title: Myeloma‐Related Disorders in Cats Commonly Present as Extramedullary Neoplasms in Contrast to Myeloma in Human Patients: 24 Cases with Clinical Follow‐up

text: Background:Myeloma‐related disorders (MRD) are rare neoplasms of plasma cells. Published case reports describe a diversity of clinical presentations with confusing terminology and diagnostic criteria as a consequence of the assumption that MRD in cats are analogous to those in dogs or humans. Objective: The aim of the study was to describe clinical, clinicopathologic and imaging findings, response to treatment, survival and possible associations with other diseases or vaccination in a large case series. A priori hypotheses were that cats with MRD commonly present with extramedullary involvement and uncommonly have radiographic bone lesions, in contrast to human patients. Animals:Twenty‐four cats with MRD confirmed by cytology or histopathology and immunohistochemistry. Method: A multicenter retrospective study was performed. Results:Two types of clinical presentation were observed. The first group (n = 17) had neoplasia involving abdominal organs, bone marrow, or both. All developed systemic clinical signs and paraproteinemia. Five of 7 cats that received chemotherapy improved clinically or had decreased serum globulin concentration (median survival, 12.3 months; range, 8.5–22 months). The second group comprised 7 cats with skin masses, 2 of which were paraproteinemic and developed rapidly worsening systemic signs. In cats without systemic signs, excision of the skin masses appeared to be associated with prolonged survival (up to 2.4 years). Cats with MRD commonly presented with extramedullary involvement (67%), versus humans with MRD (5%) (P < .001), and uncommonly presented with radiographic bone lesions (8%) versus humans with MRD (80%) (P < .001). Conclusions: Radiographic bone lesions are uncommon in cats with MRD and extramedullary presentation is common, relative to human myeloma.


title: Metagenomic sequencing complements routine diagnostics in identifying viral pathogens in lung transplant recipients with unknown etiology of respiratory infection

text: BACKGROUND: Lung transplant patients are a vulnerable group of immunosuppressed patients that are prone to frequent respiratory infections. We studied 60 episodes of respiratory symptoms in 71 lung transplant patients. Almost half of these episodes were of unknown infectious etiology despite extensive routine diagnostic testing. METHODS: We re-analyzed respiratory samples of all episodes with undetermined etiology in order to detect potential viral pathogens missed/not accounted for in routine diagnostics. Respiratory samples were enriched for viruses by filtration and nuclease digestion, whole nucleic acids extracted and randomly amplified before high throughput metagenomic virus sequencing. Viruses were identified by a bioinformatic pipeline and confirmed and quantified using specific real-time PCR. RESULTS: In completion of routine diagnostics, we identified and confirmed a viral etiology of infection by our metagenomic approach in four patients (three Rhinovirus A, one Rhinovirus B infection) despite initial negative results in specific multiplex PCR. Notably, the majority of samples were also positive for Torque teno virus (TTV) and Human Herpesvirus 7 (HHV-7). While TTV viral loads increased with immunosuppression in both throat swabs and blood samples, HHV-7 remained at low levels throughout the observation period and was restricted to the respiratory tract. CONCLUSION: This study highlights the potential of metagenomic sequencing for virus diagnostics in cases with previously unknown etiology of infection and in complex diagnostic situations such as in immunocompromised hosts.


title: The role of virus-induced regulatory T cells in immunopathology

text: In recent years, regulatory T cells have received increased attention for their role in immune responses to microbial infections. The list of microbial pathogens associated with regulatory T cell responses is growing rapidly and includes bacteria, viruses, parasites, and fungi. As the biology of regulatory T cells is revealed, we are discovering that their induction during infection is a normal aspect of immunity, necessary to limit collateral damage from inflammatory responses and aggressive immunological effectors. Thus, these cells play a critical role in maintaining the delicate balance between preventing immunopathology and allowing the immune response to clear infections. While generally successful, there are notable exceptions where regulatory T cell-mediated suppression appears to be responsible for allowing certain viruses to establish and maintain a persistent state. In this review, we will discuss our current understanding of what virus-induced regulatory T cells are, how they are induced, and what mechanisms they use to suppress immunity. The complex role of Tregs in regulating immunity to viral infections, and the consequences their activity has on disease is illustrated by a review of specific viral infections including hepatitis C virus and human immunodeficiency virus.


title: Strategies for the Prevention of the Intra-Hospital Transmission of COVID-19: A Retrospective Cohort Study

text: Coronavirus disease (COVID-19) has spread rapidly worldwide We aimed to review the strategies used by our university hospital in Daegu (South Korea) to prevent the transmission of COVID-19 within our institution We also investigated the actual situation at our hospital against the recommended guidelines We conducted a survey among patients and staff in our hospital Additionally, patients' electronic medical records were reviewed along with closed-circuit television (CCTV) recordings Various strategies and guidelines developed by our hospital have been implemented A total of 303 hospital staff and patients had exposure to 29 confirmed COVID-19 patients Of them, three tested positive for COVID-19 without further transmission The intra-hospital infection of the disease occurred when the recommended strategies and guidelines such as wearing a mask and isolating for 2 weeks were not followed In conclusion, the implementation of robust guidelines for preventing the intra-hospital transmission of COVID-19 is essential


title: A recombinant receptor-binding domain of MERS-CoV in trimeric form protects human dipeptidyl peptidase 4 (hDPP4) transgenic mice from MERS-CoV infection

text: Abstract Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV) was first identified in 2012, and it continues to threaten human health worldwide. No MERS vaccines are licensed for human use, reinforcing the urgency to develop safe and efficacious vaccines to prevent MERS. MERS-CoV spike protein forms a trimer, and its receptor-binding domain (RBD) serves as a vaccine target. Nevertheless, the protective efficacy of RBD in its native trimeric form has never been evaluated. In this study, a trimeric protein, RBD-Fd, was generated by fusing RBD with foldon trimerization motif. It bound strongly to the receptor of MERS-CoV, dipeptidyl peptidase 4 (DPP4), and elicited robust RBD-specific neutralizing antibodies in mice, maintaining long-term neutralizing activity against MERS-CoV infection. RBD-Fd potently protected hDPP4 transgenic mice from lethal MERS-CoV challenge. These results suggest that MERS-CoV RBD in its trimeric form maintains native conformation and induces protective neutralizing antibodies, making it a candidate for further therapeutic development.


title: Evaluation of potential herb-drug interactions between oseltamivir and commonly used anti-influenza Chinese medicinal herbs

text: Abstract Ethnopharmacological relevance According to Traditional Chinese Medicine theory, influenza is categorized as a warm disease or Wen Bing. The Wen Bing formulas, such as Yin-Qiao-San and Sang-Ju-Yin, are still first-line herbal therapies in combating variant influenza virus. To continue our study on the pharmacokinetic and pharmacodynamic interactions between Wen Bing formulas and oseltamivir (OS), the first-line western drug for the treatment of influenza, further interactions between OS and the eight single herbs and their relevant marker components from Wen Bing formulas were investigated in the current study. Aim of study To establish an in-vitro screening platform for investigation of the potential anti-influenza herbs/herbal components that may have pharmacokinetic and pharmacodynamic interactions with OS. Materials and methods To screen potential inhibition on OS hydrolysis, 1 μg/mL of OS is incubated with herbs/herbal components in diluted rat plasma, microsomes and human recombinant carboxylesterase 1(hCE1) under optimized conditions. MDCK-WT and MDCK-MDR1 cell lines are utilized to identify potential modification on P-gp mediated transport of OS by herbs/herbal components. Caco-2 cells with and without Gly-Sar inhibition are performed to study the uptake of OS via PEPT1 transporters. Modification on OAT3 mediated transport is verified by the uptake of OS on HEK293-MOCK/HEK293-OAT3 cells. Anti-virus effects were evaluated using plaque reduction assay on H1N1 and H3N2 viruses. Potential pharmacokinetic and pharmacodynamic interaction between OS (30 mg/kg) and the selected herb, Radix Scutellariae (RS), at 300–600 mg/kg were carried out on rats. All samples are analyzed by an LC/MS/MS method for the contents of OS and OSA. A mechanistic PK model was developed to interpret the HDI between OS and RS in rats. Results Our developed platform was successfully applied to screen the eight herbal extracts and their ten marker components on metabolic inhibition of OS and modification of OS transport mediated by P-gp, OAT3 and PEPT1. Results from six in-vitro experiments were analyzed after converting raw data from each experiment to corresponding fold-change (FC) values, based on which Radix Scutellariae (RS) were selected to have the most HDI potential with OS. By analyzing the plasma and urine pharmacokinetic data after co-administration of OS with a standardized RS extract in rats using an integrated population pharmacokinetics model, it is suggested that RS could inhibit OS hydrolysis during absorption and increase the absorbed fraction of OS, which leads to the increased ratio of OS concentration versus that of OSA in both rat plasma and urine. Never the less, the anti-virus effects of 2.5 h post-dose rat plasma were not influenced by co-administration of OS with RS. Conclusion A six-dimension in-vitro screening platform has been developed and successfully applied to find RS as a potential herb that would influence the co-administrated OS in rats. Although co-administered RS could inhibit OS hydrolysis during absorption and increase the absorbed fraction of OS, which lead to the increased ratio of OS concentration versus that of OSA in both rat plasma and urine, the anti-virus effect of OS was not influenced by co-administered RS.


title: Early Warnings: The Lessons of COVID-19 for Public Health Climate Preparedness

text: The early 2020 response to COVID-19 revealed major gaps in public health systems around the world as many were overwhelmed by a quickly-spreading new coronavirus. While the critical task at hand is turning the tide on COVID-19, this pandemic serves as a clarion call to governments and citizens alike to ensure public health systems are better prepared to meet the emergencies of the future, many of which will be climate-related. Learning from the successes as well as the failures of the pandemic response provides some guidance. We apply several recommendations of a recent World Health Organization Policy Brief on COVID-19 response to 5 key areas of public health systems – governance, information, services, determinants, and capacity – to suggest early lessons from the coronavirus pandemic for climate change preparedness. COVID-19 has demonstrated how essential public health is to well-functioning human societies and how high the economic cost of an unprepared health system can be. This pandemic provides valuable early warnings, with lessons for building public health resilience.


