S) protein offers better specificity. Amongst the different platforms, capture ELISA performed best. We found that SARS survivors all have significant levels of antibodies remaining in their blood 17 years after infection. Anti-N antibodies waned more than anti-RBD antibodies, and the latter is known to play a more important role in providing protective immunity.
This study focused on the investigation of the effectiveness of negative air ionization (NAI), photocatalytic oxidation (PCO), and the combination of NAI and PCO on the removal of aerosolized Escherichia coli, Candida famata, and [Formula: see text] vir phage under different relative humidity. The experiments were conducted with a stainless steel reactor equipped with a negative air ion generator, a photocatalytic filter, and two ultraviolet lamps with 365 nm wavelength. The removal efficiency [Formula: see text] , defined as one minus the ratio of the outlet concentration to the inlet concentration of the appropriate bioaerosol, was used to evaluate the effectiveness of the removal methods. The combination of NAI and PCO was the most efficient removal method for aerosolized E. coli [Formula: see text] , C. famata [Formula: see text] , and [Formula: see text] vir phage [Formula: see text]. In this removal method, the contributions of NAI were higher than those of PCO for the removal of E. coli and C. famata; for the removal of [Formula: see text] virus phage the contributions of NAI and PCO were comparable NAI was the least efficient removal method for bioaerosols, and the removal efficiencies are: [Formula: see text] for E. coli; [Formula: see text] for C. famata; and [Formula: see text] for [Formula: see text] vir phage.
Coronaviruses (CoVs) encode a mixture of highly conserved and novel genes, as well as genetic elements necessary for infection and pathogenesis, raising the possibility of common targets for attenuation and therapeutic design. In this study, we focused on highly conserved nonstructural protein 16 (NSP16), a viral 2′O-methyltransferase (2′O-MTase) that encodes critical functions in immune modulation and infection. Using reverse genetics, we disrupted a key motif in the conserved KDKE motif of Middle East respiratory syndrome CoV (MERS-CoV) NSP16 (D130A) and evaluated the effect on viral infection and pathogenesis. While the absence of 2′O-MTase activity had only a marginal impact on propagation and replication in Vero cells, dNSP16 mutant MERS-CoV demonstrated significant attenuation relative to the control both in primary human airway cell cultures and in vivo. Further examination indicated that dNSP16 mutant MERS-CoV had a type I interferon (IFN)-based attenuation and was partially restored in the absence of molecules of IFN-induced proteins with tetratricopeptide repeats. Importantly, the robust attenuation permitted the use of dNSP16 mutant MERS-CoV as a live attenuated vaccine platform protecting from a challenge with a mouse-adapted MERS-CoV strain. These studies demonstrate the importance of the conserved 2′O-MTase activity for CoV pathogenesis and highlight NSP16 as a conserved universal target for rapid live attenuated vaccine design in an expanding CoV outbreak setting. IMPORTANCE Coronavirus (CoV) emergence in both humans and livestock represents a significant threat to global public health, as evidenced by the sudden emergence of severe acute respiratory syndrome CoV (SARS-CoV), MERS-CoV, porcine epidemic diarrhea virus, and swine delta CoV in the 21st century. These studies describe an approach that effectively targets the highly conserved 2′O-MTase activity of CoVs for attenuation. With clear understanding of the IFN/IFIT (IFN-induced proteins with tetratricopeptide repeats)-based mechanism, NSP16 mutants provide a suitable target for a live attenuated vaccine platform, as well as therapeutic development for both current and future emergent CoV strains. Importantly, other approaches targeting other conserved pan-CoV functions have not yet proven effective against MERS-CoV, illustrating the broad applicability of targeting viral 2′O-MTase function across CoVs.
In the original publication of this article, one of the co-author name "D. de Monteverde-Robb" was inadvertently mentioned as "R. de Monteverde-Robb". The correct author name is "D. de Monteverde-Robb". This error has been corrected with this erratum.
Little is known regarding the molecular epidemiology of Middle East respiratory syndrome coronavirus (MERS-CoV) circulating in dromedaries outside Saudi Arabia. To address this knowledge gap, we sequenced 10 complete genomes of MERS-CoVs isolated from 2 live and 8 dead dromedaries from different regions in the United Arab Emirates (UAE). Phylogenetic analysis revealed one novel clade A strain, the first detected in the UAE, and nine clade B strains. Strain D998/15 had a distinct phylogenetic position within clade A, being more closely related to the dromedary isolate NRCE-HKU205 from Egypt than to the human isolates EMC/2012 and Jordan-N3/2012. A comparison of predicted protein sequences also demonstrated the existence of two clade A lineages with unique amino acid substitutions, A1 (EMC/2012 and Jordan-N3/2012) and A2 (D998/15 and NRCE-HKU205), circulating in humans and camels, respectively. The nine clade B isolates belong to three distinct lineages: B1, B3 and B5. Two B3 strains, D1271/15 and D1189.1/15, showed evidence of recombination between lineages B4 and B5 in ORF1ab. Molecular clock analysis dated the time of the most recent common ancestor (tMRCA) of clade A to March 2011 and that of clade B to November 2011. Our data support a polyphyletic origin of MERS-CoV in dromedaries and the co-circulation of diverse MERS-CoVs including recombinant strains in the UAE.
The recent coronavirus infectious disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is placing health systems in serious challenges worldwide. Shocking statistics each day has prompted the World Health Organization to officially declare the COVID-19 outbreak as a pandemic in March 2020. Preliminary studies have shown increased mortality in patients with solid cancers and infection by SARS-CoV-2. Until now, the evidence on the behavior of COVID-19 in patients with a history of thyroid cancer remains scarce, and most of the recommendations given are based on common sense. Therefore, in this viewpoint, we present a brief review of several challenges we are frequently facing during this pandemic and a series of recommendations based on what we have implemented in our clinical practice at a university hospital currently mostly dedicated to COVID-19.
Coronavirus disease 2019 (COVID-19) broke out first in Wuhan City, Hubei Province, China. In the process of controlling the pandemic, many Chinese medical staff (MS) were infected. We used government data, post mortem reports, and the medical literature on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, as well as prevention-and-control guidelines from the government, hospitals and media, to discuss the main risks factors faced by MS. We suggest that, when dealing with a similar pandemic in the future, guidance on personal protective equipment must be provided and materials reserved in advance. Also, the emergency response of medical institutions should be enhanced, and information shared with other countries facing identical severe challenges.
Concerning the two approaches to the Covid-19 case mortality rate published in the literature, namely computing the ratio of (a) the daily number of deaths to a time delayed daily number of confirmed infections; and (b) the cumulative number of deaths to confirmed infections up to a certain time, both numbers having been acquired in the middle of an outbreak, it is shown that each suffers from systematic error of a different source. We further show that in the absence of detailed knowledge of the time delay distribution of (a), the true case mortality rate is obtained by pursuing method (b) at the end of the outbreak when the fate of every case has decisively been rendered. The approach is then employed to calculate the mean case mortality rate of 13 regions of China where every case has already been resolved. This leads to a mean rate of 0.527 +/- 0.001 %.
Several obligate biotrophic phytopathogens, namely oomycetes and fungi, invade and feed on living plant cells through specialized structures known as haustoria. Deploying an arsenal of secreted proteins called effectors, these pathogens balance their parasitic propagation by subverting plant immunity without sacrificing host cells. Such secreted proteins, which are thought to be delivered by haustoria, conceivably reprogram host cells and instigate structural modifications, in addition to the modulation of various cellular processes. As effectors represent tools to assist disease resistance breeding, this short review provides a bird’s eye view on the relationship between the virulence function of effectors and their subcellular localization in host cells.
Four types of porcine epidemic diarrhea virus (PEDV) variants with a large deletion in the spike protein were detected, together with the original US PEDV, from pig fecal and oral fluid samples collected during 2016-2017 in the US. Two of the variants are similar to those identified in Japan: one contains a 194-aa deletion, the same as PEDV variant TTR-2/JPN/2014, while the other contains a 204-aa deletion, the same as PEDV variant JKa-292/CS1de204. Two new S1 NTD-del PEDV variants were found: one contains a 201-aa deletion located at residues 30-230 and the other contains a 202-aa deletion located at residues 24-225 of the S protein. This is the first report on coinfection of S1 NTD-del PEDV variants and the original US PEDV strain in US pigs, indicating that PEDV continues to evolve in pigs and might be responsible for disease pattern changes.
OBJECTIVE: To report our initial experience of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2)/acute coronary syndrome (ACS) patients undergoing standard of care invasive management. BACKGROUND: The rapid diffusion of the SARS‐CoV‐2 together with the need for isolation for infected patients might be responsible for a suboptimal treatment for SARS‐CoV‐2 ACS patients. Recently, the group of Sichuan published a protocol for COVID/ACS infected patients that see the thrombolysis as the gold standard of care. METHODS: We enrolled 31 consecutive patients affected by SARS‐COV‐2 admitted to our emergencies room for suspected ACS. RESULTS: All patients underwent urgent coronary angiography and percutaneous coronary intervention (PCI) when required except two patients with severe hypoxemia and unstable hemodynamic condition that were conservatively treated. Twenty‐one cases presented diffuse ST‐segment depression while in the remaining cases anterior and inferior ST‐elevation was present in four and six cases, respectively. PCI was performed in all cases expect two that were diagnosed as suspected myocarditis because of the absence of severe coronary disease and three with apical ballooning at ventriculography diagnostic for Tako‐Tsubo syndromes. Two patients conservatively treated died. The remaining patients undergoing PCI survived except one that required endotracheal intubation (ETI) and died at Day 6. ETI was required in five more patients while in the remaining cases CPAP was used for respiratory support. CONCLUSIONS: Urgent PCI for ACS is often required in SARS‐CoV‐2 patients improving the prognosis in all but the most advanced patients. Complete patient history and examination, routine ECG monitoring, echocardiography, and careful evaluation of changes in cardiac enzymes should be part of the regular assessment procedures also in dedicated COVID positive units.
The outcomes model most applied in continuing education for the health professions evaluation is Moore and colleagues’ conceptual framework. Examination of how the levels interact and the role of confidence and intention to change can help outcomes professionals understand better how to impact clinician practice and conductand report outcomes studies. The current study examined the relationships among knowledge and competence change, confidence change, and intention to change across 57 online oncology certified education programmes published from 2018 to 2020 on Medscape.org. Findings indicate that not only improvement in knowledge and competence but also reinforcement of knowledge and competence are significant predictors of changes in confidence. They also indicate that knowledge and competence influence intention to change through confidence.
COVID‐19, which appeared to originate in China in December 2019, has spread worldwide pandemically. Recently, a letter regarding COVID‐19 impact on dentistry has been published in this Journal (Prati et al. 2020). In Europe, Italy is the second most affected nation by COVID‐19 infection and the first for number of deaths (WHO SR). In March 2020, the Italian Ministry of Health ordered the suspension of all non‐urgent outpatient activities (including dentistry) in hospitals and clinics of the public health system, until the end of the lockdown (Press releases Italian Ministry of Health, 1).
