title: Roles of peroxiredoxins in cancer, neurodegenerative diseases and inflammatory diseases

text: Abstract Peroxiredoxins (PRDXs) are antioxidant enzymes, known to catalyze peroxide reduction to balance cellular hydrogen peroxide (H2O2) levels, which are essential for cell signaling and metabolism and act as a regulator of redox signaling. Redox signaling is a critical component of cell signaling pathways that are involved in the regulation of cell growth, metabolism, hormone signaling, immune regulation and variety of other physiological functions. Early studies demonstrated that PRDXs regulates cell growth, metabolism and immune regulation and therefore involved in the pathologic regulator or protectant of several cancers, neurodegenerative diseases and inflammatory diseases. Oxidative stress and antioxidant systems are important regulators of redox signaling regulated diseases. In addition, thiol-based redox systems through peroxiredoxins have been demonstrated to regulate several redox-dependent process related diseases. In this review article, we will discuss recent findings regarding PRDXs in the development of diseases and further discuss therapeutic approaches targeting PRDXs. Moreover, we will suggest that PRDXs could be targets of several diseases and the therapeutic agents for targeting PRDXs may have potential beneficial effects for the treatment of cancers, neurodegenerative diseases and inflammatory diseases. Future research should open new avenues for the design of novel therapeutic approaches targeting PRDXs.


title: Recommendations of the Working Groups from the Spanish Society of Intensive and Critical Care Medicine and Coronary Units (SEMICYUC) for the management of adult critically ill patients in the coronavirus disease (COVID-19)

text: Abstract On March 11, 2020, the Director-General of the World Health Organization (WHO) declared the disease caused by SARS-CoV-2 (COVID-19) as a pandemic. The spread and evolution of the pandemic is overwhelming the healthcare systems of dozens of countries and has led to a myriad of opinion papers, contingency plans, case series and emerging trials. Covering all this literature is complex. Briefly and synthetically, in line with the previous recommendations of the Working Groups, the Spanish Society of Intensive, Critical Medicine and Coronary Units (SEMICYUC) has prepared this series of basic recommendations for patient care in the context of the pandemic.


title: A comprehensive microbiological safety approach for agarose encapsulated porcine islets intended for clinical trials

text: BACKGROUND: The use of porcine islets to replace insulin‐producing islet β‐cells, destroyed during the diabetogenic disease process, presents distinct challenges if this option is to become a therapeutic reality for the treatment of type 1 diabetes. These challenges include a thorough evaluation of the microbiological safety of the islets. In this study, we describe a robust porcine islet‐screening program that provides a high level of confidence in the microbiological safety of porcine islets suitable for clinical trials. METHODS: A four‐checkpoint program systematically screens the donor herd (Large White – Yorkshire × Landrace F1 hybrid animals), individual sentinel and pancreas donor animals and, critically, the islet macrobeads themselves. Molecular assays screen for more than 30 known viruses, while electron microscopy and in vitro studies are employed to screen for potential new or divergent (emergent) viruses. RESULTS: Of 1207 monthly samples taken from random animals over a 2‐year period, only a single positive result for Transmissible gastroenteritis virus was observed, demonstrating the high level of biosecurity maintained in the source herd. Given the lack of clinical signs, positive antibody titers for Porcine reproductive and respiratory syndrome virus, Porcine parvovirus, and Influenza A confirm the efficacy of the herd vaccination program. Porcine respiratory coronavirus was found to be present in the herd, as expected for domestic swine. Tissue homogenate samples from six sentinel and 11 donor animals, over the same 2‐year period, were negative for the presence of viruses when co‐cultured with six different cell lines from four species. The absence of adventitious viruses in separate islet macrobead preparations produced from 12 individual pancreas donor animals was confirmed using validated molecular (n = 32 viruses), in vitro culture (cells from four species), and transmission electron microscopy assays (200 cell profiles per donor animal) over the same 2‐year period. There has been no evidence of viral transmission following the implantation of these same encapsulated and functional porcine islets into non‐immunosuppressed diabetic cynomolgus macaques for up to 4 years. Isolated peripheral blood mononuclear cells from all time points were negative for PCV (Type 2), PLHV, PRRSV, PCMV, and PERV‐A, PERV‐B, and PERV‐C by PCR analysis in all six recipient animals. CONCLUSION: The four‐checkpoint program is a robust and reliable method for characterization of the microbiological safety of encapsulated porcine islets intended for clinical trials.


title: Clinical Presentation and Birth Outcomes Associated with Respiratory Syncytial Virus Infection in Pregnancy

text: BACKGROUND: Respiratory syncytial virus (RSV) is the most important cause of viral pneumonia in children worldwide. A maternal vaccine may protect both the mother and infant from RSV illness. The epidemiology and clinical presentation of RSV in pregnant and postpartum women is not well-described. METHODS: Data were collected from a prospective, randomized trial of influenza immunization in pregnant women in rural southern Nepal. Women were enrolled in their second trimester of pregnancy and followed until six months postpartum. Active weekly home-based surveillance for febrile respiratory illness was performed. Mid-nasal swabs collected with episodes of respiratory illness were tested for RSV by real-time polymerase chain reaction. RESULTS: RSV was detected in 14 (0.4%) illness episodes in 3693 women over 3554 person-years of surveillance from 2011–2014. RSV incidence was 3.9/1000 person-years overall, and 11.8/1000 person-years between September and December. Seven (50%) women sought care for RSV illness; none died. Of the 7 (50%) illness episodes during pregnancy, all had live births with 2 (29%) preterm births and a median birthweight of 3060 grams. This compares to 469 (13%) preterm births and a median birthweight of 2790 grams in women without RSV during pregnancy. Of the 7 mothers with postpartum RSV infection, RSV was detected in 4 (57%) of their infants. CONCLUSIONS: RSV was an uncommon cause of febrile respiratory illness in mothers during pregnancy in Nepal. These data will inform prevention and therapeutic strategies against RSV in resource-limited settings.


title: Frequent detection of cytomegalovirus (CMV) DNA in the lower respiratory tract in CMV‐seropositive pediatric patients with underlying chronic bronchopulmonary diseases lacking canonical immunosuppression

text: Cytomegalovirus (CMV) may be a relevant cause of morbidity in patients displaying various inflammatory diseases. In this study, it was investigated whether CMV DNA is detected in the lower respiratory tract and the systemic compartment in pediatric patients with chronic or recurrent bronchopulmonary diseases. A total of 42 lower respiratory tract specimens and 11 paired plasma samples from 42 patients were analyzed for the presence of CMV DNA by real‐time PCR. The respiratory specimens were also screened for the presence of respiratory viruses and human herpesvirus 6 (HHV‐6) and 7 (HHV‐7) by PCR methods. Quantitative bacterial and fungal cultures were performed. IL‐6 levels in the respiratory specimens were quantified using ELISA. CMV DNA was detected either in the lower respiratory airways, in plasma, or both in 54.5% of CMV‐seropositive patients. The levels of IL‐6 were significantly higher in these patients than in those with no detectable levels of CMV DNA. HHV‐6 and HHV‐7 DNA were detected in three and one patients, respectively. Respiratory viruses were detected in 13 of the 42 patients. Significant growth of one or more bacterial species was observed in 17 patients. No significant association was found between the presence of CMV DNA and the detection of other microorganisms. The data indicated that the presence of CMV DNA in the lower respiratory tract is a frequent finding in children with chronic or recurrent bronchopulmonary diseases. Further, prospective observational studies are needed to assess the impact of this phenomenon, if any, on the clinical course of these patients. J. Med. Virol. 85:888–892, 2013. © 2013 Wiley Periodicals, Inc.


title: Viruses and the nucleolus: The fatal attraction

text: Abstract Viruses are small obligatory parasites and as a consequence, they have developed sophisticated strategies to exploit the host cell's functions to create an environment that favors their own replication. A common feature of most – if not all – families of human and non-human viruses concerns their interaction with the nucleolus. The nucleolus is a multifunctional nuclear domain, which, in addition to its well-known role in ribosome biogenesis, plays several crucial other functions. Viral infection induces important nucleolar alterations. Indeed, during viral infection numerous viral components localize in nucleoli, while various host nucleolar proteins are redistributed in other cell compartments or are modified, and non-nucleolar cellular proteins reach the nucleolus. This review highlights the interactions reported between the nucleolus and some human or animal viral families able to establish a latent or productive infection, selected on the basis of their known interactions with the nucleolus and the nucleolar activities, and their links with virus replication and/or pathogenesis. This article is part of a Special Issue entitled: Role of the Nucleolus in Human Disease.


title: Epidemiology of rotavirus diarrhoea in Iranian children

text: Human rotavirus is the most important cause of severe diarrhoea in infants and young children worldwide. We describe the aetiology of viral diarrhoea and the characteristics of rotavirus infection in Shahrekord, Iran. Two hundred and fifty nine children <5 years old admitted to Hajar Hospital, 245 children with acute diarrhoea attending primary health centres in Shahrekord, and 114 children hospitalised for elective surgery were selected from October 2001 to August 2002. Stool samples were screened for enteric viruses using EM. Rotaviruses were characterised using ELISA, reverse transcription‐polymerase chain reaction (RT‐PCR), and electropherotyping. One hundred and eighty six viruses were identified, of which 146 (78%) were rotavirus. The second most frequent virus was coronavirus, followed by calicivirus. Rotaviruses exhibited a marked seasonal variation, being most frequently isolated from November to February (50% of rotavirus recovered) and affected mostly children <2 years old. The RT‐PCR successfully typed 139 of the 146 (95%) rotavirus G types and 124 (85%) P types. The most frequent P type was, P[8] in 108 (74%), P[4] in 16 (11%), and was P non‐typeable in 22 (15%). Among the G types, G1 was identified in 120 (82%), G2 in 19 (13%), and was G‐non‐typeable in 7 (5%). Our results are the first report of rotavirus genotypes affecting Iranian children. The most frequent G and P types (G1, G2, P[8], and P[4]) are similar to those reported from around the world and will be covered by existing rotavirus vaccines targeting G types G1–G4. J. Med. Virol. 73:309–312, 2004. © 2004 Wiley‐Liss, Inc.


