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Antiviral agents against respiratory viruses

Outcomes of Three- Versus Six-Monthly Dispensing of Antiretroviral Treatment (ART) for Stable HIV Patients in Community ART Refill Groups: A Cluster-Randomized Trial in Zimbabwe

INTRODUCTION: Multimonth dispensing (MMD) of antiretroviral treatment (ART) aims to reduce patient-related barriers to access long-term treatment and improve health system efficiency. However, randomized evidence of its clinical effectiveness is lacking. We compared MMD within community ART refill groups (CARGs) vs. standard-of-care facility-based ART delivery in Zimbabwe. METHODS: A three-arm, cluster-randomized, pragmatic noninferiority trial was performed. Thirty health care facilities and associated CARGs were allocated to either ART collected three-monthly at facility (3MF, control); ART delivered three-monthly in CARGs (3MC); or ART delivered six-monthly in CARGs (6MC). Stable adults receiving ART ≥six months with baseline viral load (VL) <1000 copies/ml were eligible. Retention in ART care (primary outcome) and viral suppression (VS) 12 months after enrollment were compared, using regression models specified for clustering (ClinicalTrials.gov: NCT03238846). RESULTS: 4800 participants were recruited, 1919, 1335, and 1546 in arms 3MF, 3MC, and 6MC, respectively. For retention, the prespecified noninferiority limit (-3.25%, risk difference [RD]) was met for comparisons between all arms, 3MC (94.8%) vs. 3MF (93.0%), adjusted RD = 1.1% (95% CI: -0.5% to 2.8%); 6MC (95.5%) vs. 3MF: aRD = 1.2% (95% CI: -1.0% to 3.6%); and 6MC vs. 3MC: aRD = 0.1% (95% CI: -2.4% to 2.6%). VL completion at 12 months was 49%, 45%, and 8% in 3MF, 3MC, and 6MC, respectively. VS in 3MC (99.7%) was high and not different to 3MF (99.1%), relative risk = 1.0 (95% CI: 1.0-1.0). VS was marginally reduced in 6MC (92.9%) vs. 3MF, relative risk = 0.9 (95% CI: 0.9-1.0). CONCLUSION: Retention in CARGs receiving three- and six-monthly MMD was noninferior versus standard-of-care facility-based ART delivery. VS in 3MC was high. VS in six-monthly CARGs requires further evaluation.

Correlation of urine pH with the detection of cytomegalovirus by the shell vial technique

The influence of the pH of urine on the detection of cytomegalovirus (CMV) by the shell vial assay was evaluated. The pH values of 295 urine specimens ranged from 4.7 to 8.5 (mean 6.3) and were not significantly different in culture-positive versus culture-negative samples. None of the urine specimens appeared to be toxic for the cells used in the shell vial assay. We recommend inoculation of urine specimens into shell vials without adjustment of pH.

Viral infections and recurrences of febrile convulsions()

To determine whether complicated febrile seizures occur more often in children with a proven viral infection, we performed viral examinations on 144 children with febrile convulsions, of whom 112 had simple and 32 had complicated seizures. A diagnosis of virus infection was verified in 46% of the former patients and 53% of the latter. Three adenoviruses, one parainfluenza virus type 2 and one type 3, one respiratory syncytial virus, one echovirus type 11, one herpes simplex virus type 2, and one influenza B virus were isolated from the cerebrospinal fluid. A simple febrile convulsion occurred in seven children with a positive cerebrospinal fluid viral isolation, and two had a complex febrile seizure. In a follow-up of 2 to 4 years (mean 3.3 years), 21 of the 107 children with simple seizures (19.6%) and 3 of the 32 children with complicated seizures (9.4%) had recurrent febrile seizures. The children with positive evidence for a viral infection, even with a virus isolated from the cerebrospinal fluid, had no more recurrences than those without any proven viral infection. We conclude that children with a proven viral infection have no worse prognosis than those without.

O14 Has the 7-valent pneumococcal conjugate vaccine (PCV7) reduced hospital visits and admissions for pneumonia in young children in Calgary?

Avian flu virus H5N1: No proof for existence, pathogenicity, or pandemic potential; non-“H5N1” causation omitted

The Morphology of Virus-Antibody Interaction

In the field of virus study, the electron microscope technique of negative staining is now more than 10 years old, and during these years the knowledge of virus fine structure has changed beyond all recognition. This chapter describes that the immune aggregate should be incubated for 1 hour at 37°C and then left in the cold overnight. This is the optimum approach for a system, where the concentration of neither the antigen nor the antiserum is known, and maximum clumping is needed. However, with many systems these parameters have been established, and if it is known that clumping can be obtained readily, for example, as with the avian infectious bronchitis system, then incubation for 1 hour at 37°C is sufficient, followed by spinning at 10,000 rpm for half an hour. Viruses in the small to intermediate size range are ideal for immune studies, as the particles are not disproportionately larger than the antibody molecules attached to them, and interaction between them can be visualized with better than 10 a resolution. Particles as large as the poxviruses are becoming too large for good resolution of antibody molecules to be obtained, and aggregates of poxvirus particles are usually too dense to be recorded photographically except at low power. In the field of clinical virology, there is a possibility that the electron microscope technique of negative staining will become a standard method of diagnosis. As far as research is concerned, the present article seems to have described the beginnings that have been made in the visualization of several aspects of antigen-antibody interaction. Each line investigated has yielded a few answers, but of much greater importance, has led to a better understanding of what questions should be asked. At present, viral antigens can only occasionally be obtained in pure form, such that there are only a very few systems where controlled and specific virus-antigen-antibody systems can be visualized.

Tailed Bacteriophages: The Order Caudovirales

This chapter discusses the common properties of tailed phages and potential criteria for their classification as an order and situating tailed phages with respect to other viruses. Tailed bacteriophages have a common origin and constitute an order with three families, named Caudovirales. Their structured tail is unique. Tailed phages share a series of high-level taxonomic properties and show many facultative features that are unique or rare in viruses—for example, tail appendages and unusual bases. They share with other viruses, especially herpesviruses, elements of morphogenesis and lifestyle that are attributed to convergent evolution. Tailed phages present three types of lysogeny, exemplified by phages λ, Mu, and P1. Lysogeny appears as a secondary property acquired by horizontal gene transfer. Amino acid sequence alignments (notably of DNA polymerases, integrases, and peptidoglycan hydrolases) indicate frequent events of horizontal gene transfer in tailed phages. Common capsid and tail proteins have not been detected. Present-day tailed phages appear as chimeras, but their monophyletic origin is still inscribed in their morphology, genome structure, and replication strategy. It may also be evident in the three-dimensional structure of capsid and tail proteins. It is unlikely to be found in amino acid sequences because constitutive proteins must be so old that relationships were obliterated and most or all replication-, lysogeny-, and lysis-related proteins appear to have been borrowed.