title: Characterization of the Immune Response of MERS-CoV Vaccine Candidates Derived from Two Different Vectors in Mice

text: Middle East respiratory syndrome (MERS) is an acute, high-mortality-rate, severe infectious disease caused by an emerging MERS coronavirus (MERS-CoV) that causes severe respiratory diseases. The continuous spread and great pandemic potential of MERS-CoV make it necessarily important to develop effective vaccines. We previously demonstrated that the application of Gram-positive enhancer matrix (GEM) particles as a bacterial vector displaying the MERS-CoV receptor-binding domain (RBD) is a very promising MERS vaccine candidate that is capable of producing potential neutralization antibodies. We have also used the rabies virus (RV) as a viral vector to design a recombinant vaccine by expressing the MERS-CoV S1 (spike) protein on the surface of the RV. In this study, we compared the immunological efficacy of the vaccine candidates in BALB/c mice in terms of the levels of humoral and cellular immune responses. The results show that the rabies virus vector-based vaccine can induce remarkably earlier antibody response and higher levels of cellular immunity than the GEM particles vector. However, the GEM particles vector-based vaccine candidate can induce remarkably higher antibody response, even at a very low dose of 1 µg. These results indicate that vaccines constructed using different vaccine vector platforms for the same pathogen have different rates and trends in humoral and cellular immune responses in the same animal model. This discovery not only provides more alternative vaccine development platforms for MERS-CoV vaccine development, but also provides a theoretical basis for our future selection of vaccine vector platforms for other specific pathogens.


title: Susceptibility of paramyxoviruses and filoviruses to inhibition by 2′-monofluoro- and 2′-difluoro-4′-azidocytidine analogs

text: Abstract Ebolaviruses, marburgviruses, and henipaviruses are zoonotic pathogens belonging to the Filoviridae and Paramyxoviridae families. They exemplify viruses that continue to spill over into the human population, causing outbreaks characterized by high mortality and significant clinical sequelae in survivors of infection. There are currently no approved small molecule therapeutics for use in humans against these viruses. In this study, we evaluated the antiviral activity of the nucleoside analog 4′-azidocytidine (4′N3-C, R1479) and its 2′-monofluoro- and 2′-difluoro-modified analogs (2′F-4′N3-C and 2′diF-4′N3-C) against representative paramyxoviruses (Nipah virus, Hendra virus, measles virus, and human parainfluenza virus 3) and filoviruses (Ebola virus, Sudan virus, and Ravn virus). We observed enhanced antiviral activity against paramyxoviruses with both 2′diF-4′N3-C and 2′F-4′N3-C compared to R1479. On the other hand, while R1479 and 2′diF-4′N3-C inhibited filoviruses similarly to paramyxoviruses, we observed 10-fold lower filovirus inhibition by 2′F-4′N3-C. To our knowledge, this is the first study to compare the susceptibility of paramyxoviruses and filoviruses to R1479 and its 2′-fluoro-modified analogs. The activity of these compounds against negative-strand RNA viruses endorses the development of 4′-modified nucleoside analogs as broad-spectrum therapeutics against zoonotic viruses of public health importance.


title: Early occurrence of influenza A epidemics coincided with changes in occurrence of other respiratory virus infections

text: BACKGROUND: Viral interaction in which outbreaks of influenza and other common respiratory viruses might affect each other has been postulated by several short studies. Regarding longer time periods, influenza epidemics occasionally occur very early in the season, as during the 2009 pandemic. Whether early occurrence of influenza epidemics impacts outbreaks of other common seasonal viruses is not clear. OBJECTIVES: We investigated whether early occurrence of influenza outbreaks coincides with shifts in the occurrence of other common viruses, including both respiratory and non‐respiratory viruses. METHODS: We investigated time trends of and the correlation between positive laboratory diagnoses of eight common viruses in the Netherlands over a 10‐year time period (2003–2012): influenza viruses types A and B, respiratory syncytial virus (RSV), rhinovirus, coronavirus, norovirus, enterovirus, and rotavirus. We compared trends in viruses between early and late influenza seasons. RESULTS: Between 2003 and 2012, influenza B, RSV, and coronavirus showed shifts in their occurrence when influenza A epidemics occurred earlier than usual (before week 1). Although shifts were not always consistently of the same type, when influenza type A hit early, RSV outbreaks tended to be delayed, coronavirus outbreaks tended to be intensified, and influenza virus type B tended not to occur at all. Occurrence of rhinovirus, norovirus, rotavirus, and enterovirus did not change. CONCLUSION: When influenza A epidemics occured early, timing of the epidemics of several respiratory winter viruses usually occurring close in time to influenza A was affected, while trends in rhinoviruses (occurring in autumn) and trends in enteral viruses were not.


Mental health and dermatology practice in the COVID‐19 pandemic


title: Anti–SARS-CoV Immunoglobulin G in Healthcare Workers, Guangzhou, China

text: To determine the prevalence of inapparent infection with severe acute respiratory syndrome (SARS) among healthcare workers, we performed a serosurvey to test for immunoglobulin (Ig) G antibodies to the SARS coronavirus (SARS-CoV) among 1,147 healthcare workers in 3 hospitals that admitted SARS patients in mid-May 2003. Among them were 90 healthcare workers with SARS. As a reference group, 709 healthcare workers who worked in 2 hospitals that never admitted any SARS patients were similarly tested. The seroprevalence rate was 88.9% (80/90) for healthcare workers with SARS and 1.4% (15/1,057) for healthcare workers who were apparently healthy. The seroprevalence in the reference group was 0.4% (3/709). These findings suggest that inapparent infection is uncommon. Low level of immunity among unaffected healthcare workers reinforces the need for adequate personal protection and other infection control measures in hospitals to prevent future epidemics.


title: ACE1 polymorphism and progression of SARS

text: Abstract We have hypothesized that genetic predisposition influences the progression of SARS. Angiotensin converting enzyme (ACE1) insertion/deletion (I/D) polymorphism was previously reported to show association with the adult respiratory distress syndrome, which is also thought to play a key role in damaging the lung tissues in SARS cases. This time, the polymorphism was genotyped in 44 Vietnamese SARS cases, with 103 healthy controls who had had a contact with the SARS patients and 50 controls without any contact history. SARS cases were divided into either non-hypoxemic or hypoxemic groups. Despite the small sample size, the frequency of the D allele was significantly higher in the hypoxemic group than in the non-hypoxemic group (p =0.013), whereas there was no significant difference between the SARS cases and controls, irrespective of a contact history. ACE1 might be one of the candidate genes that influence the progression of pneumonia in SARS.


Incidencia de COVID-19 entre los profesionales de oftalmología


title: Simple nomogram based on initial laboratory data for predicting the probability of ICU transfer of COVID‐19 patients: Multicenter retrospective study

text: This retrospective, multicenter study investigated risk factors associated with intensive care unit (ICU) admission and transfer in 461 adult patients with confirmed coronavirus disease 2019 (COVID‐19) hospitalized from January 22 to March 14, 2020 in Hunan Province, China. Outcomes of ICU and non‐ICU patients were compared, and a simple nomogram for predicting the probability of ICU transfer after hospital admission was developed based on initial laboratory data using a Cox proportional hazards regression model. Differences in laboratory indices were observed between patients admitted to the ICU and those who were not admitted. Several independent predictors of ICU transfer in COVID‐19 patients were identified including older age (≥65 years) (hazard ratio [HR]=4.02), hypertension (HR=2.65), neutrophil count (HR=1.11), procalcitonin level (HR=3.67), prothrombin time (HR=1.28), and d‐dimer level (HR=1.25). Lymphocyte count and albumin level were negatively associated with mortality (HR=0.08 and 0.86, respectively). The developed model provides a means for identifying, at hospital admission, the subset of patients with COVID‐19 who are at high risk of progression and would require transfer to the ICU within 3 and 7 days after hospitalization. This method of early patient triage allows more effective allocation of limited medical resources. This article is protected by copyright. All rights reserved.


title: Estimating the Diversity, Completeness, and Cross-Reactivity of the T Cell Repertoire

text: In order to recognize and combat a diverse array of pathogens the immune system has a large repertoire of T cells having unique T cell receptors (TCRs) with only a few clones specific for any given antigen. We discuss how the number of different possible TCRs encoded in the genome (the potential repertoire) and the number of different TCRs present in an individual (the realized repertoire) can be measured. One puzzle is that the potential repertoire greatly exceeds the realized diversity of naïve T cells within any individual. We show that the existing hypotheses fail to explain why the immune system has the potential to generate far more diversity than is used in an individual, and propose an alternative hypothesis of “evolutionary sloppiness.” Another immunological puzzle is why mice and humans have similar repertoires even though humans have over 1000-fold more T cells. We discuss how the idea of the “protecton,” the smallest unit of protection, might explain this discrepancy and estimate the size of “protecton” based on available precursor frequencies data. We then consider T cell cross-reactivity – the ability of a T cell clone to respond to more than one epitope. We extend existing calculations to estimate the extent of expected cross-reactivity between the responses to different pathogens. Our results are consistent with two observations: a low probability of observing cross-reactivity between the immune responses to two randomly chosen pathogens; and the ensemble of memory cells being sufficiently diverse to generate cross-reactive responses to new pathogens.


title: Oblongifolin M, an active compound isolated from a Chinese medical herb Garcinia oblongifolia, potently inhibits enterovirus 71 reproduction through downregulation of ERp57

text: There is no effective drug to treat EV71 infection yet. Traditional Chinese herbs are great resources for novel antiviral compounds. Here we showed that Oblongifolin M (OM), an active compound isolated from Garcinia oblongifolia, potently inhibited EV71 infection in a dose dependent manner. To identify its potential effectors in the host cells, we successfully identified 18 proteins from 52 differentially expressed spots by comparative proteomics studies. Further studies showed that knockdown of ERp57 inhibited viral replication through downregulating viral IRES (internal ribosome entry site) activities, whereas ectopic expression of ERp57 increased IRES activity and partly rescued the inhibitory effects of OM on viral replication. We demonstrated that OM is an effective antiviral agent; and that ERp57 is one of its cellular effectors against EV71 infection.