Infections caused by Fasciola hepatica are of great importance in the veterinary field, as they cause important economic losses to livestock producers. Serodiagnostic methods, typically ELISA (with either native or recombinant antigens), are often used for early diagnosis. The use of native antigens, as in the MM3-SERO ELISA (commercialized as BIO K 211, BIO-X Diagnostics), continues to be beneficial in terms of sensitivity and specificity; however, there is interest in developing ELISA tests based on recombinant antigens to avoid the need to culture parasites. Of the antigens secreted by adult flukes, recombinant procathepsin L1 (rFhpCL1) is the most commonly tested in ELISA to date. However, although adult flukes produce three different clades of CLs (FhCL1, FhCL2, and FhCL5), to our knowledge, the diagnostic value of recombinant FhCL2 and FhCL5 has not yet been investigated. In the present study, we developed and tested three indirect ELISAs using rFhpCL1, rFhpCL2, and rFhpCL5 and evaluated their recognition by sera from sheep and cattle naturally infected with F. hepatica. Although the overall antibody response to these three rFhpCLs was similar, some animals displayed preferential recognition for particular rFhpCLs. Moreover, for cattle sera, the highest sensitivity was obtained using rFhpCL2 (97%), being equal for both rFhpCL1 and rFhpCL5 (87.9%), after adjusting cut-offs for maximum specificity. By contrast, for sheep sera, the sensitivity was 100% for the three rFhpCLs. Finally, the presence of truncated and/or partially unfolded molecules in antigen preparations is postulated as a possible source of cross-reactivity.
Abstract Nanoparticles, novel in size, shape, and surface chemistry when compared to more conventional materials, offer additional functional properties to a range of possible oral applications, from drug-delivery systems to dental implant coatings. Exploitation of the toxic properties of nanoparticles to bacteria, viruses, and fungi has increased markedly over recent years. Metal and metal oxide nanoparticles and their incorporation into other materials have been of particular interest. The potential of nanoparticles to control the formation of biofilms within the oral cavity, as a function of their antimicrobial, anti-adhesive, and delivery capabilities, is coming under close scrutiny. However, optimum formulation of materials at the nanoscale does require innovative physical and chemical approaches.
Summary A systematic survey was carried on stools from 130 children suffering of acute gastroenteritis. Electron microscopy, enzymo-linked immunosorbent assay (ELISA) and counter electrophoresis were employed. This survey allowed to the detection by electron microscopy of Rotavirus (40 cases), Coronaviruses (3 cases), Astroviruses (2 cases), Adenoviruses (2 cases) and Small Round Viruses (1 case). Serological tests (complement fixation, ELISA and counter electrophoresis) done with 86 sera showed a good correlation with results obtained with electron microscopy.
INTRODUCTION: COVID-19 represents a serious threat to patients on maintenance dialysis. The clinical setting, mortality rate and prognostic factors in these patients have not been well established. METHODS: We included all dialyzed patients with COVID-19 referred to our dialysis center between March 11 and April 11, 2020. Data were obtained through the review of the medical records and were censored at the time of data cutoff, on May 11, 2020. RESULTS: Forty-four patients on maintenance dialysis with COVID-19 were referred to our dialysis unit during the COVID-19 epidemic. Median age was 61 years IQR [51.5-72.5]. 65.9% were men. Comorbidities included hypertension (97.7%), diabetes mellitus (50%), chronic cardiac (38.6%) and respiratory (27.3%) diseases. Initial symptoms were fever (79.5%), shortness of breath (29.5%), cough (43.2%), and diarrhea (13.6%). Three profiles of severity were distinguished based on the WHO progression scale. Forty-one (93.2%) were hospitalized and only three were maintained on outpatient hemodialysis. Thirty-three (75%) patients required oxygen therapy, including 15 (45.5%) who were referred to the intensive care unit. Overall, 27.3% of patients died, and 58.5% were discharged from hospital, including only two (13.3%) of those admitted to the intensive care unit. By multivariate analysis, cough, thrombopenia < 120 G/L, LDH level greater than 2 times the upper limit of normal, and blood CRP > 175 mg/L were significantly associated with death. CONCLUSION: A major outbreak of COVID-19 occurred in the Paris Region, and spread among dialyzed patients. Our study underscores the severity of COVID-19 in these patients and identified prognostic markers.
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), first identified in December 2019 in Wuhan, China, is the virus responsible for the current pandemic known as COVID-19. We report the case of a patient with past medical history of substance abuse who presented with suspected drug overdose. He was agitated and altered in the emergency room and he was treated with benzodiazepines for his agitation. He was admitted for substance withdrawal, however his encephalopathy did not improve and he developed choreiform movements. Metabolic, infectious, and rheumatologic workup was negative until he subsequently tested positive for COVID-19. An MRI was performed which showed multiple focal enhancing lesions primarily affecting the bilateral medial putamen and left cerebellum along with subcortical lesions suggesting COVID-19 encephalopathy. He was given glucocorticoids and his mentation and choreiform movements improved. While neurologic presentations are increasingly becoming more common, encephalopathy with choreiform movements appears to be a rare manifestation of SARS-CoV-2, and may be due to direct viral invasion or, more likely, autoimmune mediated toxicity precipitated by the initial viral infection This article is protected by copyright. All rights reserved.
Building adaptation encompasses a range of construction activities that improve existing building conditions and extend the effective lives of buildings. The scopes of building adaptation projects vary, and may include rehabilitating failing structures, improving environmental performances, and changing functional uses. In order to address multiple aspects of building adaptation, different terminologies are used in the literature and in practice, including refurbishment, retrofitting, rehabilitation, renovation, restoration, modernization, conversion, adaptive reuse, material reuse, conservation, and preservation, amongst others. These terminologies are often used interchangeably with overlapping definitions, causing a lack of clarity in the addressed scope of work. An extensive literature review of terminologies related to building adaptation was conducted and the most common and applicable terminologies were identified. Recent definitions, applications, and scope for the identified terminologies are reviewed. Based on this classification, a definition framework is developed enabling precise categorization of building adaptation projects, and application is demonstrated in multiple case studies. The proposed definition framework is a valuable reference for future researchers and practitioners to clearly and consistently define the scope of work in their building adaption projects, and thus avoid the high costs arising from codes, specifications, and project descriptions that confuse these definitions.
BACKGROUND: The novel coronavirus disease (COVID-19) emerged from China in 2019 and rapidly spread worldwide. Patients with metabolic comorbid conditions are more susceptible to infection by COVID-19. Metabolic syndrome is a constellation of interlinked metabolic risk factors that predispose patients to increased risk of complications. Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and non-alcoholic steatohepatitis (NASH) is the aggressive form of NAFLD. OBJECTIVE: The aim of this study is to determine the relationship between metabolic syndrome components and the risk of COVID-19. METHODS: We reviewed data from a large commercial database (Explorys IBM) that aggregates electronic health records from 26 large nationwide healthcare systems. Using systemized nomenclature of clinical medical terms (SNOMED-CT), we identified adults with the diagnosis of metabolic syndrome and its individual components from 1999-2019. We included patients with the diagnosis of COVID-19 from December 2019 to May 2020. Comorbidities known to be associated with COVID-19 and metabolic syndrome such as obesity, diabetes mellitus, dyslipidemia, smoking, male gender, African American, and hypertension were collected. Univariable and multivariable analyses were performed to investigate whether metabolic syndrome or its individual components are independently associated with the risk of COVID-19. RESULTS: Out of 61.4 million active adult patients in the database, 8,885 (0.01%) had documented COVID-19. The cumulative incidence of COVID-19 was higher if metabolic syndrome was the primary diagnosis (0.10% vs 0.01% %, OR 7.00 [6.11–8.01]). The adjusted odds (aOR) of having COVID-19 was higher in patients if they were African Americans (OR 7.45 [7.14- 7.77]), hypertensive (aOR 2.53 [2.40 - 2.68]), obese (aOR 2.20 [2.10 2.32]), diabetic (aOR 1.41 [1.33- 1.48]) hyperlipidemic (OR 1.70 [1.56-1.74]) or diagnosed with NASH (OR 4.93 [4.05- 6.00]). There was a slight decrease in adjusted odds of having COVID-19 in males as compared to females (aOR 0.88 [0.84- 0.92]). CONCLUSION: The incidence of COVID-19 in patients with metabolic syndrome is high. Among all comorbid metabolic conditions, NASH had the strongest association with COVID-19.
The latest novel coronavirus (COVID-19) outbreak, which emerged in December 2019 in Wuhan, Hubei, China, is a significant cause of the pandemic. This outbreak is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is also commonly known as COVID-19. A typical symptom includes cough and fever, but a considerable number of patients can manifest gastrointestinal (GI) symptoms, including diarrhea, which can be the initial presentations and may or may not present with respiratory symptoms or fever. COVID-19 virus may be present in stool samples of patients infected with COVID-19, and angiotensin-converting enzyme 2 (ACE2) is a receptor for this virus, which is substantially present in GI epithelial cells. The wide availability of this receptor facilitates COVID-19 infection to be proactive and multiply in the GI tract. Although no antiviral treatments have been approved, several approaches have been proposed, and at present, optimized supportive care remains the mainstay of therapy. Elective endoscopic procedures should be delayed, but the urgent procedures should be performed as indicated. Due to the rapidly evolving data on COVID-19, it is difficult to keep up with the outpouring of information. We reviewed the mechanisms, clinical manifestation, impact on pre-existing liver diseases, and recommendations endorsed by the several GI societies for the management and prevention of its transmission.
AIMS: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly binds to ACE2 (angiotensin-converting enzyme 2) to facilitate cellular entry. Compared with the lung or respiratory tract, the human heart exhibits greater ACE2 expression. However, little substantial damage was found in the heart tissue, and no viral particles were observed in the cardiac myocytes. This study aims to analyse ACE2 and SARS-CoV-2 spike (S) protein proteases at the single-cell level, to explore the cardiac involvement in COVID-19 and improve our understanding of the potential cardiovascular implications of COVID-19. METHODS AND RESULTS: With meta-analysis, the prevalence of cardiac injury in COVID-19 patients varies from 2% [95% confidence interval (CI) 0–5%, I(2) = 0%] in non-ICU patients to 59% (95% CI 48–71%, I(2) = 85%) in non-survivors. With public single-cell sequence data analysis, ACE2 expression in the adult human heart is higher than that in the lung (adjusted P < 0.0001). Inversely, the most important S protein cleavage protease TMPRSS2 (transmembrane protease serine protease-2) in the heart exhibits an extremely lower expression than that in the lung (adjusted P < 0.0001), which may restrict entry of SARS-CoV-2 into cardiac cells. Furthermore, we discovered that other S protein proteases, CTSL (cathepsin L) and FURIN (furin, paired basic amino acid cleaving enzyme), were expressed in the adult heart at a similar level to that in the lung, which may compensate for TMPRSS2, mediating cardiac involvement in COVID-19. CONCLUSION: Compared with the lung, ACE2 is relatively more highly expressed in the human heart, while the key S protein priming protease, TMPRSS2, is rarely expressed. The low percentage of ACE2(+)/TMPRSS2(+) cells reduced heart vulnerability to SARS-CoV-2 to some degree. CTSL and FURIN may compensate for S protein priming to mediate SARS-CoV-2 infection of the heart.
