title: Micro-structured copper and nickel metal foams for wastewater disinfection: proof-of-concept and scale-up

text: It is necessary to disinfect treated wastewater prior to discharge to reduce exposure risks to humans and the environment. The currently practiced wastewater disinfection technologies are challenged by toxic by-products, chemicals and energy demand, a range of effectiveness limitations, among other concerns. An effective, eco-friendly, and energy-efficient alternative disinfection technique is desirable to modernize and enhance wastewater treatment operations. Copper and nickel micro-structured metal foams, and a conventional copper mesh, were evaluated as disinfecting surfaces for treating secondary-treated wastewater contaminated with coliform bacteria. The micro-structured copper foam was adopted for scale-up study, due to its stable and satisfactory bactericidal performance obtained over a wide range of bacterial concentrations and metal-to-liquid ratios. Three scales of experiments, using two types of reactor designs, were performed using municipal wastewater to determine the optimal scale-up factors: small lab-scale batch reactor, intermediate lab-scale batch reactor, and pilot-scale continuous tubular reactor experiments. The performance was evaluated with the aim of minimizing metal material requirement with respect to bactericidal efficiency and leaching risks at all scales. Copper foam, at or above optimal conditions, consistently inactivated over 95% of total coliforms, fecal coliforms and E.coli in wastewater at various scales, and leachate copper concentrations were determined to be below Canadian guideline values for outfall. This study successfully implemented the “structure” strategy of process intensification, and opens up the possibility to apply micro-structured copper foam in a range of other water disinfection systems, from pre-treatment to point-of-use, and should thus become a topic of further research.


title: Convalescent Plasma Therapy: A Passive Therapy for An Aggressive COVID‐19

text: As of May 19, 2020, there are in total 4,986,200 laboratory‐confirmed Coronavirus disease‐2019 (COVID‐19) cases. 2% (45,425) out of 2,657,390 active COVID‐19 cases are critically ill and might be requiring intensive care support.(1,2) Unfortunately, even after six months since its first detection, we still do not have any definitive treatment options for COVID‐19 pneumonia. This article is protected by copyright. All rights reserved.


title: It is currently unknown whether SARS‐CoV‐2 is viable in semen or whether COVID‐19 damages spermatozoa

text: Research is needed to understand the presence of the SARS‐CoV‐2 virus in semen, sexual transmissibility, and impact on sperm quality. Several studies have examined men recovering from COVID‐19, but large‐scale community‐based testing is needed to ascertain the effects on the male reproductive tract, and the potential for prolonged transmission.


title: Proper Use of Surgical N95 Respirators and Surgical Masks in the OR

text: Abstract Proper adherence to infection control precautions, including appropriate selection and use of personal protective equipment (PPE), is of significant importance to the health and well-being of perioperative personnel. Surgical masks are intended for use as a barrier to protect the wearer’s face from large droplets and splashes of blood and other body fluids; however, surgical and high-filtration surgical laser masks do not provide enough protection to be considered respiratory PPE. Potential exposure to airborne contaminants and infectious agents, including those present in surgical smoke, necessitates the use of respiratory PPE, such as a surgical N95 particulate filtering facepiece respirator. Filtering facepiece respirators greatly reduce a wide size range of particles from entering the wearer’s breathing zone and are designed to protect the user from both droplet and airborne particles. Every health care worker who must use a respirator to control hazardous exposures in the workplace must be trained to properly use the respirator and pass a fit test before using it in the workplace.


title: Soluble pattern recognition molecules: Guardians and regulators of homeostasis at airway mucosal surfaces

text: Maintenance of homeostasis at body barriers that are constantly challenged by microbes, toxins and potentially bioactive (macro)molecules requires complex, highly orchestrated mechanisms of protection. Recent discoveries in respiratory research have shed light on the unprecedented role of airway epithelial cells (AEC), which, besides immune cells homing to the lung, also significantly contribute to host defence by expressing membrane‐bound and soluble pattern recognition receptors (sPRR). Recent evidence suggests that distinct, evolutionary ancient, sPRR secreted by AEC might become activated by usually innocuous proteins, commonly referred to as allergens. We here provide a systematic overview on sPRR detectable in the mucus lining of AEC. Some of them become actively produced and secreted by AECs (like the pentraxins C‐reactive protein and pentraxin 3; the collectins mannose binding protein and surfactant proteins A and D; H‐ficolin; serum amyloid A; and the complement components C3 and C5). Others are elaborated by innate and adaptive immune cells such as monocytes/macrophages and T cells (like the pentraxins C‐reactive protein and pentraxin 3; L‐ficolin; serum amyloid A; and the complement components C3 and C5). Herein we discuss how sPRRs may contribute to homeostasis but sometimes also to overt disease (e.g. airway hyperreactivity and asthma) at the alveolar–air interface.


title: Ongoing Challenges with Healthcare-Associated Candida auris Outbreaks in Oman

text: Candida auris has emerged in the past decade as a multi-drug resistant public health threat causing health care outbreaks. Here we report epidemiological, clinical, and microbiological investigations of a C. auris outbreak in a regional Omani hospital between April 2018 and April 2019. The outbreak started in the intensive care areas (intensive care unit (ICU), coronary care unit (CCU), and high dependency unit) but cases were subsequently diagnosed in other medical and surgical units. In addition to the patients’ clinical and screening samples, environmental swabs from high touch areas and from the hands of 35 staff were collected. All the positive samples from patients and environmental screening were confirmed using MALDI-TOF, and additional ITS-rDNA sequencing was done for ten clinical and two environmental isolates. There were 32 patients positive for C. auris of which 14 (43.8%) had urinary tract infection, 11 (34.4%) had candidemia, and 7 (21.8%) had asymptomatic skin colonization. The median age was 64 years (14–88) with 17 (53.1%) male and 15 (46.9%) female patients. Prior to diagnosis, 21 (65.6%) had been admitted to the intensive care unit, and 11 (34.4%) had been nursed in medical or surgical wards. The crude mortality rate in our patient’s cohort was 53.1. Two swabs collected from a ventilator in two different beds in the ICU were positive for C. auris. None of the health care worker samples were positive. Molecular typing showed that clinical and environmental isolates were genetically similar and all belonged to the South Asian C. auris clade I. Most isolates had non-susceptible fluconazole (100%) and amphotericin B (33%) minimal inhibitory concentrations (MICs), but had low echinocandin and voriconazole MICs. Despite multimodal infection prevention and control measures, new cases continued to appear, challenging all the containment efforts.


title: Norovirus Infection in Harbor Porpoises

text: A norovirus was detected in harbor porpoises, a previously unknown host for norovirus. This norovirus had low similarity to any known norovirus. Viral RNA was detected primarily in intestinal tissue, and specific serum antibodies were detected in 8 (24%) of 34 harbor porpoises from the North Sea.


In COVID-19 Response to Congress & Administration, AGS Calls for Access to Medical Supplies, Telehealth, Among Other Needs


title: Biopotency Assays: an Integrated Application to Quality Control of Chinese Materia Medica

text: Abstract The current quality control (QC) pattern for Chinese materia medica (CMM) lacks suitable methods and indicators to evaluate their safety and efficacy effectively, which impedes the smooth development of CMM. In this review, main problems of the current QC pattern for CMM, principally focused on the content determination of constituents, were summarized and the inspiration from the QC of biological products was introduced. With the aim at introducing a suitable tool to the QC of CMM, biopotency assay and its feasibility in the QC pattern for CMM were analyzed and confirmed by relevant researches with years of practice. From the applications of biopotency assays in the QC of CMM in the last 10 years, we propose that biopotency assays should be an integral part of the QC pattern for CMM, for these assays can make the QC indicators related to the clinical safety and efficacy, supplementing the existed QC system of CMM.


Reduced prescription tacrolimus use: A cross-sectional analysis of England’s national prescription statistics during COVID-19 pandemic by region.


title: The economic cost of coronavirus lockdowns

text: ▪ Widespread lockdowns and social distancing in economies affected by the coronavirus outbreak are set to cause a massive negative short‐term impact on consumer spending and GDP. ▪ A large chunk of consumer spending is discretionary and so is very sensitive to being postponed or lost completely due to quarantines and social distancing. ▪ The early evidence from China supports the idea that up‐front effects will be large, with retail sales down 20% y/y in January–February and industrial output over 13% lower, thanks to widespread factory closures. ▪ We estimate that a three‐week lockdown affecting 50%–90% of a population would cut consumption in the three–month period featuring such a lockdown by 5%–8%, a six‐week lockdown by 9%–16%, and a 12‐week lockdown would slash it by 18%–32%. ▪ Full‐year effects depend on how quickly postponed consumption revives as outbreaks come under control. But even quick recoveries imply big full‐year losses: An initial 18% slump in consumption would still imply a full‐year loss of 9%, even if spending recovered to pre‐pandemic levels in four quarters. If recovery took eight quarters, the full‐year loss would be an enormous 14%.


title: Reactive oxygen species as an initiator of toxic innate immune responses in retort to SARS-CoV-2 in an ageing population, consider N-acetylcysteine as early therapeutic intervention

text: During the current COVID-19 pandemic, a need for evaluation of already available drugs for treatment of the disease is crucial. Hereby, based on literature review from the current pandemic and previous outbreaks with corona viruses we analyze the impact of the virus infection on cell stress responses and redox balance. High levels of mortality are noticed in elderly individuals infected with SARS-CoV2 and during the previous SARS-CoV1 outbreak. Elderly individuals maintain a chronic low level of inflammation which is associated with oxidative stress and inflammatory cytokine production, a condition that increases the severity of viral infections in this population. SARS-CoV2 infection can lead to alterations of redox balance in infected cells through modulation of NAD + biosynthesis, PARP function along with altering proteasome and mitochondrial function in the cell thereby leading to enhanced cell stress responses which further exacerbate inflammation. ROS production can increase IL-6 production and lipid peroxidation resulting in cell damage. Therefore, early treatment with anti-oxidants such as NAC during COVID-19 can be a way to bypass the excessive inflammation and cell damage that lead to severe infection.