Phosphorylation of the mouse hepatitis virus nucleocapsid protein

Analysis of the radiolabeled tryptic peptides derived from the nucleocapsid proteins of two serotypes of mouse hepatitis virus showed each to have a small number of unique peptides; however, twobiologically distinct variants of the JHM strain appeared identical. Analysis of [(32)P]-labeled nucleocapsid-derived peptides showed that phosphorylation occurs at only a few sites and that all three viruses differed in the sites of phosphorylation. No differences in the sites of phosphorylation were found between the nucleocapsid proteins derived from purified virions and the membranes or the cytosol of infected cells, suggesting that post-translational phosphorylation plays no role in the regulation of viral assembly. These data show unequivocal evidence that the nucleocapsid proteins of mouse hepatitis virus strains differ in the sites of phosphorylation.

Biological studies of the fusion function of California serogroup Bunyaviruses

Like other enveloped viruses, La Crosse virus is capable of inducing membrane fusion after exposure to mild acid. This function is known to have biological significance at the level of the whole organism, since it has been related to infection in a mouse model. In this report the process of fusion-from-within (FFWI) for LAC and other members of the California serogroup of Bunyaviruses is characterized. Like fusion-from-without, FFWI is dependent on pH, temperature, and number of virus particles present in the supernatant of fusing cells. Electron micrographs demonstrate that LAC mediated cell membrane fusion is a rapid, multi-point event, and that other than fusion of their plasma membranes, the cells do not show any morphological change. In agreement with theory, lysosomotropic agents were capable of inhibiting La Crosse virus infection. This inhibition was not due to non-specific toxic effects on infected cells. Finally, fusion studies of other California serogroup members revealed minor differences in the pH of fusion induction in some strains. These differences were consistent with the known subtyping within the serogroup.

An ELISA system for evaluating antiretroviral activity against Rauscher murine leukemia virus

A system for evaluating the activity of antiviral agents against Rauscher murine leukemia virus (R-MuLV) has been developed using an enzyme linked immunosorbent assay technique. The activity of various antiviral compounds demonstrated in this assay system has been compared to their activity in the UV-XC plaque reduction assay, which has been used historically for evaluating anti-R-MuLV compounds. The assay is based upon detection of R-MuLV encoded p30 protein production in virus infected murine cells. The assay reagents are readily available and the assay system is amenable to automated data collection systems. Cytotoxicity evaluations are conducted in parallel to the Rauscher MuLV ELISA assay in order to assess drug-induced reductions in cell viability. Cytotoxicity evaluations are important to interpretation of the ELISA results since reductions in cell viability reduce viral protein production which would indicate an antiviral drug effect. This system is less sensitive than the classical UV-XC plaque reduction assay; however, it does offer an alternative to the time-consuming and labor-intensive plaque assay.

Antibody-Mediated Destruction of Virus-Infected Cells

This chapter describes the effect of antibody on virus-infected cells with special reference to the human system. The destruction by antibody of the infected cells through the mediation of complement is described in detail based in considerable part on the contributions of the authors. Activation of the alternative pathway by the various infected cells is of special interest. The interesting effect of the antibody-dependent cell-mediated cytotoxicity (ADCC) system involving viral antigens in cell killing is also presented. Multiple additional topics are also covered, such as the effect of antibody on the expression of viral proteins both on the surface of the cell and intracellularly. Serum antibody, produced in response to virus infections, is of major importance in preventing the spread of infection by virtue of neutralizing free virus in extracellular fluids. Virus neutralization by antibody is enhanced by complement. Antibody binding to the surface of virus-infected cells can affect virus production and release in the absence of an effector system. Immunoglobulin (IgG) antibody can mediate the destruction of virus-infected cells in conjunction with complement or cytotoxic lymphocytes. In addition, at a conceptual level there is evidence to suggest that antibody may enhance and confer specificity on basic nonspecific humoral and cell-mediated defense mechanisms.

Human bocavirus 1 may suppress rhinovirus-associated immune response in wheezing children

Modulation of MHC antigen expression by viruses and oncogenes

It is becoming increasingly clear that regulation of MHC antigen expression by viruses and oncogenes, leading to either immune evasion or autoimmunity, is widespread and important in disease. At a recent meeting, which brought together workers interested in tumour immunology, viral infection and the MHC, a number of mechanisms for the regulation of MHC antigen expression were revealed and the importance of balanced expression of MHC gene products to effective immunity was underlined.

The potential use of liposome-mediated antiviral therapy

The natural targeting of liposomes to cells of the reticuloendothelial system should be exploited to examine whether selective delivery of antiviral or immunomodulatory agents could be beneficial for the treatment of viral diseases. In this review we discuss the potential use of liposomes in the treatment of virus diseases, the targeting of liposome-encapsulated immunomodulators to macrophages in order to render these cells cytolytic for virus-infected cells, and the targeting of liposome-encapsulated antiviral drugs to macrophages to achieve direct suppression of virus replication within these cells.

Muramyl peptides confer hepatoprotection against murine viral hepatitis

The hepatoprotection induced by synthetic muramyl peptides was investigated using a model of lethal murine mouse hepatitis MHV-3 virus infection. MDP and a nonpyrogenic analog, Murametide, inhibited the steep elevation of serum transaminases induced by MHV-3 irrespective of whether the immunomodulators were administered before or after the infection. A significant proportion of MDP or Murametide-treated animals, in contrast to controls, survived the MHV-3 infection. The histopathological examination of the liver revealed marked necrosis of the hepatic parenchymal cells and infiltration of the inflammatory cells in controls but not in MDP-treated animals.

Complex Carbohydrates in Drug Development

Recent advances in carbohydrate chemistry and biochemistry afford the opportunity to develop bioactive complex carbohydrates, per se, as drugs or as lead compounds in drug development. Complex carbohydrates are unique among biopolymers in their inherent potential to generate diverse molecular structures. While proteins vary only in the linear sequence of their monomer constituents, individual monosaccharides can combine at any of several sites on each carbohydrate ring, in linear or branched arrays, and with varied stereochemistry at each linkage bond. This chapter addresses some salient features of mammalian glycoconjugate structure and biosynthesis, and presents examples of the biological activities of complex carbohydrates. The chapter presents selected examples that will provide an accurate introduction to their pharmacological potential. In addition to their independent functions, oligosaccharides can modify the activities of proteins to which they are covalently attached. Many glycoprotein enzymes and hormones require glycosylation for expression and function. The chapter discusses the ancillary role of carbohydrates that is of great importance to the use of engineered glycoproteins as pharmaceuticals.