title: Adjuvant effects of mannose-binding lectin ligands on the immune response to infectious bronchitis vaccine in chickens with high or low serum mannose-binding lectin concentrations

text: Abstract Mannose-binding lectin (MBL) plays a major role in the immune response as a soluble pattern-recognition receptor. MBL deficiency and susceptibility to different types of infections have been subject to extensive studies over the last decades. In humans and chickens, several studies have shown that MBL participates in the protection of hosts against virus infections. Infectious bronchitis (IB) is a highly contagious disease of economic importance in the poultry industry caused by the coronavirus infectious bronchitis virus (IBV). MBL has earlier been described to play a potential role in the pathogenesis of IBV infection and the production of IBV-specific antibodies, which may be exploited in optimising IBV vaccine strategies. The present study shows that MBL has the capability to bind to IBV in vitro. Chickens from two inbred lines (L10H and L10L) selected for high or low MBL serum concentrations, respectively, were vaccinated against IBV with or without the addition of the MBL ligands mannan, chitosan and fructooligosaccharide (FOS). The addition of MBL ligands to the IBV vaccine, especially FOS, enhanced the production of IBV-specific IgG antibody production in L10H chickens, but not L10L chickens after the second vaccination. The addition of FOS to the vaccine also increased the number of circulating CD4+ cells in L10H chickens compared to L10L chickens. The L10H chickens as well as the L10L chickens also showed an increased number of CD4−CD8α−γδ T-cells when an MBL ligand was added to the vaccine, most pronouncedly after the first vaccination. As MBL ligands co-administered with IBV vaccine induced differences between the two chicken lines, these results indirectly suggest that MBL is involved in the immune response to IBV vaccination. Furthermore, the higher antibody response in L10H chickens receiving vaccine and FOS makes FOS a potential adjuvant candidate in an IBV vaccine.


title: The outbreak of Novel Coronavirus disease (COVID‐19) caused a worrying delay in the diagnosis of oral cancer in north‐west Italy: The Turin Metropolitan Area experience

text: Recently, the epidemic of Novel Coronavirus disease 2019 (COVID-19) has become a chief public health challenge for many countries around the world. In Italy, it started in January the 31st with the first 2 cases reported; on Monday the 13th of April, the total confirmed cases were 156.363 with 19.901 total deaths (www.who.int). Turin is the fourth Italian city, with roughly 862.000 inhabitants, and the capital of Piedmont region, one of the most affected by COVID-19.


title: Serological evidence of widespread exposure of Grenada fruit bats to chikungunya virus

text: Antibody detection against selected potentially zoonotic vector‐borne alphaviruses and flaviviruses was conducted on sera from bats from all six parishes in Grenada, West Indies. Sera were tested for (i) antibodies to flaviviruses West Nile virus, St. Louis encephalitis virus, Ilhéus virus, Bussuquara virus (BSQV), Rio Bravo virus and all four serotypes of dengue virus (DENV) by plaque reduction neutralization test (PRNT); (ii) antibodies to alphaviruses western equine encephalitis virus, Venezuelan equine encephalitis virus and eastern equine encephalitis virus by epitope‐blocking enzyme‐linked immunosorbent assay (ELISA); and (iii) antibodies to the alphavirus chikungunya (CHIKV) by PRNT. Two species of fruit bats were sampled, Artibeus jamaicensis and Artibeus lituratus, all roosting in or within 1,000 m of human settlements. Fifteen (36%) of the 42 bats tested for neutralizing antibodies to CHIKV were positive. The CHIKV‐seropositive bats lived in localities spanning five of the six parishes. All 43 bats tested for epitope‐blocking ELISA antibody to the other alphaviruses were negative, except one positive for Venezuelan equine encephalitis virus. All 50 bats tested for neutralizing antibody to flaviviruses were negative, except one that had a BSQV PRNT (80) titre of 20. The CHIKV serology results indicate that bats living close to and within human settlements were exposed to CHIKV in multiple locations. Importantly, bats for this study were trapped a year after the introduction and peak of the human CHIKV epidemic in Grenada. Thus, our data indicate that bats were exposed to CHIKV possibly during a time of marked decline in human cases.


title: Virus-like particles in MDCK cells persistently infected with Borna disease virus

text: Abstract A line of Madin Darby canine kidney (MDCK) cells persistently infected with Borna disease virus was examined by electron microscopy. Thin sections revealed the presence of intracytoplasmic virus-like particles ranging from 50–100 nm in diameter. Nuclei of the infected cells exhibited accumulation of electron-dense granular structures 15–18 nm in diameter. The intracytoplasmic particles were roughly spherical with a limiting membrane, suggesting the presence of a lipid-containing envelope. The internal structure consisted of strand-like material which in some cases was condensed underneath the envelope. The possible relationship of these particles to Boma disease virions is discussed.


title: Vaccines for COVID-19: the current state of play

text: There is a strong consensus globally that a COVID-19 vaccine is likely the most effective approach to sustainably controlling the COVID-19 pandemic. An unprecedented research effort and global coordination has resulted in a rapid development of vaccine candidates and initiation of trials. Here, we review vaccine types, and progress with 10 vaccine candidates against SARS-CoV-2 – the virus that causes COVID-19 - currently undergoing early phase human trials. We also consider the many challenges of developing and deploying a new vaccine on a global scale, and recommend caution with respect to our expectations of the timeline that may be ahead.


title: N-glycan Cryptic Antigens as Active Immunological Targets in Prostate Cancer Patients

text: Although tumor-associated abnormal glycosylation has been recognized for decades, information regarding host recognition of the evolving tumor glycome remains elusive. We report here a carbohydrate microarray analysis of a number of tumor-associated carbohydrates for their serum antibody reactivities and potential immunogenicity in humans. These are the precursors, cores and internal sequences of N-glycans. They are usually masked by other sugar moieties and belong to a class of glyco-antigens that are normally “cryptic”. However, viral expression of these carbohydrates may trigger host immune responses. For examples, HIV-1 and SARS-CoV display Man9 clusters and tri- or multi-antennary type II (Galβ1→4GlcNAc) chains (Tri/m-II), respectively; viral neutralizing antibodies often target these sugar moieties. We asked, therefore, whether prostate tumor expression of corresponding carbohydrates triggers antibody responses in vivo. Using carbohydrate microarrays, we analyzed a panel of human sera, including 17 samples from prostate cancer patients and 12 from men with Benign Prostatic Hyperplasia (BPH). We observed that IgG antibodies targeting the Man9- or Tri-/m-II-autoantigens are readily detectable in the sera of men with BPH, as well as those with cancer. Importantly, these antibody activities were selectively increased in prostate cancer patients. Thus, human immune systems actively recognize these N-glycan cryptic carbohydrates and produce targeting antibodies. This finding shads a light on a class of previously less studied immunological targets of human cancers. Identifying the diagnostic, prognostic and therapeutic values of these targets will require further investigation.


title: Circulating Exosomes from Human Lung Transplant Recipients Having Respiratory Viral Infections Contain Nucleic Acids and Activate Signaling Pathways CGAS/STING and RIG-1

text: Purpose Exosomes are membrane bound vesicles are released by cells into body fluids. Our laboratory demonstrated the presence of circulating exosomes with lung self-antigens (Collagen-V and K-α Tubulin) and donor HLA in lung transplant recipients (LTxRs) undergoing rejection. Since respiratory viral infections (RVI) is a risk factor for development of chronic lung allograft dysfunction (CLAD) post lung transplant, we postulated that RVI can lead to induction of exosomes with self-antigens containing viral DNA/RNA capable of activating innate immune signaling via cGAS/STING and RIG1 pathways, a mechanism leading to immune activation resulting in CLAD. Methods Exosomes were isolated using ultracentrifugation. Size (50-200nm) was determined using nanosight. DNA and RNA were isolated using kits and quantified on the Nanodrop. Libraries were generated using Kapa Biosystem's library kit. The raw Illumina 2x150bp pair-end reads were checked on FastQC and were aligned to the human and viral genome build from CHIPseeker Database. Validation was done using antibodies and primers for respiratory syncytial virus, coronavirus, and rhinovirus. To determine the role of exosomes to induce cell signaling and endoplasmic stress (ER), airway epithelial cells (KCC266), and Hep2 cells were incubated with exosomes from LTxRs with RVI or stable. Results Viral nucleic acid sequences were noted in higher levels in exosomes from LTxRs with RVI in comparison to stable. Comparison with human genome identified the presence of DNA sequences specific to defensins, GTPase, apoptotic cleavage, and NMDA receptor in RVI LTxRs. Further, we identified upregulation of proteins associated with cGAS/STING and RIG1 (MAVS, MDA5, IFNβ) and ER stress (PERK, ATF4 and BiP) in KCC266 and Hep2 cells incubated with exosomes from LTxRs with RVI, but not stable. In contrast, exosomes from stable LTxRs had 91 sequences for MAP kinase and cell death signaling pathways. Conclusion We conclude that LTxRs diagnosed with RVI leads to induction of circulating exosomes having unique viral nucleic acid sequences capable of inducing signaling and ER stress. This can lead to activate innate immune signaling via cGAS/STING and RIG1 pathways resulting in immune responses to viral and donor antigens resulting in CLAD.


Cardiac surgery model during COVID-19 pandemic: now it’s time to ramp up


title: The Role of Immunophilins in Viral Infection

text: BACKGROUND: Tremendous progress has been made in the past 20 years in understanding the roles played by immunophilins, and in particular the cyclophilins, in supporting the replication cycles of human viruses. A growing body of genetic and biochemical evidence and data from clinical trials confirms that cyclophilins are essential cofactors that contribute to establishing a permissive environment within the host cell that supports the replication of HIV-1 and HCV. Cyclophilin A regulates HIV-1 replication kinetics and infectivity, modulates sensitivity to host restriction factors, and cooperates in the transit of the pre-integration complex into the nucleus of infected cells. Cyclophilin A is an essential cofactor whose expression supports HCV-specific RNA replication in human hepatocytes. GENERAL SIGNIFICANCE: Peptidyl-prolyl isomerase inhibitors have been used in clinical trials to validate cyclophilins as antiviral targets for the treatment of HIV-1 and Chronic Hepatitis C virus infection and as molecular probes to identify the roles played by immunophilins in supporting the replication cycles of human viruses. SCOPE OF REVIEW: This review summarizes emerging research that defines the functions of immunophilins in supporting the replication cycles of HIV-1, HCV, HBV, coronaviruses, and other viral pathogens and describes new information that suggests a role for immunophilins in regulating innate immune responses against chronic viral infection. MAJOR CONCLUSIONS: The dependence on cyclophilins by evolutionarily distinct viruses for accomplishing various steps in replication such as viral entry, initiation of genomic nucleic acid replication, viral genome uncoating, nuclear import and nuclear entry, emphasizes the potential of cyclophilin inhibitors as therapeutic agents.


