docid: pwlcqavv

title: Two Series of Familial Cases With Unclassified Interstitial Pneumonia With Fibrosis

text: Several children presenting with mild symptoms of respiratory tract infection were diagnosed with unclassified interstitial pneumonia with fibrosis. Their clinical and radiological findings were similar to those of acute interstitial pneumonia, but there were some differences in the pathological findings. Unclassified interstitial pneumonia with fibrosis is characterized by histological findings of centrilobular distribution of alveolar damage and bronchiolar destruction with bronchiolar obliteration. This report describes two different series of familial cases of unclassified interstitial pneumonia with fibrosis, which developed almost simultaneously in the spring. Some of the individual cases showed rapidly progressive respiratory failure of unknown cause, with comparable clinical courses and similar radiological and pathological features, including lung fibrosis. Each family member was affected almost simultaneously in the spring, different kinds of viruses were detected in two patients, and all members were negative for bacterial infection, environmental and occupational agents, drugs, and radiation. These findings implicate a viral infection and/or processes related to a viral infection, such as an exaggerated or altered immune response, or an unknown inhaled environmental agent in the pathogenesis of unclassified interstitial pneumonia with fibrosis.


The START (Surgical Triage And Resource Allocation Tool) of Surgical Prioritisation during the COVID-19 Pandemic


title: The forkhead box M1 transcription factor as a candidate of target for anti‐cancer immunotherapy

text: The present study attempted to identify a target antigen for immunotherapy for cholangiocarcinoma. Forkhead box M1 (FOXM1) was selected as a candidate antigen based on the data of previous cDNA microarray analysis of clinical samples of cholangiocarcinoma. The level of FOXM1 mRNA was more than 4 times higher in cancer cells in comparison to adjacent normal epithelial cells, in all of 24 samples of cholangiocarcinoma tissues. An immunohistochemical analysis also detected FOXM1 protein in the cancer cells but not in the normal cells. Twenty‐three human FOXM1‐derived peptides predicted to bind to HLA‐A2 were analyzed to determine their ability to induce HLA‐A2‐restricted T cells in HLA‐A2 transgenic mice. FOXM1(362‐370) (YLVPIQFPV), FOXM1(373‐382) (SLVLQPSVKV), and FOXM1(640‐649) (GLMDLSTTPL) peptides primed HLA‐A2‐restricted cytotoxic T lymphocytes (CTLs) in the HLA‐A2 transgenic mice. Human CTL lines reactive to these 3 peptides could also be established from HLA‐A2‐positive healthy donors and cancer patients. Natural processing of the 3 epitopes from FOXM1 protein was confirmed by specific killing of HLA‐A2‐positive FOXM1‐transfectants by peptide‐induced CTLs. FOXM1 is expressed in various types of cancers and it is also functionally involved in oncogenic transformation and the survival of cancer cells. Therefore, FOXM1 may be a suitable target for immunotherapy against various cancers including cholangiocarcinoma.


title: Optimized DNA extraction and metagenomic sequencing of airborne microbial communities

text: Metagenomic sequencing has been widely used for the study of microbial communities from various environments such as soil, ocean, sediment and fresh water. Nonetheless, metagenomic sequencing of microbial communities in the air remains technically challenging, partly owing to the limited mass of collectable atmospheric particulate matter and the low biological content it contains. Here we present an optimized protocol for extracting up to tens of nanograms of airborne microbial genomic DNA from collected particulate matter. With an improved sequencing library preparation protocol, this quantity is sufficient for downstream applications, such as metagenomic sequencing for sampling various genes from the airborne microbial community. The described protocol takes ∼12 h of bench time over 2–3 d, and it can be performed with standard molecular biology equipment in the laboratory. A modified version of this protocol may also be used for genomic DNA extraction from other environmental samples of limited mass or low biological content.


docid: oobiqkns

title: Rapid isolation of morbillivirus nucleocapsid for genomic RNA cDNA cloning and the production of specific core protein antisera

text: Abstract A procedure is described for the rapid isolation of canine distemper virus nucleocapsid, free from contaminating viral non-core and host cellular proteins. Nucleocapsid isolated in this manner is amenable to ultrastructural evaluation, protein isolation for the production of monospecific hyperimmune serum, and genomic RNA isolation for cDNA cloning. Nucleocapsid (NC) and a defective NC variant (Df-NC) isolated from 5.5 × 107 Vero cells infected with Ond-CDV is readily visualized on cesium gradients. The calculated density for NC is 1.2976 ± 0.0033 g/ml and 1.2458 ± 0.0056 g/ml for Df-NC. Ultrastructurally, NC appears as long uninterrupted strands, 1.6 ± 0.1 μm in length, 21.2 ± 1.7 nm in diameter, with well defined capsid subunits. Df-NC are truncated with a uniform length of 85.8 ± 7.1 nm and a 24.5 ± 1.3 nm diameter. A total of 2.1 ± 0.2 μ of NC protein is obtained for every 1 × 106 cells infected; 89.7% of this mass is represented by a 61 kDa protein (N), 8.4% by a 75 kDa protein (P), and 1.9% by a 160–200 kDa protein (L), which is in agreement with the NC constituency of other paramyxoviruses. Viral N and P proteins, purified by 7.5% SDS-PAGE, were used in the production of hyperimmune serum. Specificity was demonstrated by Western blot analysis. Both antisera were capable of detecting viral antigen in persistently and lytically CDV infected cells by indirect immunofluorescence. A single high molecular weight species of nucleic acid was isolated from purified nucleocapsids compatible with a 14.6 kb morbillivirus genome. Although the efficiency of RNA extraction from purified NC was low (14.2%), sufficient RNA was obtained for gel analysis and the establishment of genomic RNA cDNA clones.


title: A lesson from a saboteur: high molecular weight kininogen (HMWK) impact in COVID‐19

text: Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is a newly identified coronavirus which has spread from China to the rest of the world causing the pandemic coronavirus disease 19 (COVID‐19). It has fatality rate that floats from 5 to 15% and the symptoms are fever, cough, myalgia and/or fatigue up to dyspnea, responsible for hospitalization and in most of the cases of artificial oxygenation. In the attempt to understand how the virus spreads and how to pharmacologically abolish it, it was highlighted that SARS‐CoV‐2 infects human cells by means of angiotensin converting enzyme 2 (ACE2), transmembrane protease serine 2 (TMPRSS2) and SARS‐CoV‐2 main protease (M(pro)). Once bound to its receptor ACE2, the other two proteases, in concert with the receptor‐mediated signaling, allow virus replication and spread throughout the body. Our attention has been focused on the role of ACE2 in that its blockade by the virus increases Bradykinin and its metabolites, well known to facilitate inflammation in the lung (responsible for cough and fever), facilitate both the coagulation and complement system, three mechanisms that are typical of angioedema, cardiovascular dysfunction and sepsis, pathologies which symptoms occur in COVID‐19 patients. Thus, we propose to pharmacologically block the kallikrein‐kinin system upstream bradykinin and the ensuing inflammation, coagulation and complement activation by means of lanadelumab, which is a clinically approved drug for hereditary angioedema.


title: Reverse transcription strand invasion based amplification (RT-SIBA): a method for rapid detection of influenza A and B

text: Rapid and accurate diagnosis of influenza viruses plays an important role in infection control, as well as in preventing the misuse of antibiotics. Isothermal nucleic acid amplification methods offer significant advantages over the polymerase chain reaction (PCR), since they are more rapid and do not require the sophisticated instruments needed for thermal cycling. We previously described a novel isothermal nucleic acid amplification method, ‘Strand Invasion Based Amplification’ (SIBA®), with high analytical sensitivity and specificity, for the detection of DNA. In this study, we describe the development of a variant of the SIBA method, namely, reverse transcription SIBA (RT-SIBA), for the rapid detection of viral RNA targets. The RT-SIBA method includes a reverse transcriptase enzyme that allows one-step reverse transcription of RNA to complementary DNA (cDNA) and simultaneous amplification and detection of the cDNA by SIBA under isothermal reaction conditions. The RT-SIBA method was found to be more sensitive than PCR for the detection of influenza A and B and could detect 100 copies of influenza RNA within 15 min. The development of RT-SIBA will enable rapid and accurate diagnosis of viral RNA targets within point-of-care or central laboratory settings. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00253-016-7491-y) contains supplementary material, which is available to authorized users.


title: Communicable Disease Surveillance Ethics in the Age of Big Data and New Technology

text: Surveillance is essential for communicable disease prevention and control. Traditional notification of demographic and clinical information, about individuals with selected (notifiable) infectious diseases, allows appropriate public health action and is protected by public health and privacy legislation, but is slow and insensitive. Big data–based electronic surveillance, by commercial bodies and government agencies (for profit or population control), which draws on a plethora of internet- and mobile device–based sources, has been widely accepted, if not universally welcomed. Similar anonymous digital sources also contain syndromic information, which can be analysed, using customised algorithms, to rapidly predict infectious disease outbreaks, but the data are nonspecific and predictions sometimes misleading. However, public health authorities could use these online sources, in combination with de-identified personal health data, to provide more accurate and earlier warning of infectious disease events—including exotic or emerging infections—even before the cause is confirmed, and allow more timely public health intervention. Achieving optimal benefits would require access to selected data from personal electronic health and laboratory (including pathogen genomic) records and the potential to (confidentially) re-identify individuals found to be involved in outbreaks, to ensure appropriate care and infection control. Despite existing widespread digital surveillance and major potential community benefits of extending its use to communicable disease control, there is considerable public disquiet about allowing public health authorities access to personal health data. Informed public discussion, greater transparency and an ethical framework will be essential to build public trust in the use of new technology for communicable disease control.


title: Synthetic approaches, structure activity relationship and biological applications for pharmacologically attractive pyrazole/pyrazoline–thiazolidine-based hybrids

text: The features of the chemistry of 4-thiazolidinone and pyrazole/pyrazolines as pharmacologically attractive scaffolds were described in a number of reviews in which the main approaches to the synthesis of mentioned heterocycles and their biological activity were analyzed. However, the pyrazole/pyrazoline–thiazolidine-based hybrids as biologically active compounds is poorly discussed in the context of pharmacophore hybrid approach. Therefore, the purpose of this review is to summarize the data about the synthesis and modification of heterocyclic systems with thiazolidine and pyrazoline or pyrazole fragments in molecules as promising objects of modern bioorganic and medicinal chemistry. The description of biological activity was focused on SAR analysis and mechanistic insights of mentioned hybrids.