Increased susceptibility of aged rats to haemorrhage and intravascular hypercoagulation following endotoxin administered in a generalized Shwartzman regime

Ageing rats are known to have an increased incidence of myocardial fibrosis and dyspnoea caused by pulmonary intravascular coagulation. In order to determine whether endotoxin can be responsible for such responses in ageing rats we have exposed rats of differing ages (2 months, 16 months and 24 months) to single or repeated (two doses 24 h apart; generalized Shwartzman regime) intravenous doses of endotoxin (E. coli 0111134). Only the 2-year-old rats reacted adversely. Two doses of endotoxin produced death, with focal myocardial necrosis, haemorrhage and pulmonary and hepatic intravascular coagulation. The increased susceptibility of aged rats to the toxic effects of endotoxin explains some of the changes found in the tissues of old rats. The sporadic nature of both cardiac failure and dyspnoea as a cause of morbidity and mortality in ageing rats may be related to the need for two endotoxin episodes in a period of 24 h to provoke a generalized Shwartzman reaction, an occurrence likely to be relatively uncommon under natural conditions.

ASYMPTOMATIC ENDEMIC ROTAVIRUS INFECTIONS IN THE NEWBORN

Between May 1, 1976, and May 14, 1977, 343 (32·5%) of 1056 5-day-old babies in newborn nurseries excreted rotaviruses. The infection-rate was highest during winter (49%). 76% of infected babies at this time were bottle-fed. 41% of neonates excreted low amounts of virus (10(8) particles/g fæces); older children tended to excrete >10(10) particles/g fæces. Infected breast-fed babies excreted less virus than those who were bottle-fed. Stools of breast-fed babies often contained clumps of complete "smooth" rotavirus particles. When the newborn nurseries were transferred to a newly built hospital wing, infection appeared in the new wards, including those admitting only new patients, within a short period. Infection was either mild (8%) or symptomless (92%), and even babies with symptoms required no treatment.

Semliki Forest Virus: A Probe for Membrane Traffic in the Animal Cell

The traffic among the cellular compartments is thought to be mediated by membrane vesicles, which bud from one compartment and fuse with the next. Despite the continuous exchange of membrane components among them, the organelles maintain their characteristic protein and lipid compositions such that the traffic remains selective, thus, avoiding intermixing of components. This membrane traffic recycles components from the cell surface to the interior of the cell and back to the cell surface again. The membrane traffic between the ER and the cell surface involves a major sorting problem. Little is known of how the animal cell has solved this problem in molecular terms. One experimental tool in this direction is provided by some enveloped animal viruses, which mature at the cell surface of infected cells. Such viruses include influenza virus, Semliki Forest virus (SFV), Sindbis virus, and vesicular stomatitis virus (VSV). They are extremely simple in makeup and hence are very well characterized. The purpose of this article is to illustrate the use of the enveloped viruses as tools in the study of membrane traffic in the animal cell. This is done in the context of the life cycle of the virus in the host cell. The article will be concerned mainly with Semliki Forest virus (SFV), which is the virus that has been worked upon in the chapter. SFV belongs to the alphaviruses, a genus of the togavirus family.

DIAGNOSIS AND MANAGEMENT OF RHINITIS

The complaint of rhinitis is one of the most frequent reasons why patients seek a physician's evaluation. Rhinitis is an inflammatory response of the nasal mucosa to various stimuli (both allergic or nonallergic). It is characterized by symptoms of nasal congestion, sneezing, nasal pruritis, and rhinorrhea.(49) The prevalence of rhinitis and the economic impact for both patient and managed care organizations dictate that clinicians carefully consider the medications available to them.

Recent Developments in Viral Gastroenteritis

In recent years impressive advances have been made in understanding viral gastroenteritis. A specific causative agent has been identified in infants and young children, and studies of a similar but distinct enteritis in piglets have given new insight into the pathogenesis of viral diarrhea. This article discusses these recent findings in veterinary and human medicine.

CLINICAL VIRAL INFECTIONS AND MULTIPLE SCLEROSIS

Over an 8 year period, 170 patients with multiple sclerosis (MS) and 134 healthy controls were assessed at monthly intervals in order to ascertain environmental factors which might be important in producing exacerbation or progression of the illness, and to compare the frequency of common viral infections in the two groups. During cumulative periods designated "at risk" (2 weeks before the onset of infection until 5 weeks afterwards) annual exacerbation rates were almost 3-fold greater than those during periods not at risk. Approximately 9% of infections were temporally related to exacerbations, whereas 27% of exacerbations were related to infections. Frequency of common infections was approximately 20-50% less in MS patients than controls; it was progressively less in those with greater disability. Even in minimally disabled patients with similar potential for infectious contacts, the infection rate was significantly less than in controls, suggesting that MS patients could have superior immune defences against common viruses.

The blind watchmaker and rational protein engineering

In the present review some scientific areas of key importance for protein engineering are discussed, such as problems involved in deducting protein sequence from DNA sequence (due to posttranscriptional editing, splicing and posttranslational modifications), modelling of protein structures by homology, NMR of large proteins (including probing the molecular surface with relaxation agents), simulation of protein structures by molecular dynamics and simulation of electrostatic effects in proteins (including pH-dependent effects). It is argued that all of these areas could be of key importance in most protein engineering projects, because they give access to increased and often unique information. In the last part of the review some potential areas for future applications of protein engineering approaches are discussed, such as non-conventional media, de novo design and nanotechnology.

Early coagulopathy in severe iron poisoning

WHAT CLINICIANS NEED TO KNOW ABOUT ANTIVIRAL DRUGS AND VIRAL RESISTANCE

During the last decade, significant advances have been made in the development and use of antiviral agents for the successful treatment of a number of viral infections.8, 51, 57 An expanding array of antiviral drugs are currently available for the management of infections caused by herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), cytomegalovirus (CMV), varicella-zoster virus (VZV), influenza A virus, respiratory syncytial virus (RSV), human immunodeficiency virus type 1 (HIV-1), papillomaviruses, and hepatitis B and C viruses. The increased number and use of antiviral agents, however, has led to the emergence of drug-resistant viruses, particularly in immunocompromised patients such as those with acquired immunodeficiency syndrome (AIDS) or hematologic malignancy or those who have undergone organ transplantation. For comprehensive reviews on specific viruses, see references 26, 41, 64, 81–83, and 102. Clinical situations that favor the development of resistance include long-term suppressive therapy, recurrent intermittent therapy, and the use of less than optimum doses of an antiviral agent. Generally, the emergence and isolation of drug-resistant viruses is associated more so with the therapeutic use of antiviral agents and does not seem to be caused by prophylactic treatment. As more patients fail to respond to appropriate therapy and additional antiviral agents are produced, it will also become important for diagnostic virology laboratories to provide rapid and practical antiviral susceptibility testing to assist physicians in defining drug resistance and choosing appropriate alternative therapies. This review describes the major antiviral agents, their mechanisms of action, and the development of drug resistance following antiviral therapy. A brief overview of the available phenotypic and genotypic susceptibility assays for detecting antiviral resistance is also discussed.