title: SARS Coronavirus-unique Domain (SUD): Three-domain Molecular Architecture in Solution and RNA Binding

text: The nonstructural protein 3 (nsp3) of the severe acute respiratory syndrome coronavirus (SARS-CoV) includes a “SARS-unique region” (SUD) consisting of three globular domains separated by short linker peptide segments. This paper reports NMR structure determinations of the C-terminal domain (SUD-C) and of a two-domain construct (SUD-MC) containing the middle domain (SUD-M) and the C-terminal domain, and NMR data on the conformational states of the N-terminal domain (SUD-N) and the SUD-NM two-domain construct. Both SUD-N and SUD-NM are monomeric and globular in solution, and in SUD-NM there is high mobility in the two-residue interdomain linking sequence, with no preferred relative orientation of the two domains. SUD-C adopts a frataxin-like fold and has structural similarity to DNA-binding domains of DNA-modifying enzymes. The structures of both SUD-M (previously determined) and SUD-C (from the present study) are maintained in SUD-MC, where the two domains are flexibly linked. Gel shift experiments showed that both SUD-C and SUD-MC bind to single-stranded RNA and recognize purine bases more strongly than pyrimidine bases, whereby SUD-MC binds to a more restricted set of purine-containing RNA sequences than SUD-M. NMR chemical shift perturbation experiments with observation of the (15)N-labeled proteins further resulted in the delineation of the RNA binding sites, i.e., in SUD-M a positively charged surface area with a pronounced cavity, and in SUD-C several residues of an antiparallel β-sheet. Overall, the present data provide evidence for molecular mechanisms involving concerted actions of SUD-M and SUD-C, which result in specific RNA-binding that might be unique to the SUD, and thus to the SARS-CoV.


title: Delayed Treatment of Diagnosed Pulmonary Tuberculosis in Taiwan

text: BACKGROUND: Mycobacterium tuberculosis infection is an ongoing public health problem in Taiwan. The National Tuberculosis Registry Campaign, a case management system, was implemented in 1997. This study examined this monitoring system to identify and characterize delayed treatment of TB patients. METHODS: Records of all tuberculosis cases treated in Taiwan from 2002 through 2005 were obtained from the National Tuberculosis Registry Campaign. Initiation of treatment more than 7 days after diagnosis was considered a long treatment delay. RESULTS: The study included 31,937 patients. The mean day of delayed treatment was 3.6 days. Most patients were treated immediately after diagnosis. The relationship between number of TB patients and days of delayed treatment after diagnosis exhibited a Power-law distribution. The long tail of the power-law distribution indicated that an extreme number occur cannot be neglected. Tuberculosis patients treated after an unusually long delay require close observation and follow up. CONCLUSION: This study found that TB control is generally acceptabl in Taiwan; however, delayed treatment increases the risk of transmission. Improving the protocol for managing confirmed TB cases can minimize disease transmission.


title: Predictors of the incidence of all-cause mortality and deaths due to diabetes and renal diseases among patients newly prescribed antihypertensive agents: A cohort study

text: Abstract Background Randomized trials have shown that the major antihypertensive drug classes are similarly effective to reduce mortality, but whether these drug class difference exists in clinical practice has been scarcely explored. This study evaluated the association between antihypertensive drug class, all-cause mortality and deaths due to diabetes or renal disease in real-life clinical settings. Methods A clinical database in Hong Kong included all patients who were prescribed their first-ever antihypertensive agents between 2001 and 2005 from the public healthcare sector. All patients were followed up for five years, and grouped according to the initial antihypertensive prescription. The associations between antihypertensive drug class, all-cause mortality or combined diabetes and renal mortality, respectively, were evaluated by Cox proportional hazard models. Results From 218,047 eligible patients, 33,288 (15.3%) died within five years after their first-ever antihypertensive prescription and among which 1055 patients (0.48%) died of diabetes or renal disease. After adjusted for age, gender, socioeconomic status, service settings, district of residence, medication adherence, and the number of comorbidities, each drug class was similarly likely to be associated with mortality due to diabetes or renal disease [Adjusted Hazard Ratios (AHR) ranged from 0.92 to 1.73, p=0.287–0.939] and all-cause mortality (AHR ranged from 0.83 to 1.02) except for beta-blockers (AHR=0.815, 95% C.I. 0.68–0.87, p=0.024) when ACEI was used as a reference group in propensity score-adjusted analysis. Conclusions These findings provide real-life evidence reinforcing that any major antihypertensive drug class is suitable as a first-line agent for management of hypertension as recommended by international guidelines.


title: Porcine deltacoronavirus induces caspase-dependent apoptosis through activation of the cytochrome c-mediated intrinsic mitochondrial pathway

text: Abstract Porcine deltacoronavirus (PDCoV), a newly discovered enteric coronavirus, is a causative agent of severe clinical diarrhea and intestinal pathological damage in piglets. As a first step toward understanding the effect of PDCoV on host cells, we elucidated mechanisms underlying the process of apoptotic cell death after PDCoV infection. The use of a pan-caspase inhibitor resulted in the inhibition of PDCoV-induced apoptosis and reduction of PDCoV replication, suggestive of the association of a caspase-dependent pathway. Furthermore, PDCoV infection necessitated the activation of the initiator caspase-9 responsible for the intrinsic mitochondrial apoptosis pathway. Experimental data indicated that PDCoV infection led to Bax-mediated mitochondrial outer membrane permeabilization (MOMP), resulting in specific relocation of the mitochondrial cytochrome c (cyt c) into the cytoplasm. Treatment with cyclosporin A (CsA), an inhibitor of mitochondrial permeability transition pore (MPTP) opening, significantly suppressed PDCoV-triggered apoptosis and viral replication. Moreover, cyt c release was completely abrogated in PDCoV-infected cells in the presence of CsA, suggesting the critical role of MPTP in intrinsic apoptosis in response to PDCoV infection. Altogether, our results indicate that PDCoV infection stimulates MOMP either via Bax recruitment or MPTP opening to permit the release of apoptogenic cyt c into the cytoplasm, thereby leading to execution of the caspase-dependent intrinsic apoptosis pathway to facilitate viral replication in vitro.


title: Hepatitis C Virus RNA Replication and Assembly: Living on the Fat of the Land

text: Hepatitis C virus (HCV) is a major global health burden accounting for around 170 million chronic infections worldwide. Although highly potent direct-acting antiviral drugs to treat chronic hepatitis C have been approved recently, owing to their high costs and limited availability and a large number of undiagnosed infections, the burden of disease is expected to rise in the next few years. In addition, HCV is an excellent paradigm for understanding the tight link between a pathogen and host cell pathways, most notably lipid metabolism. HCV extensively remodels intracellular membranes to establish its cytoplasmic replication factory and also usurps components of the intercellular lipid transport system for production of infectious virus particles. Here, we review the molecular mechanisms of viral replicase function, cellular pathways employed during HCV replication factory biogenesis, and viral, as well as cellular, determinants of progeny virus production.


title: Norwalk-like calicivirus genes in farm animals.

text: Viruses closely related to Norwalk-like viruses (NLVs) were recently found in stored stool samples from two calves (United Kingdom and Germany) and four pigs (Japan), sparking discussions about the potential for zoonotic transmission. To investigate if NLVs are commonly present in farm animals, pooled stool samples from 100 pig farms, 48 chicken farms, 43 dairy cow herds, and 75 veal calf farms from the Netherlands were assayed by reverse transcription- polymerase chain reaction amplification, using primers specific for the detection of NLVs from humans. NLV RNA was detected in 33 (44%) of the specimens from veal calf farms and two (2%) specimens from pig farms. Our data show that NLV infections until recently thought to be restricted to humans occur often in calves and sometimes in pigs. While zoonotic transmission has not been proven, these findings suggest that calves and pigs may be reservoir hosts of NLVs.


title: Emerging waterborne pathogens: can we kill them all?

text: Abstract The rapid emergence of Cryptosporidium parvum and Escherichia coli 0157:H7 have created a threat to the drinking water industry and there is a growing need to develop a strategy for recognizing potential emerging waterborne pathogens. Globalization of trade, changing population demographics and changes in treatment technology have been driving factors in the emergence of these new pathogens. An understanding of disinfectant action and microbial resistance to treatment processes is needed to better identify those pathogens likely to be of greatest concern. Recent research on microbial resistance to treatment and disinfection demonstrates that the microbial surface structure and composition and the nature of the genome are key to determining the potential for waterborne transmission of emerging pathogens.


title: Hand-hygiene mitigation strategies against global disease spreading through the air transportation network

text: Hand hygiene is considered as an efficient and cost-effective way to limit the spread of diseases and, as such, it is recommended by both the World Health Organization (WHO) and the Centres for Disease Control and Prevention (CDC). While the effect of hand washing on individual transmissibility of a disease has been studied through medical and public-health research, its potential as a mitigation strategy against a global pandemic has not been fully explored yet. In this study, we investigate contagion dynamics through the world air transportation network and analyze the impact of hand-hygiene behavioural changes of airport population against the spread of infectious diseases worldwide. Using a granular dataset of the world air transportation traffic, we build a detailed individual mobility model that controls for the correlated and recurrent nature of human travel and the waiting-time distributions of individuals at different locations. We perform a Monte-Carlo simulation study to assess the impact of different hand-washing mitigation strategies at the early stages of a global epidemic. From the simulation results we find that increasing the hand cleanliness homogeneously at all airports in the world can inhibit the impact of a potential pandemic by 24 to 69%. By quantifying and ranking the contribution of the different airports to the mitigation of an epidemic outbreak, we identify ten key airports at the core of a cost-optimal deployment of the hand-washing strategy: increasing the engagement rate at those locations alone could potentially reduce a world pandemic by 8 to 37%. This research provides evidence of the effectiveness of hand hygiene in airports on the global spread of infectious diseases, and has important implications for the way public-health policymakers may design new effective strategies to enhance hand hygiene in airports through behavioral changes.


title: The Food Systems in the Era of the Coronavirus (COVID-19) Pandemic Crisis

text: The World Health Organization (WHO) declared the outbreak of coronavirus disease (COVID-19, broadly referred to as “coronavirus”) a global pandemic, while thousands of infections and deaths are reported daily. The current article explores the food systems in the era of the COVID-19 pandemic crisis. It provides insights about the properties of bioactive ingredients of foods and herbs for the support of the human immune system against infections before discussing the possibility of COVID-19 transmission through the food chain. It also highlights the global food security issues arising from the fact that one-third of the world’s population is on lockdown. Finally, it underlines the importance of sustainability in the food chain in order to avoid or reduce the frequency of relevant food and health crises in the future.