BACKGROUND: Mathematical modelling of infectious diseases transmitted by the respiratory or close-contact route (e.g., pandemic influenza) is increasingly being used to determine the impact of possible interventions. Although mixing patterns are known to be crucial determinants for model outcome, researchers often rely on a priori contact assumptions with little or no empirical basis. We conducted a population-based prospective survey of mixing patterns in eight European countries using a common paper-diary methodology. METHODS AND FINDINGS: 7,290 participants recorded characteristics of 97,904 contacts with different individuals during one day, including age, sex, location, duration, frequency, and occurrence of physical contact. We found that mixing patterns and contact characteristics were remarkably similar across different European countries. Contact patterns were highly assortative with age: schoolchildren and young adults in particular tended to mix with people of the same age. Contacts lasting at least one hour or occurring on a daily basis mostly involved physical contact, while short duration and infrequent contacts tended to be nonphysical. Contacts at home, school, or leisure were more likely to be physical than contacts at the workplace or while travelling. Preliminary modelling indicates that 5- to 19-year-olds are expected to suffer the highest incidence during the initial epidemic phase of an emerging infection transmitted through social contacts measured here when the population is completely susceptible. CONCLUSIONS: To our knowledge, our study provides the first large-scale quantitative approach to contact patterns relevant for infections transmitted by the respiratory or close-contact route, and the results should lead to improved parameterisation of mathematical models used to design control strategies.
BACKGROUND: The recent outbreak of the coronavirus disease (COVID-19) has become an international pandemic. So far, little is known about the role of an internet approach in COVID-19 participatory surveillance. OBJECTIVE: The aim of this study is to investigate whether an online survey can provide population-level information for observing prevalence trends during the early phase of an outbreak and identifying potential risk factors of COVID-19 infection. METHODS: A 10-item online questionnaire was developed according to medical guidelines and relevant publications. It was distributed between January 24 and February 17, 2020. The characteristics of respondents and temporal changes of various questionnaire-derived indicators were analyzed. RESULTS: A total of 18,161 questionnaires were returned, including 6.45% (n=1171) from Wuhan City. Geographical distributions of the respondents were consistent with the population per province (R(2)=0.61, P<.001). History of contact significantly decreased with time, both outside Wuhan City (R(2)=0.35, P=.002) and outside Hubei Province (R(2)=0.42, P<.001). The percentage of respondents reporting a fever peaked around February 8 (R(2)=0.57, P<.001) and increased with a history of contact in the areas outside Wuhan City (risk ratio 1.31, 95% CI 1.13-1.52, P<.001). Male sex, advanced age, and lung diseases were associated with a higher risk of fever in the general population with a history of contact. CONCLUSIONS: This study shows the usefulness of an online questionnaire for the surveillance of outbreaks like COVID-19 by providing information about trends of the disease and aiding the identification of potential risk factors.
The California 99 (Cal99) variant of infectious bronchitis virus (IBV) was first recovered in 1999 from vaccinated broiler chicken flocks in Central California. The S1 hypervariable region of Cal99 genome was most closely related to Arkansas (Ark) serotype viruses. In this study, the complete genome of Cal99 was sequenced, and the structural protein genes were compared with those of commonly used IBV vaccines as well as those of isolates from naturally occurring outbreaks in different parts of the world, to elucidate potential sources of genetic material. Based on sequence comparison, the prototype Cal99 virus is similar to the apathogenic ArkDPI virus, except in the S1 gene and stretches of sequence in the S2 and M structural protein genes, which are more related to Connecticut (Conn) and Massachusetts (Mass) strain viruses, respectively. We speculate that these two fragments came from a Conn and a Mass virus, respectively, and were incorporated into a virus largely derived from ArkDPI. Since Ark, Conn and Mass strains have been simultaneously used as live vaccines in California, both point mutations and recombination among vaccine strains may have contributed to the emergence of the Cal99 variant virus. Analysis of the structural protein genes of six Cal99 isolates demonstrated that viruses of this serotype may differ substantially in the non-S1 structural genes. Finally, we performed a challenge study with Cal99 and demonstrated that the virus causes late-onset respiratory disease, with a severity comparable to that of the M41 IBV challenge strain.
Periodontal disease is a chronic multifactorial infectious and inflammatory disease associated with several chronic systemic diseases, such as diabetes, cardiovascular diseases (CVD), chronic obstructive pulmonary disease, hypertension, Alzheimer’s disease and so on. These same systemic diseases have been associated with severe COVID-19 infections. Periodontal disease is one of the most prevalent diseases globally. Several recent studies have also suggested hypotheses for the potential association between periodontal disease and severe COVID-19. All this supports the importance of good oral health also in the COVID-19 era. Thus, new strategies and approaches to identify patients at risk of periodontal disease could be beneficial to enhance secondary prevention, especially if targeted to COVID-19 risk groups. Diagnostic biomarkers for periodontal disease have been researched extensively. Potential biomarkers in oral fluid with currently available rapid non-invasive point-of-care technology, such as aMMP-8, could help to extend screening and identification of patients at risk for periodontal disease even to situations and places where professional dental expertise and equipment are limited or unavailable such as nursing and care homes, and rural and distant places. The oral fluid point-of-care technologies could also be useful in the hands of medical professionals (diabetes, CVD, etc.) to identify patients at risk for undiagnosed periodontal disease and to refer them to a dentist for examination and evaluation. Finally, if there is a causality between periodontal disease and severe COVID-19 infections, these point-of-care oral fluid biomarker technologies could possibly help also in assessing the risk of deterioration.
The new era in systems pharmacology has revolutionized the human biology. Its applicability, precise treatment, adequate response and safety measures fit into all the paradigm of medical/clinical practice. The importance of mathematical models in understanding the disease pathology and epideomology is now being realized. The advent of high-throughput technologies and the emergence of systems biology have resulted in the creation of systems pharmacogenomics and the focus is now on personalized medicine. However, there are some regulatory issues that need to be addresssed; are we ready for this universal adoption? This article details some of the infectious disease pharmacogenomics to the developments in this area.
PURPOSE: Critically ill patients with Coronavirus Disease 2019 (COVID-19) have high rates of line thrombosis. Our objective was to examine the safety and efficacy of a low dose heparinized saline (LDHS) arterial line (a-line) patency protocol in this population. MATERIALS AND METHODS: In this observational cohort study, patients ≥18 years with COVID-19 admitted to an ICU at one institution from March 20–May 25, 2020 were divided into two cohorts. Pre-LDHS patients had an episode of a-line thrombosis between March 20–April 19. Post-LDHS patients had an episode of a-line thrombosis between April 20–May 25 and received an LDHS solution (10 units/h) through their a-line pressure bag. RESULTS: Forty-one patients (pre-LDHS) and 30 patients (post-LDHS) were identified. Baseline characteristics were similar between groups, including age (61 versus 54 years; p = 0.24), median Sequential Organ Failure Assessment score (6 versus 7; p = 0.67) and systemic anticoagulation (47% versus 32%; p = 0.32). Median duration of a-line patency was significantly longer in post-LDHS versus pre-LDHS patients (8.5 versus 2.9 days; p < 0.001). The incidence of bleeding complications was similar between cohorts (13% vs. 10%; p = 0.71). CONCLUSIONS: A LDHS protocol was associated with a clinically significant improvement in a-line patency duration in COVID-19 patients, without increased bleeding risk.
BACKGROUND: The 2019 novel coronavirus (COVID-19) outbreak in Wuhan, China has attracted world-wide attention. As of March 31, 2020, a total of 82,631 cases of COVID-19 in China were confirmed by the National Health Commission (NHC) of China. METHODS: Three approaches, namely Poisson likelihood-based method (ML), exponential growth rate-based method (EGR) and stochastic Susceptible-Infected-Removed dynamic model-based method (SIR), were implemented to estimate the basic and controlled reproduction numbers. RESULTS: A total of 198 chains of transmission together with dates of symptoms onset and 139 dates of infections were identified among 14,829 confirmed cases outside Hubei Province as reported as of March 31, 2020. Based on this information, we found that the serial interval had an average of 4.60 days with a standard deviation of 5.55 days, the incubation period had an average of 8.00 days with a standard deviation of 4.75 days and the infectious period had an average of 13.96 days with a standard deviation of 5.20 days. The estimated controlled reproduction numbers, [Formula: see text] , produced by all three methods in all analyzed regions of China are significantly smaller compared with the basic reproduction numbers [Formula: see text]. CONCLUSIONS: The controlled reproduction number in China is much lower than one in all regions of China by now. It fell below one within 30 days from the implementations of unprecedent containment measures, which indicates that the strong measures taken by China government was effective to contain the epidemic. Nonetheless, efforts are still needed in order to end the current epidemic as imported cases from overseas pose a high risk of a second outbreak.
Porcine respiratory disease complex (PRDC) is one of the most important health concerns for pig producers and can involve multiple viral and bacterial pathogens. No simple, single‐reaction diagnostic test currently exists for the simultaneous detection of major pathogens commonly associated with PRDC. Furthermore, the detection of most of the bacterial pathogens implicated in PRDC currently requires time‐consuming culture‐based methods that can take several days to obtain results. In this study, a novel prototype automated microarray that integrates and automates all steps of post‐PCR microarray processing for the simultaneous detection and typing of eight bacteria and viruses commonly associated with PRDC is described along with associated multiplex reverse transcriptase PCR. The user‐friendly assay detected and differentiated between four viruses [porcine reproductive and respiratory syndrome virus (PRRSV), influenza A virus, porcine circovirus type 2, porcine respiratory corona virus], four bacteria (Mycoplasma hyopneumoniae, Pasteurella multocida, Salmonella enterica serovar Choleraesuis, Streptococcus suis), and further differentiated between type 1 and type 2 PRRSV as well as toxigenic and non‐toxigenic P. multocida. The assay accurately identified and typed a panel of 34 strains representing the eight targeted pathogens and was negative when tested with 34 relevant and/or closely related non‐target bacterial and viral species. All targets were also identified singly or in combination in a panel of clinical lung samples and/or experimentally inoculated biological material.
Bats have long been observed to be the hosts and the origin of numerous human diseases. Bats, like all mammals, rely on a number of innate immune mechanisms to combat invading pathogens, including the interferon type I, II and III responses. Ubiquitin-like interferon-stimulated gene product 15 (ISG15) is a key modulator of these interferon responses. Within these pathways, ISG15 can serve to stabilize host proteins modulating innate immune responses and act as a cytokine. Post-translational modifications of viral proteins introduced by ISG15 have also been observed to directly affect the function of numerous viral proteins. Unlike ubiquitin, which is virtually identical across all animals, comparison of ISG15s across species reveals that they are relatively divergent, with sequence identity dropping to as low as ∼58% among mammals. In addition to serving as an obstacle to the zoonotic transmission of influenza, these ISG15 species–species differences have also long been shown to have an impact on the function of viral deISGylases. Recently, the structure of the first nonhuman ISG15, originating from mouse, suggested that the structures of human ISG15 may not be reflective of other species. Here, the structure of ISG15 from the bat species Myotis davidii solved to 1.37 Å resolution is reported. Comparison of this ISG15 structure with those from human and mouse not only underscores the structural impact of ISG15 species–species differences, but also highlights a conserved hydrophobic motif formed between the two domains of ISG15. Using the papain-like deISGylase from Severe acute respiratory syndrome coronavirus as a probe, the biochemical importance of this motif in ISG15–protein engagements was illuminated.
We comparatively assessed sensitivities and specificities of 4 commercial enzyme-linked immunosorbent assays (ELISAs) and 2 rapid tests in 77 patients with polymerase chain reaction–confirmed severe acute respiratory syndrome coronavirus 2 infection, grouped by interval since symptom onset. Although test sensitivities were low (<40%) within the first 5 days after disease onset, immunoglobulin (Ig) M, IgA, and total antibody ELISAs increased in sensitivity to >80% between days 6 and 10 after symptom onset. The evaluated tests (including IgG and rapid tests) provided positive results in all patients at or after the 11th day after onset of disease. The specificities of the ELISAs were 83% (IgA), 98% (IgG), and 97% (IgM and total antibody).