title: Modelling microbial infection to address global health challenges

text: The continued growth of the world’s population and increased interconnectivity heighten the risk that infectious diseases pose for human health worldwide. Epidemiological modelling is a tool that can be used to mitigate this risk by predicting disease spread or quantifying the impact of different intervention strategies on disease transmission dynamics. We illustrate how four decades of methodological advances and improved data quality have facilitated the contribution of modelling to address global health challenges, exemplified by models for the HIV crisis, emerging pathogens and pandemic preparedness. Throughout, we discuss the importance of designing a model that is appropriate to the research question and the available data. We highlight pitfalls that can arise in model development, validation and interpretation. Close collaboration between empiricists and modellers continues to improve the accuracy of predictions and the optimization of models for public health decision-making.


title: Roles of TNF-α gene polymorphisms in the occurrence and progress of SARS-Cov infection: A case-control study

text: BACKGROUND: Host genetic factors may play a role in the occurrence and progress of SARS-Cov infection. This study was to investigate the relationship between tumor necrosis factor (TNF)-α gene polymorphisms with the occurrence of SARS-CoV infection and its role in prognosis of patients with lung interstitial fibrosis and femoral head osteonecrosis. METHODS: The association between genetic polymorphisms of TNF-α gene and susceptibility to severe acute respiratory syndromes (SARS) was conducted in a hospital-based case-control study including 75 SARS patients, 41 health care workers and 92 healthy controls. Relationships of TNF-α gene polymorphisms with interstitial lung fibrosis and femoral head osteonecrosis were carried out in two case-case studies in discharged SARS patients. PCR sequencing based typing (PCR-SBT) method was used to determine the polymorphisms of TNF-α gene in locus of the promoter region and univariate logistic analysis was conducted in analyzing the collected data. RESULTS: Compared to TT genotype, the CT genotype at the -204 locus was found associated with a protective effect on SARS with OR(95%CI) of 0.95(0.90–0.99). Also, TT genotype, CT and CC were found associated with a risk effect on femoral head necrosis with ORs(95%CI) of 5.33(1.39–20.45) and 5.67(2.74–11.71), respectively and the glucocorticoid adjusted OR of CT was 5.25(95%CI 1.18–23.46) and the combined (CT and CC) genotype OR was 6.0 (95%CI 1.60–22.55) at -1031 site of TNF-α gene. At the same time, the -863 AC genotype was manifested as another risk effect associated with femoral head necrosis with OR(95%CI) of 6.42(1.53–26.88) and the adjusted OR was 8.40(95%CI 1.76–40.02) in cured SARS patients compared to CC genotype. CONCLUSION: SNPs of TNF-α gene of promoter region may not associate with SARS-CoV infection. And these SNPs may not affect interstitial lung fibrosis in cured SARS patients. However, the -1031CT/CC and -863 AC genotypes may be risk factors of femoral head necrosis in discharged SARS patients.


title: Effects of neighborhood building density, height, greenspace, and cleanliness on indoor environment and health of building occupants

text: Abstract The influences of indoor environment quality on occupant health have long been one of the main focuses in built environment and public health research. However, evidence to this effect has been inconsistent. Furthermore, previous urban studies have indicated the interaction between urban morphology and indoor environment. This study thus goes beyond indoor environment to investigate: i) the effects of neighborhood environment on occupant health; and ii) the mediating roles of indoor environment on the neighborhood environment and occupant health relationships. To achieve this aim, buildings located in different neighborhood environment in Hong Kong are selected. Data are collected by post-occupancy evaluation (occupant health), indoor environment assessment (thermal comfort, indoor air quality, ventilation, visual comfort, and acoustic comfort) and neighborhood environment assessment (neighborhood building density, building height, cleanliness and greenspace) through questionnaire survey. Through correlation analysis, regression modelling and Sobel test, it is found that: i) occupant health is significantly affected by neighborhood building height, building density and cleanliness; ii) the relationships between neighborhood environment and occupant health are significantly mediated by indoor environment, in terms of visual and acoustic comfort; and iii) neighborhood greenspace affects occupant health indirectly through influencing indoor air quality. To cross validate the results of the survey study, which is conducted using subjective data, objective measurements and analyses are further conducted. The objective study, echoing the survey study results, indicates that buildings with lower neighborhood building density and height, and cleaner neighborhood environment have better visual (higher illuminance level) and acoustic (lower noise level) performances.


title: Acute Illness in the Athlete

text: Athletes are susceptible to many acute illnesses that can interfere with their ability to train and compete as well as potentially affecting teammates and coaching staff. A solid understanding of the preventive measures, diagnosis, and management of such diseases is paramount in the care of an athletic population.


title: Comparative analysis on the 5′-untranslated region of bovine viral diarrhea virus isolated in Korea

text: Abstract Samples of 249 bovine abortuses, one intestine, and four diarrheal stools from 254 cows were collected, and bovine viral diarrhea virus (BVDV) was detected by reverse transcription-polymerase chain reaction (RT-PCR). Subsequently, virus isolation was preformed with PCR-positive samples, and then PCR product of 5′-untranslated region (UTR) of BVDV isolate was sequenced and analyzed. Among the samples collected, 20 (from 17 bovine abortuses, one intestine, and two diarrheal stools) were positive for BVDV RT-PCR; four BVDVs (from two bovine abortuses, one intestine, and one diarrheal stool) were isolated. When the four isolates were biotyped in cell culture, one BVDV isolate from a bovine abortus was cytopathic and the others were non-cytopathic. In addition, three isolates were genotyped as BVDV-1 and one isolate from a diarrheal stool as BVDV-2. In phylogenetic analysis, it suggested that the BVDV-2 isolate in Korea is closer to the North American strains than Asian strains. This is the first report on the identification and isolation of BVDV-2 in Korea.


Abstracts for ISVEE IX


docid: nwdgphxa

title: Identification of anti-viral activity of the cardenolides, Na+/K+-ATPase inhibitors, against porcine transmissible gastroenteritis virus

text: Abstract A series of naturally occurring cardenolides that exhibit potent anti-transmissible gastroenteritis virus (TGEV) activity in swine testicular (ST) cells has been identified. In an immunofluorescence assay, these cardenolides were found to diminish the expressions of TGEV nucleocapsid and spike protein, which was used as an indication for viral replication; block TGEV infection induced apoptosis and cytopathic effects; and impart the same trend of inhibitory activity against Na+/K+-ATPase as for anti-TGEV activity. The viral titer inhibition was found to take place in a dose-dependent manner. Knocking down expression of Na+/K+-ATPase, the cellular receptor of cardenolides, in ST cells was found to significantly impair the susceptibility of ST cells to TGEV infectivity. Thus, we have identified Na+/K+-ATPase as an anti-viral drug target and its antagonists, cardenolides, a novel class of anti- TGEV agents.


title: The Future of Research and Publication on Altered H5N1 Viruses

text: Recently, we and others obtained experimental evidence that highly pathogenic avian influenza virus subtype H5 can acquire the ability to transmit via aerosols between ferrets. Upon submission of manuscripts describing the results of these studies, the US National Science Advisory Board for Biosecurity was consulted and recommended that the main conclusions of the work be published but without the experimental details and mutation data that would enable replication of the experiments. Over the past few months, these events have led to intense discussions. Should this type of experiment be conducted? If so, under what conditions? Do the scientific and public health benefits of the work and its publication outweigh the potential risks? In February 2012, public health and influenza experts discussed these issues during a World Health Organization–organized technical consultation. This perspective article reviews the current state of the field and the recommendations made during the meeting.


title: Aberrant coagulation causes a hyper-inflammatory response in severe influenza pneumonia

text: Influenza A virus (IAV) infects the respiratory tract in humans and causes significant morbidity and mortality worldwide each year. Aggressive inflammation, known as a cytokine storm, is thought to cause most of the damage in the lungs during IAV infection. Dysfunctional coagulation is a common complication in pathogenic influenza, manifested by lung endothelial activation, vascular leak, disseminated intravascular coagulation and pulmonary microembolism. Importantly, emerging evidence shows that an uncontrolled coagulation system, including both the cellular (endothelial cells and platelets) and protein (coagulation factors, anticoagulants and fibrinolysis proteases) components, contributes to the pathogenesis of influenza by augmenting viral replication and immune pathogenesis. In this review, we focus on the underlying mechanisms of the dysfunctional coagulatory response in the pathogenesis of IAV.


title: Conjunctivitis and COVID‐19: A meta‐analysis

text: There are sparse data in literature regarding conjunctivitis incidence in COVID-19 and its relationship with disease severity. The objective of this metanalysis was to assess the association between conjunctivitis and the severity of COVID-19 disease. METHODS We performed a meta-analysis with studies that included patients with severe vs non-severe form of COVID-19 infection. Severe COVID-19 infection was defined as severe pneumonia, mortality, acute respiratory distress syndrome (ARDS), use of mechanical ventilation or Intensive Care Unit (ICU) treatment. RESULTS Three studies, including 1167 patients, reported the incidence of conjunctivitis at admission to the hospital. The overall rate of conjunctivitis was 1.1%; it was 3% and 0.7% in severe and non-severe COVID-19 patients, respectively. Patients with severe COVID-19 had an increased incidence of conjunctivitis (O.R.:3.4; 95% C.I.:1.1-10.2; p=0.030). CONCLUSIONS Conjunctivitis is more frequent in severe COVID and may be a warning sign of poor outcomes. This article is protected by copyright. All rights reserved.


title: De novo assembly of highly polymorphic metagenomic data using in situ generated reference sequences and a novel BLAST-based assembly pipeline

text: BACKGROUND: The accuracy of metagenomic assembly is usually compromised by high levels of polymorphism due to divergent reads from the same genomic region recognized as different loci when sequenced and assembled together. A viral quasispecies is a group of abundant and diversified genetically related viruses found in a single carrier. Current mainstream assembly methods, such as Velvet and SOAPdenovo, were not originally intended for the assembly of such metagenomics data, and therefore demands for new methods to provide accurate and informative assembly results for metagenomic data. RESULTS: In this study, we present a hybrid method for assembling highly polymorphic data combining the partial de novo-reference assembly (PDR) strategy and the BLAST-based assembly pipeline (BBAP). The PDR strategy generates in situ reference sequences through de novo assembly of a randomly extracted partial data set which is subsequently used for the reference assembly for the full data set. BBAP employs a greedy algorithm to assemble polymorphic reads. We used 12 hepatitis B virus quasispecies NGS data sets from a previous study to assess and compare the performance of both PDR and BBAP. Analyses suggest the high polymorphism of a full metagenomic data set leads to fragmentized de novo assembly results, whereas the biased or limited representation of external reference sequences included fewer reads into the assembly with lower assembly accuracy and variation sensitivity. In comparison, the PDR generated in situ reference sequence incorporated more reads into the final PDR assembly of the full metagenomics data set along with greater accuracy and higher variation sensitivity. BBAP assembly results also suggest higher assembly efficiency and accuracy compared to other assembly methods. Additionally, BBAP assembly recovered HBV structural variants that were not observed amongst assembly results of other methods. Together, PDR/BBAP assembly results were significantly better than other compared methods. CONCLUSIONS: Both PDR and BBAP independently increased the assembly efficiency and accuracy of highly polymorphic data, and assembly performances were further improved when used together. BBAP also provides nucleotide frequency information. Together, PDR and BBAP provide powerful tools for metagenomic data studies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12859-017-1630-z) contains supplementary material, which is available to authorized users.


title: Prevalence of Henipavirus and Rubulavirus Antibodies in Pteropid Bats, Papua New Guinea

text: To determine seroprevalence of viruses in bats in Papua New Guinea, we sampled 66 bats at 3 locations. We found a seroprevalence of 55% for henipavirus (Hendra or Nipah virus) and 56% for rubulavirus (Tioman or Menangle virus). Notably, 36% of bats surveyed contained antibodies to both types of viruses, indicating concurrent or consecutive infection.