Researchers Continue Quest to Contain Spread of COVID-19: Digital technologies aim to accelerate contact tracing.


title: A Functional Genomics Approach to Henipavirus Research: The Role of Nuclear Proteins, MicroRNAs and Immune Regulators in Infection and Disease

text: Hendra and Nipah viruses (family Paramyxoviridae, genus Henipavirus) are zoonotic RNA viruses that cause lethal disease in humans and are designated as Biosafety Level 4 (BSL4) agents. Moreover, henipaviruses belong to the same group of viruses that cause disease more commonly in humans such as measles, mumps and respiratory syncytial virus. Due to the relatively recent emergence of the henipaviruses and the practical constraints of performing functional genomics studies at high levels of containment, our understanding of the henipavirus infection cycle is incomplete. In this chapter we describe recent loss-of-function (i.e. RNAi) functional genomics screens that shed light on the henipavirus–host interface at a genome-wide level. Further to this, we cross-reference RNAi results with studies probing host proteins targeted by henipavirus proteins, such as nuclear proteins and immune modulators. These functional genomics studies join a growing body of evidence demonstrating that nuclear and nucleolar host proteins play a crucial role in henipavirus infection. Furthermore these studies will underpin future efforts to define the role of nucleolar host–virus interactions in infection and disease.


title: Antioxidant Activity and Protective Effects of Tripterygium regelii Extract on Hydrogen Peroxide-Induced Injury in Human Dopaminergic Cells, SH-SY5Y

text: The present work was conducted to investigate the antioxidant activity and neuroprotective effects of Tripterygium regelii extract (TRE) on H(2)O(2)-induced apoptosis in human dopaminergic cells, SH-SY5Y. TRE possessed considerable amounts of phenolics (282.73 mg tannic acid equivalents/g of extract) and flavonoids (101.43 mg naringin equivalents/g of extract). IC(50) values for reducing power and DPPH radical scavenging activity were 52.51 and 47.83 μg, respectively. The H(2)O(2) scavenging capacity of TRE was found to be 57.68 μM × μg(−1) min(−1). By examining the effects of TRE on SH-SY5Y cells injured by H(2)O(2), we found that after incubation of cells with TRE prior to H(2)O(2) exposure, the H(2)O(2) induced cytotoxicity was significantly reversed and the apoptotic features such as change in cellular morphology, nuclear condensation and DNA fragmentation was inhibited. Moreover, TRE was very effective attenuating the disruption of mitochondrial membrane potential and apoptotic cell death induced by H(2)O(2). TRE extract effectively suppressed the up-regulation of Bax, Caspase-3 and -9, and down-regulation of Bcl-2. Moreover, TRE pretreatment evidently increased the tyrosine hydroxylase (TH) and brain-derived neurotrophic factor (BDNF) in SH-SY5Y cells. These findings demonstrate that TRE protects SH-SY5Y cells against H(2)O(2)-induced injury and antioxidant properties may account for its neuroprotective actions and suggest that TRE might potentially serve as an agent for prevention of neurodegenerative disease associated with oxidative stress.


title: The Aging of γδ T Cells

text: In the coming decades, many developed countries in the world are expecting the “greying” of their populations. This phenomenon poses unprecedented challenges to healthcare systems. Aging is one of the most important risk factors for infections and a myriad of diseases such as cancer, cardiovascular and neurodegenerative diseases. A common denominator that is implicated in these diseases is the immune system. The immune system consists of the innate and adaptive arms that complement each other to provide the host with a holistic defense system. While the diverse interactions between multiple arms of the immune system are necessary for its function, this complexity is amplified in the aging immune system as each immune cell type is affected differently—resulting in a conundrum that is especially difficult to target. Furthermore, certain cell types, such as γδ T cells, do not fit categorically into the arms of innate or adaptive immunity. In this review, we will first introduce the human γδ T cell family and its ligands before discussing parallels in mice. By covering the ontogeny and homeostasis of γδ T cells during their lifespan, we will better capture their evolution and responses to age-related stressors. Finally, we will identify knowledge gaps within these topics that can advance our understanding of the relationship between γδ T cells and aging, as well as age-related diseases such as cancer.


title: Development and application of nsp5-ELISA for the detection of antibody to infectious bronchitis virus

text: Abstract Infectious bronchitis virus (IBV) continues to be one of the most important poultry pathogens worldwide. The current commercially available enzyme-linked immunosorbent assay (ELISA) kits for IBV specific antibody detection are mostly based on the whole virion, and few serological tests based on nonstructural proteins of IBV have been developed. Herein, an alternative indirect ELISA for detection of IBV antibody was developed with IBV nonstructural protein 5 (nsp5) produced by Escherichia coli. Using an indirect immunofluorescence assay (IFA) and a commercial ELISA kit as reference, we optimized the nsp5-ELISA and determined its cut-off as 0.12. The diagnostic sensitivity (DSN), specificity (DSP) and accuracy of the nsp5-ELISA were 93.11%, 95.38% and 93.33%, respectively, compared with IFA in 660 field serum samples, and were 98.11%, 95.00% and 97.62%, respectively, compared with the commercial IBV ELISA kit (IDEXX) in 126 field sera samples. Furthermore, a time course of IBV specific antibody level detected by nsp5-ELISA following IBV infection and vaccination is consistent with that of IBV antibody detected by the commercial ELISA kit. The results presented in this study indicate that nsp5-ELISA has the potential to serve as a rapid, reliable and cost-effective method for IBV antibody detection. This study is the first to report the development of an nsp-based ELISA to detect an antibody to IBV.


title: The COVID‐19 pandemic is a crisis and opportunity for bipolar disorder

text: The ongoing COVID‐19 pandemic has to date infected more than one million people and led to tens of thousands of deaths across the globe. Thus, many governments have imposed regional or national mass shelters‐in‐place in an effort to slow its rapid spread. In this global health emergency, special attention should be paid to the potential impact of the measures taken to combat the pandemic on patients with bipolar disorders (BDs).


title: Medicolegal Considerations in Multidisciplinary Cancer Care

text: Abstract Health professionals participating in multidisciplinary team (MDT) cancer meetings may not be aware of their medicolegal obligations. This commentary aims to identify medicolegal issues concerning multidisciplinary cancer care and provides recommendations for future implementation. Predominant medicolegal issues related to MDT care were identified in the literature and include: patient consent and privacy at MDT meeting, professional liability, formal expression of dissenting views, and duty of care. Analysis of the literature prioritises several recommendations for managing these issues. With limited precedent on which to base recommendations, this article identifies the formative evidence that may guide management of these issues in future MDT practice.


title: Detection of Respiratory Viruses in Asymptomatic Children Undergoing Allogeneic Hematopoietic Cell Transplantation

text: Detection of respiratory viruses by molecular methods, in children without respiratory symptoms undergoing hematopoietic cell transplantation (HCT), has not been well described. A prospective study of 33 asymptomatic children detected respiratory viruses in 8 of 33 (24%) patients before HCT. Human rhinovirus (HRV) was detected in 5 patients, and human adenovirus (hADV) in 3 patients. Two additional patients shed HRV, and one shed human coronavirus (hCoV), post-HCT. Two patients had co-infections. Of the 11 asymptomatic patients where respiratory virus was detected, 3 (27%) later developed an upper respiratory tract infection, from the same virus.


title: Comparison of hand contamination rates and environmental contamination levels between two different glove removal methods and distances

text: BACKGROUND: Gloves are a necessary contact precaution to prevent transmission of infectious pathogens that spread by direct or indirect contact with an infected person or a contaminated environment. This article reports a study investigating hand and environmental contamination levels when health care workers (HCWs) followed two different methods of removing gloves at two distances from the rubbish bin. METHODS: Fifty HCWs performed a personal or causal glove removal method (pretest) and a Centers for Disease Control (CDC)-recommended glove removal method (posttest) at distances of 2 feet and 3 feet from the rubbish bin after the application of fluorescent solution (the simulated contaminant) onto their gloved hands. RESULTS: The incidence of the small patch of fluorescent stain (<1 cm(2)) on the front of the doffed gloves was significantly lower in the posttest than in the pretest. The incidence of small and large patches (>1 cm(2)) on the front of the doffed gloves and on the cover of the rubbish bin was significantly lower at 3 feet than at 2 feet. Health care assistants had significantly higher levels of contamination than other HCWs in the pretest but not in the posttest. There was no significant difference in hand contamination rate between pretest and posttest based on distance from the rubbish bin and type of HCW. CONCLUSION: The impact of the glove removal procedure and the distance to the bin in which used gloves are discarded should be taken into consideration on a daily basis, along with the supervision of infection control measures by minor staff.


Re: ‘Non-COVID-19 visits to emergency departments during the pandemic: the impact of fear’


title: Extensions and Adaptations of Existing Medical Information System in Order to Reduce Social Contacts During COVID-19 Pandemic

text: OBJECTIVE: The main objective of this paper is the reduction of the COVID-19 pandemic spread by increasing the degree of social distancing by using and upgrading the existing Medical Information System (MIS). MATERIAL AND METHODS: The existing MIS MEDIS.NET, currently used in the largest health center in the Balkans, has been adapted and further developed. RESULTS: During the adaptation of existing MIS MEDIS.NET 4 new and 9 existing modules were developed. A quick questionnaire for the smart triage of patients was also implemented. DISCUSSION: The adapted MIS successfully influenced the reduction of social contacts within the Health Center Nis. The need for the arrival of children and their parents to receive appropriate health certificates for the school enrolment is reduced. The therapy of chronic patients has been prolonged for 6 months via an electronic prescription. An online service for the communication between patients and the chosen physicians is provided. Possible social contacts and exposure to the viral environment of patients are reduced by making appointments in extended slots and at determined physical locations. Patients are notified per SMS or email about the availability of chosen and physician on duty. The social distancing of patients and physicians is also established by sending laboratory analyses per email or SMS. Keeping the central registry for COVID-19 is enabled throughout the country. CONCLUSION: The smart adaptation of MIS, and its collaboration with other state systems can significantly influence the reduction of social contacts and thus mitigate the consequences of COVID-19 pandemic.