The Molecular Biology of Influenza Virus Pathogenicity

It is an accepted concept that the pathogenicity of a virus is of polygenic nature. Because of their segmented genome, influenza viruses provide a suitable system to prove this concept. The studies employing virus mutants and reassortants have indicated that the pathogenicity depends on the functional integrity of each gene and on a gene constellation optimal for the infection of a given host. As a consequence, virtually every gene product of influenza virus has been reported to contribute to pathogenicity, but evidence is steadily growing that a key role has to be assigned to hemagglutinin. As the initiator of infection, hemagglutinin has a double function: (1) promotion of adsorption of the virus to the cell surface, and (2) penetration of the viral genome through a fusion process among viral and cellular membranes. Adsorption is based on the binding to neuraminic acid-containing receptors, and different virus strains display a distinct preference for specific oligosaccharides. Fusion capacity depends on proteolytic cleavage by host proteases, and variations in amino acid sequence at the cleavage site determine whether hemagglutinin is activated in a given cell. Differences in cleavability and presumably also in receptor specificity are important determinants for host tropism, spread of infection, and pathogenicity. The concept that proteolytic activation is a determinant for pathogenicity was originally derived from studies on avian influenza viruses, but there is now evidence that it may also be relevant for the disease in humans because bacterial proteases have been found to promote the development of influenza pneumonia in mammals.

Mouse hepatitis virus infection of mice causes long-term depletion of lactate dehydrogenase-elevating virus-permissive macrophages and T lymphocyte alterations

Intraperitoneal injection of pathogen-free B10.A mice with mouse hepatitis virus (MHV)-A59 resulted in a short subclinical infection which was terminated by a rapid antiviral immune response. The infection resulted in a rapid, but transient, about 10-fold increase in the number of macrophages and total cells in the peritoneum of the mice. This increase was preceded by a complete depletion of the peritoneum of the subpopulation of macrophages that supports a productive infection by lactate dehydrogenase-elevating virus (LDV). The depletion of LDV-permissive macrophages was a long-term effect; at 50 days post-infection with MHV, the proportion of LDV-permissive macrophages in the peritoneum had reached only 20% of that observed in the peritoneum of uninfected mice, whereas the total number of macrophages in the peritoneum had returned to normal. Furthermore, MHV infection resulted in a long-term alteration in the proliferative response of spleen T cells to concanavalin A (ConA) and in their ability to produce interferon γ; several times higher concentrations of ConA were required to induce a maximum proliferative response in spleen T cell populations from 5-week MHV-infected B10.A mice than in spleen T cell populations from infected companion mice but the former produced 5 times more interferon γ than the T cells from unifected mice.

Inflammation: Patterns and new concepts

Ethical aspects of vaccines and vaccination

Microbial nomenclature: A list of names and origins

Microbial nomenclature underwent a large number of changes in the 1970s. Many species of pathogens were added and many others experienced name changes. These modifications primarily were due to two unrelated factors: the use of new DNA hybridization techniques and the advent of computerized literature searches to establish historical precedence. In 1980 an approved list of microbial names was published. This list fixed and legitimized bacterial nomenclature. All future additions or alterations to it had to pass international scientific committees. This list has now been accepted by the scientific community. The derivation of these names are presented in this review.

Viral Pathogens of the Penaeid Shrimp

While significant advances that have been made in determining the role of viruses involved in various epizootics occurring in penned shrimp aquaculture, viral diseases will continue to plague the industry. A major obstacle to the study of these diseases is the lack of convenient and quantitative methodologies, such as in vitro cell culture systems to grow and study (characterize) the virus. A beginning has been made with the recent development of protocols for the consistent preparation of primary shrimp lymphoid cells, which were employed for the quanta1 assay of some of the shrimp viral pathogens. The primary cell lines have also been used to analyze the synthesis of viral proteins at the cellular level and to study viral pathogenesis. With the further successful development of additional primary cell lines from other shrimp tissues and the establishment of continuous diploid and transformed shrimp cell lines, this problem is being solved. The value of cell culture systems is becoming increasingly clear. They present several obvious advantages because (1) they are more cost effective, sensitive, and convenient than whole animals, particularly for rapid monitoring of infectivity, (2) they yield quantitatively reproducible results, and (3) viral growth kinetics, biochemical and genetic characteristics, and so on can be studied more easily. Their biggest potential use is in future molecular biology and genetic studies of shrimp viruses.

AN ENVELOPED VIRUS IN STOOLS OF CHILDREN AND ADULTS WITH GASTROENTERITIS THAT RESEMBLES THE BREDA VIRUS OF CALVES

Pleomorphic virus-like particles about 100 nm in diameter with a fringe of closely applied peplomers (7-9 nm in length) were observed by electron microscopy in the stools of 20 children and adults with gastroenteritis. In most of the samples no other viral or bacterial pathogens were detected. In form and under immune electron microscopy these virus-like particles resembled the Breda virus isolated from diarrhoeic calves. These objects may be a viral pathogen of humans.

The microbiology associated with cystic fibrosis

Summary of the II international consensus symposium on combined antiviral therapy and implications for future therapies

Persistent Viral Infections as Models for Research in Virus Chemotherapy

The acute systemic virus infection is commonly used as an experimental model in chemotherapy research despite the fact that the chance for an effective chemotherapy of acute virus infections is small. In most acute infections, virus multiplication is well advanced before the disease is expressed and treatment will, in many cases, come too late. However, control by chemotherapy might be promising for persistent virus infections, where, owing to the slow progression of the disease, sufficient time for treatment is available. Although there are various ways in which viruses can persist in their hosts, comparative studies in vitro and in vivo reveal common features that shall be briefly reviewed. Animal models with persistent virus infections are usually difficult to experiment with because of the varying length of the incubation period brought about by the complex relationship among virus replication, immune reactions, and disease.

Virology of hepatitis C virus

Hepatitis C virus (HCV) has been identified as the main causative agent of post-transfusion non-A, non-B hepatitis. Through recently developed diagnostic assays, routine serologic screening of blood donors has prevented most cases of post-transfusion hepatitis. The purpose of this paper is to comprehensively review current information regarding the virology of HCV. Recent findings on the genome organization, its relationship to other viruses, the replication of HCV ribonucleic acid, HCV translation, and HCV polyprotein expression and processing are discussed. Also reviewed are virus assembly and release, the variability of HCV and its classification into genotypes, the geographic distribution of HCV genotypes, and the biologic differences between HCV genotypes. The assays used in HCV genotyping are discussed in terms of reliability and consistency of results, and the molecular epidemiology of HCV infection is reviewed. These approaches to HCV epidemiology will prove valuable in documenting the spread of HCV in different risk groups, evaluating alternative (nonparenteral) routes of transmission, and in understanding more about the origins and evolution of HCV.