Healthcare providers are facing a coronavirus disease pandemic. This pandemic may last for many months, stressing the Canadian healthcare system in a way that has not previously been seen. Keeping healthcare providers safe, healthy, and available to work throughout this pandemic is critical. The consistent use of appropriate personal protective equipment (PPE) will help assure its availability and healthcare provider safety. The purpose of this communique is to give both anesthesiologists and other front-line healthcare providers a framework from which to understand the principles and practices surrounding PPE decision-making. We propose three types of PPE including: 1) PPE for droplet and contact precautions, 2) PPE for general airborne, droplet, and contact precautions, and 3) PPE for those performing or assisting with high-risk aerosol-generating medical procedures.
The current coronavirus disease 2019 (COVID-19) outbreak is a significant health crisis that impacts every healthcare system worldwide, and has led to a dramatic change in dealing with different diseases during the pandemic. Interventional cardiologists are frontline workers who deal with many cardiovascular emergencies, either in patients with proven COVID-19 or in suspected cases. Many heart associations worldwide are currently setting appropriate recommendations for the management of emergency cardiac interventions. In this expert opinion, the authors highlight the essential requirements in the cardiac catheterisation laboratory during the COVID-19 pandemic.
BACKGROUND: Digitalisation and artificial intelligence have an important impact on the way microbiology laboratories will work in the near future. Opportunities and challenges lay ahead to digitalise the microbiological workflows. Making an efficient use of big data, machine learning, and artificial intelligence in clinical microbiology requires a profound understanding of data handling aspects. OBJECTIVE: This review article summarizes the most important concepts of digital microbiology. The article provides microbiologists, clinicians and data scientists a viewpoint and practical examples along the diagnostic process. SOURCES: We used peer-reviewed literature identified by a Pubmed search for digitalisation, machine learning, artificial intelligence and microbiology. CONTENT: We describe the opportunities and challenges of digitalisation in microbiological diagnostic process with various examples. We also provide in this context key aspects of data structure and interoperability, as well as legal aspects. Finally, we outline the way for applications in a modern microbiology laboratory. IMPLICATIONS: We predict that digitalization and the usage of machine learning will have a profound impact on the daily routine of the laboratory staff. Along the analytical process, the most important steps should be identified, where digital technologies can be applied and provide a benefit. The education of all staff involved should be adapted to prepare for the advances in digital microbiology.
Bats carry and shed many emerging infectious disease agents including Ebola virus and SARS-like Coronaviruses, yet they rarely display clinical symptoms of infection. Bat epithelial or fibroblast cell lines were previously established to study the bat immune response against viral infection. However, the lack of professional immune cells such as dendritic cells (DC) and macrophages has greatly limited the significance of current investigations. Using Pteropus alecto (P. alecto) GM-CSF plus IL4, FLT3L and CSF-1, we successfully generated bat bone marrow-derived DC and macrophages. Cells with the phenotype, morphology and functional features of monocyte-derived DC, bona fide DC or macrophages were obtained in GM-CSF/IL4, FLT3L or CSF-1 cultures, respectively. The successful generation of the first bat bone marrow-derived immune cells paves the way to unlocking the immune mechanisms that confer host resilience to pathogens in bats.
As a phenolic acid, tannic acid can be classified into a polyphenolic group. It has been widely studied in the biomedical field of science because it presents unique antiviral as well as antibacterial properties. Tannic acid has been reported to present the activity against Influeneza A virus, Papilloma viruses, noroviruses, Herpes simplex virus type 1 and 2, and human immunodeficiency virus (HIV) as well as activity against both Gram-positive and Gram-negative bacteria as Staphylococcus aureus, Escherichia coli, Streptococcus pyogenes, Enterococcus faecalis, Pseudomonas aeruginosa, Yersinia enterocolitica, Listeria innocua. Nowadays, compounds of natural origin constitute fundaments of material science, and the trend is called “from nature to nature”. Although biopolymers have found a broad range of applications in biomedical sciences, they do not present anti-microbial activity, and their physicochemical properties are rather poor. Biopolymers, however, may be modified with organic and inorganic additives which enhance their properties. Tannic acid, like phenolic acid, is classified into a polyphenolic group and can be isolated from natural sources, e.g., a pure compound or a component of a plant extract. Numerous studies have been carried out over the application of tannic acid as an additive to biopolymer materials due to its unique properties. On the one hand, it shows antimicrobial and antiviral activity, while on the other hand, it reveals promising biological properties, i.e., enhances the cell proliferation, tissue regeneration and wound healing processes. Tannic acid is added to different biopolymers, collagen and polysaccharides as chitosan, agarose and starch. Its activity has been proven by the determination of physicochemical properties, as well as the performance of in vitro and in vivo studies. This systematics review is a summary of current studies on tannic acid properties. It presents tannic acid as an excellent natural compound which can be used to eliminate pathogenic factors as well as a revision of current studies on tannic acid composed with biopolymers and active properties of the resulting complexes.
BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has affected 18 million people and killed over 690,000 patients. Although this virus primarily causes respiratory symptoms, an increasing number of cutaneous manifestations associated with this disease have been reported. OBJECTIVE: The aim of this review was to collate and categorize the dermatologic findings reported in patients with COVID-19 and identify specific lesions that may facilitate diagnosis and prognostication. METHODS: An evidence-based review of the PubMed database was conducted on 14 May, 2020 using the search terms “Covid-19 skin,” “Covid-19 rash,” “Covid-19 exanthem,” and “Covid-19 chilblains.” Peer-reviewed publications containing original COVID-19 patient cases and a discussion of the associated cutaneous findings were included in the analysis. RESULTS: The literature search identified 115 records, of which 34 publications describing 996 patients with dermatologic conditions were included. Case reports (n = 15), case series (n = 13), and observational prospective studies (n = 4) were the most common publication types. Acral lesions resembling pseudo-chilblains were the most frequent lesion identified (40.4% of cases), appearing in young adults (mean age, 23.2 years) after the onset of extracutaneous COVID-19 symptoms (55/100 patients). Erythematous maculopapular rashes affected 21.3% of patients, most frequently impacting middle-aged adults (mean age, 53.2 years) and occurring at the same time as non-cutaneous symptoms (110/187 patients). Vesicular rashes affected 13.0% of patients, appearing in middle-aged adults (mean age, 48.3 years) after the onset of other symptoms (52/84 patients). Urticarial rashes affected 10.9% of patients, appearing in adults (mean age, 38.3 years) and occurring at the same time as non-cutaneous symptoms (46/78 patients). Vascular rashes resembling livedo or purpura were uncommon (4% of cases), appearing in elderly patients (mean age, 77.5 years) and occurring at the same time as non-cutaneous COVID-19 symptoms (18/29 patients). Erythema multiforme-like eruptions, although infrequent (3.7% of cases), affected mostly children (mean age, 12.2 years). CONCLUSIONS: Vesicular rashes may suggest an initial diagnosis of COVID-19, acral lesions may be most appropriate for epidemiological uses, and vascular rashes may be a useful prognostic marker for severe disease. As a potential correlate to disease severity, prognosis, or infectibility, it is critical that all healthcare professionals be well versed in these increasingly common cutaneous manifestations of COVID-19.
BACKGROUND: The disclosure in the media of a benefit with the use of dexamethasone in patients with COVID-19 infection sets precedents for self-medication and inappropriate use of corticosteroids. METHODS: This is a critical interpretive synthesis of the data available in the literature on the effects of the use of corticosteroids and the impact that their indiscriminate use may have on patients with diabetes. Reviews and observational and experimental studies published until June 18, 2020 were selected. RESULTS: Corticosteroids are substances derived from cholesterol metabolism that interfere with multiple aspects of glucose homeostasis. Interactions between corticoid receptors and target genes seem to be among the mechanisms responsible for the critical functions of glucocorticoids for survival and anti-inflammatory effects observed with these medications. Corticosteroids increase hepatic gluconeogenesis, reduce peripheral use of glucose and increase insulin levels. Previous studies have shown that glucocorticoids have a pro-adipogenic function, increasing deposition of abdominal fat, and lead to glucose intolerance and hypertriglyceridemia. In addition, these drugs play a role in controlling liver metabolism and can lead to the development of hepatic steatosis. Glucocorticoids reduce the recruitment of osteoblasts and increase the number of osteoclasts, which results in increased bone resorption and greater bone fragility. Moreover, these medications cause water and sodium retention and increase the response to circulating vasoconstrictors, which results in increased blood pressure levels. Chronic or high-dose use of corticosteroids can, by itself, lead to the onset of diabetes. For those who were already diagnosed with diabetes, studies show that chronic use of corticosteroids leads to a 94% higher risk of hospitalization due to diabetes complications. In addition to the direct effects on glycemic control, the effects on arterial pressure control, lipids and bone metabolism also have a potential for severe consequences in patients with diabetes. CONCLUSION: Fear and uncertainty toward a potentially serious infection may lead people to self-medication and the inappropriate and abusive use of corticosteroids. More than ever, it is necessary for health professionals to be alert and able to predict damages related to the use of these drugs, which is the first step to minimize the potential damages to come.
When sawing bone for medical or medico-legal procedures, fine, airborne dust is produced (aerosols) that can pose a health hazard when inhaled. The aim of this study was to determine the influence of saw blade frequency and contact load, bone condition, test environment, and saw blade type, on the production of aerosol particles. A custom test setup was designed, manufactured and used in 8 bone sawing experiments, using a particle counter to determine the production of aerosol particles while varying the 5 chosen parameters. The number of counted particles was highest with higher saw blade frequencies, lower saw blade contact loads, in dry completely skeletonized bone compared to fresh bone, and using an electrical oscillating saw compared to hand-sawing. Under all conditions, the high amount of aerosol counted posed potential health risks. The ventilation system that we tested was adequate in removing the produced particles, but these high-tech systems are not always available in developing countries or emergency situations. The production of aerosols can be reduced by optimizing the sawing parameters. However, even the lowest number of aerosol particles counted during the current study was high enough to cause potential health risks to practitioners. Safety precautions should be taken, such as external ventilation, proper breathing gear, and adequate protocols, to truly minimize the risk in all bone sawing scenarios.
Background: The fatal pandemics of infectious diseases and the possibility of using microorganisms as biological weapons are both rising worldwide. Hospitals are vital organizations in response to biological disasters and have a crucial role in the treatment of patients. Despite the advances in studies about hospital planning and performance during crises, there are no internationally accepted standards for hospital preparedness and disaster response. Thus, this study was designed to explain the effective factors in hospital performance during biological disasters. Methods: Qualitative content analysis with conventional approach was used in the present study. The setting was Ministry of Health and related hospitals, and other relevant ministries responsible at the time of biologic events in Islamic Republic of Iran (IR of Iran) in 2018. Participants were experts, experienced individuals providing service in the field of biological disaster planning and response, policymakers in the Ministry of Health, and other related organizations and authorities responsible for the accreditation of hospitals in IR of Iran. Data were collected using 12 semi-structured interviews in Persian language. Analysis was performed according to Graneheim method. Results: After analyzing 12 interviews, extraction resulted in 76 common codes, 28 subcategories, and 8 categories, which are as follow: detection; treatment and infection control; coordination, Resources; training and exercises; communication and information system; construction; and planning and assessment. Conclusion: Hospital management in outbreaks of infectious diseases (intentional or unintentional) is complex and requires different actions than during natural disasters. In such disasters, readiness to respond and appropriate action is a multifaceted operation. In IR of Iran, there have been few researches in the field of hospital preparation in biologic events, and the possibility of standardized assessment has be reduced due to lack of key skills in confronting biological events. It is hoped that the aggregated factors in the 8 groups of this study can evaluate hospital performance more coherently.