title: Research progress in the biological activities of 3,4,5-trimethoxycinnamic acid (TMCA) derivatives

text: TMCA (3,4,5-trimethoxycinnamic acid) ester and amide are privileged structural scaffolds in drug discovery which are widely distributed in natural products and consequently produced diverse therapeutically relevant pharmacological functions. Owing to the potential of TMCA ester and amide analogues as therapeutic agents, researches on chemical syntheses and modifications have been carried out to drug-like candidates with broad range of medicinal properties such as antitumor, antiviral, CNS (central nervous system) agents, antimicrobial, anti-inflammatory and hematologic agents for a long time. At the same time, SAR (structure-activity relationship) studies have draw greater attention among medicinal chemists, and many of the lead compounds were derived for various disease targets. However, there is an urgent need for the medicinal chemists to further exploit the precursor in developing chemical entities with promising bioactivity and druggability. This review concisely summarizes the synthesis and biological activity for TMCA ester and amide analogues. It also comprehensively reveals the relationship of significant biological activities along with SAR studies.


title: Characterization of a cold-sensitive (cs) recombinant between two influenza a strains

text: Abstract Recombinants between fowl plague virus (FPV, H7N1) and the Hong Kong (H3N2) or Singapore (H2N2) influenza virus strains carrying the hemagglutinin of FPV and the neuraminidase of the human strains form only very tiny plaques at 33°, but normal plaques at 37°. One recombinant (113/Ho) has been studied in more detail. It multiplies only very slowly at 33°, the nonpermissive temperature. Adsorption and penetration are normal at 33°, but synthesis of protein is impeded. Temperature-shift experiments suggest that the synthesis of viral mRNA is slowed at 33°. 113/Ho does not agglutinate chicken erythrocytes at 40°, as the parent viruses do. 113/Ho can be adapted to grow normally at 33°. The frequency of adaptation is comparable to reversion of a single point mutation (ca. 10−5). Recombinants which grow well at 37° but not at 33° are called cold-sensitive (cs) recombinants.


title: Respiratory Infections and Antibiotic Usage in Common Variable Immunodeficiency

text: Background Patients with common variable immunodeficiency (CVID) suffer frequent respiratory tract infections despite immunoglobulin replacement and are prescribed significant quantities of antibiotics. The clinical and microbiological nature of these exacerbations, the symptomatic triggers to take antibiotics, and the response to treatment have not been previously investigated. Objectives To describe the nature, frequency, treatment, and clinical course of respiratory tract exacerbations in patients with CVID and to describe pathogens isolated during respiratory tract exacerbations. Methods We performed a prospective diary card exercise in 69 patients with CVID recruited from a primary immunodeficiency clinic in the United Kingdom, generating 6210 days of symptom data. We collected microbiology (sputum microscopy and culture, atypical bacterial PCR, and mycobacterial culture) and virology (nasopharyngeal swab multiplex PCR) samples from symptomatic patients with CVID. Results There were 170 symptomatic exacerbations and 76 exacerbations treated by antibiotics. The strongest symptomatic predictors for commencing antibiotics were cough, shortness of breath, and purulent sputum. There was a median delay of 5 days from the onset of symptoms to commencing antibiotics. Episodes characterized by purulent sputum responded more quickly to antibiotics, whereas sore throat and upper respiratory tract symptoms responded less quickly. A pathogenic virus was isolated in 56% of respiratory exacerbations and a potentially pathogenic bacteria in 33%. Conclusions Patients with CVID delay and avoid treatment of symptomatic respiratory exacerbations, which could result in structural lung damage. However, viruses are commonly represented and illnesses dominated by upper respiratory tract symptoms respond poorly to antibiotics, suggesting that antibiotic usage could be better targeted.


title: Comparison of six different murine coronavirus jhm variants by monoclonal antibodies against the e2 glycoprotein

text: Abstract We have examined six different JHMV variants, sp-4 (recloned wt JHMV), cl-2, CNSV, DL, DS, and JHM-X, in terms of the sizes of the mRNA3 and E2 glycoprotein as well as their reactivity to a panel of monoclonal antibodies to the E2 glycoprotein. Two of these variants, sp-4 and JHM-X, were found to have smaller mRNA3 and E2 glycoprotein species compared with those of the other four variants. In addition, sp-4 and JHM-X were distinguished from the other four variants by their inability to bind to monoclonal antibodies recognizing two antigenic domains of the E2 molecule. Thus, six JHMV variants could clearly be divided into two groups with respect to the size and antigenicity of their E2 glycoproteins.


title: The great balancing act: regulation and fate of antiviral T-cell interactions

text: The fate of T lymphocytes revolves around a continuous stream of interactions between the T-cell receptor (TCR) and peptide-major histocompatibility complex (MHC) molecules. Beginning in the thymus and continuing into the periphery, these interactions, refined by accessory molecules, direct the expansion, differentiation, and function of T-cell subsets. The cellular context of T-cell engagement with antigen-presenting cells, either in lymphoid or nonlymphoid tissues, plays an important role in determining how these cells respond to antigen encounters. CD8(+) T cells are essential for clearance of a lymphocytic choriomeningitis virus (LCMV) infection, but the virus can present a number of unique challenges that antiviral T cells must overcome. Peripheral LCMV infection can lead to rapid cytolytic clearance or chronic viral persistence; central nervous system infection can result in T-cell-dependent fatal meningitis or an asymptomatic carrier state amenable to immunotherapeutic clearance. These diverse outcomes all depend upon interactions that require TCR engagement of cognate peptide-MHC complexes. In this review, we explore the diversity in antiviral T-cell behaviors resulting from TCR engagement, beginning with an overview of the immunological synapse and progressing to regulators of TCR signaling that shape the delicate balance between immunopathology and viral clearance.


title: Entry of hepatitis B and hepatitis D virus into hepatocytes: Basic insights and clinical implications

text: Summary For almost three decades following the discovery of the human Hepatitis B Virus (HBV) the early events of virus infection (attachment to hepatocytes, specific binding to a receptor on hepatocytes) remained enigmatic. The gradual improvement of tissue culture systems for HBV has enabled the identification of viral determinants for viral infectivity and facilitated the discovery of the human sodium taurocholate co-transporting polypeptide (hNTCP) as a liver specific receptor of HBV and its satellite, the human Hepatitis Delta Virus (HDV). These findings are currently leading basic and clinical research activities in new directions. (1) Stable hNTCP-expressing cell lines have become a valuable platform to study the full HBV replication cycle from its native template, the cccDNA. (2) The suitability of NTCP complemented cell culture systems for high throughput screening approaches will facilitate identification of novel host factors involved in HBV replication (including those that determine the peculiar host specificity of HBV infection) and will enable identification and development of novel drug candidates for improved therapeutics. (3) Since NTCP is a major host-specific restriction factor for HBV and HDV, hNTCP-expressing animals provide the basis for future susceptible in vivo models. (4) The concept obtained with the entry inhibitor Myrcludex B demonstrates that NTCP is a suitable target for clinical interference with viral entry. This will foster further clinical approaches aiming at curative combination therapies.


title: COVID-19 Outbreak: An Overview

text: BACKGROUND: In late December 2019, Chinese health authorities reported an outbreak of pneumonia of unknown origin in Wuhan, Hubei Province. SUMMARY: A few days later, the genome of a novel coronavirus was released (http://virological.org/t/novel-2019-coronavirus-genome/319; Wuhan-Hu-1, GenBank accession No. MN908947) and made publicly available to the scientific community. This novel coronavirus was provisionally named 2019-nCoV, now SARS-CoV-2 according to the Coronavirus Study Group of the International Committee on Taxonomy of Viruses. SARS-CoV-2 belongs to the Coronaviridae family, Betacoronavirus genus, subgenus Sarbecovirus. Since its discovery, the virus has spread globally, causing thousands of deaths and having an enormous impact on our health systems and economies. In this review, we summarize the current knowledge about the epidemiology, phylogenesis, homology modeling, and molecular diagnostics of SARS-CoV-2. KEY MESSAGES: Phylogenetic analysis is essential to understand viral evolution, whereas homology modeling is important for vaccine strategies and therapies. Highly sensitive and specific diagnostic assays are key to case identification, contact tracing, identification of the animal source, and implementation of control measures.


Hydroxychloroquine side-effects raise concerns for rheumatology patients


title: 8 Epidemic modeling and control of HIV/AIDS dynamics in populations under external interactions: A worldwide challenge

text: Abstract In this chapter the problem of the interaction between groups of subjects singularly characterized by a specific infectious disease is addressed. The dynamical characteristics of an isolated population are preliminary studied, with particular reference to the equilibrium points and their stability. Then, the effects of constant inputs on the dynamics are deeply analyzed also by numerical simulations; this analysis is propaedeutic to the study of the interaction between the groups. The interactions between the different populations are modeled as additional input/output to the single group dynamics introducing total averaged effects including all the external migration effects. This approach focuses on the changes in the dynamics of one population when interactions are present without showing the global migration fluxes, but stressing the influences on each populations. Besides the simplifications of the model, this point of view may be fruitful also with respect of the design of control actions, assuming that each group can adopt the best control strategy for her/his own specific social characteristics. The epidemic case analyzed is HIV-AIDS. This choice has been made since this virus is present all over the world, but with different levels of dangerousness and number of infected patients depending on the economic, social, and cultural habits. The model used is a recently introduced one, which describes this epidemic spread considering two compartments of susceptible people, distinguished by the level of attention with respect to the virus transmission, one of the infected individuals not aware of their status, and two classes of patients, divided according to the level of infection. Additional inputs have been introduced to model fluxes of susceptible individuals and infected but not aware individuals. These effects have been reported in numerous figures showing the results of numerical simulations.


title: Epidemiology and transmission of COVID-19 in 391 cases and 1286 of their close contacts in Shenzhen, China: a retrospective cohort study

text: Summary Background Rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Wuhan, China, prompted heightened surveillance in Shenzhen, China. The resulting data provide a rare opportunity to measure key metrics of disease course, transmission, and the impact of control measures. Methods From Jan 14 to Feb 12, 2020, the Shenzhen Center for Disease Control and Prevention identified 391 SARS-CoV-2 cases and 1286 close contacts. We compared cases identified through symptomatic surveillance and contact tracing, and estimated the time from symptom onset to confirmation, isolation, and admission to hospital. We estimated metrics of disease transmission and analysed factors influencing transmission risk. Findings Cases were older than the general population (mean age 45 years) and balanced between males (n=187) and females (n=204). 356 (91%) of 391 cases had mild or moderate clinical severity at initial assessment. As of Feb 22, 2020, three cases had died and 225 had recovered (median time to recovery 21 days; 95% CI 20–22). Cases were isolated on average 4·6 days (95% CI 4·1–5·0) after developing symptoms; contact tracing reduced this by 1·9 days (95% CI 1·1–2·7). Household contacts and those travelling with a case were at higher risk of infection (odds ratio 6·27 [95% CI 1·49–26·33] for household contacts and 7·06 [1·43–34·91] for those travelling with a case) than other close contacts. The household secondary attack rate was 11·2% (95% CI 9·1–13·8), and children were as likely to be infected as adults (infection rate 7·4% in children <10 years vs population average of 6·6%). The observed reproductive number (R) was 0·4 (95% CI 0·3–0·5), with a mean serial interval of 6·3 days (95% CI 5·2–7·6). Interpretation Our data on cases as well as their infected and uninfected close contacts provide key insights into the epidemiology of SARS-CoV-2. This analysis shows that isolation and contact tracing reduce the time during which cases are infectious in the community, thereby reducing the R. The overall impact of isolation and contact tracing, however, is uncertain and highly dependent on the number of asymptomatic cases. Moreover, children are at a similar risk of infection to the general population, although less likely to have severe symptoms; hence they should be considered in analyses of transmission and control. Funding Emergency Response Program of Harbin Institute of Technology, Emergency Response Program of Peng Cheng Laboratory, US Centers for Disease Control and Prevention.