Epidemiology and Treatment of Chronic Bronchitis and Its Exacerbations

Veterinary vaccines

Vaccination of animals for the prevention of infectious diseases has been practised for a number of years with little change in product composition. Recent advances in molecular biology, pathogenesis and immunology have laid the groundwork for the development of a new generation of veterinary vaccines based on pure subunits as well as live vectored bacteria and viruses. Along with novel methods of antigen preparation, the use of new adjuvants and delivery systems will permit targeting of the appropriate immune response as well as offering flexibility in terms of vaccination protocols. These new technologies are also being applied to the development of vaccines to enhance animal productivity and to control reproduction.

Distinctive features of foot-and-mouth disease virus, a member of the picornavirus family; aspects of virus protein synthesis, protein processing and structure

Diversity of coding strategies in influenza viruses

Influenza viruses have exploited a variety of strategies to increase their genome coding capacities. These include unspliced, spliced, alternatively spliced and bicistronic mRNAs, translation from overlapping reading frames and a coupled stop-start translation of tandem cistrons.

Structural organization, expression and chromosomal mapping of the mouse cystatin-C-encoding gene (Cst3)

Cystatin C (CstC) is a potent cysteine-proteinase inhibitor. The structure of the mouse CstC-encoding gene (Cst3) was examined by sequencing a 6.1-kb genomic DNA containing the entire gene, as well as 0.9 kb of 5′ flanking and 1.7 kb of its 3′ flanking region. The sequence revealed that the overall organization of the gene is very similar to those of the genes encoding human CstC and other type-2 Cst, with two introns at positions identical to those in the human gene. The promoter area does not contain typical TATA or CAAT ☐es. Two copies of a Spl-binding motif, GGGCGG, are present in the 5′ flanking region within 300 bp upstream from the initiation codon. A hexa-nucleotide, TGTTCT, which is a core sequence of the androgen-responsive element (ARE), is found in the promoter region. This region also contains a 21-nucleotide sequence, 5′-AGACTAGCAGCTGACTGAAGC, which contains two potential binding sites for the transcription factor, AP-1. The mouse Cst3 mRNA was detected in all of thirteen tissues examined by Northern blot analysis. Cst3 was mapped in the mouse to a position on distal chromosome 2.

Inactivation of viral antigens for vaccine preparation with particular reference to the application of binary ethylenimine

Viral antigens for human and veterinary vaccines are still inactivated with formaldehyde. This is not an ideal inactivant and the problems of formaldehyde inactivation of vaccines are discussed. Vaccines inactivated with aziridines are superior in safety and antigenicity. Aziridines inactivate viruses in a first-order reaction and the inactivation rate and endpoint can be determined. The preparation and application of the aziridine compound binary ethylenimine (BEI) and the necessary conditions for and controls of the inactivation process are described and discussed. A computer program has been written for assistance in the use of BEI for controlled inactivation of viral antigens.

Binding of Plasmodium falciparum 175-kilodalton erythrocyte binding antigen and invasion of murine erythrocytes requires N-acetylneuraminic acid but not its O-acetylated form

Sialic acid on human erythrocytes is involved in invasion by the human malaria parasite, Plasmodium falciparum. Mouse erythrocytes were used as a reagent to explore the question of whether erythrocyte sialic acid functions as a nonspecific negative charge or whether the sialic acid is a necessary structural part of the receptor for merozoites. Human erythrocytes contain N-acetylneuraminic acid (Neu5Ac), whereas mouse erythrocytes, which are also invaded by P. falciparum merozoites, contain 9-O-acetyl-N-acetylneuraminic acid (Neu5,9Ac(2)) and N-glycoloylneuraminic acid (Neu5Gc), in addition to Neu5Ac. We compared the effects of sialidase and influenza C virus esterase treatments of mouse erythrocytes on invasion and the binding of a 175-kDa P. falciparum protein (EBA-175), a sialic acid-dependent malaria ligand implicated in the invasion process. Sialidase-treated mouse erythrocytes were refractory to invasion by P. falciparum merozoites and failed to bind EBA-175. Influenza C virus esterase, which converts Neu5,9Ac(2) to Neu5Ac, increased both invasion efficiency and EBA-175 binding to mouse erythrocytes. Thus, the parasite and EBA-175 discriminate between Neu5Ac and Neu5,9Ac(2), that is, the C-9 acetyl group interferes with EBA-175 binding and invasion by P.falciparum merozoites. This indicates that sialic acid is part of a receptor for invasion.

Increased influenza A virus sialidase activity with N-acetyl-9-O-acetylneuraminic acid-containing substrates resulting from influenza C virus O-acetylesterase action()

Influenza virus type C (Johannesburg/1/66) was used as a source for the enzyme O-acetylesterase (EC 3.1.1.53) with several natural sialoglycoconjugates as substrates. The resulting products were immediately employed as substrates using influenza virus type A [(Singapore/6/86) (H1N1) or Shanghai/11/87 (H3N2)] as a source for sialidase (neuraminidase, EC 3.2.1.18). A significant increase in the percentage of sialic acid released was found when the O-acetyl group was cleaved by O-acetylesterase activity from certain substrates (bovine submandibular gland mucin, rat serum glycoproteins, human saliva glycoproteins, mouse erythrocyte stroma, chick embryonic brain gangliosides and bovine brain gangliosides). A common feature of all these substrates is that they contain N-acetyl-9-O-acetylneuraminic acid residues. By contrast, no significant increase in the release of sialic acid was detected when certain other substrates could not be de-O-acetylated by the action of influenza C esterase, either because they lacked O-acetylsialic acid (human glycophorin A, α(1)-acid glycoprotein from human serum, fetuin and porcine submandibular gland mucin) or because the 4-O-acetyl group was scarcely cleaved by the viral O-acetylesterase (equine submandibular gland mucin). The biological significance of these facts is discussed, relative to the infective capacity of influenza C virus.

Interaction of Viruses with Cell Surface Receptors

This chapter discusses the interaction of viruses with cell surface receptors. The rigorous characterizations of receptor–ligand interactions have been derived from binding studies of radiolabeled ligands in neuropharmacology and endocrinology. The definition of viral recognition sites as receptors involves three major criteria that are derived from models of ligand–receptor interactions: saturability, specificity, and competition. A variety of approaches have been used to study the interaction of viral particles with cell surface receptors or reception sites. A rigorous study of viral–receptor interactions requires the use of more than one technique as different approaches provide complementary information about viral binding. The chapter discusses membrane components that interact with viruses. The identification of the subviral components that are responsible for the binding of viruses to cell surfaces has preceded the structural understanding of the cellular receptors themselves. The chapter summarizes current data concerning the viral attachment protein (VAP) of selected viruses.