title: Stockpile Model of Personal Protective Equipment in Taiwan

text: The Taiwan Centers for Disease Control (Taiwan CDC) has established a 3-tier personal protective equipment (PPE) stockpiling framework that could maintain a minimum stockpile for the surge demand of PPE in the early stage of a pandemic. However, PPE stockpiling efforts must contend with increasing storage fees and expiration problems. In 2011, the Taiwan CDC initiated a stockpile replacement model in order to optimize the PPE stockpiling efficiency, ensure a minimum stockpile, use the government's limited funds more effectively, and achieve the goal of sustainable management. This stockpile replacement model employs a first-in-first-out principle in which the oldest stock in the central government stockpile is regularly replaced and replenished with the same amount of new and qualified products, ensuring the availability and maintenance of the minimum stockpiles. In addition, a joint electronic procurement platform has been established for merchandising the replaced PPE to local health authorities and medical and other institutions for their routine or epidemic use. In this article, we describe the PPE stockpile model in Taiwan, including the 3-tier stockpiling framework, the operational model, the components of the replacement system, implementation outcomes, epidemic supports, and the challenges and prospects of this model.


title: Ayurvedic clinical profile of COVID-19 – A preliminary report()

text: BACKGROUND: Ayurvedic clinical profiling of COVID-19 is a pre-requisite to develop standalone and integrative treatment approaches. At present, Ayurvedic clinicians do not have access to COVID-19 patients in clinical settings. In these circumstances, a preliminary clinical profiling of COVID-19 based on review of modern medical and classical Ayurvedic literature with inputs from Allopathic clinicians treating COVID-19 patients assumes significance. OBJECTIVES: This paper aims to develop an Ayurvedic clinical profile of COVID-19 by literature review supported by analysis of clinical data of a cohort of COVID-19 patients. METHODS: The typical Clinical Presentation of COVID-19 was categorized based on a cluster of symptoms with reference to “Interim Clinical Guidance for Management of Patients with Confirmed Corona Virus Disease (COVID-19)” released by the US CDC. As the clinical presentation is found to vary widely, research papers reporting clinical symptoms of patient samples from different parts of the world were also reviewed to identify outliers and atypical presentations. Case Records of fourteen COVID-19 patients treated at Medanta Hospital, Gurgaon were analyzed to compare symptomatology with data obtained from published literature. Further, a careful correlation was done with the data collected from selected Ayurvedic classical texts and expert views of clinical practitioners to arrive at a preliminary Ayurvedic clinical profile of COVID-19. RESULTS: COVID-19 can be provisionally understood from the Ayurvedic perspective as vātakapha dominant sannipātajvara of āgantu origin with pittānubandha. The asymptomatic, presymptomatic, mild, moderate, severe and critical stages of COVID-19 with varying clinical presentations have been analysed on the basis of nidāna, doṣa, dūṣya, nidānapañcaka and ṣaṭkriyākāla to present a preliminary clinical profile of the disease. CONCLUSIONS: In this paper, we have demonstrated that a preliminary clinical profiling of COVID-19 from the Ayurvedic perspective is possible through literature review supported by discussions with Allopathic clinicians as well as examination of patient case records. The provisional diagnosis proposed can be further developed with continued review of literature, wider cooperation and teamwork with Allopathic physicians and access to clinical data as well as direct clinical assessment of COVID-19 patients.


title: The tripartite architecture of the eukaryotic integral membrane protein zinc metalloprotease Ste24

text: Ste24 enzymes, a family of eukaryotic integral membrane proteins, are zinc metalloproteases (ZMPs) originally characterized as “CAAX proteases” targeting prenylated substrates, including a‐factor mating pheromone in yeast and prelamin A in humans. Recently, Ste24 was shown to also cleave nonprenylated substrates. Reduced activity of the human ortholog, HsSte24, is linked to multiple disease states (laminopathies), including progerias and lipid disorders. Ste24 possesses a unique “α‐barrel” structure consisting of seven transmembrane (TM) α‐helices encircling a large intramembranous cavity (~14 000 Å(3)). The catalytic zinc, coordinated via a HExxH…E/H motif characteristic of gluzincin ZMPs, is positioned at one of the cavity's bases. The interrelationship between Ste24 as a gluzincin, a long‐studied class of soluble ZMPs, and as a novel cavity‐containing integral membrane protein protease has been minimally explored to date. Informed by homology to well‐characterized soluble, gluzincin ZMPs, we develop a model of Ste24 that provides a conceptual framework for this enzyme family, suitable for development and interpretation of structure/function studies. The model consists of an interfacial, zinc‐containing “ZMP Core” module surrounded by a “ZMP Accessory” module, both capped by a TM helical “α‐barrel” module of as yet unknown function. Multiple sequence alignment of 58 Ste24 orthologs revealed 38 absolutely conserved residues, apportioned unequally among the ZMP Core (18), ZMP Accessory (13), and α‐barrel (7) modules. This Tripartite Architecture representation of Ste24 provides a unified image of this enzyme family.


title: SARS-CoV-2/COVID-19: Empfehlungen zu Diagnostik und Therapie

text: COVID-19, a new viral disease affecting primarily the respiratory system and the lung, has caused a pandemic with serious challenges to health systems around the world. In about 20% of patients, severe symptoms occur after a mean incubation period of 5 – 6 days; 5% of patients need intensive care therapy. Morbidity is about 1 – 2%. Protecting health care workers is of paramount importance in order to prevent hospital acquired infections. Therefore, during all procedures associated with aerosol production, a personal safety equipment consisting of a FFP2/FFP3 (N95) respiratory mask, gloves, safety glasses and a waterproof overall should be used. Therapy is based on established recommendations issued for patients with acute lung injury (ARDS). Lung protective ventilation, prone position, restrictive fluid management and an adequate management of organ failures are the mainstays of therapy. In case of fulminant lung failure, veno-venous extracorporeal membrane oxygenation may be used as a rescue in experienced centres. New, experimental therapies evolve with ever increasing frequency; currently, however, there is no evidence based recommendation possible. If off-label and compassionate use of these drugs is considered, an individual benefit-risk assessment is necessary, since serious side effects have been reported.


Implementing shared ventilation must be scientific and ethical or it risks harm


title: Temporal Association between Particulate Matter Pollution and Case Fatality Rate of COVID-19 in Wuhan

text: The coronavirus (COVID-19) epidemic reported for the first time in Wuhan, China at the end of 2019, which has caused 4,648 deaths in China as of July 10, 2020. This study explored the temporal correlation between the case fatality rate (CFR) of COVID-19 and particulate matter (PM) in Wuhan. We conducted a time series analysis to examine the temporal day-by-day associations. We observed a higher CFR of COVID-19 with increasing concentrations of inhalable particulate matter (PM) with an aerodynamic diameter of 10 μm or less (PM(10)) and fine PM with an aerodynamic diameter of 2.5 μm or less (PM(2.5)) in the temporal scale. This association may affect patients with mild to severe disease progression and affect their prognosis.


title: Neutrophils and viral-induced neurologic disease

text: Abstract Infection of the central nervous system (CNS) by neurotropic viruses represents an increasing worldwide problem in terms of morbidity and mortality for people of all ages. Although unique structural features of the blood-brain-barrier (BBB) provide a physical and physiological barrier, a number of neurotropic viruses are able to enter the CNS resulting in a variety of pathological outcomes. Nonetheless, antigen-specific lymphocytes are ultimately able to accumulate within the CNS and contribute to defense by reducing or eliminating the invading viral pathogen. Alternatively, infiltration of activated cells of the immune system may be detrimental, as these cells can contribute to neuropathology that may result in long-term cellular damage or death. More recently, myeloid cells e.g. neutrophils have been implicated in contributing to both host defense and disease in response to viral infection of the CNS. This review highlights recent studies using coronavirus-induced neurologic disease as a model to determine how neutrophils affect effective control of viral replication as well as demyelination.


title: Cross-Linked Fibrin in the Nasal Fluid of Patients with the Common Cold

text: To determine whether adherent material found on the walls of the paranasal sinuses during common colds might be fibrin clot, we examined the nasal fluid (a surrogate for sinus secretion) of 11 young adults with experimentally induced rhinovirus colds and that of 4 control subjects for the presence of fibrin. The mean concentration (± the standard error) of insoluble fibrin (measured as D-dimer) in subjects with rhinovirus colds increased from a baseline level of 0.8 ± 0.4 µg/mL to a peak of 2.4 ± 0.7 µg/mL (P = .0008) on day 4 after inoculation of the virus, but the fibrin concentration remained at baseline levels in the 4 uninfected control subjects.


title: Canine visceral leishmaniasis: Relationships between clinical status, humoral immune response, haematology and Lutzomyia (Lutzomyia) longipalpis infectivity

text: Abstract The main source of Leishmania infantum infection in humans is a naturally infected dog. This study reports on the infectivity to phlebotomine sandflies (Lutzomyia longipalpis) of serologically positive mongrel dogs that differed in clinical status, haematology and humoral responses to immunoglobulin (Ig) GT (total anti-Leishmania IgG), IgG1 and IgG2 subclasses of antibody to crude antigen of L. infantum. Forty-five female L. longipalpis were allowed to feed directly on the ears of dogs classified as asymptomatic, oligosymptomatic or symptomatic before being dissected five days later. Promastigotes were detected in 88% of the dissected sandflies. The highest rate of infectivity to sandflies was found in symptomatic dogs, followed by oligosymptomatic and asymptomatic animals. The results suggest that dogs naturally infected with L. infantum with higher total IgG and IgG2 concentrations and lower haematocrit levels were able to infect the highest proportion of L. longipalpis. No correlation was observed between anaemia and the intensity of clinical signs. Symptomatic dogs presented the highest infection rate and intensity of infection.