Managing appendicitis during the COVID‐19 pandemic in the UK


title: Test and treat COVID 65 plus - Hydroxychloroquine versus placebo in early ambulatory diagnosis and treatment of older patients with COVID19: A structured summary of a study protocol for a randomised controlled trial

text: OBJECTIVES: The aim of this trial is to identify the effect of ambulatory treatment in early COVID-19 disease with hydroxychloroquine on the rate of hospitalization or death in older patients above the age of 64. TRIAL DESIGN: Parallel, 2:1 randomization, double blind, placebo-controlled, multi-center trial. PARTICIPANTS: Male and female patients above the age of 64 (i.e. ≥65 years of age) with COVID-19 diagnosis confirmed by SARS-CoV2 positive throat swab (PCR). Patients can only be included within 3 days of symptom onset in ambulatory care if they consent to the study procedure and are able to adhere to the study visit schedule and protocol requirements (including telephone visits concerning symptoms and side effects). Severity of disease at inclusion is mild to moderate defined as not requiring hospital admission: SpO2 >94%, respiratory rate <20, mental state alert, no signs of septic shock. Cardiac risk is minimised by requiring a Tisdale score ≤ 6. Patients are recruited in the two german cities of Ulm and Tübingen in various ambulatory care settings. INTERVENTION AND COMPARATOR: Each patient will be given a first dose of 600 mg Hydroxychloroquine or the equivalent number of placebo capsules (3 capsules) at the day of inclusion. From the 2(nd) day on, each patient will get 200 mg or the equivalent number of placebo capsules twice a day (400mg/day) until day 7 (6 more does of 400 mg); a cumulative dose of 3 g. MAIN OUTCOMES: Rate of hospitalization or death at day 7 after study inclusion RANDOMISATION: All consenting adult patients having confirmed COVID-19 are randomly and blindly allocated in a 2:1 ratio to either IMP or placebo. The biostatistical center produced a randomization list (block randomization) with varying block length and stratified for the study center. This list is provided for packaging to the pharmaceutical unit which is providing encapsulated placebo and IMP. Only the pharmaceutical unit is aware of group allocation according to the randomization list. BLINDING (MASKING): Patients and investigators, as well as treating physicians are blinded to the treatment- allocation. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): In the first stage of an adaptive design 120 patients in a 2:1 ration: 72 Verum and 36 Placebo, plus an increase for 10% drop outs. After interim analysis, the total sample size will be calculated based on the effect seen in the first stage. Total sample size is estimated approximately n = 300-400 patients. TRIAL STATUS: Protocol version number: V3, 19.05.2020 Recruitment not yet started but is anticipated to begin by June 2020 and be complete by December 2020 TRIAL REGISTRATION: ClinicalTrials.gov: NCT04351516, date: 17 April 2020 EudraCT: 2020-001482-37, date: 30 March 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


title: Routine Venous Thromboembolism Prophylaxis May Be Inadequate in the Hypercoagulable State of Severe Coronavirus Disease 2019

text: The aim of this study was to determine the frequency of venous thromboembolism in critically ill coronavirus disease 2019 patients and associate a degree of inflammatory marker elevation to venous thromboembolism development. DESIGN: An observational study that identified patients with severe coronavirus disease 2019 between March 12, 2020, and March 31, 2020. Data reported are those available through May 6, 2020. SETTING: A multicenter study including three Indianapolis area academic hospitals. PATIENTS: Two-hundred forty consecutive patients with confirmed severe acute respiratory syndrome coronavirus 2 infection were admitted to one of three hospitals. One-hundred nine critically ill coronavirus disease 2019 patients admitted to the ICU were included in the analysis. INTERVENTIONS: All patients received routine subcutaneous chemical venous thromboembolism prophylaxis. MEASUREMENTS AND MAIN RESULTS: The primary outcome of this study was to determine the frequency of venous thromboembolism and the degree of inflammatory and coagulation marker elevation associated with venous thromboembolism development. Descriptive statistics outlined the frequency of venous thromboembolism at any time during severe coronavirus disease 2019. Clinical course and laboratory metrics were compared between patients that developed venous thromboembolism and patients that did not develop venous thromboembolism. Hypercoagulable thromboelastography was defined as two or more hypercoagulable parameters. MAIN RESULTS: One-hundred nine patients developed severe coronavirus disease 2019 requiring ICU care. The mean (± sd) age was 61 ± 16 years and 57% were male. Seventy-five patients (69%) were discharged home, 7 patients (6%) remain in the hospital, and 27 patients (25%) died. Venous thromboembolism was diagnosed in 31 patients (28%) 8 ± 7 days after hospital admission, including two patients diagnosed with venous thromboembolism at presentation to the hospital. Elevated admission d-dimer and peak d-dimer were associated with venous thromboembolism development (p < 0.05). d-dimer greater than 2,600 ng/mL predicted venous thromboembolism with an area under the receiver operating characteristic curve of 0.760 (95% CI, 0.661–0.858; p < 0.0001), sensitivity of 89.7%, and specificity of 59.5%. Twelve patients (11%) had thromboelastography performed and 58% of these patients had a hypercoagulable study. The calculated coagulation index was hypercoagulable in 50% of patients with thromboelastography. CONCLUSIONS: These data show that coronavirus disease 2019 results in a hypercoagulable state. Routine chemical venous thromboembolism prophylaxis may be inadequate in preventing venous thromboembolism in severe coronavirus disease 2019.


title: Virus factories: associations of cell organelles for viral replication and morphogenesis

text: Genome replication and assembly of viruses often takes place in specific intracellular compartments where viral components concentrate, thereby increasing the efficiency of the processes. For a number of viruses the formation of ‘factories’ has been described, which consist of perinuclear or cytoplasmic foci that mostly exclude host proteins and organelles but recruit specific cell organelles, building a unique structure. The formation of the viral factory involves a number of complex interactions and signalling events between viral and cell factors. Mitochondria, cytoplasmic membranes and cytoskeletal components frequently participate in the formation of viral factories, supplying basic and common needs for key steps in the viral replication cycle.


title: Preliminary Recommendations for Surgical Practice of Neurosurgery Department in the Central Epidemic Area of 2019 Coronavirus Infection

text: Since December 2019, an outbreak of coronavirus disease 2019 (COVID-19) has posed significant threats to the public health and life in China. Unlike the other 6 identified coronaviruses, the SARS-Cov-2 has a high infectious rate, a long incubation period and a variety of manifestations. In the absence of effective treatments for the virus, it becomes extremely urgent to develop scientific and standardized proposals for prevention and control of virus transmission. Hereby we focused on the surgical practice in Neurosurgery Department, Tongji Hospital, Wuhan, and drafted several recommendations based on the latest relevant guidelines and our experience. These recommendations have helped us until now to achieve ‘zero infection’ of doctors and nurses in our department, we would like to share them with other medical staff of neurosurgery to fight 2019-nCoV infection.


title: Challenges of infectious diseases in the USA

text: Summary In the USA, infectious diseases continue to exact a substantial toll on health and health-care resources. Endemic diseases such as chronic hepatitis, HIV, and other sexually transmitted infections affect millions of individuals and widen health disparities. Additional concerns include health-care-associated and foodborne infections—both of which have been targets of broad prevention efforts, with success in some areas, yet major challenges remain. Although substantial progress in reduction of the burden of vaccine-preventable diseases has been made, continued cases and outbreaks of these diseases persist, driven by various contributing factors. Worldwide, emerging and reemerging infections continue to challenge prevention and control strategies while the growing problem of antimicrobial resistance needs urgent action. An important priority for control of infectious disease is to ensure that scientific and technological advances in molecular diagnostics and bioinformatics are well integrated into public health. Broad and diverse partnerships across governments, health care, academia, and industry, and with the public, are essential to effectively reduce the burden of infectious diseases.


title: Improving public health policy through infection transmission modelling: Guidelines for creating a Community of Practice

text: BACKGROUND: Despite significant research efforts in Canada, real application of modelling in public health decision making and practice has not yet met its full potential. There is still room to better address the diversity of the Canadian population and ensure that research outcomes are translated for use within their relevant contexts. OBJECTIVES: To strengthen connections to public health practice and to broaden its scope, the Pandemic Influenza Outbreak Research Modelling team partnered with the National Collaborating Centre for Infectious Diseases to hold a national workshop. Its objectives were to: understand areas where modelling terms, methods and results are unclear; share information on how modelling can best be used in informing policy and improving practice, particularly regarding the ways to integrate a focus on health equity considerations; and sustain and advance collaborative work in the development and application of modelling in public health. METHOD: The Use of Mathematical Modelling in Public Health Decision Making for Infectious Diseases workshop brought together research modellers, public health professionals, policymakers and other experts from across the country. Invited presentations set the context for topical discussions in three sessions. A final session generated reflections and recommendations for new opportunities and tasks. CONCLUSIONS: Gaps in content and research include the lack of standard frameworks and a glossary for infectious disease modelling. Consistency in terminology, clear articulation of model parameters and assumptions, and sustained collaboration will help to bridge the divide between research and practice.