Preparation of Components

Committed to Care: Research Submitted to the National Abortion Federation’s 44th Annual Meeting

Touch Me Not: Physical Distancing in Radiology during COVID-19

There’s So Much More to Cats…

What’s next for nudging and choice architecture?

The Influence of the Variation in Sepsis Rate between Neonatal Intensive Care Units on Neonatal Outcomes in Very-Low-Birth-Weight Infants

Sepsis is commonly known to affect neonatal outcomes. We assessed how much center-to-center variability of the sepsis rate affects the outcomes of very-low-birth-weight infants (VLBWIs). 7,493 VLBWIs registered in the Korean Neonatal Network from 2013 to 2016 were classified into three groups according to the sepsis rate: low sepsis group (LS) < 25(th) percentile versus intermediate sepsis group (IS) 25(th)–75(th) versus high sepsis group (HS) ≥ 75(th). The incidence density of sepsis for the LS, IS, and HS groups were 1.17, 3.17, and 8.88 cases/1,000 person-days. After propensity score matching was done for multiple antenatal and perinatal factors, the odds ratio of death, moderate to severe bronchopulmonary dysplasia and/or death, periventricular leukomalacia, and survival without major morbidities for the HS group were 2.0 (95% confidence interval 1.4–2.8), 1.9 (1.5–2.4), 1.5 (1.1–2.3) and 0.7 (0.5–0.8) when compared with the IS group, and 2.2 (1.6–3.2), 2.3 (1.8–2.9), 2.0 (1.3–2.9), and 0.7 (0.6–0.9) when compared with the LS group. There were no significant differences in those outcomes between the LS and IS groups. Hence, nationwide quality improvements to control the sepsis rate especially in units with a high sepsis rate will be helpful to improve the outcomes of VLBWIs.

Corona-Krise trifft auf Strukturprobleme im Gesundheitswesen

Wirtschaft unter Schock — Finanzpolitik hält dagegen

According to the leading German economic research institutes, the German economy is experiencing a drastic slump as a result of the corona pandemic. In order to slow down the wave of infection, the state has severely restricted economic activity in Germany. As a result, GDP is expected to shrink by 4.2% this year. The recession is leaving clear traces on the labour market and the national budget. At its peak, the unemployment rate will soar to 5.9% and the number of short-time workers to 2.4 million. This year, the fiscal policy stabilisation measures will lead to a record deficit in the general government budget of 159 billion euro. After the shutdown, the economy will gradually recover. Accordingly, the increase in GDP next year will be strong at 5.8%. This forecast is associated with considerable downside risks, e.g. because the pandemic can be slowed faster or because the recovery of economic activity will be less successful than expected or there may be a new wave of infection.

Vermögensverteilung und Wirtschaftskrisen

Nachfrageorientierte Klimapolitik — Evidenz aus der Corona-Krise

Human Influenza Virus Infections

Seasonal and pandemic influenza are the two faces of respiratory infections caused by influenza viruses in humans. As seasonal influenza occurs on an annual basis, the circulating virus strains are closely monitored and a yearly updated vaccination is provided, especially to identified risk populations. Nonetheless, influenza virus infection may result in pneumonia and acute respiratory failure, frequently complicated by bacterial coinfection. Pandemics are, in contrary, unexpected rare events related to the emergence of a reassorted human-pathogenic influenza A virus (IAV) strains that often causes increased morbidity and spreads extremely rapidly in the immunologically naive human population, with huge clinical and economic impact. Accordingly, particular efforts are made to advance our knowledge on the disease biology and pathology and recent studies have brought new insights into IAV adaptation mechanisms to the human host, as well as into the key players in disease pathogenesis on the host side. Current antiviral strategies are only efficient at the early stages of the disease and are challenged by the genomic instability of the virus, highlighting the need for novel antiviral therapies targeting the pulmonary host response to improve viral clearance, reduce the risk of bacterial coinfection, and prevent or attenuate acute lung injury. This review article summarizes our current knowledge on the molecular basis of influenza infection and disease progression, the key players in pathogenesis driving severe disease and progression to lung failure, as well as available and envisioned prevention and treatment strategies against influenza virus infection.

BvDU Kurz notiert

In Vivo Assembly of Nanoparticles Achieved through Synergy of Structure‐Based Protein Engineering and Synthetic DNA Generates Enhanced Adaptive Immunity

Nanotechnologies are considered to be of growing importance to the vaccine field. Through decoration of immunogens on multivalent nanoparticles, designed nanovaccines can elicit improved humoral immunity. However, significant practical and monetary challenges in large‐scale production of nanovaccines have impeded their widespread clinical translation. Here, an alternative approach is illustrated integrating computational protein modeling and adaptive electroporation‐mediated synthetic DNA delivery, thus enabling direct in vivo production of nanovaccines. DNA‐launched nanoparticles are demonstrated displaying an HIV immunogen spontaneously self‐assembled in vivo. DNA‐launched nanovaccines induce stronger humoral responses than their monomeric counterparts in both mice and guinea pigs, and uniquely elicit CD8+ effector T‐cell immunity as compared to recombinant protein nanovaccines. Improvements in vaccine responses recapitulate when DNA‐launched nanovaccines with alternative scaffolds and decorated antigen are designed and evaluated. Finally, evaluation of functional immune responses induced by DLnanovaccines demonstrates that, in comparison to control mice or mice immunized with DNA‐encoded hemagglutinin monomer, mice immunized with a DNA‐launched hemagglutinin nanoparticle vaccine fully survive a lethal influenza challenge, and have substantially lower viral load, weight loss, and influenza‐induced lung pathology. Additional study of these next‐generation in vivo‐produced nanovaccines may offer advantages for immunization against multiple disease targets.

1H-Imidazole-2,5-Dicarboxamides as NS4A Peptidomimetics: Identification of a New Approach to Inhibit HCV-NS3 Protease

The nonstructural (NS) protein NS3/4A protease is a critical factor for hepatitis C virus (HCV) maturation that requires activation by NS4A. Synthetic peptide mutants of NS4A were found to inhibit NS3 function. The bridging from peptide inhibitors to heterocyclic peptidomimetics of NS4A has not been considered in the literature and, therefore, we decided to explore this strategy for developing a new class of NS3 inhibitors. In this report, a structure-based design approach was used to convert the bound form of NS4A into 1H-imidazole-2,5-dicarboxamide derivatives as first generation peptidomimetics. This scaffold mimics the buried amino acid sequence Ile-25` to Arg-28` at the core of NS4A(21`–33`) needed to activate the NS3 protease. Some of the synthesized compounds (Coded MOC) were able to compete with and displace NS4A(21`–33`) for binding to NS3. For instance, N(5)-(4-guanidinobutyl)-N(2)-(n-hexyl)-1H-imidazole-2,5-dicarboxamide (MOC-24) inhibited the binding of NS4A(21`–33`) with a competition half maximal inhibitory concentration (IC(50)) of 1.9 ± 0.12 µM in a fluorescence anisotropy assay and stabilized the denaturation of NS3 by increasing the aggregation temperature (40% compared to NS4A(21`–33`)). MOC-24 also inhibited NS3 protease activity in a fluorometric assay. Molecular dynamics simulations were conducted to rationalize the differences in structure–activity relationship (SAR) between the active MOC-24 and the inactive MOC-26. Our data show that MOC compounds are possibly the first examples of NS4A peptidomimetics that have demonstrated promising activities against NS3 proteins.