title: Patient reported outcomes of breast cancer patients during the COVID-19 outbreak in the epicenter of China: A cross sectional survey study

text: PURPOSE: We aimed to analyze the psychological status in breast cancer (BC) patients in the epicenter of the COVID-19 pandemic. PATIENTS AND METHODS: A total of 658 individuals were recruited from multiple breast cancer centers in Hubei Province. Online questionnaires were conducted, and included demographic information, clinical features, and four Patient Reported Outcomes (PROs) scales (GAP-7, PHQ-9, ISI, and IES-R). Multivariable logistic regression analysis was designed to identify potential factors on mental health outcomes. RESULTS: Questionnaires were collected from February 16 to 19, 2020, the peak time point of COVID-19 outbreak in China. 46.2% BC patients had to modify planned necessary anti-cancer treatment during the outbreak. 8.9% and 9.3% patients reported severe anxiety and severe depression, respectively. 20.8% and 4.0% patients showed severe distress and insomnia, respectively. Multivariable logistic regression analysis demonstrated poor general condition, shorter duration after BC diagnosis, aggressive BC molecular subtypes and close contact with COVID-19 patients as independent factors associated with anxiety. Poor general condition and CVC (central venous catheter) flushing delay were independently association factors depression. In terms of insomnia, poor generation condition was the only associated independent factor. Poor physical condition and treatment discontinuation were underlying risk factors for distress based on multivariable analysis. CONCLUSION: High rates of anxiety, depression, distress, and insomnia were observed in patients with breast cancer during the COVID-19 outbreak. Special attention should be paid to psychological status of breast cancer patients especially those with poor general condition, treatment discontinuation, aggressive molecular subtypes and metastatic breast cancer.


title: Detection of specific antibody responses to vaccination in variable flying foxes (Pteropus hypomelanus)

text: Abstract Megachiropteran bats are biologically important both as endangered species and reservoirs for emerging human pathogens. Reliable detection of antibodies to specific pathogens in bats is thus epidemiologically critical. Eight variable flying foxes (Pteropus hypomelanus) were immunized with 2,4-dinitrophenylated bovine serum albumin (DNP-BSA). Each bat received monthly inoculations for 2 months. Affinity-purified IgG was used for production of polyclonal and monoclonal anti-variable flying fox IgG antibodies. ELISA and western blot analysis were used to monitor immune responses and for assessment of polyclonal and monoclonal antibody species cross-reactivity. Protein G, polyclonal antibodies, and monoclonal antibodies detected specific anti-DNP antibody responses in immunized variable flying foxes, with protein G being the most sensitive, followed by monoclonal antibodies and then polyclonal antibodies. While the polyclonal antibody was found to cross-react well against IgG of all bat species tested, some non-specific background was observed. The monoclonal antibody was found to cross-react well against IgG of six other species in the genus Pteropus and to cross-react less strongly against IgG from Eidolon helvum or Phyllostomus hastatus. Protein G distinguished best between vaccinated and unvaccinated bats, and these results validate the use of protein G for detection of bat IgG. Monoclonal antibodies developed in this study recognized immunoglobulins from other members of the genus Pteropus well, and may be useful in applications where specific detection of Pteropus IgG is needed.


The economic and mental health costs of COVID-19 to immigrants


Comment on: “Care for critically ill patients with COVID-19: don’t forget the eyes”


title: Comparing insights from clinic-based versus community-based outbreak investigations: a case study of chikungunya in Bangladesh

text: Abstract Background Outbreak investigations typically focus their efforts on identifying cases that present at healthcare facilities. However, these cases rarely represent all cases in the wider community. In this context, community-based investigations may provide additional insight into key risk factors for infection, however, the benefits of these more laborious data collection strategies remains unclear. Methods We used different subsets of the data from a comprehensive outbreak investigation to compare the inferences we make in alternative investigation strategies. Results The outbreak investigation team interviewed 1,933 individuals from 460 homes. 364 (18%) of individuals had symptoms consistent with chikungunya. A theoretical clinic-based study would have identified 26% of the cases. Adding in community-based cases provided an overall estimate of the attack rate in the community. Comparison with controls from the same household revealed that those with at least secondary education had a reduced risk. Finally, enrolling residents from households across the community allowed us to characterize spatial heterogeneity of risk and identify the type of clothing usually worn and travel history as risk factors. This also revealed that household-level use of mosquito control was not associated with infection. Conclusions These findings highlight that while clinic-based studies may be easier to conduct, they only provide limited insight into the burden and risk factors for disease. Enrolling people who escaped from infection, both in the household and in the community allows a step change in our understanding of the spread of a pathogen and maximizes opportunities for control.


title: Prevalence, specificity, and clinical association of anti-phospholipid antibodies in COVID-19 patients: are the antibodies really guilty?

text: Background. Critically ill patients with coronavirus disease 2019 (COVID-19) have a profound hypercoagulable state and often develop coagulopathy which leads to organ failure and death. Because of a prolonged activated partial-thromboplastin time (aPTT), a relationship with anti-phospholipid antibodies (aPL) has been proposed, but results are controversial. Functional assays for aPL (i.e., lupus anticoagulant) can be influenced by concomitant anticoagulation and/or high levels of C reactive protein. The presence of anti-cardiolipin (aCL), anti-beta2-glycoprotein I (anti-{beta}2GPI and anti-phosphatidylserine/prothrombin (aPS/PT) antibodies was not investigated systematically. Epitope specificity of anti-{beta}2GPI antibodies was not reported. Aim. To evaluate the prevalence and the clinical association of aPL in a large cohort of COVID-19 patients, and to characterize the epitope specificity of anti-{beta}2GPI antibodies. Methods. ELISA and chemiluminescence assays were used to test 122 sera of patients suffering from severe COVID-19. Of them, 16 displayed major thrombotic events. Results. Anti-{beta}2GPI IgG/IgA/IgM were the most frequent in 15.6/6.6/9.0% of patients, while aCL IgG/IgM were detected in 5.7/6.6% by ELISA. Comparable values were found by chemiluminescence. aPS/PT IgG/IgM were detectable in 2.5 and 9.8% by ELISA. No association between thrombosis and aPL was found. Reactivity against domain 1 and 4-5 of {beta}2GPI was limited to 3/58 (5.2%) tested sera for each domain and did not correlate with aCL/anti-{beta}2GPI nor with thrombosis. Conclusion. aPL show a low prevalence in COVID-19 patients and are not associated with major thrombotic events. aPL in COVID-19 patients are mainly directed against {beta}2GPI but display an epitope specificity different from antibodies in antiphospholipid syndrome.


Blunt answer: Cracking the puzzle of elastic solids' toughness


title: Antagonizing cytokine-mediated JAK-STAT signaling by porcine reproductive and respiratory syndrome virus

text: Abstract Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway is activated by myriad cytokines, which are involved in regulation of cell growth, proliferation, differentiation, apoptosis, angiogenesis, immunity and inflammatory response. Because of its significance in immune response, JAK-STAT pathway is often targeted by pathogens, including porcine reproductive and respiratory syndrome virus (PRRSV). PRRSV causes reproductive failure in sows and respiratory disease in pigs of all ages. A typical feature of the immune response to PRRSV infection in pigs is delayed production and low titer of virus neutralizing antibodies, and weak cell-mediated immune response. One of the possible reasons for the weak protective immune response is that PRRSV interferes with cytokine-mediated JAK-STAT signaling. PRRSV inhibits interferon-activated JAK-STAT signaling by blocking nuclear translocation of STAT1 and STAT2. The mechanism is that PRRSV non-structural protein 1β (nsp1β) induces degradation of karyopherin α1 (KPNA1), a critical adaptor in nucleo-cytoplasmic transport. PRRSV also antagonizes IL6-activated JAK-STAT3 signaling via inducing degradation of STAT3. In this review, we briefly introduce JAK-STAT signaling, summarize the PRRSV interference with it, and provide perspective on the perturbation in the context of PRRSV-elicited immune response.


Abstract SARS-CoV membrane protein could be detected easily using Western blotting in non-denaturing condition but not regular denaturing treatment. Boiling treatment, causing the aggregation of SARS-CoV membrane protein in the stacking gels, results in the failure to detect the membrane protein in the separating gels. Aggregated membrane proteins could not be dissociated by 1% Triton-X 100, 6M urea, or 2% SDS. The region with amino acid residues from 51 to 170 is responsible for thermal aggregation of SARS-CoV membrane protein. Hydrophobic regions with amino acid residues from 61 to 90, from 91 to 100, from 136 to 170, are essential for this protein aggregation. Thermal aggregation of SARS-CoV membrane protein is not unique among structural proteins of coronaviruses. However, SARS-CoV membrane protein seems to be more sensitive to heat treatment, since the membrane protein of MHV-JHM, another member of the Coronaviridae, would not aggregate after the same treatment. Therefore, if SARS-CoV membrane protein needs to be analyzed using SDS-PAGE, boiling should be avoided. Thermal aggregation of SARS-CoV membrane protein may be one of the reasons for the inactivation of this virus by heat. The unusual property of SARS-CoV membrane protein aggregation induced by heat also provides a model for the study of protein aggregation.


title: First complete genome sequence of parainfluenza virus 5 isolated from lesser panda

text: Parainfluenza virus 5 (PIV5) is widespread in mammals and humans. Up to now, there is little information about PIV5 infection in lesser pandas. In this study, a PIV5 variant (named ZJQ-221) was isolated from a lesser panda with respiratory disease in Guangzhou zoo in Guangdong province, southern China. The full-length genome of ZJQ-221 was found to be 15,246 nucleotides and consisted of seven non-overlapping genes encoding eight proteins (i.e., NP, V, P, M, F, SH, HN and L). Sequence alignment and genetic analysis revealed that ZJQ-221 shared a close relationship with a PIV5 strain of canine-origin (1168-1) from South Korea. The findings of this study confirm the presence of PIV5 in lesser panda and indicate this mammal as a possible natural reservoir. Furthermore they highlight the urgent need to strengthen viral surveillance and control of PIV5 in zoo animals. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00705-017-3245-0) contains supplementary material, which is available to authorized users.


title: Molecular characterization of RIG-I, STAT-1 and IFN-beta in the horseshoe bat

text: Abstract Wild Chinese horseshoe bats have been proven to be natural reservoirs of SARS-like coronaviruses. However, the molecular characterization of key proteins in bats still needs to be explored further. In this study, we used cloning and bioinformatics to analyze the sequence of RIG-I, STAT-1 and IFN-β in the immortalized cell lines from Rhinolophus affinis and Rhinolophus sinicus. Then, we treated different bat cells, mouse embryonic fibroblasts (MEF) and splenocytes with polyinosinic–polycytidylic acid (polyI:C) and vesicular stomatitis virus (VSV) to assess and compare antiviral immune responses between bats and mice. Our results demonstrated that bat RIG-I, STAT-1 and IFN-β showed close homology with human, mouse, pig and rhesus monkey. RIG-I and STAT-1 were both highly expressed in bat spleen. Furthermore, IFN-β was induced by polyI:C and VSV in both bat and mouse cells. These findings have provided new insight into the potential characteristics of the bat innate immune system against viral infection.