title: Cepharanthine: An update of its mode of action, pharmacological properties and medical applications

text: Abstract Background Cepharanthine (CEP) is a drug used in Japan since the 1950s to treat a number of acute and chronic diseases, including treatment of leukopenia, snake bites, xerostomia and alopecia. It is the only approved drug for Human use in the large class of bisbenzylisoquinoline alkaloids. This natural product, mainly isolated from the plant Stephania cephalantha Hayata, exhibits multiple pharmacological properties including anti-oxidative, anti-inflammatory, immuno-regulatory, anti-cancer, anti-viral and anti-parasitic properties. Purpose The mechanism of action of CEP is multifactorial. The drug exerts membrane effects (modulation of efflux pumps, membrane rigidification) as well as different intracellular and nuclear effects. CEP interferes with several metabolic axes, primarily with the AMP-activated protein kinase (AMPK) and NFκB signaling pathways. In particular, the anti-inflammatory effects of CEP rely on AMPK activation and NFκB inhibition. Conclusion In this review, the historical discovery and development of CEP are retraced, and the key mediators involved in its mode of action are presented. The past, present, and future of CEP are recapitulated. This review also suggests new opportunities to extend the clinical applications of this well-tolerated old Japanese drug.


title: The status of hospital dentistry in Taiwan in October 2019

text: BACKGROUND/PURPOSE: Dental care has been officially incorporated into the hospital accreditation system in Taiwan since 2015. The geographical distribution of dentist manpower still remains in an unbalanced status as shown by the dentist-to-population ratio. This study tried to assess the dental manpower issue in terms of the status of hospital dentistry, and hence provided two organizational-level suggestions with their policy implications. MATERIALS AND METHODS: This study utilized the secondary data analysis to evaluate the dental manpower in dental departments of medical centers, regional hospitals, and district hospitals in different regions of Taiwan in October 2019. RESULTS: Our results found that the dental manpower including the numbers of general dentists and dental specialists was highest in medical centers, followed by regional hospitals and district hospitals. Moreover, the dental resources and manpower were mostly concentrated in the northern region of Taiwan, followed by the central and southern regions of Taiwan, the eastern region of Taiwan, and offshore islands. CONCLUSION: The hospital dentistry in Taiwan develops toward large-scale and specialization. Both hospital general dentists and dental specialists are concentrated in the medical centers, especially the medical centers in the northern region of Taiwan, indicating the problem of oversupply in the northern Taiwan and unbalanced distribution of dentists among the regions in Taiwan. Therefore, the responsibilities of the hospitals in metropolitan areas are to develop the elderly and disabled dentistry and to assist with oral health promotion and oral disease prevention in remote areas to reduce the urban-rural gap in dental resources in Taiwan.


title: Validation of the Impact of Event Scale-Revised for adolescents experiencing the floods and mudslides

text: Abstract The purpose of this study was to validate the Impact of Event Scale-Revised (IES-R) for adolescents who had experienced the floods and mudslides caused by Typhoon Morakot in Taiwan. The internal consistency, construct validity, and criteria validity of the instrument were examined. Principal component analysis followed by an oblique rotation was used to derive a three-factor solution. These factors were labeled intrusion, hyperarousal, and avoidance; all three factors together accounted for 58.1% of the variance. The total Cronbach’s alpha of 0.94 reflected the good internal consistency of the instrument. With reference to diagnosis of posttraumatic stress disorder, the IES-R cutoff point for posttraumatic stress disorder was 19 of 20 with a sensitivity of 85.7% and specificity of 84.1%. In conclusion, the IES-R can be used as a reliable and valid instrument when evaluating psychological distress among adolescents who have experienced a natural disaster, such as flooding and mudslides.


title: Human bocavirus 1 infects commercially-available primary human airway epithelium cultures productively

text: Human bocavirus 1 (HBoV1), a human parvovirus, belongs to the genus Bocavirus of the Parvoviridae family. It causes wheezing in young children with acute respiratory tract infections. HBoV1 has been shown to infect polarized human airway epithelium (HAE) made in house, and induces airway epithelial damage. In this study, two commercially-available HAE cultures, EpiAirway and MucilAir HAE, were examined for HBoV1 infection. Both HAE cultures support fully productive HBoV1 infection. Infected EpiAirway and MucilAir HAE cultures showed loss of cilia, disruption of the tight junction barrier, and a significant decrease in transepithelial electrical resistance. Notably, HBoV1 persistent infection was demonstrated by maintaining HBoV1-infected EpiAirway HAE for as long as 50 days. After 2 days post-infection, progeny virus was produced consistently daily at a level of over 2 × 10(8) viral genome copies per culture (0.6 cm(2)). This study is the first to use commercial sources of HAE cultures for HBoV1 infection. The availability of these cultures will enable a wide range of laboratories to study HBoV1 infection.


Additional Barrier to Protect Healthcare Workers During Intubation


title: Algorithmic trading in turbulent markets

text: Abstract Does Algorithmic Trading (AT) exacerbate price swings in turbulent markets? We find that stocks with high AT experience less price drops (surges) on days when the market declines (increases) for more than 2%. This result is consistent with the view that AT minimizes price pressures and mitigates transitory pricing errors. Further analyses show that the net imbalances of AT liquidity demand and supply orders have smaller price impacts compared to non-AT net order imbalances and algorithmic traders reduce their price pressure by executing their trades based on the prevailing volume-weighted average prices.


title: EVIDENCE OF A VIRAL ÆTIOLOGY IN ENDEMIC (BALKAN) NEPHROPATHY

text: Abstract Segmental and focal pathological changes were found in the glomeruli and tubules of postoperative renal-biopsy specimens from seven cases of clinically confirmed endemic (Balkan) nephropathy. In the glomeruli, there was mesangial reaction and segmental thickening of the basement membrane with subendothelial and membranous depositions. In the tubules there was spongiform degeneration and fusion of cells. In all the cells of the nephron numerous cytoplasmic vesicles containing free and budding particles (80-200 nm) were found. These particles had the characteristics of a coronavirus. Balkan nephropathy occurs almost exclusively in people who have been in close contact with pigs. Coronaviruses have been isolated from pigs, and it is suggested that a slow coronavirus infection causes endemic nephropathy in man.


title: Recombinant viral sialate-O-acetylesterases

text: Viral O-acetylesterases were first identified in several viruses, including influenza C viruses and coronaviruses. These enzymes are capable of removing cellular receptors from the surface of target cells. Hence they are also known as “receptor destroying” enzymes. We have cloned and expressed several recombinant viral O-acetylesterases. These enzymes were secreted from Sf9 insect cells as chimeric proteins fused to eGFP. A purification scheme to isolate the recombinant O-acetylesterase of influenza C virus was developed. The recombinant enzymes derived from influenza C viruses specifically hydrolyze 9-O-acetylated sialic acids, while that of sialodacryoadenitis virus, a rat coronavirus related to mouse hepatitis virus, is specific for 4-O-acetylated sialic acid. The recombinant esterases were shown to specifically de-O-acetylate sialic acids on glycoconjugates. We have also expressed esterase knockout proteins of the influenza C virus hemagglutinin-esterase. The recombinant viral proteins can be used to unambiguously identify O-acetylated acids in a variety of assays. Published in 2004..


title: Successful Treatment of Legionnaires’ Disease with Tigecycline in an Immunocompromised Man with a Legion of Antibiotic Allergies

text: Legionella species are Gram-negative bacilli that are relatively rare causes of community-acquired pneumonia but can be associated with significant morbidity and mortality if unrecognized or improperly treated. Limited data exist regarding the use of tigecycline, a third generation glycylcycline, in the treatment of Legionnaires' disease. We present an immunocompromised patient with Legionnaires' disease and allergies to both fluoroquinolones and macrolides, which are first-line treatment options for Legionnaires' disease. He was successfully treated using tigecycline, a third generation glycylcycline, indicating that tigecycline may serve as a safe and effective alternative therapeuticl option for treatment of Legionnaires’ disease.


title: COVID-19 Cardiovascular Epidemiology, Cellular Pathogenesis, Clinical Manifestations and Management

text: Abstract Coronavirus Disease 2019 (COVID-19) is a rapidly progressing global pandemic that may present with a variety of cardiac manifestations including, but not limited to, myocardial injury, myocardial infarction, arrhythmias, heart failure, cardiomyopathy, shock, thromboembolism, and cardiac arrest. These cardiovascular effects are worse in patients who have pre-existing cardiac conditions such as coronary artery disease, hypertension, diabetes mellitus, and coagulation abnormalities. Other predisposing risk factors include advanced age, immunocompromised state, and underlying systemic inflammatory conditions. Here we review the cellular pathophysiology, clinical manifestations and treatment modalities of the cardiac manifestations seen in patients with COVID-19.


title: Atherosclerosis as Pathogenetic Substrate for Sars-Cov2 Cytokine Storm

text: The severe acute respiratory syndrome coronavirus 2 (Sars-CoV-2) outbreak is a public health emergency affecting different regions around the world The lungs are often damaged due to the presence of Sars-CoV-2 binding receptor ACE2 on epithelial alveolar cells Severity of infection varies from complete absence of symptomatology to more aggressive symptoms, characterized by sudden acute respiratory distress syndrome (ARDS), multiorgan failure, and sepsis, requiring treatment in intensive care unit (ICU) It is not still clear why the immune system is not able to efficiently suppress viral replication in a small percentage of patients It has been documented as pathological conditions affecting the cardiovascular system, strongly associated to atherosclerotic progression, such as heart failure (HF), coronary heart disease (CHD), hypertension (HTN) and diabetes mellitus (DM), could serve as predictive factors for severity and susceptibility during Sars-CoV-2 infection Atherosclerotic progression, as a chronic inflammation process, is characterized by immune system dysregulation leading to pro-inflammatory patterns, including interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and IL-1beta Reviewing immune system and inflammation profiles in atherosclerosis and laboratory results reported in severe COVID-19 infections, we hypothesized a pathogenetic correlation Atherosclerosis may be an ideal pathogenetic substrate for high viral replication ability, leading to adverse outcomes, as reported in patients with cardiovascular factors The level of atherosclerotic progression may affect a different degree of severe infection;in a vicious circle, feeding itself, Sars-CoV-2 may exacerbate atherosclerotic evolution due to excessive and aberrant plasmatic concentration of cytokines


title: Randomized, placebo‐controlled, double‐blind trial with interferon‐α with and without amantadine sulphate in primary interferon‐α nonresponders with chronic hepatitis C

text: In primary interferon‐α (IFN‐α) nonresponders with chronic hepatitis C, retreatment with IFN‐α has only limited efficacy with sustained response rates below 10%. Therefore, the aims of the present study were to compare the efficacy and safety of IFN‐α alone or in combination with amantadine sulphate in nonresponders to previous IFN‐α monotherapy. Fifty‐five IFN‐α nonresponders with chronic hepatitis C (mean age: 46.6 years) received IFN‐α 6 MIU thrice weekly for 24 weeks followed by 3 MIU thrice weekly for additional 24 weeks. Amantadine sulphate (n=26) or a matched placebo (n=29) was given orally twice daily for 48 weeks. Because of a low initial response rate at week 12 (13/55 patients) and a high breakthrough rate (8/13 patients) after IFN‐α dose reduction in week 24, a virological end‐of‐treatment response with undetectable serum HCV‐RNA (< 1000 copies/mL) was achieved in only five patients (IFN‐α/amantadine sulphate, one patient; IFN‐α/placebo, four patients). After 24 weeks follow‐up a sustained virological response was observed in only two patients receiving IFN‐α and placebo. Health‐related quality‐of‐life analysis showed a substantial improvement of the Profile of Mood States (POMS) scale concerning the subscales fatigue (P < 0.05) and vigor (P < 0.05) in patients receiving combined IFN‐α/amantadine sulphate treatment compared with those treated with IFN‐α alone. IFN‐α/amantadine sulphate combination therapy was well tolerated without any serious adverse events. In conclusion, retreatment with IFN‐α and amantadine sulphate does not increase the low sustained virological response rates of IFN‐α therapy in primary IFN‐α nonresponders with chronic hepatitis C, but may lead to a sustained improvement of health‐related quality‐of‐life.