SARS‐CoV‐2 pandemic and recurrent dengue epidemics in tropical countries have turned into a global health threat. While both virus‐caused infections may only reveal light symptoms, they can also cause severe diseases. Here, we review the possible antibody‐dependent enhancement (ADE) occurrence, known for dengue infections, when there is a second infection with a different virus strain. Consequently, preexisting antibodies do not neutralize infection, but enhance it, possibly by triggering Fcγ receptor‐mediated virus uptake. No clinical data exist indicating such mechanism for SARS‐CoV‐2, but previous coronavirus infections or infection of SARS‐CoV‐2 convalescent with different SARS‐CoV‐2 strains could promote ADE, as experimentally shown for antibodies against the MERS‐CoV or SARS‐CoV spike S protein. © 2020 International Society for Advancement of Cytometry
BACKGROUND: Cancer seems to have an independent adverse prognostic effect on COVID-19-related mortality, but uncertainty exists regarding its effect across different patient subgroups. We report a population-based analysis of patients hospitalised with COVID-19 with prior or current solid cancer versus those without cancer. METHODS: We analysed data of adult patients registered until 24 May 2020 in the Belgian nationwide database of Sciensano. The primary objective was in-hospital mortality within 30 days of COVID-19 diagnosis among patients with solid cancer versus patients without cancer. Severe event occurrence, a composite of intensive care unit admission, invasive ventilation and/or death, was a secondary objective. These endpoints were analysed across different patient subgroups. Multivariable logistic regression models were used to analyse the association between cancer and clinical characteristics (baseline analysis) and the effect of cancer on in-hospital mortality and on severe event occurrence, adjusting for clinical characteristics (in-hospital analysis). RESULTS: A total of 13 594 patients (of whom 1187 with solid cancer (8.7%)) were evaluable for the baseline analysis and 10 486 (892 with solid cancer (8.5%)) for the in-hospital analysis. Patients with cancer were older and presented with less symptoms/signs and lung imaging alterations. The 30-day in-hospital mortality was higher in patients with solid cancer compared with patients without cancer (31.7% vs 20.0%, respectively; adjusted OR (aOR) 1.34; 95% CI 1.13 to 1.58). The aOR was 3.84 (95% CI 1.94 to 7.59) among younger patients (<60 years) and 2.27 (95% CI 1.41 to 3.64) among patients without other comorbidities. Severe event occurrence was similar in both groups (36.7% vs 28.8%; aOR 1.10; 95% CI 0.95 to 1.29). CONCLUSIONS: This population-based analysis demonstrates that solid cancer is an independent adverse prognostic factor for in-hospital mortality among patients with COVID-19. This adverse effect was more pronounced among younger patients and those without other comorbidities. Patients with solid cancer should be prioritised in vaccination campaigns and in tailored containment measurements.
Abstract The COVID-19 (SARS-CoV-2) pandemic has massively distorted our health care systems and caused catastrophic consequences in our affected communities. The number of victims continues to increase and patients at risk can only be protected to a degree, since the virulent state may be asymptomatic. Risk factors concerning COVID-19-induced morbidity and mortality include advanced age, an impaired immune system, cardiovascular or pulmonary diseases, obesity, diabetes mellitus, and cancer treated with chemotherapy. Here within, we discuss the risk and impact of COVID-19 in patients with mastocytosis and mast cell activation syndromes. As no published data are yet available, expert opinions are, by necessity, based on case experience and reports from patients. Whereas the overall risk to acquire the SARS-CoV-2 virus may not be elevated in mast cell disease, certain conditions may increase the risk of infected patients to develop severe COVID-19. These factors include certain co-morbidities, mast cell activation-related events affecting the cardiovascular or bronchopulmonary system and chemotherapy or immunosuppressive drugs. Therefore, such treatments should be carefully evaluated on a case-by-case basis during a COVID-19 infection. By contrast, other therapies, such as anti-mediator-type drugs, venom immunotherapy, or vitamin D, should be continued. Overall, patients with mast cell disorders should follow the general and local guidelines in the COVID-19 pandemic and advice from their medical provider.
Background: One month after the first COVID-19 infection was recorded, Portugal counted 18 051 cases and 599 deaths from COVID-19. To understand the overall impact on mortality of the pandemic of COVID-19, we estimated the excess mortality registered in Portugal during the first month of the epidemic, from March 16 until April 14 using two different methods. Methods: We compared the observed and expected daily deaths (historical average number from daily death registrations in the past 10 years) and used 2 standard deviations confidence limit for all-cause mortality by age and specific mortality cause, considering the last 6 years. An adapted ARIMA model was also tested to validate the estimated number of all-cause deaths during the study period. Results: Between March 16 and April 14, there was an excess of 1,255 all-cause deaths, 14% more than expected. The number of daily deaths often surpassed the 2 standard deviations confidence limit. The excess mortality occurred mostly in people aged 75+. Forty-nine percent (49%) of the estimated excess deaths were registered as due to COVID-19, The other 51% registered as other natural causes. Conclusion: Even though Portugal took early containment measures against COVID-19, and the population complied massively with those measures, there was significant excess mortality during the first month of the pandemic, mostly among people aged 75+. Only half of the excess mortality was registered as directly due do COVID-19.
Aquaporins are small channel proteins which facilitate the diffusion of water and small neutral molecules across biological membranes. Compared with animals, plant genomes encode numerous aquaporins, which display a large variety of subcellular localization patterns. More specifically, plant aquaporins of the plasma membrane intrinsic protein (PIP) subfamily were first described as plasma membrane (PM)-resident proteins, but recent research has demonstrated that the trafficking and subcellular localization of these proteins are complex and highly regulated. In the past few years, PIPs emerged as new model proteins to study subcellular sorting and membrane dynamics in plant cells. At least two distinct sorting motifs (one cytosolic, the other buried in the membrane) are required to direct PIPs to the PM. Hetero-oligomerization and interaction with SNAREs (soluble N-ethylmaleimide-sensitive factor protein attachment protein receptors) also influence the subcellular trafficking of PIPs. In addition to these constitutive processes, both the progression of PIPs through the secretory pathway and their dynamics at the PM are responsive to changing environmental conditions.
Abstract This research examines how patient experience is affected by various generational cohorts’ perceived ease of use and usefulness of healthcare patient portals and how this experience, in turn, shapes cohort technology use. Results suggest that digital technology needs to be designed and implemented with cohorts in mind. This study complements research in digital technology and customer experience by highlighting the relevance of generational cohort differences, that is whether they adopted digital technology (i.e., Generation X) or always had digital technology, (i.e., Millennials) on a patient’s experience.
As hospitals have experienced a surge of Covid‐19 patients, investigators of Covid‐19 treatment trials face a difficult problem: when an institution has more eligible and interested patients than trial slots, who should be enrolled? Defining a clear strategy for selecting participants for “high‐demand” Covid‐19 treatment trials is important to avoid ad hoc and potentially biased decision‐making by local investigators, which could inadvertently compromise a trial's social value, participants' interests, or fairness. In this article, we propose a set of ethical criteria for evaluating participant‐selection strategies for such trials. We argue that the pandemic context—in particular, great urgency to develop safe and effective treatments, uncertainty surrounding Covid‐19, and strain on the health care system that limits the time and effort available for trial enrollment—favors participant‐selection strategies that optimize the ease of enrollment and, ideally, social value. A lottery and, where possible, a weighted lottery have important advantages in these respects.
BACKGROUND: The incidence of Japanese encephalitis (JE) has been dramatically reduced in China after sufficient vaccine coverage. The live-attenuated Japanese encephalitis virus (JEV) vaccine SA14–14-2 is believed to have strongly contribute to this decrease. Another vaccine that seems to have decreased in importance is an inactivated vaccine based on the JEV P3 strain, which is considered to be modifiable, such as being transformed into a DNA vaccine to improve its immunogenicity. METHODS: In this study, the protective efficacy induced by the Japanese encephalitis DNA vaccine candidate pV-JP3ME encoding the premembrane (prM) and envelope (E) proteins of the P3 strain was assessed in BALB/c mice. The prM/E genes of the JEV P3 strain were subcloned into the vector pVAX1 (pV) to construct pV-JP3ME. RESULTS: The plasmid DNA was immunized into BALB/c mice, and high titers of IgG antibody and neutralizing antibody (nAb) against JEV were detected. The key cytokines in splenocytes were secreted upon stimulation with JEV antigens. Finally, complete protective efficacy was generated after challenge with the JEV P3 strain in the mice. CONCLUSIONS: The DNA vaccine pV-JP3ME based on the JEV P3 strain in this study can induce specific humoral immune and cytokine responses and provide complete protection against JEV in mice.
INTRODUCTION: Viral respiratory infections cause major morbidity and mortality in preterm infants. We have performed a prospective study in our neonatal intensive care unit (NICU) to determine the incidence of respiratory infections, their impact and the epidemiology and outcome in high risk neonates. PATIENTS AND METHODS: From September 2011 to May 2013 a prospective study was conducted in all preterm infants <32 weeks gestational age and in all term newborns admitted to NICU for any pathology that was anticipated to have an admission exceeding two weeks. A nasopharyngeal aspirate (NPA) was collected the first day of life and weekly until discharge for virologic study with polymerase chain reaction. When these babies presented respiratory symptoms a new NPA was collected at this moment. A clinical form was filled by the physician. RESULTS: A total of 60 infants were analysed: 30 (50%) had a gestational age <32 weeks and 36 (60%) weighed less than 1500 g. We collected a total of 256 nasopharyngeal aspirate samples, 24 of them being positive (9.3%). These 24 positive samples corresponded to 13 infants in our cohort (21.6% of the patients). Of them, 9 were symptomatic and had 11 episodes of infection (2 patients had two different episodes with negative control between them). The most frequently identified virus was rhinovirus in (19) 79% of cases. The most frequent clinical data was the presence or increase in apneas (75%) and the need for oxygenotherapy. CONCLUSIONS: HRV infections are prevalent in the NICU, and preterm infants have a high risk of infections with clinical relevance.
BackgroundCoronavirus disease 2019 (COVID-19) triggered by infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been widely pandemic all over the world. The aim of this study was to analyze the influence factors of death risk among 200 COVID-19 patients. MethodsTwo hundred patients with confirmed SARS-CoV-2 infection were recruited. Demographic data and clinical characteristics were collected from electronic medical records. Biochemical indexes on admission were measured and patients prognosis was tracked. The association of demographic data, clinical characteristics and biochemical indexes with death risk was analyzed. ResultsOf 200 COVID-19 patients, 163 (81.5%) had at least one of comorbidities, including diabetes, hypertension, hepatic disease, cardiac disease, chronic pulmonary disease and others. Among all patients, critical cases, defined as oxygenation index lower than 200, accounted for 26.2%. Severe cases, oxygenation index from 200 to 300, were 29.7%. Besides, common cases, oxygenation index higher than 300, accounted for 44.1%. At the end of follow-up, 34 (17%) were died on mean 10.9 day after hospitalization. Stratified analysis revealed that older ages, lower oxygenation index and comorbidities elevated death risk of COVID-19 patients. On admission, 85.5% COVID-19 patients were with at least one of extrapulmonary organ injuries. Univariable logistic regression showed that ALT and TBIL, two indexes of hepatic injury, AST, myoglobin and LDH, AST/ALT ratio, several markers of myocardial injury, creatinine, urea nitrogen and uric acid, three indexes of renal injury, were positively associated with death risk of COVID-19 patients. Multivariable logistic regression revealed that AST/ALT ratio, urea nitrogen, TBIL and LDH on admission were positively correlated with death risk of COVID-19 patients. ConclusionOlder age, lower oxygenation index and comorbidities on admission elevate death risk of COVID-19 patients. AST/ALT ratio, urea nitrogen, TBIL and LDH on admission may be potential prognostic indicators. Early hospitalization is of great significance to prevent multiple organ damage and improve the survival of COVID-19 patients. SummaryIn this hospital-based case-cohort study, we found that serum urea nitrogen, TBIL, LDH and AST/ALT ratio, several markers of extrapulmonary organ injuries, were positively correlated with death risk of COVID-19 patients. We provide evidence for the first time that multiple organ damage on admission influences the prognosis of COVID-19 patients. Early hospitalization is beneficial for elevating the survival rate of COVID-19 patients especially critical ill patients.