docid: vlpdirjs

title: Host-related nucleotide composition and codon usage as driving forces in the recent evolution of the Astroviridae

text: Abstract The evolutionary history of the Astroviridae comprises the ancient separation between avian and mammalian astrovirus lineages followed by diversification among mammalian astroviruses. The latter process included several cross-species transmissions. We found that the recent, but not the ancient, evolution of astroviruses was associated with a switch in nucleotide composition and codon usage among non-human mammalian versus human/avian astroviruses. Virus and hosts phylogenies based on codon usage agreed with each other and matched the hosts' evolutionary emergence order. This recent switch in driving forces acting at the synonymous level points to the adaptation of codon usage by viruses to that of their hosts after cross-species transmissions. This is the first demonstration of nucleotide composition and codon usage being active driving forces during the recent evolutionary history of a virus group in the host–parasite system.


docid: oscbagdq

title: Molecular and diagnostic clinical virology in real time

text: During the last decade, the application of both qualitative and quantitative nucleic acid detection techniques has had a major impact on diagnostics in clinical virology. Both signal and target amplification-based systems are currently used routinely in most if not all virology laboratories. However, commercial assays are only available for a very limited number of targets, and this has resulted in the development and introduction of assays developed in-house for most viral targets. With improved and automated nucleic acid sample isolation techniques, as well as real-time detection methods, a new generation of assays for most clinically important viruses is being developed. These technological improvements also make it possible to generate results with a very short turnaround time. As an example of a more individual-patient disease-management concept, we have introduced in our clinical setting the quantitative detection of Epstein–Barr virus (EBV) in T-cell-depleted allogeneic stem cell transplant patients. This has enabled us to develop models for pre-emptive anti-B-cell immunotherapy for EBV reactivation, and for reducing not only the incidence of EBV lymphoproliferative disease (EBV-LPD), but the virus-related mortality. It is now also feasible to introduce molecular testing for those viruses that can easily be detected using classical virological methods, such as culture techniques or antigen detection. Prospective studies are needed to evaluate the clinical importance of the additional positive samples detected. It should, however, be clear that a complete exchange of technology is unlikely to occur, and that complementary methods should stay operational, making possible the discovery of new viruses. Furthermore, the ability to characterise viruses more easily by sequencing opens new possibilities for epidemiological studies. There is also an urgent need, with regard to molecular diagnostic methods, for the introduction and use of standardised materials and participation in international quality control programmes. Finally, with the introduction of a universal internal control throughout the whole procedure, the accuracy of the results generated is warranted.


title: Survey of COVID-19 Disease Among Orthopaedic Surgeons in Wuhan, People’s Republic of China

text: Coronavirus disease 2019 (COVID-19) broke out in Wuhan, the People’s Republic of China, in December 2019 and now is a pandemic all around the world. Some orthopaedic surgeons in Wuhan were infected with COVID-19. METHODS: We conducted a survey to identify the orthopaedic surgeons who were infected with COVID-19 in Wuhan. A self-administered questionnaire was distributed to collect information such as social demographic variables, clinical manifestations, exposure history, awareness of the outbreak, infection control training provided by hospitals, and individual protection practices. To further explore the possible risk factors at the individual level, a 1:2 matched case-control study was conducted. RESULTS: A total of 26 orthopaedic surgeons from 8 hospitals in Wuhan were identified as having COVID-19. The incidence in each hospital varied from 1.5% to 20.7%. The onset of symptoms was from January 13 to February 5, 2020, and peaked on January 23, 8 days prior to the peak of the public epidemic. The suspected sites of exposure were general wards (79.2%), public places at the hospital (20.8%), operating rooms (12.5%), the intensive care unit (4.2%), and the outpatient clinic (4.2%). There was transmission from these doctors to others in 25% of cases, including to family members (20.8%), to colleagues (4.2%), to patients (4.2%), and to friends (4.2%). Participation in real-time training on prevention measures was found to have a protective effect against COVID-19 (odds ratio [OR], 0.12). Not wearing an N95 respirator was found to be a risk factor (OR, 5.20 [95% confidence interval (CI), 1.09 to 25.00]). Wearing respirators or masks all of the time was found to be protective (OR, 0.15). Severe fatigue was found to be a risk factor (OR, 4 [95% CI, 1 to 16]) for infection with COVID-19. CONCLUSIONS: Orthopaedic surgeons are at risk during the COVID-19 pandemic. Common places of work could be contaminated. Orthopaedic surgeons have to be more vigilant and take more precautions to avoid infection with COVID-19. LEVEL OF EVIDENCE: Diagnostic Level IV. See Instructions for Authors for a complete description of levels of evidence.


title: Most rotavirus strains require the cation-independent mannose-6-phosphate receptor, sortilin-1, and cathepsins to enter cells

text: Abstract Cathepsins, endosomal acid proteases, are transported from the trans-Golgi network to late endosomes by the mannose-6-phosphate receptor (M6PR). We have previously demonstrated that some rotavirus strains, like UK, Wa, WI61, DS-1, and YM, require the cation-dependent (CD-) M6PR and cathepsins to enter from late endosomes to the cytoplasm in MA104 cells, while other strains, like the simian strain RRV, which enter cells from maturing endosomes, do not. However, the role of other trans-Golgi network-late endosome transporters, such as the cation-independent (CI-) M6PR and sortillin-1, has not been evaluated. In this work, we found that several rotavirus strains that require the CD-M6PR for cell entry are also dependent on CI-M6PR and sortilin-1. Furthermore, we showed that the infectivity of all these rotavirus strains also requires cathepsins to enter not only MA104 cells, but also human intestinal Caco-2 cells. This study identifies sortilin-1 as a novel cell factor necessary for the infectivity of a virus; in addition, our results strongly suggest that cathepsins could be common cell factors needed for the infectivity of most rotavirus strains.


title: Spatial modelling, risk mapping, change detection, and outbreak trend analysis of coronavirus (COVID-19) in Iran (days between 19 February to 14 June 2020)

text: Abstract Objectives Coronavirus disease 2019 (COVID-19) represents a major pandemic threat that has spread to more than 212 countries and 2 international conveyance with more than 432,902 recorded deaths and 7,898,442 confirmed global worldwide so far (on June 14, 2020). It is crucial to investigate the spatial drivers to prevent and control the epidemic of COVID-19. Methods This is the first comprehensive study of COVID-19 in Iran and it undertakes spatial modeling, risk mapping, change detection, and outbreak trend analysis of the disease spread. Four main steps were taken: comparison of Iranian coronavirus data with the global trends; prediction of mortality trends using regression modelling; spatial modelling, risk mapping, and change detection using the random forest (RF) machine learning technique (MLT); and validation of the modelled risk map. Results The results show that from February 19 to June 14, 2020 the average growth rates (GR) of COVID-19 deaths and the total number of COVID-19 cases in Iran were 1.08 and 1.10, respectively. Based on World Health Organisation (WHO) data, Iran’s fatality (deaths/0.1 M pop) is 10.53. Other countries’ fatality rates were, for comparison, Belgium – 83.32, UK – 61.39, Spain – 58.04, Italy – 56.73, Sweden – 48.28, France – 45.04, USA – 35.52, Canada – 21.49, Brazil – 20.10, Peru – 19.70, Chile – 16.20, Mexico– 12.80, and Germany – 10.58. This fatality rate for China is 0.32 (deaths/0.1 M pop). The heatmap of the infected areas over time identified two critical time intervals for the COVID-19 outbreak in Iran. The provinces were classified in terms of disease and death rates into a large primary group and three provinces that had critical outbreaks that were separate from others. The heatmap of countries of the world show that China and Italy were distinguished from other countries in terms of nine viral infection-related parameters. The regression models for death cases showed an increasing trend but with some evidences of turning. A polynomial relationship was identified between coronavirus infection rate and province population density. In addition, a third-degree polynomial regression model for deaths showed an increasing trend recently, indicating that subsequent measures taken to cope with the outbreak have been insufficient and ineffective. The general trend of deaths in Iran is similar to the worlds, but it shows lower volatility. Change detection of COVID-19 risk maps with a random forest model for the period from March 11th to March 18th showed an increasing trend in COVID-19 in Iran’s provinces. It is worth noting that using the LASSO MLT to evaluate variables’ importance indicated that the most important variables were distance from bus stations, bakeries, hospitals, mosques, ATMs (automated teller machines), banks, and the minimum temperature of the coldest month. Conclusions We believe that the risk maps provided by this study is the primary, fundamental step for managing and controlling COVID-19 in Iran and its provinces.


title: Acute Stroke Care in the Coronavirus Disease 2019 Pandemic

text: Abstract Coronavirus disease 2019 (COVID-19) is a pandemic respiratory disease with serious public health risk, and has taken the world off guard with its rapid spread. As the COVID-19 pandemic intensifies, overwhelming the healthcare system and the medical community, current practice for the management of acute ischemic stroke (AIS) will require modification, and guidelines should be relaxed while maintaining high standard quality of care. The aim of these suggestions is to avoid contributing to the rapid spread of COVID-19 as well as to conserve what are likely to be very limited resources (including personnel, intensive care/hospital beds as well as physicians) while maintain high quality care for patients with AIS. We present our recommendations for the management of acute stroke during the COVID-19 pandemics.


title: Genetic diversity, infection prevalence, and possible transmission routes of Bartonella spp. in vampire bats

text: Bartonella spp. are globally distributed bacteria that cause endocarditis in humans and domestic animals. Recent work has suggested bats as zoonotic reservoirs of some human Bartonella infections; however, the ecological and spatiotemporal patterns of infection in bats remain largely unknown. Here we studied the genetic diversity, prevalence of infection across seasons and years, individual risk factors, and possible transmission routes of Bartonella in populations of common vampire bats (Desmodus rotundus) in Peru and Belize, for which high infection prevalence has previously been reported. Phylogenetic analysis of the gltA gene for a subset of PCR-positive blood samples revealed sequences that were related to Bartonella described from vampire bats from Mexico, other Neotropical bat species, and streblid bat flies. Sequences associated with vampire bats clustered significantly by country but commonly spanned Central and South America, implying limited spatial structure. Stable and nonzero Bartonella prevalence between years supported endemic transmission in all sites. The odds of Bartonella infection for individual bats was unrelated to the intensity of bat flies ectoparasitism, but nearly all infected bats were infested, which precluded conclusive assessment of support for vector-borne transmission. While metagenomic sequencing found no strong evidence of Bartonella DNA in pooled bat saliva and fecal samples, we detected PCR positivity in individual saliva and feces, suggesting the potential for bacterial transmission through both direct contact (i.e., biting) and environmental (i.e., fecal) exposures. Further investigating the relative contributions of direct contact, environmental, and vector-borne transmission for bat Bartonella is an important next step to predict infection dynamics within bats and the risks of human and livestock exposures.