Low risk of SARS‐CoV‐2 transmission through the ocular surface


title: Blinded Case‐Control Study of the Relationship between Human Coronavirus NL63 and Kawasaki Syndrome

text: We conducted a blinded, case‐control, retrospective study in pediatric patients hospitalized at The Children’s Hospital, Denver, Colorado, to determine whether human coronavirus (HCoV)–NL63 infection is associated with Kawasaki syndrome (KS). Over the course of a 7‐month period, nasopharyngeal‐wash samples from 2 (7.7%) of 26 consecutive children with KS and 4 (7.7%) of 52 matched control subjects tested positive for HCoV‐NL63 by reverse transcription–polymerase chain reaction. These data suggest that, although HCoV‐NL63 was circulating in children in our community during the time of the study, the prevalence of infection with HCoV‐NL63 was not greater in patients with KS than in control subjects.


title: First-calving age and first-lactation milk production on Dutch dairy farms

text: Abstract Farmers attempting to reduce first-calving age (FCA) need to understand which rearing management factors influence FCA and first-lactation milk production (FLP). Reduced FCA might be associated with lower FLP. This study describes the association between herd FCA, FLP, and several herd-level health and rearing management variables and describes the association between FCA and FLP at the cow level. It uses data from a 2010 survey of 100 Dutch dairy farms about general management, colostrum and milk feeding, housing, cleanliness, healthcare, disease, and breeding. It also used available data on FCA and 305-d FLP at both cow and herd level. The associations between median FCA and median FLP of the herd and herd-level health and rearing management variables were determined using multivariate regression analysis. The median FCA was associated with minimum age of first insemination, feeding of waste milk, and the amount of milk given preweaning. The median FLP was associated with median FCA and vaccination status for bovine respiratory syncytial virus. The association between FCA and FLP (based on 8,454 heifers) was analyzed with a single-effect linear mixed model, where the dependent variable was either FCA or relative FCA (defined as the difference between FCA of the heifer and median FCA of the herd to which they belonged). Heifers having an FCA of 24mo produced, on average, 7,164kg of milk per 305d, and calving 1mo earlier gave 143kg less milk per 305d. When FCA did not deviate from the median herd FCA, heifers produced, on average, 7,272kg of milk per 305d. From the median FCA of the herd, heifers calving 1mo earlier produced 90kg of milk per 305d less, and heifers calving 1mo later produced 86kg per 305d more. This is the first study that explained FLP using relative FCA. It assumes that heifers raised within the same farm have similar development because they are similarly managed. Similar management is reflected by the median FCA of the herd, with a deviation of the heifer’s FCA from median FCA reflecting the heifer’s development relative to the herd’s average. The advantage of using relative FCA was that it accounts for between-farm differences in rearing management. It showed that earlier insemination without adjusting management to ensure sufficient development lowers FLP. An economic optimum exists between rearing costs, FCA, and FLP and, as a consequence, decisions with regard to young stock management should be made with care.


title: Similar recombination-activating gene (RAG) mutations result in similar immunobiological effects but in different clinical phenotypes

text: Background V(D)J recombination takes place during lymphocyte development to generate a large repertoire of T- and B-cell receptors. Mutations in recombination-activating gene 1 (RAG1) and RAG2 result in loss or reduction of V(D)J recombination. It is known that different mutations in RAG genes vary in residual recombinase activity and give rise to a broad spectrum of clinical phenotypes. Objective We sought to study the immunologic mechanisms causing the clinical spectrum of RAG deficiency. Methods We included 22 patients with similar RAG1 mutations (c.519delT or c.368_369delAA) resulting in N-terminal truncated RAG1 protein with residual recombination activity but presenting with different clinical phenotypes. We studied precursor B-cell development, immunoglobulin and T-cell receptor repertoire formation, receptor editing, and B- and T-cell numbers. Results Clinically, patients were divided into 3 main categories: T−B− severe combined immunodeficiency, Omenn syndrome, and combined immunodeficiency. All patients showed a block in the precursor B-cell development, low B- and T-cell numbers, normal immunoglobulin gene use, limited B- and T-cell repertoires, and slightly impaired receptor editing. Conclusion This study demonstrates that similar RAG mutations can result in similar immunobiological effects but different clinical phenotypes, indicating that the level of residual recombinase activity is not the only determinant for clinical outcome. We postulate a model in which the type and moment of antigenic pressure affect the clinical phenotypes of these patients.


title: Membrane alterations induced by nonstructural proteins of human norovirus

text: Human noroviruses (huNoV) are the most frequent cause of non-bacterial acute gastroenteritis worldwide, particularly genogroup II genotype 4 (GII.4) variants. The viral nonstructural (NS) proteins encoded by the ORF1 polyprotein induce vesical clusters harboring the viral replication sites. Little is known so far about the ultrastructure of these replication organelles or the contribution of individual NS proteins to their biogenesis. We compared the ultrastructural changes induced by expression of norovirus ORF1 polyproteins with those induced upon infection with murine norovirus (MNV). Characteristic membrane alterations induced by ORF1 expression resembled those found in MNV infected cells, consisting of vesicle accumulations likely built from the endoplasmic reticulum (ER) which included single membrane vesicles (SMVs), double membrane vesicles (DMVs) and multi membrane vesicles (MMVs). In-depth analysis using electron tomography suggested that MMVs originate through the enwrapping of SMVs with tubular structures similar to mechanisms reported for picornaviruses. Expression of GII.4 NS1-2, NS3 and NS4 fused to GFP revealed distinct membrane alterations when analyzed by correlative light and electron microscopy. Expression of NS1-2 induced proliferation of smooth ER membranes forming long tubular structures that were affected by mutations in the active center of the putative NS1-2 hydrolase domain. NS3 was associated with ER membranes around lipid droplets (LDs) and induced the formation of convoluted membranes, which were even more pronounced in case of NS4. Interestingly, NS4 was the only GII.4 protein capable of inducing SMV and DMV formation when expressed individually. Our work provides the first ultrastructural analysis of norovirus GII.4 induced vesicle clusters and suggests that their morphology and biogenesis is most similar to picornaviruses. We further identified NS4 as a key factor in the formation of membrane alterations of huNoV and provide models of the putative membrane topologies of NS1-2, NS3 and NS4 to guide future studies.


docid: qpmeyqwf

title: Controlling infectious disease outbreaks: Lessons from mathematical modelling

text: Epidemiological analysis and mathematical models are now essential tools in understanding the dynamics of infectious diseases and in designing public health strategies to contain them. They have provided fundamental concepts, such as the basic and effective reproduction number, generation times, epidemic growth rates, and the role of pre-symptomatic infectiousness, which are crucial in characterising infectious diseases. These concepts are outlined and their relevance in designing control policies for outbreaks is discussed. They are illustrated using examples from the 2003 severe acute respiratory syndrome outbreak, which was brought under control within a year, and from pandemic influenza planning, where mathematical models have been used extensively.


title: Avian influenza A (H5N1)

text: Abstract Since their reemergence in 2003, highly pathogenic avian influenza A (H5N1) viruses have reached endemic levels among poultry in several southeast Asian countries and have caused a still increasing number of more than 100 reported human infections with high mortality. These developments have ignited global fears of an imminent influenza pandemic. The current knowledge of the virology, clinical spectrum, diagnosis and treatment of human influenza H5N1 virus infections is reviewed herein.


title: One health—Transdisciplinary opportunities for SETAC leadership in integrating and improving the health of people, animals, and the environment

text: One Health is a collaborative, transdisciplinary effort working locally, nationally, and globally to improve health for people, animals, plants, and the environment. The term is relatively new (from ∼2003), and it is increasingly common to see One Health included by name in interinstitutional research partnerships, conferences, communications, and organizational frameworks, particularly those championed by the human health and veterinary medical communities. Environmental quality is arguably the least developed component within the One Health framework, but can be guided by expertise within the Society of Environmental Toxicology and Chemistry (SETAC). Despite SETAC's long history of tripartite (academic, government, business) interdisciplinary environmental science activities, the term “One Health” is seldom used in SETAC communications (i.e., many of SETAC's activities are guided by One Health, but it is called by other names in SETAC's journals, newsletters, and presentations). Accordingly, the objective of this Focus article is to introduce the One Health concept to the SETAC membership. The article discusses the origins, evolution, and utility of the One Health approach as an organizational framework and provides key examples of ways in which SETAC expertise can benefit the One Health community. The authors assert that One Health needs SETAC and, to be most effective, SETAC needs One Health. Given that One Health to date has focused too little on the environment, on ecosystems, and on contaminants, SETAC's constructive involvement in One Health presents an opportunity to accelerate actions that will ultimately better protect human and ecosystem health. Environ Toxicol Chem 2016;35:2383–2391. © 2016 SETAC


docid: gvdrffyy

title: Latent growth curves and predictors of depressive symptoms among Chinese adolescent earthquake survivors

text: Abstract The objective of this longitudinal study was to identify growth curves and related predictors of depressive symptoms among Chinese adolescent earthquake survivors. A total of 1573 adolescent survivors of the 8-magnitude Wenchuan earthquake were assessed through the Depression Self-Rating Scale for Children (cutoff for probable clinical depression: 15), Social Support Rate Scale, Adolescent Self-Rating Life Events Checklist, and a self-designed questionnaire covering earthquake exposure and demographic information at 6-, 12-, 18-, 24- and 30-months after the earthquake. Data were analyzed using growth mixture modeling (GMM) and multinomial logistic regression. The prevalence rates of depressive symptoms were 27.6%, 40.6%, 30.9%, 37.5% and 29.8% at 6-, 12-, 18-, 24- and 30-months, respectively. GMM analysis showed four patterns of growth curves for depressive symptoms: chronic depression (25.6% of the sample), recovery (1.7%), delayed depression (4.3%), and resilience (68.4%). Female gender was related with decreased probability of resilience. Direct witness of tragic scenes during the earthquake was related with higher risk for chronic depression. More negative life events and fewer social support were also common predictors of not developing the resilience pattern. The need of providing appropriate individualized interventions for high-risk adolescent earthquake survivors is indicated.