BACKGROUND: Depression is a serious personal and public mental health problem. Self-reporting is the main method used to diagnose depression and to determine the severity of depression. However, it is not easy to discover patients with depression owing to feelings of shame in disclosing or discussing their mental health conditions with others. Moreover, self-reporting is time-consuming, and usually leads to missing a certain number of cases. Therefore, automatic discovery of patients with depression from other sources such as social media has been attracting increasing attention. Social media, as one of the most important daily communication systems, connects large quantities of people, including individuals with depression, and provides a channel to discover patients with depression. In this study, we investigated deep-learning methods for depression risk prediction using data from Chinese microblogs, which have potential to discover more patients with depression and to trace their mental health conditions. OBJECTIVE: The aim of this study was to explore the potential of state-of-the-art deep-learning methods on depression risk prediction from Chinese microblogs. METHODS: Deep-learning methods with pretrained language representation models, including bidirectional encoder representations from transformers (BERT), robustly optimized BERT pretraining approach (RoBERTa), and generalized autoregressive pretraining for language understanding (XLNET), were investigated for depression risk prediction, and were compared with previous methods on a manually annotated benchmark dataset. Depression risk was assessed at four levels from 0 to 3, where 0, 1, 2, and 3 denote no inclination, and mild, moderate, and severe depression risk, respectively. The dataset was collected from the Chinese microblog Weibo. We also compared different deep-learning methods with pretrained language representation models in two settings: (1) publicly released pretrained language representation models, and (2) language representation models further pretrained on a large-scale unlabeled dataset collected from Weibo. Precision, recall, and F1 scores were used as performance evaluation measures. RESULTS: Among the three deep-learning methods, BERT achieved the best performance with a microaveraged F1 score of 0.856. RoBERTa achieved the best performance with a macroaveraged F1 score of 0.424 on depression risk at levels 1, 2, and 3, which represents a new benchmark result on the dataset. The further pretrained language representation models demonstrated improvement over publicly released prediction models. CONCLUSIONS: We applied deep-learning methods with pretrained language representation models to automatically predict depression risk using data from Chinese microblogs. The experimental results showed that the deep-learning methods performed better than previous methods, and have greater potential to discover patients with depression and to trace their mental health conditions.
Recent evidence has suggested that IL-10-producing effector CD8(+) T cells play an important role in regulating excessive inflammation during acute viral infections. However, the cellular and molecular cues regulating the development of IL-10-producing effector CD8(+) T cells are not completely defined. Here we show that type I interferons (IFNs) are required for the development of IL-10-producing effector CD8(+) T cells during influenza virus infection. We find that type I IFNs can enhance IL-27 production by lung antigen presenting cells, thereby facilitating IL-10-producing CD8(+) T cell development through a CD8(+) T cell non-autonomous way. Surprisingly, we also demonstrate that direct type I IFN signaling in CD8(+) T cells is required for the maximal generation of IL-10-producing CD8(+) T cells. Type I IFN signaling in CD8(+) T cells, in cooperation with IL-27 and IL-2 signaling, promotes and sustains the expression of IRF4 and Blimp-1, two transcription factors required for the production of IL-10 by effector CD8(+) T cells. Our data have revealed a critical role of the innate antiviral effector cytokines in regulating the production of a regulatory cytokine by effector CD8(+) T cells during respiratory virus infection. The potential implications of these findings for influenza virus infection are also discussed.
A mainstay of personal protective equipment (PPE) during the COVID-19 pandemic is the N95 filtering facepiece respirator. N95 respirators are commonly used to protect healthcare workers from respiratory pathogens, including the novel coronavirus SARS-CoV-2, and are increasingly employed by other frontline workers and the general public. Under routine circumstances, these masks are disposable, single-use items, but extended use and reuse practices have been broadly enacted to alleviate critical supply shortages during the COVID-19 pandemic. While extended-time single use presents a low risk of pathogen transfer, repeated donning and doffing of potentially contaminated masks presents increased risk of pathogen transfer. Therefore, efficient and safe decontamination methods for N95 masks are needed to reduce the risk of reuse and mitigate local supply shortages. Here we review the available literature concerning use of germicidal ultraviolet-C (UV-C) light to decontaminate N95 masks. We propose a practical method for repeated point-of-use decontamination, using commercially-available UV-C crosslinker boxes from molecular biology laboratories or a simple low-cost, custom-designed and fabricated device to expose each side of the mask to 800-1200 mJ/cm2 of UV-C. We measure the dose that penetrated to the interior of the respirators and model the potential germicidal action on SARS-CoV-2. Our experimental results, in combination with modeled data, suggest that a two-minute UV-C treatment cycle should induce a >3-log-order reduction in viral bioburden on the surface of the respirators, and a 2-log order reduction throughout the interior. The resulting exposure is 100-fold less than the dose expected to damage the masks, facilitating repeated decontamination. As such, UV-C germicidal irradiation (UVGI) is a practical strategy for small-scale point-of-use decontamination of N95s.
During this coronavirus disease-19 (COVID-19) pandemic, all the countries are emphasizing on procurement of more and more sophisticated machineries for the intensive care unit (ICU) like ventilators. But do all countries have to follow the same? The requirements are different for low- and middle-income countries like India, which are resource limited. The ventilators require oxygen supply and manpower to function which are deficient in these countries. These countries might do well only by procurement of oxygen delivery machinery, as most of the patients of COVID require oxygen only. Only approx. Five percent of COVID-19 patients require ventilators. Moreover, the patients on ventilators have high mortality. Thus, low-resource countries need to redefine their priority as to how to utilize their resources. This manuscript emphasizes the need for the same. HOW TO CITE THIS ARTICLE: Aggarwal R, Trikha A. Acquiring Ventilators: Fighter Planes without High-octane Fuel and Pilots: Indian Perspective in COVID Era. Indian J Crit Care Med 2020;24(8):735–736.
Patients with severe coronavirus disease 2019 (COVID-19) from infection with acute respiratory syndrome coronavirus 2 (SARS-CoV-2), mount a profound inflammatory response and are predisposed to thrombotic complications [1]. Pulmonary vein thrombosis is a rare disease process resulting in pulmonary congestion, infarction, and potential mortality. This report describes a patient with COVID-19 requiring veno-venous extracorporeal membrane oxygenation (VV-ECMO) for hypoxic respiratory failure, who developed hemorrhagic infarction of the right lower lobe. During emergency exploration, the patient was found to have a right inferior vein thrombosis and marked lobar hemorrhage mandating lobectomy.
BACKGROUND: In March 2020, the World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a pandemic. Currently, data on changes in sexual behavior during the COVID-19 outbreak are limited. AIM: The present study aimed to obtain a preliminary understanding of the changes in people’s sexual behavior, as a result of the pandemic and explore the context in which they manifest. METHODS: A convenience sample of 270 men and 189 women who completed an online survey consisting of 12 items plus an additional question were included in the study. OUTCOMES: The study outcomes were obtained using a study-specific questionnaire to assess the changes in people’s sexual behavior. RESULTS: While there was a wide range of individual responses, our results showed that 44% of participants reported a decrease in the number of sexual partners and about 37% of participants reported a decrease in sexual frequency. Multiple regression analysis showed that age, partner relationship and sexual desire were closely related to sexual frequency. In addition, we found that most individuals with risky sexual experiences had a rapid reduction in risky sexual behavior. CLINICAL IMPLICATIONS: The current findings contribute to identifying another potential health implication associated with the COVID-19 pandemic and report preliminary evidence of the need to provide potential interventions for the population. STRENGTH & LIMITATIONS: This study is the first to perform a preliminary exploration of sexual behavior during the COVID-19 outbreak. The generalizability of the results is limited, given that only a small convenience sample was used. CONCLUSION: During the height of the COVID-19 outbreak, overall sexual activity, frequency, and risky behaviors declined significantly among young men and women in China.
BACKGROUND: The ongoing coronavirus disease 19 (COVID‐19) is posing a threat to the public health globally. Serological test for SARS‐CoV‐2 antibody can improve early diagnosis of COVID‐19 and serves as a valuable supplement to RNA detection. METHOD: A SARS‐CoV‐2 IgG/IgM combined antibody test strip based on colloidal gold immunochromatography assay was developed, with both spike protein and nucleocapsid protein of SARS‐CoV‐2 antigen used for antibody detection. From 3 medical institutions across China, serum or plasma of 170 patients with confirmed COVID‐19 diagnosis and 300 normal controls were collected and tested with the strip. Sensitivity, specificity, kappa coefficient, receiver operating characteristic (ROC) curve, and area under the curve (AUC) were analyzed. Positive rates in different medical centers, age group, gender, and different disease course were compared. RESULTS: 158 out 170 samples from confirmed COVID‐19 patients had positive results from the test, and 296 out of 300 samples from normal controls had negative results. The kit was 92.9% sensitive and 98.7% specific. The positive rate was 77.3% during the first week after disease onset, but reached 100% since day 9. AUC and kappa coefficient were 0.958 and 0.926, respectively, which showed the consistency of the test results with the standard diagnosis. Age or gender caused little variations in the kit sensitivity. CONCLUSION: The rapid, easy‐to‐use SARS‐CoV‐2 IgG/IgM combined antibody test kit has a superior performance, which can help with accurate diagnosis and thus timely treatment and isolation of COVID‐19 patients, that contributes to the better control of the global pandemic.
The grass carp accounts for a large proportion of aquacultural production in China, but the hemorrhagic disease caused by grass carp reovirus (GCRV) infection often causes huge economic losses to the industry. Interleukin 17 (IL-17) is an important cytokine that plays a critical role in the inflammatory and immune responses. Although IL-17 family members have been extensively studied in mammals, our knowledge of the activity of IL-17 proteins in teleosts in response to viral infection is still limited. In this study, the role of IL-17 in GCRV infection and its mechanism were investigated. The expression levels of IL-17AF1, IL-17AF2, and IL-17AF3 in Ctenopharyngodon idella kidney (CIK) cells gradually increased from 6 h after infection with GCRV. The nuclear translocation of p65, which acts in the NF-κB signaling pathway, was also increased by GCRV infection. The overexpression of IL-17AF1, IL-17AF2, or IL-17AF3 also promoted the nuclear translocation of p65 and the levels of phospho-IκBα in CIK cells, and reduced the expression of the viral structural protein VP7. An NF-κB signal inhibitor abolished the inhibition of GCRV infection by IL-17 proteins. These results suggested that the NF-κB signaling pathway was activated by the overexpression of IL-17 proteins, resulting in the inhibition of viral infection. In conclusion, in this study, we demonstrated that IL-17AF1, IL-17AF2, and IL-17AF3 acted as immune cytokines, exerting an antiviral effect by activating the NF-κB signaling pathway.