Uganda’s First 100 COVID-19 Cases: Trends and Lessons


title: A hybrid multi-scale model of COVID-19 transmission dynamics to assess the potential of non-pharmaceutical interventions

text: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that emerged in Wuhan, China in December 2019. It has caused a global outbreak which represents a major threat to global health. Public health resorted to non-pharmaceutical interventions such as social distancing and lockdown to slow down the spread of the pandemic. However, the effect of each of these measures remains hard to quantify. We design a multi-scale model that simulates the transmission dynamics of COVID-19. We describe the motion of individual agents using a social force model. Each agent can be either susceptible, infected, quarantined, immunized or deceased. The model considers both mechanisms of direct and indirect transmission. We parameterize the model to reproduce the early dynamics of disease spread in Italy. We show that panic situations increase the risk of infection transmission in crowds despite social distancing measures. Next, we reveal that pre-symptomatic transmission accelerates the onset of the exponential growth of cases. After that, we demonstrate that the persistence of SARS-CoV-2 on hard surfaces determines the number of cases reached during the peak of the epidemic. Then, we show that the restricted movement of the individuals flattens the epidemic curve. Finally, model predictions suggest that measures stricter than social distancing and lockdown were used to control the epidemic in Wuhan, China.


title: Risk factors for death from canine parvoviral-related disease in Australia

text: Abstract Canine parvovirus (CPV) is a highly contagious cause of serious and often fatal disease in dogs worldwide despite the availability of safe and efficacious vaccines. Although a number of studies have focussed on identifying risk factors in disease development, risk factors associated with death from CPV are largely unknown. In this study we analysed a total of 1451 CPV cases reported from an Australian surveillance system – using univariate and multivariate techniques – to determine significant risk factors associated with death and euthanasia. A crude case fatality rate of 42.3% was estimated – higher than has been reported previously. We found that 3.3% of CPV cases had a history of vaccination in the previous 12 months, despite having completed the primary puppy vaccination course. The majority (89.5%) of these cases occurred in dogs <12 months of age, indicating failure of the primary vaccination course to provide protective immunity (most likely due to interference of the vaccine antigen with maternal antibodies but other reasons are discussed). Extending the age at which the final puppy vaccination is administered might be one of several strategies to consider. The final multivariate model showed that in non-litter CPV cases, risk of death was significantly associated with season of diagnosis (summer) and pedigree type (hounds and non-sporting dogs). Euthanasia in non-litter CPV cases was significantly associated with season of diagnosis (summer), state of residence (Northern Territory/South Australia/Tasmania combined), age (<six months) and vaccination status (unvaccinated and unknown). No significant risk factors associated with death were identified in cases in which there was more than one puppy in a litter infected. The risk factors identified in this study can be used as prognostic indicators for veterinarians faced with CPV cases. The possible explanations for the associations identified and their clinical relevance to CPV case outcome are discussed


title: The Effects of Temperature and Relative Humidity on the Viability of the SARS Coronavirus

text: The main route of transmission of SARS CoV infection is presumed to be respiratory droplets. However the virus is also detectable in other body fluids and excreta. The stability of the virus at different temperatures and relative humidity on smooth surfaces were studied. The dried virus on smooth surfaces retained its viability for over 5 days at temperatures of 22–25°C and relative humidity of 40–50%, that is, typical air-conditioned environments. However, virus viability was rapidly lost (>3 log(10)) at higher temperatures and higher relative humidity (e.g., 38°C, and relative humidity of >95%). The better stability of SARS coronavirus at low temperature and low humidity environment may facilitate its transmission in community in subtropical area (such as Hong Kong) during the spring and in air-conditioned environments. It may also explain why some Asian countries in tropical area (such as Malaysia, Indonesia or Thailand) with high temperature and high relative humidity environment did not have major community outbreaks of SARS.


title: Interactions of coronaviruses with ACE2, angiotensin II, and RAS inhibitors—lessons from available evidence and insights into COVID-19

text: The rapid spread of a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to an ongoing pandemic of coronavirus disease 2019 (COVID-19). Recently, angiotensin-converting enzyme 2 (ACE2) has been shown to be a functional receptor for SARS-CoV-2 to enter host target cells. Given that angiotensin receptor blockers (ARBs) and an ACE inhibitor (ACEI) upregulated ACE2 expression in animal studies, the concern might arise regarding whether ARBs and ACEIs would increase the morbidity and mortality of COVID-19. On the other hand, animal data suggested a potential protective effect of ARBs against COVID-19 pneumonia because an ARB prevented the aggravation of acute lung injury in mice infected with SARS-CoV, which is closely related to SARS-CoV-2. Importantly, however, there is no clinical or experimental evidence supporting that ARBs and ACEIs either augment the susceptibility to SARS-CoV-2 or aggravate the severity and outcomes of COVID-19 at present. Until further data are available, it is recommended that ARB and ACEI medications be continued for the treatment of patients with cardiovascular disease and hypertension, especially those at high risk, according to guideline-directed medical therapy based on the currently available evidence.


title: Tracheostomy time‐out: New safety tool in the setting of COVID‐19

text: Tracheostomy procedures have a high risk of aerosol generation. Airway providers have reflected on ways to mitigate the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) transmission risks when approaching a surgical airway. To standardize institutional safety measures with tracheostomy, we advocate using a dedicated tracheostomy time‐out applicable to all patients including those suspected of having COVID‐19. The aim of the tracheostomy time‐out is to reduce preventable errors that may increase the risk of transmission of SARS‐CoV‐2.


Better patient identification could help fight the coronavirus


Elevated nucleoprotein-induced interferon-γ release in COVID-19 patients detected in a SARS-CoV-2 enzyme-linked immunosorbent spot assay


Transporters of nucleotide sugars, nucleotide sulfate and ATP in the Golgi apparatus membrane: Where next?


title: COVID‐19 associated pulmonary aspergillosis

text: OBJECTIVES: Patients with acute respiratory distress syndrome (ARDS) due to viral infection are at risk for secondary complications like invasive aspergillosis. Our study evaluates coronavirus disease 19 (COVID‐19) associated invasive aspergillosis at a single centre in Cologne, Germany. METHODS: A retrospective chart review of all patients with COVID‐19 associated ARDS admitted to the medical or surgical intensive care unit at the University Hospital of Cologne, Cologne, Germany. RESULTS: COVID‐19 associated invasive pulmonary aspergillosis was found in five of 19 consecutive critically ill patients with moderate to severe ARDS. CONCLUSION: Clinicians caring for patients with ARDS due to COVID‐19 should consider invasive pulmonary aspergillosis and subject respiratory samples to comprehensive analysis to detect co‐infection.


title: A simple magnetic nanoparticles-based viral RNA extraction method for efficient detection of SARS-CoV-2

text: The ongoing outbreak of the novel coronavirus disease 2019 (COVID-19) originating from Wuhan, China, draws worldwide concerns due to its long incubation period and strong infectivity. Although RT-PCR-based molecular diagnosis techniques are being widely applied for clinical diagnosis currently, timely and accurate diagnosis are still limited due to labour intensive and time-consuming operations of these techniques. To address the issue, herein we report the synthesis of poly (amino ester) with carboxyl groups (PC)-coated magnetic nanoparticles (pcMNPs), and the development of pcMNPs-based viral RNA extraction method for the sensitive detection of COVID-19 causing virus, the SARS-CoV-2. This method combines the lysis and binding steps into one step, and the pcMNPs-RNA complexes can be directly introduced into subsequent RT-PCR reactions. The simplified process can purify viral RNA from multiple samples within 20 min using a simple manual method or an automated high-throughput approach. By identifying two different regions (ORFlab and N gene) of viral RNA, a 10-copy sensitivity and a strong linear correlation between 10 and 105 copies of SARS-CoV-2 pseudovirus particles are achieved. Benefitting from the simplicity and excellent performances, this new extraction method can dramatically reduce the turn-around time and operational requirements in current molecular diagnosis of COVID-19, in particular for the early clinical diagnosis.


title: Inhibitory and combinatorial effect of diphyllin, a v-ATPase blocker, on influenza viruses

text: An influenza pandemic poses a serious threat to humans and animals. Conventional treatments against influenza include two classes of pathogen-targeting antivirals: M2 ion channel blockers (such as amantadine) and neuraminidase inhibitors (such as oseltamivir). Examination of the mechanism of influenza viral infection has shown that endosomal acidification plays a major role in facilitating the fusion between viral and endosomal membranes. This pathway has led to investigations on vacuolar ATPase (v-ATPase) activity, whose role as a regulating factor on influenza virus replication has been verified in extensive genome-wide screenings. Blocking v-ATPase activity thus presents the opportunity to interfere with influenza viral infection by preventing the pH-dependent membrane fusion between endosomes and virions. This study aims to apply diphyllin, a natural compound shown to be as a novel v-ATPase inhibitor, as a potential antiviral for various influenza virus strains using cell-based assays. The results show that diphyllin alters cellular susceptibility to influenza viruses through the inhibition of endosomal acidification, thus interfering with downstream virus replication, including that of known drug-resistant strains. In addition, combinatorial treatment of the host-targeting diphyllin with pathogen-targeting therapeutics (oseltamivir and amantadine) demonstrates enhanced antiviral effects and cell protection in vitro.