title: Dynamic Regulation of SARS-CoV-2 Binding and Cell Entry Mechanisms in Remodeled Human Ventricular Myocardium

text: SUMMARY Using serial analysis of myocardial gene expression employing endomyocardial biopsy starting material in a dilated cardiomyopathy cohort, we show that the SARS-CoV-2 cardiac myocyte receptor ACE2 is upregulated with remodeling and with reverse remodeling down-regulates into the normal range. The proteases responsible for virus-cell membrane fusion were expressed but not regulated with remodeling. In addition, a new candidate for CoV-2 cell binding and entry was identified, the integrin ITGA5. The upregulation in ACE2 in remodeled LVs may explain worse outcomes in COVID-19 patients with underlying myocardial disorders, and counteracting ACE2 upregulation is a possible therapeutic approach to minimizing cardiac damage.


title: Carbohydrate-induced conformational changes strongly modulate the antigenicity of coronavirus TGEV glycoproteins S and M

text: Abstract The carbohydrate composition and the immunoreactivity of the S and M glycoproteins of the coronavirus TGEV were studied at different stages of their maturation. The biosynthesis of S and M was analyzed in the presence of tunicamycin and monensin. The effect of treatment with endoglycosidases H and F and glycopeptidase F on the precursors and mature forms of S and M were also examined. Species 175K and 29K were characterized as high mannose forms of S and M, respectively, and species 220K and 30–36K as complex type glycosylated forms of these two proteins. M was present mainly as a 29K species in mature virions whereas the 175K form of S was not detected, thus implying that the two proteins undergo Golgi modifications at a far different efficiency. Anti-S and -M monoclonal antibodies were examined for their reactivity towards polypeptide species either treated with endo H or produced in the presence of tunicamycin. It was found that (i) among the four major antigenic sites previously defined (Delmas et al., 1986), only site C (amino acids 363 to 371) was notably expressed by the unglycosylated S polypeptide 155K, whereas the three other sites were dependent upon core-glycosylation, (ii) three of the four anti-M mAbs tested did not recognize the unglycosylated M polypeptide 26K. These data led us to conclude that co-translational, but not terminal glycosylation is an essential requirement for both acquisition and maintenance of the antigenicity of TGEV glycoproteins.


docid: thtsulcy

title: A mixed integer linear programming model to reconstruct phylogenies from single nucleotide polymorphism haplotypes under the maximum parsimony criterion

text: BACKGROUND: Phylogeny estimation from aligned haplotype sequences has attracted more and more attention in the recent years due to its importance in analysis of many fine-scale genetic data. Its application fields range from medical research, to drug discovery, to epidemiology, to population dynamics. The literature on molecular phylogenetics proposes a number of criteria for selecting a phylogeny from among plausible alternatives. Usually, such criteria can be expressed by means of objective functions, and the phylogenies that optimize them are referred to as optimal. One of the most important estimation criteria is the parsimony which states that the optimal phylogeny T(∗)for a set [Formula: see text] of n haplotype sequences over a common set of variable loci is the one that satisfies the following requirements: (i) it has the shortest length and (ii) it is such that, for each pair of distinct haplotypes [Formula: see text] , the sum of the edge weights belonging to the path from h(i) to h(j) in T(∗) is not smaller than the observed number of changes between h(i) and h(j). Finding the most parsimonious phylogeny for [Formula: see text] involves solving an optimization problem, called the Most Parsimonious Phylogeny Estimation Problem (MPPEP), which is [Formula: see text]-hard in many of its versions. RESULTS: In this article we investigate a recent version of the MPPEP that arises when input data consist of single nucleotide polymorphism haplotypes extracted from a population of individuals on a common genomic region. Specifically, we explore the prospects for improving on the implicit enumeration strategy of implicit enumeration strategy used in previous work using a novel problem formulation and a series of strengthening valid inequalities and preliminary symmetry breaking constraints to more precisely bound the solution space and accelerate implicit enumeration of possible optimal phylogenies. We present the basic formulation and then introduce a series of provable valid constraints to reduce the solution space. We then prove that these constraints can often lead to significant reductions in the gap between the optimal solution and its non-integral linear programming bound relative to the prior art as well as often substantially faster processing of moderately hard problem instances. CONCLUSION: We provide an indication of the conditions under which such an optimal enumeration approach is likely to be feasible, suggesting that these strategies are usable for relatively large numbers of taxa, although with stricter limits on numbers of variable sites. The work thus provides methodology suitable for provably optimal solution of some harder instances that resist all prior approaches.


title: Public knowledge, attitudes and practices towards COVID-19: A cross-sectional study in Malaysia

text: In an effort to mitigate the outbreak of COVID-19, many countries have imposed drastic lockdown, movement control or shelter in place orders on their residents. The effectiveness of these mitigation measures is highly dependent on cooperation and compliance of all members of society. The knowledge, attitudes and practices people hold toward the disease play an integral role in determining a society’s readiness to accept behavioural change measures from health authorities. The aim of this study was to determine the knowledge levels, attitudes and practices toward COVID-19 among the Malaysian public. A cross-sectional online survey of 4,850 Malaysian residents was conducted between 27(th) March and 3(rd) April 2020. The survey instrument consisted of demographic characteristics, 13 items on knowledge, 3 items on attitudes and 3 items on practices, modified from a previously published questionnaire on COVID-19. Descriptive statistics, chi-square tests, t-tests and one-way analysis of variance (ANOVA) were conducted. The overall correct rate of the knowledge questionnaire was 80.5%. Most participants held positive attitudes toward the successful control of COVID-19 (83.1%), the ability of Malaysia to conquer the disease (95.9%) and the way the Malaysian government was handling the crisis (89.9%). Most participants were also taking precautions such as avoiding crowds (83.4%) and practising proper hand hygiene (87.8%) in the week before the movement control order started. However, the wearing of face masks was less common (51.2%). This survey is among the first to assess knowledge, attitudes and practice in response to the COVID-19 pandemic in Malaysia. The results highlight the importance of consistent messaging from health authorities and the government as well as the need for tailored health education programs to improve levels of knowledge, attitudes and practices.


title: Engineering H5N1 avian influenza viruses to study human adaptation

text: Two studies of H5N1 avian influenza viruses that had been genetically engineered to render them transmissible between ferrets have proved highly controversial. Divergent opinions exist about the importance of these studies of influenza transmission and about potential ‘dual use’ research implications. No consensus has developed yet about how to balance these concerns. After not recommending immediate full publication of earlier, less complete versions of the studies, the United States National Science Advisory Board for Biosecurity subsequently recommended full publication of more complete manuscripts; however, controversy about this and similar research remains.


title: Foot and mouth disease virus undergoes non-progressive replication in mice peritoneal macrophages and induces M1 polarization

text: Abstract Despite the fact that macrophages link the innate and adaptive arms of immunity, it’s role in the early infection of foot and mouth disease virus (FMDV) is largely unknown. Recently, depletion of macrophages in vivo after vaccination has shown to drastically diminish the protection against FMDV challenge in mouse model. Even the ability of macrophages to reduce or resist FMDV infection is not known hitherto. Therefore, we examined the replication ability of FMDV in mice peritoneal macrophages and the responsiveness in terms of macrophage polarization and cytokine production. Negative strand specific RT-PCR indicated replication of FMDV RNA in macrophages. Absolute quantitation of FMDV transcripts, immunofluorescence studies and titre of the infectious progeny virus revealed that replication peaked at 12 hpi and significantly declined by 18 hpi indicating non-progressive replication in the infected macrophages. Further, significant up regulation of inducible nitric oxide synthase by 8 –12 hpi and increase of M1 specific CD11c + cells by 42.6 % after infection showed that FMDV induce M1 polarization. A significant up regulation of TNFα and IL12 transcripts at 8 hpi supported that M1 macrophages were functional. Further, we studied the expression of Type I to III interferons (IFN) and other antiviral molecules. The results indicate a marked up regulation of Type I IFNα and β by 9.2 and 11.2 fold, respectively at 8 hpi. Of the four IFN stimulated genes (ISG), viperin showed a significant up regulation by 286-fold at 12 hpi in the mice macrophages. In conclusion, the results suggest that replication of FMDV in mice peritoneal macrophages is non-progressive with up regulation of Type I IFN and ISGs. Further, FMDV induces M1 polarization in murine peritoneal macrophages.


title: Do viruses subvert cholesterol homeostasis to induce host cubic membranes?

text: Biological membranes with cubic morphology are a hallmark of stressed or diseased cellular conditions; both protein–protein interactions and lipid alterations appear to contribute to their biogenesis, yet their specific cellular functions are unknown. The occurrence of cubic membranes strikingly correlates with viral infections; notably, virus entry, proliferation, and release are processes closely linked to cellular cholesterol metabolism, and dys-regulation of cholesterol synthesis at the level of HMG-CoA reductase also induces cubic membrane formation, in the absence of viral infection. We propose that virus-induced cubic membranes could result from viral interference of cellular cholesterol homeostasis, generating a protective membrane environment to facilitate virus assembly and proliferation. Preventing cubic membrane formation might thus disrupt the ‘virus factory’ and offer new avenues to combat viral infections.


title: Gastrointestinal Disorders of the Cat

text: Several areas of feline gastroenterology deserve critical attention in the near future. For example, as compared with the dog, little is known about the various causes of malabsorptive disease in the cat. So frequently, intestinal biopsy samples reveal nothing more than intestinal thickening with fibrosis and nonspecific mild cellular infiltration, and the inciting cause is never determined. It is, perhaps, wrong to be critical about the use of the bark of Berberis vulgaris and the root of Rheum in modern feline gastroenterology, since most of us occasionally use unconventional therapies. It has been rumored that I have been known to advocate the daily addition of a tablespoon of pumpkin-pie filling to the food of cats suffering from recurrent constipation and acquired megacolon. The rumors are true, and colonic evacuation is sometimes promoted with the use of this unusual bulking agent after traditional drug therapy has failed. We all have our weaknesses!