Who gets to define ‘the COVID-19 problem’? Expert politics in a pandemic


title: RECOMENDACIONES DE CONSENSO SEPAR – AEER SOBRE LA UTILIDAD DE LA ECOGRAFIA TORÁCICA EN EL MANEJO DEL PACIENTE CON SOSPECHA O INFECCION CONFIRMADA CON COVID-19

text: RESUMEN La gran afectación pulmonar producida por la infección del COVID-19 hace necesaria una herramienta diagnóstica rápida que complemente el test diagnóstico mediante PCR y que además sea útil en la evaluación de la progresión de las lesiones pulmonares. Ya que la mayoría de estas son periféricas en este documento de consenso proponemos el uso de la ecografía torácica para el diagnóstico precoz y la evaluación diaria de la progresión de lesiones pulmonares por un solo explorador sin necesidad de utilizar la TC de tórax. En este consenso se propone la realización de una exploración sistemática ecográfica del tórax dividiéndolo por cuadrantes e identificando los signos ecográficos que se relacionen con el tipo de afectación parenquimatosa o pleural que tiene el paciente: líneas A, líneas B, condensación parenquimatosa, línea pleural y derrame pleural. Estos hallazgos nos facilitarán la toma de decisiones respecto al manejo del paciente, tanto en la decisión del lugar de ingreso del paciente como en el tipo de tratamiento que debemos pautar. Abstract The great pulmonary affectation produced by the COVID-19 infection, requires a fast diagnostic tool that complements the diagnostic test by PCR and which is also useful in evaluating the progression of lung lesions. Since most of these are peripheral, in this consensus document we propose the use of thoracic ultrasound for early diagnosis and for the daily evaluation of the progression of lung lesions by a single explorer without the need to use the chest CT. In this consensus, it is proposed to carry out a systematic ultrasound examination of the thorax dividing it by quadrants and therefore identifying the ultrasound signs that are related to the type of parenchymal or pleural affectation that the patient has: A lines, B lines, parenchymal condensation, pleural line and pleural effusion. These findings will facilitate the decision making regarding the patient management, both when deciding the place of admission of the patient and the type of treatment to be prescribed


title: The SARS-CoV S glycoprotein: expression and functional characterization

text: Abstract We have cloned, expressed, and characterized the full-length and various soluble fragments of the SARS-CoV (Tor2 isolate) S glycoprotein. Cells expressing S fused with receptor-expressing cells at neutral pH suggesting that the recombinant glycoprotein is functional, its membrane fusogenic activity does not require other viral proteins, and that low pH is not required for triggering membrane fusion; fusion was not observed at low receptor concentrations. S and its soluble ectodomain, Se, were not cleaved to any significant degree. They ran at about 180–200kDa in SDS gels suggesting post-translational modifications as predicted by previous computer analysis and observed for other coronaviruses. Fragments containing the N-terminal amino acid residues 17–537 and 272–537 but not 17–276 bound specifically to Vero E6 cells and purified soluble receptor, ACE2, recently identified by M. Farzan and co-workers [Nature 426 (2003) 450–454]. Together with data for inhibition of binding by antibodies developed against peptides from S, these findings suggest that the receptor-binding domain is located between amino acid residues 303 and 537. These results also confirm that ACE2 is a functional receptor for the SARS virus and may help in the elucidation of the mechanisms of SARS-CoV entry and in the development of vaccine immunogens and entry inhibitors.


title: Preliminary studies on feline coronavirus distribution in naturally and experimentally infected cats

text: Abstract The shedding, tissue distribution and quasispecies composition of feline coronaviruses were studied in naturally and experimentally infected cats. The infection remained subclinical, but the majority of the animals shed the virus via faeces throughout the experiment. Sequences corresponding to the viral nucleocapsid region were amplified by reverse-transcription polymerase chain reaction from the cortex, dura mater, pancreas, lungs, third eyelid, and the heart muscle in four cases. Interestingly, the ORF7b viral region – a supposed virulence factor – was detected in fewer organs, raising the possibility that this region can be affected by deletions during virus replication in vivo. It is demonstrated that the composition of the viral quasispecies differs between organs, and that genomic regions with different functions undergo distinct processes of selection, which should be considered during the evolution of feline coronaviruses.


title: SARS vaccines: where are we?

text: In this review, the current state of vaccine development against human severe acute respiratory syndrome (SARS) coronavirus, focusing on recently published data is assessed. We discuss which strategies have been assessed immunologically and which have been evaluated in SARS coronavirus challenge models. We discuss inactivated vaccines, virally and bacterially vectored vaccines, recombinant protein and DNA vaccines, as well as the use of attenuated vaccines. Data regarding the correlates of protection, animal models and the available evidence regarding potential vaccine enhancement of SARS disease are discussed. While there is much evidence that various vaccine strategies against SARS are safe and immunogenic, vaccinated animals still display significant disease upon challenge. Current data suggest that intranasal vaccination may be crucial and that new or combination strategies may be required for good protective efficacy against SARS in humans.


title: The Impact of RSV-Associated Respiratory Disease on Children in Asia

text: Acute respiratory tract infections (ARTIs) are leading contributors to the global infectious disease burden, which is estimated to be 112,900,000 disability adjusted life years. Viruses contribute to the etiology of ARTIs in a big way compared with other microorganisms. Since the discovery of respiratory syncytial virus (RSV) 61 years ago, the virus has been recognized as a major cause of ARTI and hospitalization in children. The morbidity and mortality attributable to RSV infection appear to be higher in infants < 3 months and in those with known risk factors such as prematurity, chronic lung, and congenital heart diseases. Crowded living conditions, exposure to tobacco smoke, and industrial or other types of air pollution also increase the risk of RSV-associated ARTI. Many epidemiological studies have been conducted in developed countries to understand the seasonal patterns and risk factors associated with RSV infections. Dearth of information on RSV-associated morbidity and mortality in Asian and developing countries indicates the need for regional reviews to evaluate RSV-associated disease burden in these countries. Epidemiological studies including surveillance is the key to track the disease burden including risk factors, seasonality, morbidity, and mortality associated with RSV infection in these countries. These data will contribute to improve the clinical diagnosis and plan preventive strategies in resource-limited developing countries.


title: Unique Signatures of Long Noncoding RNA Expression in Response to Virus Infection and Altered Innate Immune Signaling

text: Studies of the host response to virus infection typically focus on protein-coding genes. However, non-protein-coding RNAs (ncRNAs) are transcribed in mammalian cells, and the roles of many of these ncRNAs remain enigmas. Using next-generation sequencing, we performed a whole-transcriptome analysis of the host response to severe acute respiratory syndrome coronavirus (SARS-CoV) infection across four founder mouse strains of the Collaborative Cross. We observed differential expression of approximately 500 annotated, long ncRNAs and 1,000 nonannotated genomic regions during infection. Moreover, studies of a subset of these ncRNAs and genomic regions showed the following. (i) Most were similarly regulated in response to influenza virus infection. (ii) They had distinctive kinetic expression profiles in type I interferon receptor and STAT1 knockout mice during SARS-CoV infection, including unique signatures of ncRNA expression associated with lethal infection. (iii) Over 40% were similarly regulated in vitro in response to both influenza virus infection and interferon treatment. These findings represent the first discovery of the widespread differential expression of long ncRNAs in response to virus infection and suggest that ncRNAs are involved in regulating the host response, including innate immunity. At the same time, virus infection models provide a unique platform for studying the biology and regulation of ncRNAs.


title: Establishing benchmarks and metrics for disruptive technologies, inappropriate and obsolete tests in the clinical laboratory

text: Abstract Benchmarks and metrics related to laboratory test utilization are based on evidence-based medical literature that may suffer from a positive publication bias. Guidelines are only as good as the data reviewed to create them. Disruptive technologies require time for appropriate use to be established before utilization review will be meaningful. Metrics include monitoring the use of obsolete tests and the inappropriate use of lab tests. Test utilization by clients in a hospital outreach program can be used to monitor the impact of new clients on lab workload. A multi-disciplinary laboratory utilization committee is the most effective tool for modifying bad habits, and reviewing and approving new tests for the lab formulary or by sending them out to a reference lab.


title: Dogs (Canis familiaris) as Sentinels for Human Infectious Disease and Application to Canadian Populations: A Systematic Review

text: In a world where climate change, vector expansion, human activity, and pathogen dispersal do not respect boundaries, the human–animal–pathogen interface has become less defined. Consequently, a One Health approach to disease surveillance and control has generated much interest across several disciplines. This systematic review evaluates current global research on the use of domestic dogs as sentinels for human infectious disease, and critically appraises how this may be applied within Canada. Results highlighted a bias in research from high- and middle-income-economy countries, with 35% of the studies describing data from the Latin America/Caribbean region, 25% from North America, and 11% from the European/Central Asia region. Bacteria were the most studied type of infectious agent, followed by protozoa, viruses, helminths, and fungi. Only six out of 142 studies described disease in Canada: four researched a variety of pathogens within Indigenous communities, one researched Borrelia burgdorferi in British Columbia, and one researched arboviruses in Quebec. Results from this review suggest that dogs could provide excellent sentinels for certain infectious-disease pathogens in Canada, yet are currently overlooked. Further research into the use of dog-sentinel surveillance is specifically recommended for California serogroup viruses, Chikungunya virus, West Nile virus, Lyme borreliosis, Rickettsia spp., Ehrlichia spp., and Dirofilaria immitis.


title: Physician deaths from corona virus (COVID-19) disease

text: BACKGROUND: The COVID-19 pandemic has caused much morbidity and mortality to patients but also health care providers. AIMS: We tabulated the cases of physician deaths from COVID-19 associated with front-line work in hopes of mitigating future events. METHODS: On 15 April 2020, a Google internet search was performed using the keywords ‘doctor’, ‘physician’, ‘death’, ‘COVID’ and ‘coronavirus’ in English and Farsi, and Chinese using the Baidu search engine. The age, sex and medical speciality of physicians who died from COVID-19 in the line of duty were recorded. Individuals greater than 90 years of age were excluded. RESULTS: We found 278 physicians who died with COVID-19 infection, but complete details were missing for 108 individuals. The average age of the physicians was 63.7 years with a median age of 66 years, and 90% were male (235/261). General practitioners and emergency room doctors (108/254), respirologists (5/254), internal medicine specialists (13/254) and anaesthesiologists (6/254) comprised 52% of those dying. Two per cent of the deceased were epidemiologists (5/254), 2% were infectious disease specialists (4/254), 6% were dentists (16/254), 4% were ENT (9/254) and 3% were ophthalmologists (8/254). The countries with the most reported physician deaths were Italy (121/278; 44%), Iran (43/278; 15%), Philippines (21/278; 8%), Indonesia (17/278; 6%), China (16/278; 6%), Spain (12/278; 4%), USA (12/278; 4%) and UK (11/278;4%). CONCLUSIONS: Physicians from all specialities may die from COVID. Lack of personal protective equipment was cited as a common cause of death. Consideration should be made to exclude older physicians from front-line work.