title: The first case of hourglass-like constriction neuropathy of a digital nerve

text: Abstract Neuropathies of digital nerves are an infrequent phenomenon and their causes are most often mechanical. A rare cause of acute neuropathy is hourglass-like fascicular constriction of a nerve due to torsion. Although several cases of hourglass-like constriction have been described in the literature, none to our knowledge involved digital nerves. In this report, we present the first case of hourglass-like constriction of a digital nerve.


title: Clinical features of human metapneumovirus genotypes in children with acute lower respiratory tract infection in Changsha, China

text: To explore the epidemiological and clinical features of different human metapneumovirus (hMPV) genotypes in hospitalized children. Reverse transcription polymerase chain reaction (RT‐PCR) or PCR was employed to screen for both hMPV and other common respiratory viruses in 2613 nasopharyngeal aspirate specimens collected from children with lower respiratory tract infections from September 2007 to February 2011 (a period of 3.5 years). The demographics and clinical presentations of patients infected with different genotypes of hMPV were compared. A total of 135 samples were positive for hMPV (positive detection rate: 5.2%). Co‐infection with other viruses was observed in 45.9% (62/135) of cases, and human bocavirus was the most common additional respiratory virus. The most common symptoms included cough, fever, and wheezing. The M gene was sequenced for 135 isolates; of these, genotype A was identified in 72.6% (98/135) of patients, and genotype B was identified in 27.4% (37/135) of patients. The predominant genotype of hMPV changed over the 3.5‐year study period from genotype A2b to A2b or B1 and then to predominantly B1. Most of clinical features were similar between patients infected with different hMPV genotypes. These results suggested that hMPV is an important viral pathogen in pediatric patients with acute lower respiratory tract infection in Changsha. The hMPV subtypes A2b and B1 were found to co‐circulate. The different hMPV genotypes exhibit similar clinical characteristics. J. Med. Virol. 87:1839–1845, 2015. © 2015 Wiley Periodicals, Inc.


title: Elective, Non-urgent Procedures and Aesthetic Surgery in the Wake of SARS–COVID-19: Considerations Regarding Safety, Feasibility and Impact on Clinical Management

text: BACKGROUND: The worldwide spread of a novel coronavirus disease (COVID-19) has led to a near total stop of non-urgent, elective surgeries across all specialties in most affected countries. In the field of aesthetic surgery, the self-imposed moratorium for all aesthetic surgery procedures recommended by most international scientific societies has been adopted by many surgeons worldwide and resulted in a huge socioeconomic impact for most private practices and clinics. An important question still unanswered in most countries is when and how should elective/aesthetic procedures be scheduled again and what kind of organizational changes are necessary to protect patients and healthcare workers when clinics and practices reopen. Defining manageable, evidence-based protocols for testing, surgical/procedural risk mitigation and clinical flow management/contamination management will be paramount for the safety of non-urgent surgical procedures. METHODS: We conducted a MEDLINE/PubMed research for all available publications on COVID-19 and surgery and COVID-19 and anesthesia. Articles and referenced literature describing possible procedural impact factors leading to exacerbation of the clinical evolution of COVID-19-positive patients were identified to perform risk stratification for elective surgery. Based on these impact factors, considerations for patient selection, choice of procedural complexity, duration of procedure, type of anesthesia, etc., are discussed in this article and translated into algorithms for surgical/anesthesia risk management and clinical management. Current recommendations and published protocols on contamination control, avoidance of cross-contamination and procedural patient flow are reviewed. A COVID-19 testing guideline protocol for patients planning to undergo elective aesthetic surgery is presented and recommendations are made regarding adaptation of current patient information/informed consent forms and patient health questionnaires. CONCLUSION: The COVID-19 crisis has led to unprecedented challenges in the acute management of the crisis, and the wave only recently seems to flatten out in some countries. The adaptation of surgical and procedural steps for a risk-minimizing management of potential COVID-19-positive patients seeking to undergo elective aesthetic procedures in the wake of that wave will present the next big challenge for the aesthetic surgery community. We propose a clinical algorithm to enhance patient safety in elective surgery in the context of COVID-19 and to minimize cross-contamination between healthcare workers and patients. New evidence-based guidelines regarding surgical risk stratification, testing, and clinical flow management/contamination management are proposed. We believe that only the continuous development and broad implementation of guidelines like the ones proposed in this paper will allow an early reintegration of all aesthetic procedures into the scope of surgical care currently performed and to prepare the elective surgical specialties better for a possible second wave of the pandemic. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.


docid: xtjtvldh

title: 2′-5′oligoadenylate synthetase 1 (2-5 OAS1) polymorphism is associated with prostate cancer

text: BACKGROUND: 2′ -5′ –oligoadenylate synthetase (2-5 OAS1), an antiviral, pro-apoptotic and anti-proliferative gene converts ATP to a series of 2′ -5′ –oligoadenylates (2-5A). 2-5A in turn activates RNaseL, a candidate hereditary prostate cancer gene. OAS1 polymorphism (rs2660) has been associated with increased susceptibility to infections and various diseases. In general, the low enzyme activity AA genotype promotes susceptibility whereas high enzyme activity GG genotype confers protection. In this study we investigated the association of this functional polymorphism (rs2660) in OAS1 with prostate cancer. METHODS: Sample size and power was calculated using the PGA software. Genomic DNA from a controls (n=140) and prostate cancer patients (n=164) were used for genotyping SNPs rs2660, rs1131454 and rs34137742 on all samples. Statistical analysis was performed using logistic regression model. RESULTS: Significant association was observed between rs2660 genotype (A/G) and prostate cancer. Genotype AA increased the risk whereas GG genotype decreased the risk of prostate cancer. The GG genotype was not observed in the African American samples. The AA genotype also increased the risk of prostate cancer with age. CONCLUSIONS: OAS1 SNP rs2660 AA genotype is significantly associated with prostate cancer whereas GG genotype protects against prostate cancer. OAS1 rs2660 could be a prostate cancer susceptibility polymorphism, a significant observation especially in a context of the OAS1-RNaseL pathway. Thus a functional defect in OAS1 due to rs2660 SNP can not only attenuate RNaseL function, but can also alter cell growth and apoptosis independent of RNaseL.


title: Indirect effects of COVID-19 on the environment

text: Abstract This research aims to show the positive and negative indirect effects of COVID-19 on the environment, particularly in the most affected countries such as China, USA, Italy, and Spain. Our research shows that there is a significant association between contingency measures and improvement in air quality, clean beaches and environmental noise reduction. On the other hand, there are also negative secondary aspects such as the reduction in recycling and the increase in waste, further endangering the contamination of physical spaces (water and land), in addition to air. Global economic activity is expected to return in the coming months in most countries (even if slowly), so decreasing GHG concentrations during a short period is not a sustainable way to clean up our environment.


title: Care of Adult Refugees with Chronic Conditions

text: Refugees share a common experience of displacement from their country of origin, migration, and resettlement in an unfamiliar country. More than 17 million people have fled their home countries due to war, generalized violence, and persecution. US primary care physicians must care for their immediate and long-term medical needs. Challenges include (1) language and cultural barriers, (2) high rates of mental health disorders, (3) higher prevalence of latent infections, and (4) different explanatory models for chronic diseases. This article discusses management strategies for common challenges that arise in the primary care of refugees.


title: An efficient three-component, one-pot synthesis of 2-alkylthio-4-amino-5-cyano-6-aryl(alkyl)pyrimidines in water

text: A convenient and practical method for the synthesis of 2-alkylthio-4-amino-5-cyano-6-aryl(alkyl)pyrimidines has been developed via a three-component, one-pot reaction from aldehydes, malononitrile and S-alkylisothiouronium salts in water at room temperature. A series of polysubstituted pyrimidines were prepared by this method in moderate to excellent yields. In addition, two kinds of pyrimidine-fused heterocyclic derivatives with potential pharmacological activity were constructed from our 2-alkylthio-4-amino-5-cyano-6-arylpyrimidines. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11030-012-9376-z) contains supplementary material, which is available to authorized users.


title: Bovine coronavirus I protein synthesis follows ribosomal scanning on the bicistronic N mRNA

text: Abstract The mRNA encoding the 49-kDa nucleocapsid protein (N) of the bovine coronavirus is bicistronic. A 23-kDa protein, termed the I protein for the ‘internal’ open reading frame (ORF), is also synthesized but in the +1 reading frame beginning 61 nt downstream of the N start codon. Sequences flanking the N and I start codons suggest that the I ORF might be accessed by scanning ribosomes passing over the N start codon. Here we test this idea and demonstrate with translation studies both in vitro and in vivo that the I protein is synthesized according to the leaky scanning model for initiation of translation on the subgenomic N mRNA molecule.