Resilience of the restructured obstetric anaesthesia training program during the COVID-19 outbreak in Singapore


title: The Effect of Steroid Use in Hospitalized Adults With Respiratory Syncytial Virus-Related Illness

text: RATIONALE: Systemic glucocorticosteroids (steroids) are commonly prescribed for patients with exacerbations of COPD during acute viral infections such as respiratory syncytial virus (RSV). The effects of short-term high-dose steroid treatment on viral load and adaptive immunity to RSV have not been examined in adults. OBJECTIVES: The objectives of this study were to measure peak viral load and duration of viral shedding, serum and nasal cytokines, RSV-specific antibody response, and lymphocyte subsets in patients admitted to the hospital with RSV infection and to compare patients treated with steroids to patients untreated with steroids. METHODS: Hospitalized adults who tested positive for RSV by reverse transcription-polymerase chain reaction (RT-PCR) on admission had respiratory samples collected for quantitative RT-PCR and cytokine analysis. Serum and nasal secretions were tested for RSV antibody and lymphocyte subsets were analyzed by flow cytometry at 2 days, 2 weeks, and 1 month. MAIN RESULTS: Thirty-three of 50 (66%) patients hospitalized with RSV received systemic steroids for a mean duration of 11 days. Those who received steroids more frequently wheezed and were less often febrile. There were no serious adverse events related to steroids and no significant differences in peak viral load, duration of RSV shedding, nasal cytokines, or lymphocyte subsets in patients treated with steroids and patients untreated with steroids. Antibody responses to RSV were slightly blunted in the steroid-treated group. CONCLUSIONS: Short courses of systemic steroids in patients hospitalized with RSV infection did not affect viral load or shedding. Humoral immunity may be mildly diminished, and thus potential benefits of systemic steroids must be balanced against potential risks.


title: Novel SARS-CoV-2/COVID-19: Origin, pathogenesis, genes and genetic variations, immune responses and phylogenetic analysis

text: In this review, we focused on the origins of the novel coronavirus (SARS-CoV-2), origin, pathogenesis, immune responses, genes and genetic variations, phylogenetic analyses, and potential therapeutic strategies to summarize approaches for developing broadly effective preventions and vaccines to cope COVID-19. Towards the end of 2019, SARS-CoV-2 has emerged in association with the SARS, later was named COVID-19 caused an environment of chaos worldwide and infected a massive number of lives. Since these epidemics or pandemics had spread to 210 countries and territories around the world and 2 international conveyances with 6,467,229 confirmed cases, including, 382,766 deaths, as of June 03, 2020 (https://www.worldometers.info/coronavirus/), hence the World Health Organization declared it as a global Public Health Emergency. There are no clinically approved vaccines or antiviral drugs available for either of new or old corona infections; thus, the development of effective therapeutic and preventive strategies that can be readily available to cope with these strains.


title: Severe lower respiratory tract infection in infants and toddlers from a non-affluent population: viral etiology and co-detection as risk factors

text: BACKGROUND: Lower respiratory tract infection (LRTI) is a major cause of pediatric morbidity and mortality, especially among non-affluent communities. In this study we determine the impact of respiratory viruses and how viral co-detections/infections can affect clinical LRTI severity in children in a hospital setting. METHODS: Patients younger than 3 years of age admitted to a tertiary hospital in Brazil during the months of high prevalence of respiratory viruses had samples collected from nasopharyngeal aspiration. These samples were tested for 13 different respiratory viruses through real-time PCR (rt-PCR). Patients were followed during hospitalization, and clinical data and population characteristics were collected during that period and at discharge to evaluate severity markers, especially length of hospital stay and oxygen use. Univariate regression analyses identified potential risk factors and multivariate logistic regressions were used to determine the impact of specific viral detections as well as viral co-detections in relation to clinical outcomes. RESULTS: We analyzed 260 episodes of LRTI with a viral detection rate of 85% (n = 222). Co-detection was observed in 65% of all virus-positive episodes. The most prevalent virus was Respiratory Syncytial Virus (RSV) (54%), followed by Human Metapneumovirus (hMPV) (32%) and Human Rhinovirus (HRV) (21%). In the multivariate models, infants with co-detection of HRV + RSV stayed 4.5 extra days (p = 0.004), when compared to infants without the co-detection. The same trends were observed for the outcome of days of supplemental oxygen use. CONCLUSIONS: Although RSV remains as the main cause of LRTI in infants our study indicates an increase in the length of hospital stay and oxygen use in infants with HRV detected by RT-PCR compared to those without HRV. Moreover, one can speculate that when HRV is detected simultaneously with RSV there is an additive effect that may be reflected in more severe clinical outcome. Also, our study identified a significant number of children infected by recently identified viruses, such as hMPV and Human Bocavirus (HBov), and this is a novel finding for poor communities from developing countries.


title: Nosocomial infection with SARS-Cov-2 within Departments of Digestive Surgery

text: Summary Introduction The COVID-19 pandemic imposed a drastic reduction in surgical activity in order to respond to the influx of hospital patients and to protect uninfected patients by avoiding hospitalization. However, little is known about the risk of infection during hospitalization or its consequences. The aim of this work was to report a series of patients hospitalized on digestive surgery services who developed a nosocomial infection with SARS-Cov-2 virus. Methods This is a non-interventional retrospective study carried out within three departments of digestive surgery. The clinical, biological and radiological data of the patients who developed a nosocomial infection with SARS-Cov-2 were collected from the computerized medical record. Results From March 1, 2020 to April 5, 2020, among 305 patients admitted to digestive surgery services, 15 (4.9%) developed evident nosocomial infection with SARS-Cov-2. There were nine men and six women, with a median age of 62 years (35–68 years). All patients had co-morbidities. The reasons for hospitalization were: surgical treatment of cancer (n =5), complex emergencies (n =5), treatment of complications linked to cancer or its treatment (n =3), gastroplasty (n =1), and stoma closure (n =1). The median time from admission to diagnosis of SARS-Cov-2 infection was 34 days (5–61 days). In 12 patients (80%), the diagnosis was made after a hospital stay of more than 14 days (15–63 days). At the end of the follow-up, two patients had died, seven were hospitalized with two of them on respiratory assistance, and six patients were discharged post-hospitalization. Conclusions The risk of SARS-Cov-2 infection during hospitalization or following digestive surgery is a real and potentially serious risk. Measures are necessary to minimize this risk in order to return to safe surgical activity.


title: VHL negatively regulates SARS coronavirus replication by modulating nsp16 ubiquitination and stability

text: Abstract Eukaryotic cellular and most viral RNAs carry a 5′-terminal cap structure, a 5′-5′ triphosphate linkage between the 5′ end of the RNA and a guanosine nucleotide (cap-0). SARS coronavirus (SARS-CoV) nonstructural protein nsp16 functions as a methyltransferase, to methylate mRNA cap-0 structure at the ribose 2′-O position of the first nucleotide to form cap-1 structures. However, whether there is interplay between nsp16 and host proteins was not yet clear. In this report, we identified several potential cellular nsp16-interacting proteins from a human thymus cDNA library by yeast two-hybrid screening. VHL, one of these proteins, was proven to interact with nsp16 both in vitro and in vivo. Further studies showed that VHL can inhibit SARS-CoV replication by regulating nsp16 ubiquitination and promoting its degradation. Our results have revealed the role of cellular VHL in the regulation of SARS-CoV replication.


title: The clinical value of biomarkers in respiratory complications in hematopoietic SCT

text: To determine the role of biomarkers in the clinical management of respiratory complications (RC) in hematopoietic stem cell transplantation (HSCT) recipients, we have prospectively evaluated a cohort of 175 patients followed-up for 1 year after HSCT. To avoid misinterpretation, we have excluded both unidentified respiratory infections (RI) and mixed RI. A total of 64 RC were included. Plasma levels of C-reactive protein (CRP), procalcitonin (PCT) and proadrenomedullin (proADM) were measured at diagnosis and on day 3 and 7. Different cytokines were evaluated in serum on the first day. No HSCT recipients without RC were included as a control group. Compared with RI, non-infectious RC showed a significant increase in CRP, proADM and interleukin 6 on day 0 (P=0.005; P=0.03 and P=0.04, respectively). When only RI were considered, we observed that bacterial–fungal PI showed higher levels of CRP (P=0.02), PCT (P=0.04) and proADM (P<0.01). Persistent low levels of proADM biomarkers suggest viral infection (specificity and positive predictive value 100%). Patients dying of RC had PCT and proADM levels higher than survivors (P=0.002 and P=0.03, respectively). In HSCT recipients biomarkers increase in both infectious and non-infectious RC. They may have utility in the assessment of the severity of RC and in suspecting a viral etiology. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/bmt.2016.280) contains supplementary material, which is available to authorized users.


title: Understanding Unreported Cases in the COVID-19 Epidemic Outbreak in Wuhan, China, and the Importance of Major Public Health Interventions

text: We develop a mathematical model to provide epidemic predictions for the COVID-19 epidemic in Wuhan, China. We use reported case data up to 31 January 2020 from the Chinese Center for Disease Control and Prevention and the Wuhan Municipal Health Commission to parameterize the model. From the parameterized model, we identify the number of unreported cases. We then use the model to project the epidemic forward with varying levels of public health interventions. The model predictions emphasize the importance of major public health interventions in controlling COVID-19 epidemics.