Porcine hemagglutinating encephalomyelitis virus (PHEV) causes vomiting and wasting disease (VWD) or encephalomyelitis, and primarily affects pigs under 3 weeks of age. In this study, we detected PHEV from clinically ill pigs in conventional pig farms in South Korea. From November 2009 to March 2010, a total of 239 pig tissue samples from 91 farms were tested by nested RT-PCR. Among 239 samples, 22 samples from 17 farms were positive for PHEV. The detection rate of suckling pigs, weaning pigs, growers and finishers were 14.3% (12/84), 6.5% (7/107), 7% (3/43), and 0% (0/5), respectively. Symptoms were neurological, respiratory, enteric sign (diarrhea), or nasal bleeding. All pigs were co-infected with other viruses and bacteria and this might have resulted in age variation and clinical signs in the affected pigs. Phylogenetic analysis showed that the PHEV-positive samples and PHEV reference strains were clustered in the same group. These findings imply the presence of only one genogroup of PHEV, regardless of porcine age, clinical signs, and geographical location.
The COVID-19 pandemic has resulted in over 33 million confirmed cases and over 1 million deaths globally, as of 1 October 2020. During the lockdown and restrictions placed on public activities and gatherings, green spaces have become one of the only sources of resilience amidst the coronavirus pandemic, in part because of their positive effects on psychological, physical and social cohesion and spiritual wellness. This study analyzes the impacts of COVID-19 and government response policies to the pandemic on park visitation at global, regional and national levels and assesses the importance of parks during this global pandemic. The data we collected primarily from Google’s Community Mobility Reports and the Oxford Coronavirus Government Response Tracker. The results for most countries included in the analysis show that park visitation has increased since February 16th, 2020 compared to visitor numbers prior to the COVID-19 pandemic. Restrictions on social gathering, movement, and the closure of workplace and indoor recreational places, are correlated with more visits to parks. Stay-at-home restrictions and government stringency index are negatively associated with park visits at a global scale. Demand from residents for parks and outdoor green spaces has increased since the outbreak began, and highlights the important role and benefits provided by parks, especially urban and community parks, under the COVID-19 pandemic. We provide recommendations for park managers and other decision-makers in terms of park management and planning during health crises, as well as for park design and development. In particular, parks could be utilized during pandemics to increase the physical and mental health and social well-being of individuals. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11676-020-01249-w) contains supplementary material, which is available to authorised users.
COVID-19 is associated with lymphopenia and cytokine storm, but no information is available on specific cellular immune responses to SARS-CoV-2. Here, we characterized SARS-CoV-2-specific CD4+ and CD8+ T-cells in patients with acute respiratory distress syndrome. The spike protein (S) proved a potent T-cell antigen and specific T-cells predominantly produced Th1 cytokines. These novel data are important in vaccine design and will facilitate evaluation of vaccine candidate immunogenicity.
In this work, we use a within-host viral dynamic model to describe the SARS-CoV-2 kinetics in host. Chest radiograph score data are used to estimate the parameters of that model. Our result shows that the basic reproductive number of SARS-CoV-2 in host growth is around 3.79. Using the same method we also estimate the basic reproductive number of MERS virus is 8.16 which is higher than SARS-CoV-2. The PRCC method is used to analyze the sensitivities of model parameters and the drug effects on virus growth are also implemented to analyze the model.
To determine the epidemiologic and clinical features of a 2008 outbreak of Hendra virus infection in a veterinary clinic in Australia, we investigated the equine case-series. Four of 5 infected horses died, as did 1 of 2 infected staff members. Clinical manifestation in horses was predominantly neurologic. Preclinical transmission appears likely.
Zika virus (ZIKV) remained largely quiescent for nearly six decades after its first appearance in 1947. ZIKV reappeared after 2007, resulting in a declaration of an international “public health emergency” in 2016 by the World Health Organization (WHO). Until this time, ZIKV was considered to induce only mild illness, but it has now been established as the cause of severe clinical manifestations, including fetal anomalies, neurological problems, and autoimmune disorders. Infection during pregnancy can cause congenital brain abnormalities, including microcephaly and neurological degeneration, and in other cases, Guillain-Barré syndrome, making infections with ZIKV a substantial public health concern. Genomic and molecular investigations are underway to investigate ZIKV pathology and its recent enhanced pathogenicity, as well as to design safe and potent vaccines, drugs, and therapeutics. This review describes progress in the design and development of various anti-ZIKV therapeutics, including drugs targeting virus entry into cells and the helicase protein, nucleosides, inhibitors of NS3 protein, small molecules, methyltransferase inhibitors, interferons, repurposed drugs, drugs designed with the aid of computers, neutralizing antibodies, convalescent serum, antibodies that limit antibody-dependent enhancement, and herbal medicines. Additionally, covalent inhibitors of viral protein expression and anti-Toll-like receptor molecules are discussed. To counter ZIKV-associated disease, we need to make rapid progress in developing novel therapies that work effectually to inhibit ZIKV.
Mutations in desmosomal Plakophilin-2 (PKP2) are the most prevalent drivers of arrhythmogenic cardiomyopathy (ACM) and a common cause of sudden cardiac death in young athletes. However, partner proteins that elucidate PKP2 cellular mechanism to understand cardiac dysfunction in ACM are mostly unknown. Here we identify the actin-based motor proteins Myh9 and Myh10 as key PKP2 interactors, and demonstrate that the expression of the ACM-related PKP2 mutant R735X alters actin fiber organization and cell mechanical stiffness. We also show that SARS-CoV-2 Nsp1 protein acts similarly to this known pathogenic R735X mutant, altering the actomyosin component distribution on cardiac cells. Our data reveal that the viral Nsp1 hijacks PKP2 into the cytoplasm and mimics the effect of delocalized R735X mutant. These results demonstrate that cytoplasmic PKP2, wildtype or mutant, induces the collapse of the actomyosin network, since shRNA-PKP2 knockdown maintains the cell structure, validating a critical role of PKP2 localization in the regulation of actomyosin architecture. The fact that Nsp1 and PKP2 mutant R735X share similar phenotypes also suggests that direct SARS-CoV-2 heart infection could induce a transient ACM-like disease in COVID-19 patients, which may contribute to right ventricle dysfunction, observed in patients with poor survival prognosis. Highlights The specific cardiac isoform Plakophilin-2a (PKP2) interacts with Myh9 and Myh10. PKP2 delocalization alters actomyosin cytoskeleton component organization. SARS-CoV-2 Nsp1 protein hijacks PKP2 from the desmosome into the soluble fraction where it is downregulated. Viral Nsp1 collapses the actomyosin cytoskeleton and phenocopies the arrhythmogenic cardiomyopathy-related mutant R735X.
The ongoing pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), necessitates strategies to identify prophylactic and therapeutic drug candidates for rapid clinical deployment. A high-throughput, high-content imaging assay of human HeLa cells expressing the SARS-CoV-2 receptor ACE2 was used to screen ReFRAME, a best-in-class drug repurposing library. From nearly 12,000 compounds, we identified 66 compounds capable of selectively inhibiting SARS-CoV-2 replication in human cells. Twenty-four of these drugs show additive activity in combination with the RNA-dependent RNA polymerase inhibitor remdesivir and may afford increased in vivo efficacy. We also identified synergistic interaction of the nucleoside analog riboprine and a folate antagonist 10-deazaaminopterin with remdesivir. Overall, seven clinically approved drugs (halofantrine, amiodarone, nelfinavir, simeprevir, manidipine, ozanimod, osimertinib) and 19 compounds in other stages of development may have the potential to be repurposed as SARS-CoV-2 oral therapeutics based on their potency, pharmacokinetic and human safety profiles.
Drugs that could lessen the death toll in a flu pandemic do exist. But global stockpiles are too small, and the countries at most immediate risk are among the worst prepared. Alison Abbott reports.
The study aimed to validate the proficiency of nicotine binding with the soluble angiotensin-converting enzyme II receptor (sACE2) with or without SARS-CoV-2 in the context of its binding affinity. Modelled human sACE2 and the spike (S1) protein of Indian SARS-CoV-2 (INS1) docked with each other. On the other hand, nicotine docked with sACE2 in the presence or absence of SARS-CoV-2. Nicotine established a stable interaction with negatively charged Asp368 of sACE2, which in turn binds with amino acids like Thr362, Lys363, Thr365, Thr371, and Ala372. In the presence of nicotine, INS1 and sACE2 showed a reduced binding affinity score of -12.6 kcal/mol (Vs -15.7 kcal/mol without nicotine), and a lowered interface area of 1933.6 Å(2) (Vs 2057.3Å(2) without nicotine). The neuronal nicotinic acetylcholine receptor and angiotensin-converting enzyme 2 (ACE2) receptor showed 19.85 % sequence identity among themselves. Following these receptors possessed conserved Trp302 and Cys344 amino acids between them for nicotine binding. However, nicotine showed a higher binding affinity score of -6.33 kcal/mol for the sACE2-INS1 complex than the sACE2 alone with -5.24 kcal/mol. A lowered inhibitory constant value of 22.95µM recorded while nicotine interacted with the sACE2-INS1 complex over the sACE2 alone with 151.69 µM. In summary, nicotine showed a profound binding affinity for the sACE2-INS1 complex than the sACE2 alone paving for the clinical trials to validate its therapeutic efficacy as a bitter compound against the SARS-CoV-2 virulence.
Host miRNAs are known as important regulators of virus replication and pathogenesis. They can interact with various viruses through several possible mechanisms including direct binding of viral RNA. Identification of human miRNAs involved in coronavirus-host interplay becomes important due to the ongoing COVID-19 pandemic. In this article we performed computational prediction of high-confidence direct interactions between miRNAs and seven human coronavirus RNAs. As a result, we identified six miRNAs (miR-21-3p, miR-195-5p, miR-16-5p, miR-3065-5p, miR-424-5p and miR-421) with high binding probability across all analyzed viruses. Further bioinformatic analysis of binding sites revealed high conservativity of miRNA binding regions within RNAs of human coronaviruses and their strains. In order to discover the entire miRNA-virus interplay we further analyzed lungs miRNome of SARS-CoV infected mice using publicly available miRNA sequencing data. We found that miRNA miR-21-3p has the largest probability of binding the human coronavirus RNAs and being dramatically up-regulated in mouse lungs during infection induced by SARS-CoV.
Many colleges and other organizations are considering testing plans to return to operation as the COVID19 pandemic continues. The temporal dynamics of viral load and test false negative rate have the potential to alter the apparent efficacy of testing, as testing must identify a sick individual prior to that person transmitting the virus to one or more people and isolate them. High levels of presymptomatic spread and high false negative rates for testing make it difficult to successfully test an individual in the time frame necessary to stop viral spread. Here, we develop a stochastic agent-based model of COVID19 in a university sized population, considering the dynamics of both viral load and false negative rate of tests on the ability of testing to combat viral spread. We find that the undetectable period of SARS-CoV-2 can lead to an apparent false negative rate of ~17% in the presence of a hypothetical perfect test, while full implementation of dynamic false negative rates reported in the literature leads to an overall false negative rate of ~48%. We then compare testing while varying fraction of the population and the frequency of testing. We find that these assumptions about viral load and false negative rate lead to a requirement for high levels of both frequency and fraction of population tested in order to bring the apparent Reproduction number (Rt) below 1. We conclude that it is important to consider the non-uniform dynamics of viral spread and false negative rate in order to produce realistic testing plans that will lead to the desired reduction in Rt to control viral spread.