title: Status of SARS-CoV-2 infection in patients on renal replacement therapy Report of the COVID-19 Registry of the Spanish Society of Nephrology (SEN)

text: Summary The recent appearance of the SARS-CoV-2 coronavirus pandemic has had a significant impact on the general population. Patients on renal replacement therapy (RRT) have not been unaware of this situation and due to their characteristics they are especially vulnerable. We present the results of the analysis of the COVID-19 Registry of the Spanish Society of Nephrology. Material and methods The Registry began operating on March 18th, 2020. It collects epidemiological variables, contagion and diagnosis data, signs and symptoms, treatments and outcomes. It is an “online” registry. Patients were diagnosed with SARS-Cov-2 infection based on the results of the PCR of the virus, carried out both in patients who had manifested compatible symptoms or had suspicious signs, as well as in those who had undergone screening after some contact. acquainted with another patient. Results As of April 11, the Registry had data on 868 patients, from all the Autonomous Communities. The most represented form of TRS is in-center hemodialysis (ICH) followed by transplant patients. Symptoms are similar to the general population. A very high percentage (85%) required hospital admission, 8% in intensive care units. The most used treatments were hydroxychloroquine, lopinavir-ritonavir, and steroids. Mortality is high and reaches 23%; deceased patients were more frequently on ICH, developed pneumonia more frequently, and received less frequently lopinavir-ritonavir and steroids. Age and pneumonia were independently associated with the risk of death. Conclusions SARS-CoV-2 infection already affects a significant number of Spanish patients on RRT, mainly those on ICH, hospitalization rates are very high and mortality is high; age and the development of pneumonia are factors associated with mortality.


Volunteerism and Humanitarian Efforts in Surgery


title: Assessing the use of mobile phone data to describe recurrent mobility patterns in spatial epidemic models

text: The recent availability of large-scale call detail record data has substantially improved our ability of quantifying human travel patterns with broad applications in epidemiology. Notwithstanding a number of successful case studies, previous works have shown that using different mobility data sources, such as mobile phone data or census surveys, to parametrize infectious disease models can generate divergent outcomes. Thus, it remains unclear to what extent epidemic modelling results may vary when using different proxies for human movements. Here, we systematically compare 658 000 simulated outbreaks generated with a spatially structured epidemic model based on two different human mobility networks: a commuting network of France extracted from mobile phone data and another extracted from a census survey. We compare epidemic patterns originating from all the 329 possible outbreak seed locations and identify the structural network properties of the seeding nodes that best predict spatial and temporal epidemic patterns to be alike. We find that similarity of simulated epidemics is significantly correlated to connectivity, traffic and population size of the seeding nodes, suggesting that the adequacy of mobile phone data for infectious disease models becomes higher when epidemics spread between highly connected and heavily populated locations, such as large urban areas.


title: Exploring Nursing Intention, Stress, and Professionalism in Response to Infectious Disease Emergencies: The Experience of Local Public Hospital Nurses During the 2015 MERS Outbreak in South Korea

text: Summary Purpose This study aimed to examine levels of stress and professionalism of nurses who provided nursing care during the 2015 Middle East respiratory syndrome outbreak based on their experience, to investigate the nurses' intention to respond to possible future outbreaks in relation to their experience during the outbreak, and to determine the relationship between the outbreak experience and nursing intention considering stress and professionalism. Methods A self-administered questionnaire was designed based on modifications of related questionnaires, and used to assess levels of stress, professionalism, and nursing intention according to participants' experiences during the outbreak. Multiple regression analysis was used to examine the relationship between the outbreak nursing experience and nursing intention considering stress and nursing professionalism. Results The overall stress, professionalism, and nursing intention scores for the firsthand experience group were 33.72, 103.00, and 16.92, respectively, whereas those of the secondhand experience group were 32.25, 98.99, and 15.60, respectively. There were significant differences in professionalism and nursing intention scores between the groups (p = .001 and p < .001, respectively). The regression analysis revealed that the regression estimate between stress and nursing intention was B(SE) = −0.08(0.02), beta = −0.21, p < .001 and the regression estimate between professionalism in nursing and nursing intention was B(SE) = 0.05(0.01), beta = 0.23, p < .001. Conclusion Prior outbreak nursing experience was importantly associated with intention to provide care for patients with a newly emerging infectious disease in the future considering stress and professionalism. Gathering information about nurses' experience of epidemics and regular assessment of job stress and professionalism are required.


title: Aging increases the systemic molecular degree of inflammatory perturbation in patients with tuberculosis

text: Tuberculosis (TB) is a chronic infection that can affect individuals of all ages. The description of determinants of immunopathogenesis in TB is of tremendous interest due to the perspective of finding a reliable host-directed therapy to reduce disease burden. The association between specific biomarker profiles related to inflammation and the diverse clinical disease presentations in TB has been extensively studied in adults. However, relatively scarce data on profiling the inflammatory responses in pediatric TB are available. Here, we employed the molecular degree of perturbation (MDP) score adapted to plasma biomarkers in two distinct databanks from studies that examined either adults or children presenting with pulmonary or extrapulmonary disease. We used multidimensional statistical analyses to characterize the impact of age on the overall changes in the systemic inflammation profiles in subpopulation of TB patients. Our findings indicate that TB results in significant increases in molecular perturbation, with the highest values being detected in adult patients. Furthermore, there were unique differences in the biomarker perturbation patterns and the overall degree of inflammation according to disease site and age. Importantly, the molecular degree of perturbation was not influenced by sex. Our results revealed that aging is an important determinant of the differences in quality and magnitude of systemic inflammatory perturbation in distinct clinical forms of TB.


Preparation for a pandemic: influenza A H1N1


Correlation between PCR Examination Rate among the Population and the Containment of Pandemic of COVID-19


title: Health and zoonotic Infections of snow leopards Panthera unica in the South Gobi desert of Mongolia

text: Background: Snow leopards, Panthera uncia, are a threatened apex predator, scattered across the mountains of Central and South Asia. Disease threats to wild snow leopards have not been investigated.Methods and Results: Between 2008 and 2015, twenty snow leopards in the South Gobi desert of Mongolia were captured and immobilised for health screening and radio-collaring. Blood samples and external parasites were collected for pathogen analyses using enzyme-linked immunosorbent assay (ELISA), microscopic agglutination test (MAT), and next-generation sequencing (NGS) techniques. The animals showed no clinical signs of disease, however, serum antibodies to significant zoonotic pathogens were detected. These pathogens included, Coxiella burnetii, (25% prevalence), Leptospira spp., (20%), and Toxoplasma gondii (20%). Ticks collected from snow leopards contained potentially zoonotic bacteria from the genera Bacillus, Bacteroides, Campylobacter, Coxiella, Rickettsia, Staphylococcus and Streptococcus.Conclusions: The zoonotic pathogens identified in this study, in the short-term did not appear to cause illness in the snow leopards, but have caused illness in other wild felids. Therefore, surveillance for pathogens should be implemented to monitor for potential longer- term disease impacts on this snow leopard population.


title: The atypical pneumonias: clinical diagnosis and importance

text: ABSTRACT The most common atypical pneumonias are caused by three zoonotic pathogens, Chlamydia psittaci (psittacosis), Francisella tularensis (tularemia), and Coxiella burnetii (Q fever), and three non-zoonotic pathogens, Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella. These atypical agents, unlike the typical pathogens, often cause extrapulmonary manifestations. Atypical CAPs are systemic infectious diseases with a pulmonary component and may be differentiated clinically from typical CAPs by the pattern of extrapulmonary organ involvement which is characteristic for each atypical CAP. Zoonotic pneumonias may be eliminated from diagnostic consideration with a negative contact history. The commonest clinical problem is to differentiate legionnaire's disease from typical CAP as well as from C. pneumoniae or M. pneumonia infection. Legionella is the most important atypical pathogen in terms of severity. It may be clinically differentiated from typical CAP and other atypical pathogens by the use of a weighted point system of syndromic diagnosis based on the characteristic pattern of extrapulmonary features. Because legionnaire's disease often presents as severe CAP, a presumptive diagnosis of Legionella should prompt specific testing and empirical anti-Legionella therapy such as the Winthrop-University Hospital Infectious Disease Division's weighted point score system. Most atypical pathogens are difficult or dangerous to isolate and a definitive laboratory diagnosis is usually based on indirect, i.e., direct flourescent antibody (DFA), indirect flourescent antibody (IFA). Atypical CAP is virtually always monomicrobial; increased IFA IgG tests indicate past exposure and not concurrent infection. Anti-Legionella antibiotics include macrolides, doxycycline, rifampin, quinolones, and telithromycin. The drugs with the highest level of anti-Legionella activity are quinolones and telithromycin. Therapy is usually continued for 2 weeks if potent anti-Legionella drugs are used. In adults, M. pneumoniae and C. pneumoniae my exacerbate or cause asthma. The importance of the atypical pneumonias is not related to their frequency (~15% of CAPs), but to difficulties in their diagnosis, and their nonresponsiveness to β-lactam therapy. Because of the potential role of C. pneumoniae in coronary artery disease and multiple sclerosis (MS), and the role of M. pneumoniae and C. pneumoniae in causing or exacerbating asthma, atypical CAPs also have public health importance.


title: Gender difference in knowledge of tuberculosis and associated health-care seeking behaviors: a cross-sectional study in a rural area of China

text: BACKGROUND: Tuberculosis (TB) detection under the national TB control program in China follows passive case-finding guidelines, which could be influenced by the accessibility of health service and patient's health-care seeking behaviors. One intriguing topic is the correlation between men and women's knowledge on TB and their health-care seeking behaviors. METHODS: Two cross-sectional studies were separately carried out in Yangzhong County, a rural area of China. One study, by using systematic sampling method, including 1,200 subjects, was conducted to investigate the TB knowledge among general population. Another study in the same source population screened 33,549 people aged 15 years or over among 20 stratified cluster-sampled villages for identifying prolonged cough patients at households and individual interviews were then carried out. Gender difference in the knowledge of TB and health-care seeking behaviors was analyzed particularly. RESULTS: Among general population, only 16.0% (men 17.1% vs. women 15.0%) knew the prolonged cough with the duration of 3 weeks or longer was a symptom for suspicious TB. Fewer women than men knew the local appointed health facility for TB diagnosis and treatment as well as the current free TB service policy. Moreover, women were less likely to learn information about TB and share it with others on their own initiatives. On the contrary, after the onset of the prolonged cough, women (79.2%) were more likely to seek health-care than men (58.6%) did. However, a large part of women preferred to visit the lower level non-hospital health facilities at first such as village clinics and drugstores. CONCLUSION: TB and DOTS program were not well known by rural Chinese. Gender issues should be considered to reduce diagnostic delay of TB and improve both men and women's access to qualified health facility for TB care. Strengthening awareness of TB and improving the accessibility of health-care service is essential in TB control strategy, especially under the current vertical TB control system.