Contemporary Concise Review 2018: Respiratory infections and tuberculosis


title: Heteroleptic copper phenanthroline complexes in motion: From stand-alone devices to multi-component machinery

text: Abstract Two and a half decades of copper phenanthroline-based switches, devices and machines have illustrated the rich dynamic nature of these metal complexes. With an emphasis on the metal-ligand dissociation as the rate-determining step the present review summarizes not only spectacular examples of machinery, but also highlights rate data collected during a variety of investigations. Copper-ligand exchange reactions are mostly triggered by redox processes, addition of metal ions or addition of ligands. While the rate data spread over >8 orders of magnitude, individual effects of solvent, steric bulk, flexibility, σ-basicity and the trajectory (intra- vs. intermolecular dissociation) have large impact. Unfortunately, in many cases the exact mechanism in the rate-determining step (nucleophile-induced vs. monomolecular metal-ligand dissociation) has not been determined, suggesting to invest further efforts in the physical (in)organic chemistry of such coordination-driven systems.


title: Clinical Significance of Blue‐Green Neutrophil and Monocyte Cytoplasmic Inclusions in SARS‐CoV‐2 Positive Critically Ill Patients

text: Identification of blue‐green cytoplasmic inclusions in neutrophils and/or monocytes on peripheral blood smears is a rare, and likely underreported, finding described in few case reports and small case series studies in critically ill patients with acute liver dysfunction and lactic acidosis (Courville, et al 2017, Gorup, et al 2018, Haberichter and Crisan 2017, Harris, et al 2009, Hodgkins and Jones 2019, Hodgson, et al 2015, Jazaerly and Gabali 2014, Patel, et al 2017, Sin, et al 2019, Soos, et al 2019, Vicente‐Steijn, et al 2020). As these inclusions are thought to herald poor prognosis and death shortly after identification, they have been referred to as “green crystals of death” or “critical green inclusions”.


title: Pathology of the Testis and Its Adnexa Aleksander Talerman Lawrence M.

text: Unknown


title: Prediction of functional class of novel viral proteins by a statistical learning method irrespective of sequence similarity

text: Abstract The function of a substantial percentage of the putative protein-coding open reading frames (ORFs) in viral genomes is unknown. As their sequence is not similar to that of proteins of known function, the function of these ORFs cannot be assigned on the basis of sequence similarity. Methods complement or in combination with sequence similarity-based approaches are being explored. The web-based software SVMProt (http://jing.cz3.nus.edu.sg/cgi-bin/svmprot.cgi) to some extent assigns protein functional family irrespective of sequence similarity and has been found to be useful for studying distantly related proteins [Cai, C.Z., Han, L.Y., Ji, Z.L., Chen, X., Chen, Y.Z., 2003. SVM-Prot: web-based support vector machine software for functional classification of a protein from its primary sequence. Nucleic Acids Res. 31(13): 3692–3697]. Here 25 novel viral proteins are selected to test the capability of SVMProt for functional family assignment of viral proteins whose function cannot be confidently predicted on by sequence similarity methods at present. These proteins are without a sequence homolog in the Swissprot database, with its precise function provided in the literature, and not included in the training sets of SVMProt. The predicted functional classes of 72% of these proteins match the literature-described function, which is compared to the overall accuracy of 87% for SVMProt functional class assignment of 34582 proteins. This suggests that SVMProt to some extent is capable of functional class assignment irrespective of sequence similarity and it is potentially useful for facilitating functional study of novel viral proteins.


docid: piwdsazx

title: Spread of a neurotropic murine coronavirus into the CNS via the trigeminal and olfactory nerves

text: Abstract The route of entry into the central nervous system (CNS) of most neurotropic viruses has not been established. The coronavirus, mouse hepatitis virus strain JHM (MHV-JHM), causes acute encephalomyelitis and acute and chronic demyelinating diseases and is an important model system for virus-induced neurological disease. Suckling C578L/6 mice infected intranasally with MHV-JHM develop either the acute encephalomyelitis or a late onset, symptomatic demyelinating encephalomyelitis, depending on whether they are nursed by unimmunized or immunized dams. Analysis by in situ hybridization was used to determine the route of entry of MHV-JHM into the CNS in these mice. At early times, viral RNA was detected only in the trigeminal and olfactory nerves and in their immediate connections in all mice. A few days later, MHV-JHM RNA was found throughout the brain in mice dying of the acute encephalomyelitis, but remained confined to the entry sites in mice which did not develop acute disease. These results suggest that MHV-JHM enters the CNS via an interneuronal route in all mice, but that the presence of maternal antibody prevents the dissemination of virus via extracellular fluid. In addition, MHV-JHM may establish low-level persistence in the trigeminal or olfactory nerve or in one of its connections in mice that do not develop acute encephalomyelitis.


Detection of bat coronaviruses in the bat population in Taiwan


Response to the commentary by Alexandra A. Chudnovsky on ‘Assessing nitrogen dioxide (NO 2 ) levels as a contributing factor to coronavirus (COVID-19) fatality’


title: Recombinant Dengue virus protein NS2B alters membrane permeability in different membrane models

text: BACKGROUND: One of the main phenomena occurring in cellular membranes during virus infection is a change in membrane permeability. It has been observed that numerous viral proteins can oligomerize and form structures known as viroporins that alter the permeability of membranes. Previous findings have identified such proteins in cells infected with Japanese encephalitis virus (JEV), a member of the same family that Dengue virus (DENV) belongs to (Flaviviridae). In the present work, we investigated whether the small hydrophobic DENV protein NS2B serves a viroporin function. METHODS: We cloned the DENV NS2B sequence and expressed it in a bacterial expression system. Subsequently, we evaluated the effect of DENV NS2B on membranes when NS2B was overexpressed, measured bacterial growth restriction, and evaluated changes of permeability to hygromycin. The NS2B protein was purified by affinity chromatography, and crosslinking assays were performed to determine the presence of oligomers. Hemolysis assays and transmission electron microscopy were performed to identify structures involved in permeability changes. RESULTS: The DENV-2 NS2B protein showed similitude with the JEV viroporin. The DENV-2 NS2B protein possessed the ability to change the membrane permeability in bacteria, to restrict bacterial cell growth, and to enable membrane permeability to hygromycin B. The NS2B protein formed trimers that could participate in cell lysis and generate organized structures on eukaryotes membranes. CONCLUSIONS: Our data suggest that the DENV-2 NS2B viral protein is capable of oligomerizing and organizing to form pore-like structures in different lipid environments, thereby modifying the permeability of cell membranes.


title: Virucidal activity of a new hand disinfectant with reduced ethanol content: comparison with other alcohol-based formulations

text: Summary A new formula with reduced ethanol content (55%) in combination with 10% propan-1-ol, 5.9% propan-1.2-diol, 5.7% butan-1.3-diol and 0.7% phosphoric acid exhibited a broad spectrum of virucidal activity. In quantitative suspension tests, with and without protein load, this formulation reduced the infectivity titre of seven enveloped (influenza A and B, herpes simplex 1 and 2, bovine corona, respiratory syncytial, vaccinia, hepatitis B, bovine viral diarrhoea) and four non-enveloped (hepatitis A, polio, rota, feline calici) viruses >103-fold within 30s. In comparative testing, only 95% ethanol showed similar levels of activity. In fingerpad tests, the formulation produced a log10 reduction factor of the titre of poliovirus type 1 (Sabin) of 3.04 in 30s compared with 1.32 by 60% propan-2-ol. Testing against feline calicivirus produced a log10 reduction factor of 2.38 by the test formulation; in contrast, the log10 reduction factors with 70% ethanol and 70% propan-1-ol were 0.68 and 0.70, respectively.


docid: zutavvrf

title: Thiol-based angiotensin-converting enzyme 2 inhibitors: P1′ modifications for the exploration of the S1′ subsite

text: Abstract Explorations of the S1′ subsite of ACE2 via modifications of the P1′ methylene biphenyl moiety of thiol-based metalloprotease inhibitors led to improvements in ACE2 selectivity versus ACE and NEP, while maintaining potent ACE2 inhibition.


title: Study of LZ-word distribution and its application for sequence comparison

text: Abstract Lempel–Ziv complexity has been widely used for sequence comparison and achieved promising results, but until now components' distribution in exhaustive history has not been studied. This paper investigated the whole distribution of LZ-words and presented a novel statistical method for sequence comparison. With the components' length in mind, we revised Lempel–Ziv complexity and obtained various sets of LZ-words. Instead of calculating the LZ-words' contents, we defined a series of set operations on LZ-word set to compare biological sequences. In order to assess the effectiveness of the proposed method, we performed two sets of experiments and compared it with alignment-based methods.


title: Identifying and Interrupting Superspreading Events—Implications for Control of Severe Acute Respiratory Syndrome Coronavirus 2

text: It appears inevitable that severe acute respiratory syndrome coronavirus 2 will continue to spread. Although we still have limited information on the epidemiology of this virus, there have been multiple reports of superspreading events (SSEs), which are associated with both explosive growth early in an outbreak and sustained transmission in later stages. Although SSEs appear to be difficult to predict and therefore difficult to prevent, core public health actions can prevent and reduce the number and impact of SSEs. To prevent and control of SSEs, speed is essential. Prevention and mitigation of SSEs depends, first and foremost, on quickly recognizing and understanding these events, particularly within healthcare settings. Better understanding transmission dynamics associated with SSEs, identifying and mitigating high-risk settings, strict adherence to healthcare infection prevention and control measures, and timely implementation of nonpharmaceutical interventions can help prevent and control severe acute respiratory syndrome coronavirus 2, as well as future infectious disease outbreaks.


Exploring the risk of severe COVID-19 infection in hidradenitis suppurativa patients


title: Business models shifts: Impact of Covid-19

text: No amount of crystal ball gazing may help us fathom the full impact of the Covid-19 (C-19) crisis on business organizations in a distinct manner. Given the lack of precedence, any such analyses seem to demand routine revisions as we progress further up the “number of infected” curve. Most countries of the world have imposed restrictions on social congregations or even people working in close proximity to each other. Industries that produce and deliver information products and services therefore, have continued to function while those that manufacture physical products especially labor-intensive firms were forced to minimize operations or temporarily shut down. However, in most countries, physical products which were essential in nature were reluctantly permitted to be manufactured given the need for them in people’s everyday life. In this viewpoint, I draw upon three dimensions – information intensity of product/service, information intensity of process/value chain; along with a third dimension – essential nature of the product/service to help understand the immediate implications of C-19. I also present some anecdotal evidences of attempts to alter business models in these circumstances in order to address the challenges that certain product characteristics impose but at the same capitalize on the business opportunities presented by the essentiality of the products.


title: Evidence of Australian bat lyssavirus infection in diverse Australian bat taxa

text: Historically, Australia was considered free of rabies and rabies-like viruses. Thus, the identification of Australian bat lyssavirus (ABLV) in 1996 in a debilitated bat found by a member of the public precipitated both public health consternation and a revision of lyssavirus taxonomy. Subsequent observational studies sought to elaborate the occurrence and frequency of ABLV infection in Australian bats. This paper describes the taxonomic diversity of bat species showing evidence of ABLV infection to better inform public health considerations. Blood and/or brain samples were collected from two cohorts of bats (wild-caught and diagnostic submissions) from four Australian states or territories between April 1996 and October 2002. Fresh brain impression smears were tested for ABLV antigen using fluorescein-labelled anti-rabies monoclonal globulin (CENTOCOR) in a direct fluorescent antibody test; sera were tested for the presence of neutralising antibodies using a rapid fluorescent focus inhibition test. A total of 3,217 samples from 2,633 bats were collected and screened: brain samples from 1,461 wild-caught bats and 1086 submitted bats from at least 16 genera and seven families, and blood samples from 656 wild-caught bats and 14 submitted bats from 14 genera and seven families. Evidence of ABLV infection was found in five of the six families of bats occurring in Australia, and in three of the four Australian states/territories surveyed, supporting the historic presence of the virus in Australia. While the infection prevalence in the wild-caught cohort is evidently low, the significantly higher infection prevalence in rescued bats in urban settings represents a clear and present public health significance because of the higher risk of human exposure.