Labdane diterpenes are widespread classes of natural compounds present in variety of marine and terrestrial organisms and plants. Many of them represents “natural libraries” of compounds with interesting biological activities due to differently functionalized drimane nucleus exploitable for potential pharmacological applications. The transient receptor potential channel subfamily V member 4 (TRPV4) channel has recently emerged as a pharmacological target for several respiratory diseases, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Inspired by the labdane-like bicyclic core, a series of homodrimane-derived esters and amides was designed and synthesized by modifying the flexible tail in position 1 of (+)-sclareolide, an oxidized derivative of the bioactive labdane-type diterpene sclareol. The potency and selectivity towards rTRPV4 and hTRPV1 receptors were assessed by calcium influx cellular assays. Molecular determinants critical for eliciting TRPV4 antagonism were identified by structure-activity relationships. Among the selective TRPV4 antagonists identified, compound 6 was the most active with an IC(50) of 5.3 μM. This study represents the first report of semisynthetic homodrimane TRPV4 antagonists, selective over TRPV1, and potentially useful as pharmacological tools for the development of novel TRPV4 channel modulators.
Ribophorins I and II are type I transmembrane glycoproteins of the ER that are segregated to the rough domains of this organelle. Both ribophorins appear to be part of the translocation apparatus for nascent polypeptides that is associated with membrane-bound ribosomes and participate in the formation of a proteinaceous network within the ER membrane that also includes other components of the translocation apparatus. The ribophorins are both highly stable proteins that lack O- linked sugars but each contains one high mannose N-linked oligosaccharide that remains endo H sensitive throughout their lifetimes. We have previously shown (Tsao, Y. S., N. E. Ivessa, M. Adesnik, D. D. Sabatini, and G. Kreibich. 1992. J. Cell Biol. 116:57- 67) that a COOH-terminally truncated variant of ribophorin I that contains only the first 332 amino acids of the luminal domain (RI332), when synthesized in permanent transformants of HeLa cells, undergoes a rapid degradation with biphasic kinetics in the ER itself and in a second, as yet unidentified nonlysosomal pre-Golgi compartment. We now show that in cells treated with brefeldin A (BFA) RI332 molecules undergo rapid O-glycosylation in a multistep process that involves the sequential addition of N-acetylgalactosamine, galactose, and terminal sialic acid residues. Addition of O-linked sugars affected all newly synthesized RI332 molecules and was completed soon after synthesis with a half time of about 10 min. In the same cells, intact ribophorins I and II also underwent O-linked glycosylation in the presence of BFA, but these molecules were modified only during a short time period immediately after their synthesis was completed, and the modification affected only a fraction of the newly synthesized polypeptides. More important, these molecules synthesized before the addition of BFA were not modified by O-glycosylation. The same is true for ribophorin I when overexpressed in HeLa cells although it is significantly less stable than the native polypeptide in control cells. We, therefore, conclude that soon after their synthesis, ribophorins lose their susceptibility to the relocated Golgi enzymes that effect the O-glycosylation, most likely as a consequence of a conformational change in the ribophorins that occurs during their maturation, although it cannot be excluded that rapid integration of these molecules into a supramolecular complex in the ER membrane leads to their inaccessibility to these enzymes.
BackgroundSARS-CoV-2, a positive-sense RNA virus in the family Coronaviridae, has caused a worldwide pandemic of coronavirus disease 2019 or COVID-19 Coronaviruses generate a tiered series of subgenomic RNAs (sgRNAs) through a process involving homology between transcriptional regulatory sequences (TRS) located after the leader sequence in the 5 UTR (the TRS-L) and TRS located near the start of structural and accessory proteins (TRS-B) near the 3 end of the genome. In addition to the canonical sgRNAs generated by SARS-CoV-2, non-canonical sgRNAs (nc-sgRNAs) have been reported. However, the consistency of these nc-sgRNAs across viral isolates and infection conditions is unknown. The comprehensive definition of SARS-CoV-2 RNA products is a key step in understanding SARS-CoV-2 pathogenesis. MethodsHere, we report an integrative analysis of eight independent SARS-CoV-2 transcriptomes generated using three sequencing strategies, five host systems, and seven viral isolates. Read-mapping to the SARS-CoV-2 genome was used to determine the 5 and 3 coordinates of all identified junctions in viral RNAs identified in these samples. ResultsUsing junctional abundances, we show nc-sgRNAs make up as much as 33% of total sgRNAs in vitro, are largely consistent in abundance across independent transcriptomes, and increase in abundance over time during in vitro infection. By assessing the homology between sequences flanking the 5 and 3 junction points, we show that nc-sgRNAs are not associated with TRS-like homology. By incorporating read coverage information, we find strong evidence for subgenomic RNAs that contain only 5 regions of ORF1a. Finally, we show that non-canonical junctions change the landscape of viral open reading frames. ConclusionsWe identify canonical and non-canonical junctions in SARS-CoV-2 sgRNAs and show that these RNA products are consistently generated across many independent viral isolates and sequencing approaches. These analyses highlight the diverse transcriptional activity of SARS-CoV-2 and offer important insights into SARS-CoV-2 biology.
BACKGROUND: High rates of potentially pathogenic bacteria and respiratory viruses can be detected in the upper respiratory tract of healthy children. Investigating presence of and associations between these pathogens in healthy individuals is still a rather unexplored field of research, but may have implications for interpreting findings during disease. METHODOLOGY/PRINCIPAL FINDINGS: We selected 986 nasopharyngeal samples from 433 6- to 24-month-old healthy children that had participated in a randomized controlled trial. We determined the presence of 20 common respiratory viruses using real-time PCR. Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Staphylococcus aureus were identified by conventional culture methods. Information on risk factors was obtained by questionnaires. We performed multivariate logistic regression analyses followed by partial correlation analysis to identify the overall pattern of associations. S. pneumoniae colonization was positively associated with the presence of H. influenzae (adjusted odds ratio 1.60, 95% confidence interval 1.18–2.16), M. catarrhalis (1.78, 1.29–2.47), human rhinoviruses (1.63, 1.19–2.22) and enteroviruses (1.97, 1.26–3.10), and negatively associated with S. aureus presence (0.59, 0.35–0.98). H. influenzae was positively associated with human rhinoviruses (1.63, 1.22–2.18) and respiratory syncytial viruses (2.78, 1.06–7.28). M. catarrhalis colonization was positively associated with coronaviruses (1.99, 1.01–3.93) and adenoviruses (3.69, 1.29–10.56), and negatively with S. aureus carriage (0.42, 0.25–0.69). We observed a strong positive association between S. aureus and influenza viruses (4.87, 1.59–14.89). In addition, human rhinoviruses and enteroviruses were positively correlated (2.40, 1.66–3.47), as were enteroviruses and human bocavirus, WU polyomavirus, parainfluenza viruses, and human parechovirus. A negative association was observed between human rhinoviruses and coronaviruses. CONCLUSIONS/SIGNIFICANCE: Our data revealed high viral and bacterial prevalence rates and distinct bacterial-bacterial, viral-bacterial and viral-viral associations in healthy children, hinting towards the complexity and potential dynamics of microbial communities in the upper respiratory tract. This warrants careful consideration when associating microbial presence with specific respiratory diseases.
BACKGROUND: Contact tracing remains a critical part of controlling COVID-19 spread. Many countries have developed novel software applications (Apps) in an effort to augment traditional contact tracing methods. AIM: Conduct a national survey of the Irish population to examine barriers and levers to the use of a contact tracing App. METHODS: Adult participants were invited to respond via an online survey weblink sent via e-mail and messaging Apps and posted on our university website and on popular social media platforms, prior to launch of the national App solution. RESULTS: A total of 8088 responses were received, with all 26 counties of the Republic of Ireland represented. Fifty-four percent of respondents said they would definitely download a contact-tracing App, while 30% said they would probably download a contact tracing App. Ninety-five percent of respondents identified at least one reason for them to download such an App, with the most common reasons being the potential for the App to help family members and friends and a sense of responsibility to the wider community. Fifty-nine percent identified at least one reason not to download the App, with the most common reasons being fear that technology companies or the government might use the App technology for greater surveillance after the pandemic. CONCLUSION: The Irish citizens surveyed expressed high levels of willingness to download a public health–backed App to augment contact tracing. Concerns raised regarding privacy and data security will be critical if the App is to achieve the large-scale adoption and ongoing use required for its effective operation.
Abstract Background Emergency Departments (EDs) need to be prepared to manage crises and disasters in both the short and long term. The COVID-19 pandemic has necessitated a rapid overhaul of several aspects of ED operations in preparation for a sustained response. Objective of the Review:We present the management of the COVID-19 crisis in three EDs (one large academic site, and two community sites) within the same health system. Discussion Aspects of ED throughput, including patient screening, patient room placement, and disposition are reviewed, along with departmental communication procedures and staffing models. Visitor policies are additionally discussed. Special considerations are given to airway management and the care of psychiatric patients. Brief guidance around the use of personal protective equipment is also included. Conclusions A crisis like the COVID-19 pandemic requires careful planning to facilitate urgent restructuring of many aspects of an ED. By sharing our departments’ responses to the COVID-19 pandemic, we hope other departments can better prepare for this crisis and the next.
OBJECTIVE: The epidemiology of psychiatric symptoms among COVID-19 patients is poorly characterized. This paper seeks to identify the prevalence of anxiety, depression, and acute stress disorder among hospitalized patients with COVID-19. METHODS: Adult patients recently admitted to non-ICU medical ward settings with COVID-19 were eligible for enrollment. Enrolled patients were screened for depression, anxiety, and delirium. Subsequently, patients were followed by phone after two weeks and re-screened for depression, anxiety, and acute stress disorder symptoms. Subjects’ medical records were abstracted for clinical data. RESULTS: 58 subjects were enrolled of whom 44 completed the study. Initially, 36% of subjects had elevated anxiety symptoms and 29% elevated depression symptoms. At two-week follow-up, 9% had elevated anxiety symptoms, 20% elevated depression symptoms, and 25% mild-to-moderate acute stress disorder symptoms. Discharge to home was not associated with improvement in psychiatric symptoms. CONCLUSION: A significant number of patients hospitalized with COVID-19 experience symptoms of depression and anxiety. While anxiety improves following index admission, depression remains fairly stable. Furthermore, a significant minority of patients experience acute stress disorder symptoms, though these are largely mild-to-moderate.
Muscle wasting is an unmet medical need which leads to a reduction of myofiber diameter and a negative impact on the functional performance of daily activities. We previously found that a new neuroprotective drug called NeuroHeal reduced muscle atrophy produced by transient denervation. Aiming to decipher whether NeuroHeal has a direct role in muscle biology, we used herein different models of muscle atrophy: one caused by chronic denervation, another caused by hindlimb immobilization, and lastly, an in vitro model of myotube atrophy with Tumor Necrosis Factor-α (TNFα). In all these models, we observed that NeuroHeal reduced muscle atrophy and that SIRT1 activation seems to be required for that. The treatment downregulated some critical markers of protein degradation: Muscle Ring Finger 1 (MuRF1), K48 poly-Ub chains, and p62/SQSTM1. Moreover, it seems to restore the autophagy flux associated with denervation. Hence, we envisage a prospective use of NeuroHeal at clinics for different myopathies.