title: CoMFA/CoMSIA/HQSAR and Docking Study of the Binding Mode of Selective Cyclooxygenase (COX‐2) Inhibitors

text: The intermolecular interaction between four types of anti‐inflammatory inhibitors (oxazoles, pyrazoles, pyrroles and imidazoles) and COX‐2 receptor was studied. The results of docking suggest that they have similar interaction mechanism. The most active compounds of these four types of inhibitors could both form several hydrogen bonds with residues His90, Arg513, Leu352 and Arg120, and develop hydrophobic interaction with residues Phe518, Leu352 and Leu359. This is consistent with the investigation reported by R. G. Kurumbail et al. (Nature. 1996, 384, 644‐648). A common 3D‐QSAR model could be constructed with these four categories of COX‐2 inhibitors using the method of docking‐ guided conformer selection. The cross‐validated q(2) values are found as 0.741 and 0.632 for CoMFA and CoMSIA respectively. And the non‐cross‐validated r(2) values are 0.887 and 0.885. 54 inhibitors constitute the test set used to validate the model. The results show that this model possesses good predictive ability for diverse COX‐2 inhibitors. Furthermore, a HQSAR model was used to evaluate the influence of substituents on anti‐inflammatory activity. Compared with the results of previous works, our model possesses significantly better prediction ability. It could help us to well understand the interaction mechanism between inhibitors and COX‐2 receptor, and to make quantitative prediction of their inhibitory activities.


title: Factors determining the diffusion of COVID-19 and suggested strategy to prevent future accelerated viral infectivity similar to COVID

text: Abstract This study has two goals. The first is to explain the geo-environmental determinants of the accelerated diffusion of COVID-19 in Italy that is generating a high level of deaths. The second is to suggest a strategy to cope with future epidemic threats having accelerated viral infectivity in society. Using data on N = 55 Italian province capitals, and data of infected individuals at as of April 7th, 2020, results reveal that the accelerate and vast diffusion of COVID-19 in North Italy has a high association with air pollution of cities measured with days exceeding the limits set for PM10 (particulate matter 10 μm or less in diameter) or ozone in previous years. In particular, hinterland cities with average higher number of days exceeding the limits set for PM10 (and a low intensity of wind speed) have a very high number of infected people on 7th April 2020 (arithmetic mean about 2200 infected, with average polluted days greater than 80), than coastal cities also having days of exceeding the limits set for PM10 or ozone but with high intensity of wind speed (arithmetic mean about 944.70 infected individuals, with about 60 average polluted days); moreover, cities having more than 100 days of air pollution (exceeding the limits set for PM10), they have a very high average number of infected people (about 3350 infected individuals, 7th April 2020), whereas cities having less than 100 days of air pollution, they have a lower average number of infected individuals (about 1014). The findings here also suggest that to minimize the impact of future epidemics similar to COVID-19, the max number of days per year in which Italian provincial capitals can exceed the limits set for PM10 or for ozone, considering their meteorological conditions, is about 48 days. Moreover, results here reveal that the explanatory variable of air pollution in cities under study seems to be a more important predictor in the initial phase of diffusion (on 17th March 2020, b1 = 1.27, p < 0.001) than interpersonal contacts (b2 = 0.31, p < 0.05). In the second phase of maturity of the transmission dynamics of COVID-19, air pollution reduces intensity (on 7th April 2020 with b′1 = 0.81, p < 0.001) also because of indirect effect of lockdown, whereas coefficient of transmission by interpersonal contacts has stability (b′2 = 0.31, p < 0.01). This result reveals that accelerated transmissions dynamics of COVID-19 is due to mainly to the mechanism of “air pollution-to-human transmission” rather than “human-to-human transmission”. Overall, then, transmission dynamics of viral infectivity, such as COVID-19, is due to systemic causes: general factors that are the same for all regions (e.g., biological characteristics of virus, incubation period, etc.) and specific factors which are different for each region (e.g., complex interaction between air pollution, meteorological conditions and biological characteristics of viral infectivity) and health level of individuals (habits, immune system, age, sex, etc.). Lessons learned for COVID-19 in the case study of Italy suggest that a proactive strategy to cope with future epidemics is to also apply especially an environmental and sustainable policy based on reduction of levels of air pollution mainly in hinterland and polluting cities- having low wind speed, high percentage of moisture and fog days-that seem to have an environment that may damage immune system of people and foster a fast transmission dynamics of viral infectivity in society. Hence, in the presence of polluting industrialization in regions that can trigger the mechanism of air pollution-to-human transmission dynamics of viral infectivity, this study must conclude that a comprehensive strategy to prevent future epidemics similar to COVID-19 has to be also designed in environmental and socioeconomic terms, that is also based on sustainability science and environmental science, and not only in terms of biology, healthcare and health sector.


title: Highlights of marine natural products having parallel scaffolds found from marine-derived bacteria, sponges, and tunicates

text: Marine-derived bacteria are a prolific source of a wide range of structurally diverse natural products. This review, dedicated to Professor William Fenical, begins by showcasing many seminal discoveries made at the University of California San Diego from marine-derived actinomycetes. Discussed early on is the 20-year journey of discovery and advancement of the seminal actinomycetes natural product salinosporamide A into Phase III anticancer clinical trials. There are many fascinating parallels discussed that were gleaned from the comparative literature of marine sponge, tunicate, and bacteria-derived natural products. Identifying bacterial biosynthetic machinery housed in sponge and tunicate holobionts through both culture-independent and culture-dependent approaches is another important and expanding subject that is analyzed. Work reviewed herein also evaluates the hypotheses that many marine invertebrate-derived natural products are biosynthesised by associated or symbiotic bacteria. The insights and outcomes from metagenomic sequencing and synthetic biology to expand molecule discovery continue to provide exciting outcomes and they are predicted to be the source of the next generation of novel marine natural product chemical scaffolds.


A cured patient with 2019-nCoV pneumonia


title: Viral Etiologies of Acute Respiratory Infections among Hospitalized Vietnamese Children in Ho Chi Minh City, 2004–2008

text: BACKGROUND: The dominant viral etiologies responsible for acute respiratory infections (ARIs) are poorly understood, particularly among hospitalized children in resource-limited tropical countries where morbidity and mortality caused by ARIs are highest. Improved etiological insight is needed to improve clinical management and prevention. OBJECTIVES: We conducted a three-year prospective descriptive study of severe respiratory illness among children from 2 months to 13 years of age within the largest referral hospital for infectious diseases in southern Vietnam. METHODS: Molecular detection for 15 viral species and subtypes was performed on three types of respiratory specimens (nose, throat swabs and nasopharyngeal aspirates) using a multiplex RT-PCR kit (Seeplex™ RV detection, Seegene) and additional monoplex real-time RT-PCRs. RESULTS: A total of 309 children were enrolled from November 2004 to January 2008. Viruses were identified in 72% (222/309) of cases, including respiratory syncytial virus (24%), influenza virus A and B (17%), human bocavirus (16%), enterovirus (9%), human coronavirus (8%), human metapneumovirus (7%), parainfluenza virus 1–3 (6%), adenovirus (5%), and human rhinovirus A (4%). Co-infections with multiple viruses were detected in 20% (62/309) of patients. When combined, diagnostic yields in nose and throat swabs were similar to nasopharyngeal aspirates. CONCLUSION: Similar to other parts in the world, RSV and influenza were the predominant viral pathogens detected in Vietnamese hospitalized children. Combined nasal and throat swabs are the specimens of choice for sensitive molecular detection of a broad panel of viral agents. Further research is required to better understand the clinical significance of single versus multiple viral coinfections and to address the role of bacterial (co-)infections involved in severe respiratory illness.


title: Antiviral activity of itraconazole against type I feline coronavirus infection

text: Feline coronaviruses (FCoVs) are the causative agents of severe systemic disease (feline infectious peritonitis: FIP) in domestic and wild cats. FCoVs have been classified into serotypes I and II. Type I FCoV is the dominant serotype (approximately 70–90%) worldwide. Therefore, it is necessary to provide antiviral agents for type I FCoV infection. In this study, we demonstrated that itraconazole (ICZ), practically used for fungal infections in cats, inhibits the type I FCoV infection. ICZ also exhibited antiviral effect in cells after viral infection, suggesting that ICZ could potentially be used as a therapeutic.


title: Bipolar disorder, COVID‐19, and the risk of relapse

text: The novel coronavirus disease (COVID‐19) pandemic represents a global health crisis which can directly or indirectly affect the mental health of millions of people around the world. There are certain aspects of this pandemic, and of the measures necessary for this control, which are of particular concern for patients with bipolar disorders, particularly as regards the risk of relapse.