title: Screening for Antiviral Activities of Isolated Compounds from Essential Oils

text: Essential oil of star anise as well as phenylpropanoids and sesquiterpenes, for example, trans-anethole, eugenol, β-eudesmol, farnesol, β-caryophyllene and β-caryophyllene oxide, which are present in many essential oils, were examined for their antiviral activity against herpes simplex virus type 1 (HSV-1) in vitro. Antiviral activity was analyzed by plaque reduction assays and mode of antiviral action was determined by addition of the drugs to uninfected cells, to the virus prior to infection or to herpesvirus-infected cells. Star anise oil reduced viral infectivity by >99%, phenylpropanoids inhibited HSV infectivity by about 60–80% and sesquiterpenes suppressed herpes virus infection by 40–98%. Both, star anise essential oil and all isolated compounds exhibited anti-HSV-1 activity by direct inactivation of free virus particles in viral suspension assays. All tested drugs interacted in a dose-dependent manner with herpesvirus particles, thereby inactivating viral infectivity. Star anise oil, rich in trans-anethole, revealed a high selectivity index of 160 against HSV, whereas among the isolated compounds only β-caryophyllene displayed a high selectivity index of 140. The presence of β-caryophyllene in many essential oils might contribute strongly to their antiviral ability. These results indicate that phenylpropanoids and sesquiterpenes present in essential oils contribute to their antiviral activity against HSV.


title: The MiR-17-92 Gene Cluster is a Blood-based Marker for Cancer Detection in Non-small-cell Lung Cancer

text: BACKGROUND: Lung cancer is one of the most malignant cancers threatening human health. The miR-17-92 gene cluster is a highly conserved oncogene cluster encoding six miRNAs: miR-17, miR-18a, miR-19a, miR-19b-1, miR-20a and miR-92a. This study explored whether these miRNAs can be used as diagnostic markers for non-small-cell lung cancer (NSCLC). METHODS: Serum samples were collected from healthy subjects (n = 23) and NSCLC patients at various stages (n = 74). Serum RNA was extracted by the TRIzol-glycogen method, and cDNA libraries were constructed by reverse transcription. Quantitative real-time polymerase chain reaction (qRT-PCR) was utilized to detect the expression levels of the 6 miRNAs. RESULTS: The expression levels of the six miRNAs varied in different stages of NSCLC. Thus, two receiver operating characteristic (ROC) curves, i.e., normal subjects and stage I-III patients and normal subjects and stage IV patients, of each miRNA were established to determine the interval of normal ΔCt values. The two areas under the curve (AUCs) of each miRNA were investigated (miR-17: 0.8097 and 1.000; miR-18a: 0.7388 and 0.9907; miR-19a/19b: 0.8451 and 0.5104; miR-20a: 0.8975 and 1.000; miR-92a: 0.8097 and 0.8342). In addition, a high positive correlation was discovered between miR-17 and miR-20a expression. Combining these two miRNAs can improve the screening effect of NSCLC. CONCLUSION: The miR-17-92 gene cluster can likely serve as a diagnostic marker in NSCLC.


title: Structures of the Middle East respiratory syndrome coronavirus 3C-like protease reveal insights into substrate specificity

text: Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly pathogenic virus that causes severe respiratory illness accompanied by multi-organ dysfunction, resulting in a case fatality rate of approximately 40%. As found in other coronaviruses, the majority of the positive-stranded RNA MERS-CoV genome is translated into two polyproteins, one created by a ribosomal frameshift, that are cleaved at three sites by a papain-like protease and at 11 sites by a 3C-like protease (3CL(pro)). Since 3CL(pro) is essential for viral replication, it is a leading candidate for therapeutic intervention. To accelerate the development of 3CL(pro) inhibitors, three crystal structures of a catalytically inactive variant (C148A) of the MERS-CoV 3CL(pro) enzyme were determined. The aim was to co-crystallize the inactive enzyme with a peptide substrate. Fortuitously, however, in two of the structures the C-terminus of one protomer is bound in the active site of a neighboring molecule, providing a snapshot of an enzyme–product complex. In the third structure, two of the three protomers in the asymmetric unit form a homodimer similar to that of SARS-CoV 3CL(pro); however, the third protomer adopts a radically different conformation that is likely to correspond to a crystallographic monomer, indicative of substantial structural plasticity in the enzyme. The results presented here provide a foundation for the structure-based design of small-molecule inhibitors of the MERS-CoV 3CL(pro) enzyme.


title: Additive treatment considerations in COVID‐19 – the clinician´s perspective on extracorporeal adjunctive purification techniques

text: The aim of this document is to inform the scientific community of sparse preliminary results regarding advanced supportive therapies and technology‐driven systems in addition to highlighting the benefits and possibilities of performing concise research during challenging times. Advanced organ support for lung and heart offers the possibility to buy the time needed for recovery. However, remaining a bridging strategy, extracorporeal life support cannot act as the ultimate treatment of the underlying COVID‐19 disease. Appropriate patient selection criteria addressed by experts and scientific organizations, such Extracorporeal Life Support Organization and World Health Organization may provide significant help in the difficult decision‐making and to reduce mortality in patients with profound respiratory and/or cardiac failure due to COVID‐19. Severe, systemic cytokine‐mediated inflammation associated with the SARS‐CoV‐2 has also been described. Effects of crosstalk between coagulation and inflammatory pathways appear to significantly affect disease progression and lead to poor outcomes. Multiple therapeutic strategies, including antibody therapies (such as Tocilizumab, Sarilumab, Siltuximab), therapeutic plasma exchange (TPE), and blood purification techniques for direct removal of cytokines, including filtration, dialysis (diffusion), and adsorption are available. Further, we believe, that research should be facilitated and promoted, particularly under the guidance of recognized scientific societies or expert‐based multicenter investigation, with rapid communication of critical and relevant information to enhance better appraisal of patient profiles, complications, and treatment modalities.


title: Nuclease escape elements protect messenger RNA against cleavage by multiple viral endonucleases

text: During lytic Kaposi’s sarcoma-associated herpesvirus (KSHV) infection, the viral endonu-clease SOX promotes widespread degradation of cytoplasmic messenger RNA (mRNA). However, select mRNAs, including the transcript encoding interleukin-6 (IL-6), escape SOX-induced cleavage. IL-6 escape is mediated through a 3’ UTR RNA regulatory element that overrides the SOX targeting mechanism. Here, we reveal that this protective RNA element functions to broadly restrict cleavage by a range of homologous and non-homologous viral endonucleases. However, it does not impede cleavage by cellular endonucleases. The IL-6 protective sequence may be representative of a larger class of nuclease escape elements, as we identified a similar protective element in the GADD45B mRNA. The IL-6 and GADD45B-derived elements display similarities in their sequence, putative structure, and several associated RNA binding proteins. However, the overall composition of their ribonucleoprotein complexes appears distinct, leading to differences in the breadth of nucleases restricted. These findings highlight how RNA elements can selectively control transcript abundance in the background of widespread virus-induced mRNA degradation. The ability of viruses to control the host gene expression environment is crucial to promote viral infection. Many viruses express factors that reduce host gene expression through widespread mRNA decay. However, some mRNAs escape this fate, like the transcript encoding the immunoregulatory cytokine IL-6 during KSHV infection. IL-6 escape relies on an RNA regulatory element located in its 3’UTR and involves the recruitment of a protective protein complex. Here, we show that this escape extends beyond KSHV to a variety of related and unrelated viral endonucleases. However, the IL-6 element does not protect against cellular endonucleases, revealing for the first time a virus-specific nuclease escape element. We identified a related escape element in the GADD45B mRNA, which displays several similarities with the IL-6 element. However, these elements assemble a largely distinct complex of proteins, leading to differences in the breadth of their protective capacity. Collectively, these findings reveal how a putative new class of RNA elements function to control RNA fate in the background of widespread mRNA degradation by viral endonucleases.


International Engagement Is Critical to Fighting Epidemics


title: IFIT1: A dual sensor and effector molecule that detects non-2'-O methylated viral RNA and inhibits its translation

text: Our understanding of the antiviral actions of IFIT1, one of the most strongly induced interferon stimulated genes (ISGs), has advanced remarkably within the last few years. This review focuses on the recent cellular, biochemical, and structural discoveries that have provided new insight as to how IFIT1 functions as both a sensor and effector molecule of the cellular innate immune system. IFIT1 can detect viral RNA lacking 2’-O methylation on their cap structures or displaying a 5’-triphosphate moiety and inhibit their translation or sequester them from active replication. Because of these inhibitory actions, many viruses have evolved unique mechanisms to evade IFIT1 to facilitate replication, spread of infection, and disease pathogenesis.


title: New frontiers in applied veterinary point‐of‐capture diagnostics: Toward early detection and control of zoonotic influenza

text: Among the chief limitations in achieving early detection and control of animal‐origin influenza of pandemic potential in high‐risk livestock populations is the existing lag time between sample collection and diagnostic result. Advances in molecular diagnostics are permitting deployment of affordable, rapid, highly sensitive, and specific point‐of‐capture assays, providing opportunities for targeted surveillance driving containment strategies with potentially compelling returns on investment. Interrupting disease transmission at source holds promise of disrupting cycles of animal‐origin influenza incursion to endemicity and limiting impact on animal production, food security, and public health. Adoption of new point‐of‐capture diagnostics should be undertaken in the context of promoting robust veterinary services systems and parallel support for operationalizing pre‐authorized plans and communication strategies that will ensure that the full potential of these new platforms is realized.