Therapeutic management of severe hypothermia with veno-arterial ECMO: where do we stand? Case report and review of the current literature

BACKGROUND: Severe accidental hypothermia is associated with high morbidity and mortality. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) provides an efficient rewarming method with complete cardiopulmonary support. The use of VA-ECMO for this indication has greatly improved the vital and functional prognosis of patients. CASE PRESENTATION: We report a case of a 46-year-old patient who was treated for severe hypothermia with a temperature of 22.4 °C along with initial cardiac arrest, whose progression was favorable after the implementation of VA-ECMO support. Two months after initial cardiac arrest, the patient was reassessed and showed signs of complete recovery with regard to his mental and physical capacities. CONCLUSIONS: The recent international publications and groups of experts recommend the use of VA ECMO as the gold standard therapy to treat severe hypothermia. Therefore, it seems suitable to update the current knowledge on the topic by analysing the latest international publications. The performance of this technique calls into question ethical and economic factors. Two distinct medical teams tried to identify and regroup prognosis factors in predictive survival scores. They raise the question of the utility of these scores in clinical practice. Indeed, according to which survival rate should we proceed to prolonged resuscitation and implement VA-ECMO? Additional studies will be needed for external approval of these survival scores, and additional reflection by experts will be required.

Clinical efficacy and safety of polymyxins based versus non-polymyxins based therapies in the infections caused by carbapenem-resistant Acinetobacter baumannii: a systematic review and meta-analysis

BACKGROUND: The prevalence of infections due to carbapenem-resistant Acinetobacter baumannii (CRAB) is on the rise worldwide. Polymyxins are considered as last-resort drugs for CRAB infections, but there is still controversy regarding the efficacy and safety of polymyxins based therapies in CRAB infections. The present systematic review was designed to compare the efficacy and safety of polymyxins based therapies versus non-polymyxins based therapies in CRAB infections. METHODS: We performed a systematic literature search in PubMed, Embase, CINAHL, Cochrane Library, and clinicaltrials.gov to identify eligible studies reporting the clinical outcomes of patients with CRAB infections. The meta-analysis employed a random-effects model to estimate the odds ratio (OR) and standardized mean difference (SMD) with 95% confidence interval (CI). The primary outcome was 1-month mortality for any cause. We also examined clinical response, microbiological response, length of stay in hospital, and adverse events. RESULTS: Eleven eligible studies were analyzed (1052 patients in total), including 2 randomized clinical trials. Serious risk of bias was found in 8 out of the 11 studies. There was no statistically significant difference between polymyxins based therapies and non-polymyxins based therapies in 1-month mortality for any cause (OR, 0.95; 95% CI, 0.59 to 1.53), microbiological response (OR, 3.83; 95% CI, 0.90 to 16.29) and length of stay in hospital (SMD, 0.24; 95% CI, − 0.08 to 0.56). The pooled OR of clinical response indicated a significant difference in favor of polymyxin based therapies (OR, 1.99; 95% CI, 1.31 to 3.03). The pooled OR of adverse events showed that non-polymyxins based therapies were associated with fewer adverse events (OR, 4.32; 95% CI, 1.39 to 13.48). CONCLUSION: The performance of polymyxins based therapies was better than non-polymyxin based therapies in clinical response rate and similar to non-polymyxin based therapies in terms of 1-month mortality and microbiological response in treating CRAB infections. Due to the limitations of our study, we cannot draw a firm conclusion on the optimal treatment of CRAB infections, but polymyxins would be a relatively effective treatment for CRAB infections. Adequate and well-designed large scale randomized controlled trials are required to clarify the relative efficacy of polymyxins based and non-polymyxins based therapies.

Severity and outcomes of influenza-related pneumonia in type A and B strains in China, 2013–2019

BACKGROUND: Inconsistencies exist regarding the severity of illness caused by different influenza strains. The aim of this study was to compare the clinical outcomes of hospitalized adults and adolescents with influenza-related pneumonia (Flu-p) from type A and type B strains in China. METHODS: We retrospectively reviewed data from Flu-p patients in five hospitals in China from January 2013 to May 2019. Multivariate logistic and Cox regression models were used to assess the effects of influenza virus subtypes on clinical outcomes, and to explore the risk factors of 30-day mortality for Flu-p patients. RESULTS: In total, 963 laboratory-confirmed influenza A-related pneumonia (FluA-p) and 386 influenza B-related pneumonia (FluB-p) patients were included. Upon adjustment for confounders, multivariate logistic regression models showed that FluA-p was associated with an increased risk of invasive ventilation (adjusted odds ratio [aOR]: 3.824, 95% confidence interval [CI]: 2.279–6.414; P < 0.001), admittance to intensive care unit (aOR: 1.630, 95% CI: 1.074–2.473, P = 0.022) and 30-day mortality (aOR: 2.427, 95% CI: 1.568–3.756, P < 0.001) compared to FluB-p. Multivariate Cox regression models confirmed that influenza A virus infection (hazard ratio: 2.637, 95% CI: 1.134–6.131, P = 0.024) was an independent predictor for 30-day mortality in Flu-p patients. CONCLUSIONS: The severity of illness and clinical outcomes of FluA-p patients are more severe than FluB-p. This highlights the importance of identifying the virus strain during the management of severe influenza.