title: O(6)-alkylguanine-DNA Alkyltransferases in Microbes Living on the Edge: From Stability to Applicability

text: The genome of living cells is continuously exposed to endogenous and exogenous attacks, and this is particularly amplified at high temperatures. Alkylating agents cause DNA damage, leading to mutations and cell death; for this reason, they also play a central role in chemotherapy treatments. A class of enzymes known as AGTs (alkylguanine-DNA-alkyltransferases) protects the DNA from mutations caused by alkylating agents, in particular in the recognition and repair of alkylated guanines in O(6)-position. The peculiar irreversible self-alkylation reaction of these enzymes triggered numerous studies, especially on the human homologue, in order to identify effective inhibitors in the fight against cancer. In modern biotechnology, engineered variants of AGTs are developed to be used as protein tags for the attachment of chemical ligands. In the last decade, research on AGTs from (hyper)thermophilic sources proved useful as a model system to clarify numerous phenomena, also common for mesophilic enzymes. This review traces recent progress in this class of thermozymes, emphasizing their usefulness in basic research and their consequent advantages for in vivo and in vitro biotechnological applications.


docid: mqpovrms

title: Viruses and Bioterrorism ☆

text: Abstract The target for a terrorist attack with a viral agent can range from humans to animals and plants. However, the use of a viral agent may pose a challenge due to problems associated with acquisition, cultivation, and dissemination. Agricultural targets are of concern as they would require relatively little specialized expertise and technology and can have large economic consequences. Viral agents are prone to genetic variation and mutation, and can be manipulated or created in the laboratory. Unlike bacterial diseases, many of which are treatable with antimicrobials, there are fewer medical countermeasures to employ when dealing with viral infections.


title: Integrated wetlands for food production

text: Abstract The widespread use of compound pelleted feeds and chemical fertilizers in modern food production contribute to a vast amount of residual nutrients into the production system and adjacent ecosystem are major factors causing eutrophication. Furthermore, the extensive development and application of chemical compounds (such as chemical pesticides, disinfectants and hormones used in enhancing productivity) in food production process are hazardous to the ecosystems, as well as human health. These unsustainable food production patterns cannot sustain human living in the long run. Wetlands are perceived as self-decontamination ecosystems with high productivities. This review gives an overview about wetlands which are being integrated with food production processes, focusing on aquaculture.


title: A newly discovered human pneumovirus isolated from young children with respiratory tract disease

text: From 28 young children in the Netherlands, we isolated a paramyxovirus that was identified as a tentative new member of the Metapneumovirus genus based on virological data, sequence homology and gene constellation. Previously, avian pneumovirus was the sole member of this recently assigned genus, hence the provisional name for the newly discovered virus: human metapneumovirus. The clinical symptoms of the children from whom the virus was isolated were similar to those caused by human respiratory syncytial virus infection, ranging from upper respiratory tract disease to severe bronchiolitis and pneumonia. Serological studies showed that by the age of five years, virtually all children in the Netherlands have been exposed to human metapneumovirus and that the virus has been circulating in humans for at least 50 years.


title: Acute kidney injury is associated with the mortality of coronavirus disease 2019

text: We read with great interest the recent article "Analysis of 92 deceased patients with COVID-19" by Yang et al. published in the Journal of medical virology. The authors observed that 14 patients suffered renal injury after infection of SARS-CoV-2 in 92 deceased patients with coronavirus disease 2019 (COVID-19), although none of them had chronic renal insufficiency. This article is protected by copyright. All rights reserved.


docid: ymphhmrk

title: Disease threats to the endangered Iberian lynx (Lynx pardinus)

text: Abstract The Iberian lynx, (Lynx pardinus), is the most endangered felid in the world. To determine whether sympatric carnivores are reservoirs of pathogens posing a disease risk for the lynx, evidence of exposure to 17 viral, bacterial and protozoan agents was investigated in 176 carnivores comprising 26 free-living lynx, 53 domestic cats, 28 dogs, 33 red foxes (Vulpes vulpes), 24 Egyptian mongooses (Herpestes ichneumon), 10 common genets (Genetta genetta) and 2 Eurasian badgers (Meles meles) in the areas inhabited by the last two populations of Iberian lynx, both in Andalusia (South-Western Spain). The results indicated that the lynx had low rates of contact with viral pathogens, with one seropositive finding each for feline leukemia virus, parvovirus and canine adenovirus-1, whereas contact with bacteria and protozoa appeared more frequent. Active infections with parvovirus, Ehrlichia spp., Mycobacterium bovis, Leptospira interrogans and Cytauxzoon spp. were confirmed. In contrast, 53% of the domestic cats were exposed to some infectious agent (prevalence range 4.5–11.4%). Antibodies to canine distemper virus and parvovirus were frequently found in dogs (32% and 42%, respectively) and foxes (30% and 12%). Past or present infections with parvovirus, Ehrlichia spp., Chlamydophila spp., M. bovis, Salmonella enterica, L. interrogans, Toxoplasma gondii, and Neospora caninum were also detected in these and other species surveyed. Questionnaires to owners revealed that 14% of the dogs but none of the cats had been vaccinated, and no cat had been neutered. Based on the apparent absence of acquired immunity of the lynx against infectious agents, the frequent detection of agents among sympatric carnivores, and the reported lack of immunocompetence of the Iberian lynx, a disease outbreak among the local abundant carnivores may pose a serious disease risk for lynx conservation.


title: Easier access to mechanical ventilation worldwide: an urgent need for low income countries, especially in face of the growing COVID-19 crisis

text: Combining easy-to-build noninvasive ventilator and open-source hardware description, may allow for adequate availability of ventilators to patients in low- and middle-income countries. This is urgently needed in the growing COVID-19 epidemic. https://bit.ly/3f8ZkUR


title: Hematologic, hepatic, and renal function changes in hospitalized patients with Middle East respiratory syndrome coronavirus

text: BACKGROUND: There are no longitudinal data on the changes in hematologic, hepatic, and renal function findings in patients with Middle East respiratory syndrome coronavirus (MERS‐CoV) infection. METHODS: This is a retrospective cohort study of 16 MERS‐CoV patients, to describe the hematological, hepatic, and renal findings of patients with MERS‐CoV. RESULTS: During the 21 days of observation, there was no significant change in the hepatic panel or creatinine tests. There was a significant increase in the mean ± SD of the white blood cell count from 8.3 ± 4.6 to 14.53 ± 7 (P value = 0.001) and an increase in mean ± SD of the absolute neutrophil count from 6.33 ± 4.2 to 12 ± 5.5 (P value = 0.015). Leukocytosis was observed in 31% (5/16) of the patients on day 1 and in 80% (4/5) on day 21. Transient leukopenia developed in 6% (1/16) of the patients on day 1 and in 13% (1/8) on day 8. None of the patients had neutropenia. Lymphopenia was a prominent feature with a rate of 44% (7/16) of the patients on day 1 and 60% (3/5) on day 21. Lymphocytosis was not a feature of MERS‐CoV infection. Thrombocytopenia developed in 31% (5/16) of the patients on day 1 and 40% (2/5) on day 21. Thrombocytosis was not a prominent feature and was observed in 6% (1/16) of the patients on day 1 and 17% (1/6) on day 9. CONCLUSIONS: Patients with MERS‐CoV infection showed variable hematologic parameters over time. Lymphocytosis and neutropenia were not features of MERS‐CoV infection.


title: Chapter 2 Virus Replication

text: Abstract The replication processes used by individual viruses is highly variable. However, all viruses must attach to a susceptible host cell, enter the cell, disassemble the virus particle (uncoating), replicate its own genetic material and express the associated proteins, assemble new virus particles, and escape from the infected cell (release). This chapter will outline the general processes involved in each of these steps.


title: Using ICD-10 codes to identify elective epilepsy monitoring unit admissions from administrative billing data: A validation study

text: Video-electroencephalogram (EEG) monitoring in the epilepsy monitoring unit (EMU) is essential for managing epilepsy and seizure mimics. Evaluation of care in the EMU would benefit from a validated code set capable of identifying EMU admissions from administrative databases comprised of large, diverse cohorts. We assessed the ability of code-based queries to parse EMU admissions from administrative billing records in a large academic medical center over a four-year period, 2016–2019. We applied prespecified queries for admissions coded as follows: 1) elective, 2) receiving video-EEG monitoring, and 3) including diagnoses typically required by major US healthcare payers for EMU admission. Sensitivity (Sn), specificity (Sp), and predictive value positive/negative (PVP, PVN) were determined. Two approaches were highly effective. Incorporating epilepsy, seizure, or seizure mimic codes as the admitting diagnosis (assigned at admission; Sn 96.3%, Sp 100.0%, PVP 98.3%, and PVN 100.0%) or the principal diagnosis (assigned after discharge; Sn 94.9%, Sp 100.0%, PVP 98.8%, and PVN 100.0%) identified elective adult EMU admissions with comparable reliability (p = 0.096). The addition of surgical procedure codes further separated EMU admissions for intracranial EEG monitoring. When applied to larger, more comprehensive datasets, these code-based queries should enhance our understanding of EMU utilization and access to care on a scalable basis.


title: Antibody Repertoire of Human Polyclonal Antibodies Against Ebola Virus Glycoprotein Generated After Deoxyribonucleic Acid and Protein Vaccination of Transchromosomal Bovines

text: Several Ebola vaccines and therapeutics are under clinical development. However, limited knowledge exists on the quality of antibody response generated by different Ebola vaccines. In this study, antibody repertoire induced by vaccination of transchromosomal bovine (TcB) with Ebola virus (EBOV) glycoprotein ([GP]; recombinant GP [rGP]) encoded by either deoxyribonucleic acid (DNA) or nanoparticle-based vaccine platform was analyzed using EBOV genome fragment phage display library and surface plasmon resonance (SPR)-based real-time kinetics assay to measure antibody affinity maturation to both native and partially denatured Ebola GP as well as GP containing the receptor binding domain but lacking the mucin-like domain. Immunoglobulin (IgG) obtained from rGP nanoparticle-vaccinated TcB demonstrated ~4-fold higher binding affinity compared with DNA-vaccinated TcB-induced IgG against the native rGP’s. The rGP nanoparticle vaccine generated a more robust and diverse antibody immune response to the native EBOV-GP compared with the DNA vaccine, which may explain the protective efficacy observed for these antibody preparations.