Letter to the Editor: Screening All Pregnant Women Admitted To Labor And Delivery For The Virus Responsible For COVID-19


title: Time-trend analysis of medicine sales and shortages during COVID-19 outbreak: Data from community pharmacies

text: BACKGROUND: COVID-19 is a worldwide public health concern. Disruptions in the drug market are expected and shortages might worsen. Community pharmacies can contribute to early identification and report of medicines’ supply and demand issues. OBJECTIVE: The aim of this study is to characterize the impact of the COVID-19 outbreak on outpatient medicines’ sales and shortages. METHODS: A retrospective, time-trend analysis of medicine sales, shortages and laboratory-confirmed COVID-19 cases was performed from February 1st to April 30th, 2020, and its homologous period (regarding sales only). A detailed analysis of 6 pharmaceutical substances was performed. All data were subjected to rescaling using the min-max normalization method, in order to become comparable. Data analysis was performed using Microsoft® Excel. RESULTS: The pandemic resulted in an increase in medicines’ demand and reported shortages during the early stage of the outbreak. The maximum proportion of medicine sales was registered on March 13th, 2020, 4 days after the WHO declared COVID-19 a pandemic. By the end of March, sales have already dropped to proportions similar to those of 2019. The maximum proportion of drug shortages was reached about one week after the sales peak and by the end of the study period were below those recorded in the pre-COVID-19 period. The analyzed drugs were paracetamol, ascorbic acid, dapagliflozin plus metformin, rosuvastatin plus ezetimibe, formoterol, and hydroxychloroquine, as these pharmaceutical substances registered the highest growth rate in sales and shortages when compared to the same period in the previous year. Hydroxychloroquine showed the most different pattern trends on sales and shortages of these medicines. CONCLUSIONS: Pharmacies can provide timely and real-world data regarding sales and shortages. The adopted measures to guarantee the continuous supply of the medicine market seem to have worked. The long-term impacts of this pandemic are unknown and should continue to be closely monitored.


title: Tauroursodeoxycholic acid (TUDCA) inhibits influenza A viral infection by disrupting viral proton channel M2

text: Abstract Influenza is a persistent threat to human health and there is a continuing requirement for updating anti-influenza strategies. Initiated by observations of different endoplasmic reticulum (ER) responses of host to seasonal H1N1 and highly pathogenic avian influenza (HPAI) A H5N1 infections, we identified an alternative antiviral role of tauroursodeoxycholic acid (TUDCA), a clinically available ER stress inhibitor, both in vitro and in vivo. Rather than modulating ER stress in host cells, TUDCA abolished the proton conductivity of viral M2 by disrupting its oligomeric states, which induces inefficient viral infection. We also showed that M2 penetrated cells, whose intracellular uptake depended on its proton channel activity, an effect observed in both TUDCA and M2 inhibitor amantadine. The identification and application of TUDCA as an inhibitor of M2 proton channel will expand our understanding of IAV biology and complement current anti-IAV arsenals.


title: Pneumonia in the tropics: Report from the Task Force on tropical diseases by the World Federation of Societies of Intensive and Critical Care Medicine

text: Abstract The aetiology of community acquired pneumonia varies according to the region in which it is acquired. This review discusses those causes of CAP that occur in the tropics and might not be readily recognizable when transplanted to other sites. Various forms of pneumonia including the viral causes such as influenza (seasonal and avian varieties), the coronaviruses and the Hantavirus as well as bacterial causes, specifically the pneumonic form of Yersinia pestis and melioidosis are discussed.


title: A comparative genetic analysis between collagen‐induced arthritis and pristane‐induced arthritis

text: OBJECTIVE: To compare the genetic regulation of collagen‐induced arthritis (CIA) with that of pristane‐induced arthritis (PIA) in rats. METHODS: A genome‐wide linkage analysis of an (E3 × DA)DA backcross of rats with CIA (n = 364 male rats; the same strain combinations as previously used to determine the genetic control of PIA) was performed. The strongest loci in both CIA and PIA (i.e., Cia12/Pia4 and Cia13/Pia7) were isolated in congenic strains. Susceptibility in both congenic strains was tested in rats with CIA and in rats with PIA. RESULTS: We found a striking, although not complete, similarity of the arthritis‐controlling loci in CIA and in PIA, as well as the previously defined loci associated with cartilage destruction, antibody production, and the acute‐phase response. All major PIA quantitative trait loci (QTLs) identified in early severe arthritis were also strong regulators of CIA. The 2 strongest QTLs, Cia12/Pia4 on chromosome 12 and Cia13/Pia7 on chromosome 4, were also analyzed in congenic strains with DA or E3 as the background genome. Consistent with the results of linkage analysis, the congenic strain experiments showed that the chromosome 4 locus was more penetrant in CIA than in PIA, while the chromosome 12 locus almost completely dominated the control of PIA severity. CONCLUSION: The underlying genetic control of CIA was found to have many, but not all, pathogenic mechanisms in common with PIA, despite the use of a cartilage‐specific antigen (type II collagen) to induce CIA but not PIA.


title: Informing the measurement of wellbeing among young people living with HIV in sub-Saharan Africa for policy evaluations: a mixed-methods systematic review

text: Young people living with HIV (YPLHIV) in sub-Saharan Africa (SSA) are at high risk of having a poor quality of life. Addressing wellbeing explicitly within HIV/AIDS policies could assist mitigation efforts. However, guidance on wellbeing measures to evaluate policies for YPLHIV is scarce. The aims of this mixed-methods review were to identify: i) key dimensions of wellbeing and ii) wellbeing measures that align to these dimensions among YPLHIV (15–24 years) in SSA. We searched six social science and medical databases, including grey literature. We included studies that examined correlates and lived experiences of wellbeing, among YPLHIV in SSA, from January 2000 to May 2019. Two reviewers independently screened abstracts and full texts and assessed methodological quality of included articles. We analysed quantitative and qualitative data using descriptive and meta-ethnographic approaches, respectively. Thereafter, we integrated findings using a framework approach. We identified 6527 citations. Of these, 10 quantitative and 30 qualitative studies were included. Being male, higher educational status, less stigma and more social support were likely correlates of wellbeing. Themes that shaped experiences suggestive of wellbeing were: 1) acceptance and belonging— stigma, social support; 2) coping; 3) standard of living. Our final synthesis found that the following dimensions potentially characterise wellbeing: self-acceptance, belonging, autonomy; positive relations, environmental mastery, purpose in life. Wellbeing for YPLHIV is multi-dimensional and relational. Relevant measures include the Personal Wellbeing Index, Ryff’s Psychological Wellbeing Scale and Mental Health Continuum Short Form. However, psychometric evaluations of these scales among YPLHIV in SSA are needed.


title: A delayed vaccinated epidemic model with nonlinear incidence rate and Lévy jumps

text: Abstract A stochastic susceptible–infectious–recovered epidemic model with nonlinear incidence rate is formulated to discuss the effects of temporary immunity, vaccination, and Le.́vy jumps on the transmission of diseases. We first determine the existence of a unique global positive solution and a positively invariant set for the stochastic system. Sufficient conditions for extinction and persistence in the mean of the disease are then achieved by constructing suitable Lyapunov functions. Based on the analysis, we conclude that noise intensity and the validity period of vaccination greatly influence the transmission dynamics of the system.


title: Immune-complex glomerulonephritis in cats: a retrospective study based on clinico-pathological data, histopathology and ultrastructural features

text: BACKGROUND: Chronic kidney disease (CKD) has typically a non-immune mediated origin in cats and immune-complex glomerulonephritis (ICGN) is scarcely described. Aims of this study were to characterize ICGN by light and electron microscopy and identify associations with clinico-pathological findings. In addition, comparisons between cats with ICGN and non immune-complex glomerulonephritis (non-ICGN) were performed. Renal samples examined between 2010 and 2019 were considered if both light and electron microscopy were performed. Signalment, feline immunodeficiency virus (FIV) and leukemia virus (FeLV) status, serum creatinine concentration, urine protein-to-creatinine (UPC) ratio, systolic blood pressure (SBP) and International Renal Interest Society (IRIS) stage were retrieved and used for comparisons. RESULTS: Sixty-eight client-owned cats were included. Thirty-seven cats (54.4%) had ICGN and 31 (45.6%) non-ICGN. Eighteen (48.6%) with ICGN had membranous glomerulonephropathy (MGN), 14 (37.8%) membranoproliferative glomerulonephritis (MPGN), and 5 (13.5%) mesangioproliferative glomerulonephritis (MeGN). Clinico-pathological data were not associated with any type of ICGN. Among cats with non-ICGN, 11 (35.5%) had end-stage CKD, 9 (29%) focal segmental glomerulosclerosis, 6 (19.4%) global and multifocal mesangiosclerosis, 2 (6.5%) glomerular atrophy, 2 (6.5%) renal dysplasia and 1 (3.1%) amyloidosis. Eight (25.8%) cats with non-ICGN had chronic interstitial nephritis (CIN) grade 1, 13 (41.9%) grade 2 and 10 (32.3%) grade 3; creatinine and UPC ratio increased with CIN grades (p = 0.001, p < 0.001). Cats with ICGN were more frequently FIV or FeLV-infected (OR:11.4; 95%CI:1.4–94.4; p = 0.024), had higher UPC ratio (OR:6.8; 95%CI:2.5–18.2; p < 0.001) and were younger (OR:0.9; 95%CI:0.7–1.0; p = 0.042) than cats with non-ICGN. CONCLUSIONS: MGN and MPGN were the most common morphological diagnoses of ICGN in cats. Unfortunately, none of the investigated findings differentiated ICGN morphological diagnoses. Serum creatinine concentration and UPC ratio were directly associated with grades of CIN (p = 0.001 and p < 0.001, respectively), confirming previous literature. More ICGN than non-ICGN was observed in cats with retroviral infections, younger cats and higher UPC ratio.


title: During Aspergillus Infection, Monocyte-Derived DCs, Neutrophils, and Plasmacytoid DCs Enhance Innate Immune Defense through CXCR3-Dependent Crosstalk

text: Aspergillus fumigatus, a ubiquitous mold, is a common cause of invasive aspergillosis (IA) in immunocompromised patients. Host defense against IA relies on lung-infiltrating neutrophils and monocyte-derived dendritic cells (Mo-DCs). Here, we demonstrate that plasmacytoid dendritic cells (pDCs), which are prototypically antiviral cells, participate in innate immune crosstalk underlying mucosal antifungal immunity. Aspergillus-infected murine Mo-DCs and neutrophils recruited pDCs to the lung by releasing the CXCR3 ligands, CXCL9 and CXCL10, in a Dectin-1 and Card9- and type I and III interferon signaling-dependent manner, respectively. During aspergillosis, circulating pDCs entered the lung in response to CXCR3-dependent signals. Via targeted pDC ablation, we found that pDCs were essential for host defense in the presence of normal neutrophil and Mo-DC numbers. Although interactions between pDC and fungal cells were not detected, pDCs regulated neutrophil NADPH oxidase activity and conidial killing. Thus, pDCs act as positive feedback amplifiers of neutrophil effector activity against inhaled mold conidia.