docid: bdyalfcd

title: The first avian influenza A (H7N9) viral infection in humans in Zhejiang Province, China: a death report

text: This study reports the first death caused by a novel avian influenza A (H7N9) virus in Zhejiang Province, China. The patient had chronic hepatitis B and history of exposure to poultry. The patient initially complained of diarrhea and influenza-like symptoms on March 7 and 14 respectively. The disease progressed to severe pneumonia, sustained hypoxia, and coagulation abnormalities. The patient died on March 27 because of respiratory failure, multiple organ failure, and disseminated intravascular coagulation without oseltamivir treatment. This H7N9 virus from Zhejiang is highly similar to isolates obtained from Shanghai, Jiangsu, Anhui, etc. Analysis of hemagglutinin, neuramidinase, and matrix genes indicated that the isolates share the same avian origin, have low virulence, and are sensitive to oseltamivir, but are resistant to adamantine. Only the isolate that caused the fatality exhibited substitution of Q226I in the HA gene, which indicates a potentially enhanced human affinity. The secondary transmission rate was 1.6% (2/125). Only two health workers presented with influenza-like symptoms, and they subsequently tested negative for H7N9 RNA. In conclusion, underlying disease, late diagnosis, and untimely antiviral treatment are possible high-risk factors for infections and death caused by the lowpathogenicity avian influenza A (H7N9). Person-to-person transmission of the H7N9 virus was not detected among close contacts, but such transmission should be investigated in the future. Expanding and enhancing surveillance will help in the early discovery and diagnosis of suspected cases, which will reduce the number of severe cases and deaths.


title: Cancer care during the spread of coronavirus disease 2019 (COVID-19) in Italy: young oncologists’ perspective

text: Click here to listen to the Podcast.


title: Human genetic approaches to diseases of lymphocyte activation

text: Our laboratory focuses on the study of the molecular regulation of T lymphocyte homeostasis, particularly as it relates to immunological tolerance, apoptosis, and autoimmune diseases. Through intense molecular research on the regulation of lymphocyte fate, the Fas receptor and other tumor necrosis factor receptors as well as their ligands have emerged as key regulators of T lymphocyte apoptosis. We are studying genetic abnormalities of this death pathway, particularly in the context of autoimmune lymphoproliferative syndrome (ALPS) and other non-ALPS conditions affecting lymphocyte homeostasis. These studies have led to further investigations of the regulation of the NF-κB signaling pathway, the molecular basis for programmed cell death and viral cytopathicity, mechanisms of autoimmunity, and regulation of mature T-cell tolerance. Our investigations promise to provide insight into the molecular mechanisms behind the regulation of immune response and contribute to the development of novel diagnostic and treatment methods for autoimmune diseases.


title: T Cell Responses during Acute Respiratory Virus Infection

text: Abstract The T cell response is an integral and essential part of the host immune response to acute virus infection. Each viral pathogen has unique, frequently nuanced, aspects to its replication, which affects the host response and as a consequence the capacity of the virus to produce disease. There are, however, common features to the T cell response to viruses, which produce acute limited infection. This is true whether virus replication is restricted to a single site, for example, the respiratory tract (RT), CNS etc., or replication is in multiple sites throughout the body. In describing below the acute T cell response to virus infection, we employ acute virus infection of the RT as a convenient model to explore this process of virus infection and the host response. We divide the process into three phases: the induction (initiation) of the response, the expression of antiviral effector activity resulting in virus elimination, and the resolution of inflammation with restoration of tissue homeostasis.


Impacto de la pandemia COVID-19 sobre los ingresos hospitalarios en cardiología


title: Racial demographics and COVID-19 confirmed cases and deaths: a correlational analysis of 2886 US counties

text: BACKGROUND: Recent news reports state that racial minority groups, such as African–Americans, are experiencing a greater COVID-19 burden, as measured by confirmed cases and deaths. Limited racial data is available on a national level. METHODS: We conducted the first nationwide analysis to examine COVID-19 and race on a county level. We obtained datasets on COVID-19 cases and deaths, and racial population totals, by US county. We examined if correlations exist between the racial percentages and percentages of confirmed COVID-19 cases and deaths by county. RESULTS: A positive correlation existed between percentages of African–Americans living in a county and who have COVID-19 (r = 0.254, P < 0.0001), who have died from COVID-19 (r = 0.268, P < 0.0001), and case mortality (r = 0.055, P = 0.003). Positive correlations also existed between percentages of Asian–Americans living in counties and these factors. Negative correlations existed between percentages of Whites living in counties and these factors. CONCLUSIONS: A weak, albeit very significant, positive relationship exists between the percentage of African–Americans living in a county and the percentage of COVID-19 confirmed cases, confirmed deaths and case mortality in the county. This is in support of many city and statewide analyses, and we urge for targeted resources towards work that further examine these racial associations.


title: Length Variation of DC-SIGN and L-SIGN Neck-Region has no Impact on Tuberculosis Susceptibility

text: The C-type lectins DC-SIGN and L-SIGN are important pathogen-recognition receptors of the human innate immune system. Both lectins have been shown to interact with a vast range of infectious agents, including Mycobacterium tuberculosis, the etiologic agent of tuberculosis in humans. In addition, DC-SIGN and L-SIGN possess a neck region, made up of a variable number of 23 amino acid tandem repeats, which plays a crucial role in the tetramerization of these proteins and support of the carbohydrate recognition domain. The length of the neck region, which shows variable levels of polymorphism, can critically influence the pathogen binding properties of these two receptors. We therefore investigated the impact of the DC-SIGN and L-SIGN neck-region length variation on the outcome of tuberculosis by screening this polymorphism in a large cohort of Coloured South African origin. The analyses of 711 individuals, including 351 tuberculosis patients and 360 healthy controls, revealed that none of the DC-SIGN and L-SIGN neck-region variants or genotypes seems to influence the individual susceptibility to develop tuberculosis.


title: First Case of Focal Epilepsy Associated with SARS‐Coronavirus‐2

text: A healthy patient presented to Klinikum Altmühlfranken Weißenburg Hospital, Germany, with two‐morning attacks of painful muscle spasm in left upper and lower limbs, without altered consciousness. Full examinations, radiological imaging, electroencephalography, lumbar puncture, and autoimmune profile were either normal or not consistent. Subsequent epileptic episodes were observed on admission day and following days; thus, the patient was diagnosed with focal epilepsy. The patient started to develop a fever and severe cough at day 4, and SARS‐Coronavirus‐2 was confirmed through a nasopharyngeal swap. She received anticonvulsants and symptomatic treatments and completely recovered. This report emphasizes on potential nervous system involvement in SARS‐Coronavirus‐2 pathogenesis. This article is protected by copyright. All rights reserved.


title: Double-quencher probes improve detection sensitivity toward Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in a reverse-transcription polymerase chain reaction (RT-PCR) assay

text: BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which emerged in the city of Wuhan, Hubei Province, China, has spread worldwide and is threatening human life. The detection of SARS-CoV-2 is critical for preventing new outbreaks, curbing disease spread, and managing patients. Currently, a reverse-transcription polymerase chain reaction (RT-PCR) assay is used to detect the virus in clinical laboratories. However, although this assay is considered to have high specificity, its sensitivity is reportedly as low as 60–70%. Improved sensitivity is, therefore, urgently required. METHODS: We used the primers and single-quencher probes recommended by the CDC (N1, N2 and N3) in the USA and the NIID (N1 and N2) in Japan. In addition, we designed double-quencher probes according to the virus sequence provided by the NIID to develop a further assay (termed the YCH assay [N1 and N2]). Using these assays, we conducted RT-PCR with serially diluted DNA positive controls to assess and compare the detection sensitivity of the three assays. Furthermore, 66 nasopharyngeal swabs were tested to determine the diagnostic performances. RESULTS: The threshold cycle (Ct) value of the RT-PCR was relatively low for the CDC and YCH assays compared with the NIID assay. Serial dilution assays showed that both the CDC and YCH assays could detect low copy numbers of the DNA positive control. The background fluorescence signal at the baseline was lower for the YCH assay compared with the NIID assay. We assessed the diagnostic performance between single- (NIID) and double-quencher (YCH) probes using 66 nasopharyngeal swabs. When the results of YCH-N2 assay were used as a reference, each assay detected SARS-CoV-2 with positive percent agreements of 56% for NIID-N1, 61% for YCH-N1, and 94% for NIID-N2, and 100% negative percent agreements for NIID-N1, YCH-N1 and NIID-N2. CONCLUSION: Double-quencher probes decreased the background fluorescence and improved the detection sensitivity of RT-PCR for SARS-CoV-2.


title: A single-center, retrospective study of COVID-19 features in children: a descriptive investigation

text: BACKGROUND: Compared to adults, there are relatively few studies on COVID-19 infection in children, and even less focusing on the unique features of COVID-19 in children in terms of laboratory findings, locations of computerized tomography (CT) lesions, and the role of CT in evaluating clinical recovery. The objective of this study is to report the results from patients at Wuhan Children’s Hospital, located within the initial center of the outbreak. METHODS: Clinical, imaging, and laboratory data of 76 children were collected retrospectively and analyzed with the Fisher exact test and Cox regression statistical methods. RESULTS: Among 50 children with a positive COVID-19 real-time reverse-transcriptase polymerase chain reaction (PCR), five had negative PCR results initially but showed positive results in subsequent tests. Eight (16%) patients had lymphopenia, seven (14%) with thrombocytopenia, four (8%) with lymphocytosis, two (4%) with thrombocytosis, ten (20%) with elevated C-reactive protein, four (8%) with hemoglobin above, and six (12%) with below standard reference values. Seven (14%) of the 50 had no radiologic evidence of disease on chest CT. For the 43 patients who had abnormal CT findings, in addition to previously reported patterns of ground-glass opacity (67%), local patchy shadowing (37%), local bilateral patchy shadowing (21%), and lesion location of lower lobes (65%), other CT features include that an overwhelming number of pediatric patients had lesions in the subpleural area (95%) and 22 of the 28 lower lobe lesions were in the posterior segment (78%). Lesions in most of the 15 patients (67%) who received chest CT at discharge were not completely absorbed, and 26% of these pediatric patients had CT lesions that were either unchanged or worse. CONCLUSIONS: There were a few differences between COVID-19 children and COVID-19 adults in terms of laboratory findings and CT characteristics. CT is a powerful tool to detect and characterize COVID-19 pneumonia but has little utility in evaluating clinical recovery for children. These results oppose current COVID-19 hospital discharge criteria in China, as one requirement is that pulmonary imaging must show significant lesion absorption prior to discharge. These differences between pediatric and adult cases of COVID-19 may necessitate pediatric-specific discharge criteria.


title: Implementation of Quaternary Prevention in the Korean Healthcare System: Lessons From the 2015 Middle East Respiratory Syndrome Coronavirus Outbreak in the Republic of Korea

text: Quaternary prevention should be implemented to minimize harm to patients because the ultimate goal of medicine is to prevent disease and promote health. Primary care physicians have a major responsibility in quaternary prevention, and the establishment of clinical epidemiology as a distinct field of study would create a role charged with minimizing patient harm arising from over-medicalization.