title: Clinical prevention and population health Curriculum framework for health professions

text: Abstract The Clinical Prevention and Population Health Curriculum Framework is the initial product of the Healthy People Curriculum Task Force convened by the Association of Teachers of Preventive Medicine and the Association of Academic Health Centers. The Task Force includes representatives of allopathic and osteopathic medicine, nursing and nurse practitioners, dentistry, pharmacy, and physician assistants. The Task Force aims to accomplish the Healthy People 2010 goal of increasing the prevention content of clinical health professional education. The Curriculum Framework provides a structure for organizing curriculum, monitoring curriculum, and communicating within and among professions. The Framework contains four components: evidence base for practice, clinical preventive services–health promotion, health systems and health policy, and community aspects of practice. The full Framework includes 19 domains. The title “Clinical Prevention and Population Health” has been carefully chosen to include both individual- and population-oriented prevention efforts. It is recommended that all participating clinical health professions use this title when referring to this area of curriculum. The Task Force recommends that each profession systematically determine whether appropriate items in the Curriculum Framework are included in its standardized examinations for licensure and certification and for program accreditation.


title: Population pharmacokinetics and pharmacodynamics of chloroquine in a Plasmodium vivax volunteer infection study

text: Chloroquine has been used for the treatment of malaria for more than 70 years; however, chloroquine pharmacokinetic (PK) and pharmacodynamic (PD) profile in Plasmodium vivax malaria is poorly understood. The objective of this study was to describe the PKPD relationship of chloroquine and its major metabolite, desethylchloroquine, in a P. vivax volunteer infection study. We analyzed data from 24 healthy subjects who were inoculated with blood‐stage P. vivax malaria and administered a standard treatment course of chloroquine. The PK of chloroquine and desethylchloroquine was described by a two‐compartment model with first‐order absorption and elimination. The relationship between plasma and whole blood concentrations of chloroquine and P. vivax parasitemia was characterized by a PKPD delayed response model, where the equilibration half‐lives were 32.7 h (95% CI: 27.4–40.5) for plasma data and 24.1 h (95% CI: 19.0–32.7) for whole blood data. The estimated parasite multiplication rate was 17 folds per 48 hours (95% CI: 14–20) and maximum parasite killing rate by chloroquine was 0.213 h(‐1) (95% CI: 0.196–0.230), translating to a parasite clearance half‐life of 4.5 h (95% CI: 4.1–5.0) and a parasite reduction ratio of 400 every 48 hours (95% CI: 320–500). This is the first study that characterized the PKPD relationship between chloroquine plasma and whole blood concentrations and P. vivax clearance using a semi‐mechanistic population PKPD modelling. This PKPD model can be used to optimize dosing scenarios and to identify optimal dosing regimens for chloroquine where resistance to chloroquine is increasing.


title: Development of Hepatocyte‐like Cell Derived from Human Induced Pluripotent Stem cell as a Host for Clinically Isolated Hepatitis C Virus

text: This unit describes protocols to develop hepatocyte‐like cells (HLCs) starting from mesenchymal stem cells (MSCs) as a natural host for hepatitis C virus (HCV). These include the preparation of MSCs from bone marrow, the reprogramming of MSCs into induced pluripotent stem cells (iPSCs), and the differentiation of iPSCs into HLCs. This unit also incorporates the characterization of the resulting cells at each stage. Another section entails the preparations of HCV. The sources of HCV are either the clinically isolated HCV (HCVser) and the conventional JFH‐1 genotype. The last section is the infection protocol coupled with the measurement of viral titer. © 2017 by John Wiley & Sons, Inc.


title: Mathematical assessment of the impact of non-pharmaceutical interventions on curtailing the 2019 novel Coronavirus

text: A pandemic of a novel Coronavirus emerged in December of 2019 (COVID-19), causing devastating public health impact across the world. In the absence of a safe and effective vaccine or antivirals, strategies for controlling and mitigating the burden of the pandemic are focused on non-pharmaceutical interventions, such as social-distancing, contact-tracing, quarantine, isolation, and the use of face-masks in public. We develop a new mathematical model for assessing the population-level impact of the aforementioned control and mitigation strategies. Rigorous analysis of the model shows that the disease-free equilibrium is locally-asymptotically stable if a certain epidemiological threshold, known as the reproduction number (denoted by [Formula: see text]), is less than unity. Simulations of the model, using data relevant to COVID-19 transmission dynamics in the US state of New York and the entire US, show that the pandemic burden will peak in mid and late April, respectively. The worst-case scenario projections for cumulative mortality (based on the baseline levels of anti-COVID non-pharmaceutical interventions considered in the study) decrease dramatically by 80% and 64%, respectively, if the strict social-distancing measures implemented are maintained until the end of May or June, 2020. The duration and timing of the relaxation or termination of the strict social-distancing measures are crucially-important in determining the future trajectory of the COVID-19 pandemic. This study shows that early termination of the strict social-distancing measures could trigger a devastating second wave with burden similar to those projected before the onset of the strict social-distancing measures were implemented. The use of efficacious face-masks (such as surgical masks, with estimated efficacy [Formula: see text] 70%) in public could lead to the elimination of the pandemic if at least 70% of the residents of New York state use such masks in public consistently (nationwide, a compliance of at least 80% will be required using such masks). The use of low efficacy masks, such as cloth masks (of estimated efficacy less than 30%), could also lead to significant reduction of COVID-19 burden (albeit, they are not able to lead to elimination). Combining low efficacy masks with improved levels of the other anti-COVID-19 intervention strategies can lead to the elimination of the pandemic. This study emphasizes the important role social-distancing plays in curtailing the burden of COVID-19. Increases in the adherence level of social-distancing protocols result in dramatic reduction of the burden of the pandemic, and the timely implementation of social-distancing measures in numerous states of the US may have averted a catastrophic outcome with respect to the burden of COVID-19. Using face-masks in public (including the low efficacy cloth masks) is very useful in minimizing community transmission and burden of COVID-19, provided their coverage level is high. The masks coverage needed to eliminate COVID-19 decreases if the masks-based intervention is combined with the strict social-distancing strategy.


docid: uohbxoeb

title: Remdesivir for the Treatment of Covid-19 — Preliminary Report

text: BACKGROUND: Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), none have yet been shown to be efficacious. METHODS: We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults hospitalized with Covid-19 with evidence of lower respiratory tract involvement. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only. RESULTS: A total of 1063 patients underwent randomization. The data and safety monitoring board recommended early unblinding of the results on the basis of findings from an analysis that showed shortened time to recovery in the remdesivir group. Preliminary results from the 1059 patients (538 assigned to remdesivir and 521 to placebo) with data available after randomization indicated that those who received remdesivir had a median recovery time of 11 days (95% confidence interval [CI], 9 to 12), as compared with 15 days (95% CI, 13 to 19) in those who received placebo (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; P<0.001). The Kaplan-Meier estimates of mortality by 14 days were 7.1% with remdesivir and 11.9% with placebo (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04). Serious adverse events were reported for 114 of the 541 patients in the remdesivir group who underwent randomization (21.1%) and 141 of the 522 patients in the placebo group who underwent randomization (27.0%). CONCLUSIONS: Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with Covid-19 and evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTT-1 ClinicalTrials.gov number, NCT04280705.)


title: Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study

text: BACKGROUND: Over 40 000 patients with COVID-19 have been hospitalised in New York City (NY, USA) as of April 28, 2020. Data on the epidemiology, clinical course, and outcomes of critically ill patients with COVID-19 in this setting are needed. METHODS: This prospective observational cohort study took place at two NewYork-Presbyterian hospitals affiliated with Columbia University Irving Medical Center in northern Manhattan. We prospectively identified adult patients (aged ≥18 years) admitted to both hospitals from March 2 to April 1, 2020, who were diagnosed with laboratory-confirmed COVID-19 and were critically ill with acute hypoxaemic respiratory failure, and collected clinical, biomarker, and treatment data. The primary outcome was the rate of in-hospital death. Secondary outcomes included frequency and duration of invasive mechanical ventilation, frequency of vasopressor use and renal replacement therapy, and time to in-hospital clinical deterioration following admission. The relation between clinical risk factors, biomarkers, and in-hospital mortality was modelled using Cox proportional hazards regression. Follow-up time was right-censored on April 28, 2020 so that each patient had at least 28 days of observation. FINDINGS: Between March 2 and April 1, 2020, 1150 adults were admitted to both hospitals with laboratory-confirmed COVID-19, of which 257 (22%) were critically ill. The median age of patients was 62 years (IQR 51–72), 171 (67%) were men. 212 (82%) patients had at least one chronic illness, the most common of which were hypertension (162 [63%]) and diabetes (92 [36%]). 119 (46%) patients had obesity. As of April 28, 2020, 101 (39%) patients had died and 94 (37%) remained hospitalised. 203 (79%) patients received invasive mechanical ventilation for a median of 18 days (IQR 9–28), 170 (66%) of 257 patients received vasopressors and 79 (31%) received renal replacement therapy. The median time to in-hospital deterioration was 3 days (IQR 1–6). In the multivariable Cox model, older age (adjusted hazard ratio [aHR] 1·31 [1·09–1·57] per 10-year increase), chronic cardiac disease (aHR 1·76 [1·08–2·86]), chronic pulmonary disease (aHR 2·94 [1·48–5·84]), higher concentrations of interleukin-6 (aHR 1·11 [95%CI 1·02–1·20] per decile increase), and higher concentrations of D-dimer (aHR 1·10 [1·01–1·19] per decile increase) were independently associated with in-hospital mortality. INTERPRETATION: Critical illness among patients hospitalised with COVID-19 in New York City is common and associated with a high frequency of invasive mechanical ventilation, extrapulmonary organ dysfunction, and substantial in-hospital mortality. FUNDING: National Institute of Allergy and Infectious Diseases and the National Center for Advancing Translational Sciences, National Institutes of Health, and the Columbia University Irving Institute for Clinical and Translational Research.