title: Pylons ablaze: Examining the role of 5G COVID‐19 conspiracy beliefs and support for violence

text: Amid increased acts of violence against telecommunication engineers and property, this pre‐registered study (N = 601 Britons) investigated the association between beliefs in 5G COVID‐19 conspiracy theories and the justification and willingness to use violence. Findings revealed that belief in 5G COVID‐19 conspiracy theories was positively correlated with state anger, which in turn, was associated with a greater justification of real‐life and hypothetical violence in response to an alleged link between 5G mobile technology and COVID‐19, alongside a greater intent to engage in similar behaviours in the future. Moreover, these associations were strongest for those highest in paranoia. Furthermore, we show that these patterns are not specific to 5G conspiratorial beliefs: General conspiracy mentality was positively associated with justification and willingness for general violence, an effect mediated by heightened state anger, especially for those most paranoid in the case of justification of violence. Such research provides novel evidence on why and when conspiracy beliefs may justify the use of violence.


title: Eating and exercise behaviors in eating disorders and the general population during the COVID‐19 pandemic in Australia: Initial results from the COLLATE project

text: OBJECTIVE: Emerging evidence suggests that the coronavirus (COVID‐19) pandemic may be negatively impacting mental health. The impact on eating and exercise behaviors is, however, currently unknown. This study aimed to identify changes in eating and exercise behaviors in an Australian sample among individuals with an eating disorder, and the general population, amidst the COVID‐19 pandemic outbreak. METHOD: A total of 5,469 participants, 180 of whom self‐reported an eating disorder history, completed questions relating to changes in eating and exercise behaviors since the emergence of the pandemic, as part of the COLLATE (COvid‐19 and you: mentaL heaLth in AusTralia now survEy) project; a national survey launched in Australia on April 1, 2020. RESULTS: In the eating disorders group, increased restricting, binge eating, purging, and exercise behaviors were found. In the general population, both increased restricting and binge eating behaviors were reported; however, respondents reported less exercise relative to before the pandemic. DISCUSSION: The findings have important implications for providing greater monitoring and support for eating disorder patients during the COVID‐19 pandemic. In addition, the mental and physical health impacts of changed eating and exercise behaviors in the general population need to be acknowledged and monitored for potential long‐term consequences.


Delayed emergency surgical presentation: impact of corona virus disease (COVID‐19) on non‐COVID patients


title: Genetic links between the acute‐phase response and arthritis development in rats

text: OBJECTIVE: The acute‐phase inflammatory response is closely correlated with the development of rheumatoid arthritis, but the pathophysiologic role of its specific components is largely unknown. We investigated the genetic control of the acute‐phase protein response in pristane‐induced arthritis (PIA), which is a chronic erosive arthritis model in rats. METHODS: Plasma levels of the acute‐phase proteins interleukin‐6 (IL‐6), α(1)‐acid glycoprotein (orosomucoid), fibrinogen, and α(1)‐inhibitor(3) were quantified in 3 strains of rats during the development and progression of disease: DA and LEW.1F, which are susceptible to arthritis, and E3, which is resistant. Genetic linkage analysis was performed on an F(2) intercross between E3 and DA to determine the genetic control of the acute‐phase response in arthritis. Elevated levels of α(1)‐acid glycoprotein were associated with acute inflammation, whereas levels of IL‐6 were increased during the entire course of the disease. RESULTS: Using these acute‐phase markers as quantitative traits in linkage analysis revealed a colocalization of loci controlling the acute‐phase response and regions previously shown to control the development of arthritis in chromosomes 10, 12, and 14. In addition, 2 loci that were not associated with arthritis were found to regulate serum levels of the acute‐phase protein Apr1 (acute‐phase response 1) at the telomeric end of chromosome 12 and Apr2 on chromosome 5. CONCLUSION: The PIA model in rats is a useful tool for understanding some of the pathways leading to chronic erosive arthritis. The analysis of acute‐phase proteins in PIA and its application as quantitative traits for studying the genetics of arthritis will promote the understanding of the genetic regulation of the acute‐phase response.


title: Rapid molecular detection of macrolide resistance

text: BACKGROUND: Emerging antimicrobial resistance is a significant threat to human health. However, methods for rapidly diagnosing antimicrobial resistance generally require multi-day culture-based assays. Macrolide efflux gene A, mef(A), provides resistance against erythromycin and azithromycin and is known to be laterally transferred among a wide range of bacterial species. METHODS: We use Recombinase Polymerase Assay (RPA) to detect the antimicrobial resistance gene mef(A) from raw lysates without nucleic acid purification. To validate these results we performed broth dilution assays to assess antimicrobial resistance to erythromycin and ampicillin (a negative control). RESULTS: We validate the detection of mef(A) in raw lysates of Streptococcus pyogenes, S. pneumoniae, S. salivarius, and Enterococcus faecium bacterial lysates within 7–10 min of assay time. We show that detection of mef(A) accurately predicts real antimicrobial resistance assessed by traditional culture methods, and that the assay is robust to high levels of spiked-in non-specific nucleic acid contaminant. The assay was unaffected by single-nucleotide polymorphisms within divergent mef(A) gene sequences, strengthening its utility as a robust diagnostic tool. CONCLUSIONS: This finding opens the door to implementation of rapid genomic diagnostics in a clinical setting, while providing researchers a rapid, cost-effective tool to track antibiotic resistance in both pathogens and commensal strains.


title: Mining of Ebola virus entry inhibitors identifies approved drugs as two-pore channel pore blockers

text: Abstract Two-pore channels (TPCs) are Ca2+-permeable ion channels localised to the endo-lysosomal system where they regulate trafficking of various cargoes including viruses. As a result, TPCs are emerging as important drug targets. However, their pharmacology is ill-defined. There are no approved drugs to target them. And their mechanism of ligand activation is largely unknown. Here, we identify a number of FDA-approved drugs as TPC pore blockers. Using a model of the pore of human TPC2 based on recent structures of mammalian TPCs, we virtually screened a database of ~1500 approved drugs. Because TPCs have recently emerged as novel host factors for Ebola virus entry, we reasoned that Ebola virus entry inhibitors may exert their effects through inhibition of TPCs. Cross-referencing hits from the TPC virtual screen with two recent high throughput anti-Ebola screens yielded approved drugs targeting dopamine and estrogen receptors as common hits. These compounds inhibited endogenous NAADP-evoked Ca2+ release from sea urchin egg homogenates, NAADP-mediated channel activity of TPC2 re-routed to the plasma membrane, and PI(3,5)P2-mediated channel activity of TPC2 expressed in enlarged lysosomes. Mechanistically, single channel analyses showed that the drugs reduced mean open time consistent with a direct action on the pore. Functionally, drug potency in blocking TPC2 activity correlated with inhibition of Ebola virus-like particle entry. Our results expand TPC pharmacology through the identification of approved drugs as novel blockers, support a role for TPCs in Ebola virus entry, and provide insight into the mechanisms underlying channel regulation. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech.


title: Chapter 10 Plant-Based Peroral Vaccines

text: Abstract Data about the development of plant-made peroral vaccines are stated on the base of transgenic plants. Different aspects of plant made vaccines (PMV) with their peculiarities and with a plethora of advantages are discussed, in comparison with traditional vaccines. The results disclosing the characteristics of the creation of PMV of both preventive and therapeutic actions are presented. The role of regulatory genes in the increase of the production of antigenic proteins, and in the activation of the glycosylation that enhances the efficiency of PMV, is discussed, according to preventive and therapeutic vaccines and plantibodies.


title: β-sitosterol ameliorates influenza A virus-induced proinflammatory response and acute lung injury in mice by disrupting the cross-talk between RIG-I and IFN/STAT signaling

text: β-Sitosterol (24-ethyl-5-cholestene-3-ol) is a common phytosterol Chinese medical plants that has been shown to possess antioxidant and anti-inflammatory activity. In this study we investigated the effects of β-sitosterol on influenza virus-induced inflammation and acute lung injury and the molecular mechanisms. We demonstrate that β-sitosterol (150–450 μg/mL) dose-dependently suppresses inflammatory response through NF-κB and p38 mitogen-activated protein kinase (MAPK) signaling in influenza A virus (IAV)-infected cells, which was accompanied by decreased induction of interferons (IFNs) (including Type I and III IFN). Furthermore, we revealed that the anti-inflammatory effect of β-sitosterol resulted from its inhibitory effect on retinoic acid-inducible gene I (RIG-I) signaling, led to decreased STAT1 signaling, thus affecting the transcriptional activity of ISGF3 (interferon-stimulated gene factor 3) complexes and resulting in abrogation of the IAV-induced proinflammatory amplification effect in IFN-sensitized cells. Moreover, β-sitosterol treatment attenuated RIG-I-mediated apoptotic injury of alveolar epithelial cells (AEC) via downregulation of pro-apoptotic factors. In a mouse model of influenza, pre-administration of β-sitosterol (50, 200 mg·kg(−1)·d(−1), i.g., for 2 days) dose-dependently ameliorated IAV-mediated recruitment of pathogenic cytotoxic T cells and immune dysregulation. In addition, pre-administration of β-sitosterol protected mice from lethal IAV infection. Our data suggest that β-sitosterol blocks the immune response mediated by RIG-I signaling and deleterious IFN production, providing a potential benefit for the treatment of influenza.


Medical Student Mobilization During a Pandemic: The Ochsner Clinical School Response to COVID-19


title: Orchitis: A Complication of Severe Acute Respiratory Syndrome (SARS)(1)

text: Severe acute respiratory syndrome (SARS) coronavirus has been known to damage multiple organs; however, little is known about its impact on the reproductive system. In the present study, we analyzed the pathological changes of testes from six patients who died of SARS. Results suggested that SARS caused orchitis. All SARS testes displayed widespread germ cell destruction, few or no spermatozoon in the seminiferous tubule, thickened basement membrane, and leukocyte infiltration. The numbers of CD3+ T lymphocytes and CD68+ macrophages increased significantly in the interstitial tissue compared with the control group (P < 0.05). SARS viral genomic sequences were not detected in the testes by in situ hybridization. Immunohistochemistry demonstrated abundant IgG precipitation in the seminiferous epithelium of SARS testes, indicating possible immune response as the cause for the damage. Our findings indicated that orchitis is a complication of SARS. It further suggests that the reproductive functions should be followed and evaluated in recovered male SARS patients.


title: An emergency medical services transfer authorization center in response to the Toronto severe acute respiratory syndrome outbreak

text: Abstract Objective To describe the rapid development and implementation of an innovative emergency medical services (EMS) command, control, and tracking system to mitigate the risk of iatrogenic spread of severe acute respiratory syndrome (SARS) among health care facilities, health care workers, and patients in Ontario, Canada, as a result of interfacility patient transfers. Methods A working group of stakeholders in health care and transport medicine developed and implemented a medically based command, control, and tracking center for all interfacility (including acute and long-term care) patient transfers in Ontario, Canada. Development and implementation took place in three distinct but overlapping phases: needs assessment, design and implementation, and expansion and ongoing operations. Results The needs assessment, design, and implementation were completed in less than 48 hours using existing EMS infrastructure and personnel. The center was successfully handling more than 500 requests for interfacility patient transfer per day within 36 hours of operation and more than 1,100 requests per day within two weeks. Expansion into a new physical space enables 40 staff to process up to 1,500 requests per day. There was no reported spread of SARS resulting from interfacility patient transfers since the center began operation on April 1, 2003, and anecdotal evidence demonstrates it identified up to 13 new SARS cases. The center continues to operate as a part of Ontario's commitment as a result of diligence in transport medicine and infection control, even though no new cases of SARS were reported since June 12, 2003. Further study is needed to determine its overall efficacy at risk mitigation. Conclusions Rapid establishment of an EMS-based command, control, and tracking center is possible in the setting of a public health emergency. In addition to risk mitigation, this type of center could provide syndromic surveillance in real time and provide the earliest indication of a potential threat to public health in acute and long-term care facilities.