title: WHO's next? Changing authority in global health governance after Ebola

text: The World Health Organization (WHO) occupies a central place in the system of global health governance and plays a key role in the control of epidemics and pandemics. The 2014 Ebola crisis in West Africa, however, saw widespread and sustained criticism of its performance, leading many to call for its reform and even replacement. This article moves on from initial analyses of the WHO's ‘failure’, to argue that the crisis has led to a shift in its authority as a global governor. It argues that the WHO's traditional basis of authority was largely expert and delegated; that it provided technical advice and normative guidance, and that its authority was ‘on loan’ from member states, who exerted considerable influence over the WHO. Its actions during the West African Ebola outbreak remained consistent with this, but it was unable to cope with what the outbreak required. The criticisms both of the WHO and the wider system of global health governance, however, have opened up a space where the balance of authority is shifting to one based more heavily on capacity—the ability to act in a crisis. If such a shift is realized, it will create different expectations of the WHO which, if they are not fulfilled, may lead to trust in the organisation declining and its legitimacy being compromised.


title: Airway and serum biochemical correlates of refractory neutrophilic asthma

text: Background Despite progress in the diagnosis and management of asthma, many patients have poorly controlled or refractory asthma (RA). The mechanism of this RA is not well understood. Objective We sought to explore the relationship between neutrophils and other biomarkers of RA. Method Sixty patients with RA, 30 patients with nonrefractory asthma (NRA), and 20 healthy subjects were enrolled. We performed a comprehensive characterization of these study subjects, which included laboratory and pulmonary function studies, chest computed tomography, and bronchoscopy with bronchoalveolar lavage (BAL). We analyzed BAL fluid and serum for a total of 244 biomolecules using a multiplex assay and correlated them with clinical and other laboratory parameters. Results RA was significantly different from NRA with regard to pulmonary function indices, bronchial basement membrane thickness, and BAL fluid neutrophil and lymphocyte counts but not eosinophil counts. BAL fluid neutrophil counts negatively and positively correlated with forced vital capacity and age, respectively. Of the 244 biomolecules studied, 52 and 14 biomolecules from BAL fluid and serum, respectively, were significantly different among the study groups. Thirteen of these 52 molecules correlated with BAL fluid neutrophil counts. BAL fluid from 40% of patients with RA was positive for a pathogenic microbe. Infection-negative neutrophilic RA was associated with an increase in levels of select biomarkers of inflammation in the serum, suggesting the presence of systemic inflammation. Conclusions RA was associated with increased numbers of neutrophils and proneutrophilic biomolecules in the airways. Subclinical infection was present in 40% of patients with RA, which likely contributed to neutrophilic inflammation. A subgroup of patients with noninfected neutrophilic RA was associated with systemic inflammation.


The Fellowship Milieu in Adult Cardiothoracic Anesthesiology – fostering psychological wellbeing during the coronavirus crisis


title: Mental health in trouble

text: We are already seeing the pandemic's effects on mental health, and we need to act urgently to avoid a full-blown crisis, says Sam Howells


title: “Slit-Lamp Infection Protector Cover for COVID-19”

text: Supplemental Digital Content is Available in the Text.


title: Involvement of the renin-angiotensin system in the progression of severe hand-foot-and-mouth disease

text: BACKGROUND: Hand-foot-and-mouth disease (HFMD) is generally considered as a mild exanthematous disease to infants and young children worldwide. HFMD cases are usually mild and self-limiting but for few cases leads to complicated severe clinical outcomes, and even death. Previous studies have indicated that serum Ang II levels in patients with H7N9 infection were related to the severity of infection. However, the mechanisms underlying the pathogenesis of severe HFMD remain unclear. This study was undertaken to clarify the role of the renin-angiotensin system (RAS) in the progression of severe HFMD. METHODS: In the present study, 162 children including HFMD patients and healthy controls were recruited. The data was analyzed by time-series fashion. Concentrations of angiotensin II (Ang II) and noradrenaline (NA) in serum of patients were measured with ELISA. We established a mouse model for enterovirus 71 (EV71) infection and determined concentrations of Ang II, NA in tissue lysates at 3, 5 and 7 days post infection (dpi). RESULTS: The concentrations of Ang II and NA in serum of the HFMD patients with mild or severe symptoms were significantly higher than that in healthy controls. Additionally, the concentrations of Ang II and NA in serum of severe cases were significantly higher than those mild cases and the increased concentrations of Ang II and NA showed the same time trend during the progression of HFMD in the severe cases. Furthermore, the concentrations of Ang II and NA in target organs of EV71-infected mice including brains, skeletal muscle, and lungs were increased with the progression of EV71 infection in mice. Histopathological alterations were observed in the brains, skeletal muscle and lungs of EV71-infected mice. CONCLUSION: Our study suggested that activation of the RAS is implicated in the pathogenesis of severe HFMD.


title: Immunogenicity of a malaria parasite antigen displayed by Lactococcus lactis in oral immunisations

text: A putative protective protein from Plasmodium falciparum merozoites, MSA2, was expressed in two different ways on the cell surface of the Gram-positive food-grade bacterium, Lactococcus lactis. The first display format exploits an LPXTG-type anchoring motif of the lactococcal proteinase PrtP to covalently anchor MSA2 to the genetically modified producer cells. In a second display format, MSA2 was fused to the peptidoglycan-binding domain (Protein Anchor) of the lactococcal cell wall hydrolase AcmA and was non-covalently rebound to the surface of non-genetically modified, non-living high-binder L. lactis cells, termed Gram-positive enhancer matrix (GEM) particles. The L. lactis recombinants carrying covalently bound MSA2 were used to immunise rabbits through nasal and oral routes. The highest levels of IgG antibodies reacting with near-native MSA2 on merozoites was elicited by oral administration. Intestinal antibodies to MSA2 were produced only after oral immunisation. MSA2-specific T(h)-cell activation could be demonstrated. Based on these results, the immunogenicity in oral immunisations of MSA2, bound non-covalently to non-genetically modified L. lactis GEM particles, was compared with MSA2 that was bound covalently to genetically modified L. lactis. These two forms elicited similar titres of serum antibodies. The results illustrate the potential of using non-genetically modified L. lactis as a safe vaccine delivery vehicle to elicit systemic antibodies, thereby avoiding the dissemination of recombinant DNA into the environment.


Response letter


title: CLEC4M is associated with poor prognosis and promotes cisplatin resistance in NSCLC patients

text: Cisplatin-based chemotherapy is the foundation of treatment for major non-small cell lung cancer (NSCLC) patients. However, cisplatin resistance is still a challenging issue, and the molecular mechanisms underlying this resistance remain to be fully explored. CLEC4M, a Ca(2+)-dependent C-type lectin, has recently been found to correlate with tumourigenesis. This study mainly focused on whether CLEC4M impacts clinical prognosis and how CLEC4M contributes to cisplatin resistance in NSCLC. Our results found that CLEC4M was correlated with poor prognosis in patients with lung cancer. In addition, a positive association between CLEC4M expression and the IC50 values of cisplatin was found, which suggests that CLEC4M may impact cisplatin sensitivity. In vitro results from cultured A549 and H1299 cells confirmed that CLEC4M could enhance cisplatin resistance, while CLEC4M knockdown led to higher sensitivity to cisplatin in these cells. Further experiments showed that the underlying mechanisms included inhibition of cisplatin-induced cell apoptosis by CLEC4M and improved DNA repair capacity by upregulating XPA and ERCC1 expression. In addition, CLEC4M was able to promote cell migration with or without cisplatin treatment. Collectively, these findings suggest the potential clinical significance of CLEC4M inhibition in overcoming cisplatin resistance in NSCLC patients.


title: Apoptosis in astrovirus-infected CaCo-2 cells

text: Abstract Cell death processes during human astrovirus replication in CaCo-2 cells and their underlying mechanisms were investigated. Morphological and biochemical alterations typical of apoptosis were analyzed in infected cells using a combination of techniques, including DAPI staining, the sub-G0/G1 technique and the TUNEL assay. The onset of apoptosis was directly proportional to the virus multiplicity of infection. Transient expression experiments showed a direct link between astrovirus ORF1a encoded proteins and apoptosis induction. A computer analysis of the astrovirus genome revealed the presence of a death domain in the nonstructural protein p38 of unknown function, encoded in ORF1a. Apoptosis inhibition experiments suggested the involvement of caspase 8 in the apoptotic response, and led to a reduction in the infectivity of the virus progeny released to the supernatant. We conclude that apoptotic death of host cells seems necessary for efficient human astrovirus replication and particle maturation.


title: Wuhan and Hubei COVID-19 mortality analysis reveals the critical role of timely supply of medical resources

text: • COVID-19 mortality rates in Wuhan and Hubei decay exponentially. • COVID-19 mortality rates outside Hubei and Wuhan are nearly constant. • COVID-19 recovery rates in Wuhan and Hubei grow exponentially. • Over 40,000 aided health workers help Hubei to effectively treat patients. • Newly supplied beds allow over 38,000 patients in Wuhan to be treated in hospitals.


title: Searching for safe-haven assets during the COVID-19 pandemic

text: Abstract The ongoing COVID-19 pandemic has shaken the global financial system and caused great turmoil. Facing unprecedented risks in the markets, people have increasing needs to find a safe haven for their investments. Given that the nature of this crisis is a combination of multiple problems, it is substantially different from all other financial crises known to us. It is therefore urgent to re-evaluate the safe-haven role of some traditional asset types, namely, gold, cryptocurrency, foreign exchange and commodities. This paper introduces a sequential monitoring procedure to detect changes in the left-quantiles of asset returns, and to assess whether a tail change in the equity index can be offset by introducing a safe-haven asset into a simple mean-variance portfolio. The sample studied covers a training period between August–December 2019 and a testing period of December 2019–March 2020. Furthermore, we calculate the cross-quantilogram between pair-wise asset returns and compare their directional predictability on left-quantiles in both normal market conditions and the COVID-19 period. The main results show that the role of safe haven becomes less effective for most of the assets considered in this paper, while gold and soybean commodity futures remain robust as safe-haven assets during this pandemic.