No Change in Cesarean Section Rate During COVID-19 Pandemic in New York City


COVID-19 and the rush for self-medication and self-dosing with ivermectin: A word of caution


title: A rapid review of evidence and recommendations from the SIOPE Radiation Oncology working group to help mitigate for reduced paediatric radiotherapy capacity during the COVID-19 pandemic or other crises

text: Abstract Objective To derive evidence-based recommendations for the optimal utilisation of resources during unexpected shortage of radiotherapy capacity. Methods and materials We have undertaken a rapid review of published literature on the role of radiotherapy in the multimodality treatment of paediatric cancers governing the European practice of paediatric radiotherapy. The derived data has been discussed with expert paediatric radiation oncologists to derive a hierarchy of recommendations. Results The general recommendations to mitigate the potential detriment of an unexpected shortage of radiotherapy facilities include: (1) maintain current standards of care as long as possible (2) refer to another specialist paediatric radiotherapy department with similar level of expertise (3) prioritise use of existing radiotherapy resources to treat patients with tumours where radiotherapy has the most effect on clinical outcome (4) use chemotherapy to defer the start of radiotherapy where timing of radiotherapy is not expected to be detrimental (5) active surveillance for low-grade tumours if appropriate and (6) consider iso-effective hypofractionated radiotherapy regimens only for selected patients with predicted poor prognosis. The effectiveness of radiotherapy and recommendations for prioritisation of its use for common and challenging paediatric tumours are discussed. Conclusion This review provides evidence-based treatment recommendations during unexpected shortage of paediatric radiotherapy facilities. It has wider applications for the optimal utilization of facilities, to improve clinical outcome in low- and middle-income countries, where limited resources continue to be a challenge.


title: Tetraspanin CD9 affects HPV16 infection by modulating ADAM17 activity and the ERK signalling pathway

text: Human papillomaviruses (HPV) are causative agents of various tumours such as cervical cancer. HPV binding to the cell surface of keratinocytes leads to virus endocytosis at tetraspanin enriched microdomains. Complex interactions of the capsid proteins with host proteins as well as ADAM17-dependent ERK1/2 signal transduction enable the entry platform assembly of the oncogenic HPV type 16. Here, we studied the importance of tetraspanin CD9, also known as TSPAN29, in HPV16 infection of different epithelial cells. We found that both overexpression and loss of the tetraspanin decreased infection rates in cells with low endogenous CD9 levels, while reduction of CD9 expression in keratinocytes that exhibit high-CD9 protein amounts, led to an increase of infection. Therefore, we concluded that low-CD9 supports infection. Moreover, we found that changes in CD9 amounts affect the shedding of the ADAM17 substrate transforming growth factor alpha (TGFα) and the downstream phosphorylation of ERK. These effects correlate with those on infection rates suggesting that a specific CD9 optimum promotes ADAM17 activity, ERK signalling and virus infection. Together, our findings implicate that CD9 regulates HPV16 infection through the modulation of ADAM17 sheddase activity. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00430-020-00671-5) contains supplementary material, which is available to authorized users.


title: Chapter 30 Measles

text: Abstract Measles is a highly contagious disease characterized by a prodromal illness of fever, cough, coryza, and conjunctivitis followed by the appearance of a generalized maculopapular rash. Measles virus is a nonsegmented, single-stranded, negative-sense RNA virus and a member of the Morbillivirus genus in the family of Paramyxoviridae. Although RNA viruses have high mutation rates, measles virus is an antigenically monotypic virus and the surface proteins responsible for inducing protective immunity have retained their antigenic structure. The public health significance is that measles vaccines developed decades ago from a single measles virus strain remain protective worldwide. Prior to the development and widespread use of measles vaccine, 30 million cases of measles were estimated to occur each year, resulting in more than 1 million deaths. Several live, attenuated measles vaccines are available, either as single-antigen vaccines or in combination with rubella and mumps vaccines (MR and MMR vaccines). Most of the currently used measles vaccines were derived from the Edmonston strain of measles virus that was isolated by Enders and Peebles in 1954. Measles vaccines are recommended for all susceptible children and adults for whom the vaccine is not contraindicated. Despite progress in reducing measles mortality, measles remains a major cause of vaccine-preventable death and an important cause of morbidity and mortality in children, particularly sub-Saharan Africa and in Asia. The ideal measles vaccine would be inexpensive, safe, heat-stable, immunogenic in neonates or very young infants, and administered as a single dose without needle or syringe. A number of vaccine candidates with some of these characteristics are undergoing preclinical studies, including DNA vaccines and various viral and bacterial vectored vaccines. The high infectivity of measles virus is a characteristic suitable to a biothreat agent. However, increasingly high levels of measles vaccination coverage throughout the world as part of accelerated measles control efforts would protect many from the deliberate use of measles virus as a biothreat agent. Genetic engineering of a measles virus strain that was not neutralized by antibodies induced by the current attenuated measles vaccines would likely have reduced infectivity, as suggested by the fact that wild-type measles viruses have not mutated to alter their neutralizing epitopes. Measles virus meets many of the biological criteria for disease eradication. Measles virus has no nonhuman reservoir, can be accurately diagnosed, and measles vaccination is a highly effective intervention. Where measles virus differs from smallpox and polio viruses is that it is more highly infectious, necessitating higher levels of population immunity to interrupt transmission. It remains unclear whether the threat from bioterrorism precludes stopping measles vaccination after eradication, but provision of a second opportunity for measles vaccination likely could be stopped following eradication.


title: Procalcitonin as a prognostic marker for sepsis based on SEPSIS‐3

text: BACKGROUND: The revised definition of sepsis is life‐threatening organ dysfunction caused by a dysregulated host response to infection (SEPSIS‐3). The objective of this study was to evaluate procalcitonin (PCT) for the diagnosis and prognosis of sepsis using SEPSIS‐3. METHODS: We enrolled 248 patients, who were admitted to the emergency department with suspected bacterial infection from June 2016 to February 2017. Definite bacterial infection was defined by proven culture results, and probable bacterial infection was based on diagnostic modalities other than culture. The sequential organ failure assessment (SOFA) score of 2 points or more from the baseline was diagnosed as sepsis. PCT was measured by the AFIAS‐6 immunoassay system (Boditech Med Inc.) using whole blood. White blood cell (WBC), C‐reactive protein (CRP), and erythrocyte sedimentation rate (ERS) were evaluated. RESULTS: The final diagnosis was sepsis in 185 patients with infection of respiratory and genitourinary tract constituted 84.6%. The area under the receiver operating characteristic curve (AUROC) with 95% confidence interval (CI) was as follows: PCT, 0.682 (0.589‐0.765); CRP, 0.583 (0.487‐0.673); ESR, 0.540 (0.515‐0.699); and WBC, 0.611 (0.455‐0.633), respectively. In multivariate analysis, age, SOFA, and PCT (log scale) predicted non‐survivors with an odds ratio with 95% confidence interval of 1.055 (1.008‐1.105), 1.303 (1.142‐1.486), and 2.004 (1.240‐3.238), respectively. Among sepsis group, initial PCT was increased in non‐survivor (23.2 ng/dL) compared to survivor group (8.1 ng/dL) with statistical significance (P = .005). CONCLUSIONS: PCT could support and predict the unfavorable prognosis of sepsis based on SEPSIS‐3, whereas diagnostic potential of PCT requires further evaluations.


title: SARS Coronavirus Detection

text: We developed a set of three real-time reverse transcription–polymerase chain reaction (PCR) assays that amplify three different regions of the SARS-associated coronavirus (SARS-CoV), can be run in parallel or in a single tube, and can detect <10 genome equivalents of SARS-CoV. The assays consider all currently available SARS-CoV sequences and are optimized for two prominent real-time PCR platforms.


title: Viral Respiratory Tract Infections in Allogeneic Hematopoietic Stem Cell Transplantation Recipients in the Era of Molecular Testing

text: Abstract Viral respiratory tract infection (vRTI) is a significant cause of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study aimed to assess the epidemiologic characteristics, risk factors, and outcomes of vRTI occurring in the period from conditioning to 100 days after allo-HSCT in the era of molecular testing. This study was a retrospective record review of patients who underwent allo-HSCT at Royal Melbourne Hospital between January 2010 and December 2015. Symptomatic patients were tested using respiratory multiplex polymerase chain reaction (PCR). Logistic regression and Kaplan-Meier analysis were used to identify risk factors for vRTI and the risk of death or intensive care unit (ICU) admission, respectively. A total of 382 patients were reviewed, and 65 episodes of vRTI were identified in 56 patients (14.7%). Rhinovirus accounted for the majority of infections (69.2%). The majority of episodes presented initially with upper respiratory tract infection (58.5%), with 28.9% of them progressing to lower respiratory tract infection. Eleven episodes (16.9%) were associated with ICU admission. There were no deaths directly due to vRTI. Previous autologous HSCT was associated with an increased risk of vRTI (odds ratio, 2.1; 95% confidence interval, 1.0 to 4.1). The risks of death (P = .47) or ICU admission (P = .65) were not significantly different by vRTI status. vRTI is common in the first 100 days after allo-HSCT and is associated with ICU admission.