Latest trends in L. infantum infection in dogs in Spain, Part II: current clinical management and control according to a national survey of veterinary practitioners

BACKGROUND: Canine leishmaniosis (CanL) is a parasitic zoonotic disease, endemic in the Mediterranean basin including Spain. While knowledge about CanL, its management, treatment, prevention and control mounts, it remains unclear whether all clinical veterinarians follow the same international recommendations, such as those of the LeishVet group. This study was thus designed to assess recent trends in the clinical management of CanL in veterinary clinics across Spain through a questionnaire-based survey. Results were compared with those of a prior national multicenter questionnaire administered by our research team in 2005. METHODS: A questionnaire consisting of 28 questions about CanL was developed using Google Forms and distributed by email to 1428 veterinary clinics in Spain. Questions were designed to obtain data on common clinical signs, techniques and complementary exams used to diagnose the disease, and on its monitoring, treatment and control measures. Data were collected in a database for statistical analysis. RESULTS: Completed questionnaires were returned by 295 clinics. Compared to the situation in 2005, responses indicate that clinical signs of CanL have not changed significantly, cutaneous lesions being still the most prevalent sign observed by practitioners. Quantitative serological techniques are considered an adequate approach to diagnosis, provided their results are supported by the findings of a thorough physical exam, as well as complementary tests (complete blood count, biochemical profile, plasma protein electrophoretogram and complete urinalysis). Treatment protocols and check-ups follow international recommendations. Finally, a multimodal approach is being endorsed to adequately control CanL including preventive measures such as annual serological check-ups and the combination of repellents and vaccines. Additionally, owners are being better informed about CanL by veterinarians, which translates to the improved control of this zoonosis. CONCLUSIONS: The clinical management of CanL has recently undergone significant changes owing to improvements in clinical knowledge of the disease, more unified international criteria, improved diagnostic techniques and their adequate interpretation, as well as a greater awareness of the disease transmitted to owners. [Image: see text]

Infektionen als Notfall der Onkologie: Übersicht über die aktuellen Leitlinien

BACKGROUND: Patients with oncologic diseases, particularly those with hematologic malignancies, are at an increased risk of common infections and unique treatment-related complications with high mortality and morbidity. The annual incidence and prevalence of cancer in Germany is rising. Although modern treatments have generally led to improved survival, increasing age, comorbidities, and frailty of the patients require multidisciplinary strategies for handling complex therapeutic concepts and treatment of the associated complications. METHODS: A selective literature search and guidelines from the European Society for Medical Oncology (ESMO), the German Society of Hematology and Medical Oncology (Deutsche Gesellschaft für Hämatologie und Medizinische Onkologie, DGHO), the Infectious Diseases Working Group of the DGHO (Arbeitsgemeinschaft Infektionen in der Hämatologie und Onkologie, AGIHO), and the American Society of Clinical Oncology (ASCO) formed the basis of this study. CONCLUSION: Recognition of severe infections in cancer patients and their discrimination from treatment-associated complications is a challenge. Neutropenic fever is the most frequent infectious emergency in oncology. Early empiric treatment with broad-spectrum antibiotics and escalated diagnostic strategies are needed to successfully treat this vulnerable patient group. In this article, a range of potentially life-threatening infections in immunocompromised patients are discussed.

Public health response to two imported, epidemiologically related cases of Lassa fever in the Netherlands (ex Sierra Leone), November 2019

On 20 November 2019, Lassa fever was diagnosed in a physician repatriated from Sierra Leone to the Netherlands. A second physician with suspected Lassa fever, repatriated a few days later from the same healthcare facility, was confirmed infected with Lassa virus on 21 November. Comprehensive contact monitoring involving high- and low-risk contacts proved to be feasible and follow-up of the contacts did not reveal any case of secondary transmission in the Netherlands.

Mulling over meetings

Net woody vegetation increase confined to seasonally inundated lowlands in an Australian tropical savanna, Victoria River District, Northern Territory

Abstract Georeferenced digital aerial photographs were used to assess changes in overstorey vegetation cover since 1948 in the Victoria River District, Northern Territory, Australia, across a range of lowland tropical savanna habitats and with explicit consideration of known and variable site‐specific grazing and fire management histories. Vegetation surveys at corresponding locations on the ground identified five distinct woody vegetation communities defined primarily by water drainage and secondarily by soil characteristics. Air‐photo analyses revealed that, contrary to popular perceptions and in contrast to results from other habitats, there has been no generalized net increase in overstorey woody vegetation cover across the full range of lowland savanna habitats. Rather, different habitats exhibited distinctly different vegetation change mechanisms: low‐lying seasonally inundated ‘wet’ habitats have experienced woody vegetation increase since 1948, whereas well‐drained ‘dry’ habitats have experienced overstorey vegetation stability or loss. In almost every instance woody vegetation increase could be attributed to the invasion or proliferation of a single species, Melaleuca minutifolia F.Muell. The extent of M. minutifolia increase was unrelated to historical grazing/fire regime. Demographic analyses for this species revealed that recruitment was often episodic and that synchronized recruitment events occurred uniformly across the full range of historical management treatments, most likely as a consequence of favourable climatic conditions in years with an extended wet season. Heavy grazing facilitated juvenile survival and/or recruitment, most likely by reducing grassy fuel loads and eliminating landscape fire. We conclude that while there has been no generalized net increase in overstorey woody vegetation cover in lowland environments, savanna dynamics are complex, and multiple change mechanisms have occurred simultaneously in different habitats, some of which have been significantly transformed since 1948. Where net woody vegetation increase has occurred it is primarily a natural consequence of episodic M. minutifolia establishment in climatically favourable years, but the extent and magnitude of this effect is likely mediated by fire/grazing regime.

Habitat structure is more important than vegetation composition for local‐level management of native terrestrial reptile and small mammal species living in urban remnants: A case study from Brisbane, Australia

Abstract As urban areas continue to expand and replace natural and agricultural landscapes, the ability to manage and conserve native wildlife within urban environments is becoming increasingly important. To do so we first need to understand species' responses to local‐level habitat attributes in order to inform the decision‐making process and on‐ground conservation actions. Patterns in the occurrence of native terrestrial reptile and small mammal species in 59 sites located in remnant urban habitat fragments of Brisbane City were assessed against local‐level environmental characteristics of each site. Cluster analysis, multidimensional scaling ordination, and principal axis correlation were used to investigate relationships between species' occurrences and environmental characteristics. Native reptiles were most strongly associated with the presence of termite mounds, a high amount of fallen woody material, and a moderate amount of weed cover. Native small mammals were most strongly associated with the presence of grass trees (Xanthorrhoea spp.), and both reptiles and small mammals were negatively influenced by increased soil compaction. Significant floristic characteristics were considered to be important as structural, rather than compositional, habitat elements. Therefore, habitat structure, rather than vegetation composition, appears to be most important for determining native, terrestrial reptile and small mammal species assemblages in urban forest fragments. We discuss the management implications in relation to human disturbances and local‐level management of urban remnants.

The loss of aquatic and riparian plant communities: Implications for their consumers in a riverine food web

Abstract Human induced alterations to rivers and steams have resulted in significant changes to the structure and diversity of riparian and aquatic plant communities. These changes will impact on the dynamics of riverine carbon cycles and food web structure and function. Here we investigate the principal sources of organic carbon supporting local shredder communities across a gradient in different levels of anthropogenic development along riverine reaches, in South Australia. In forested/wooded reaches with minimum to limited development, semi‐emergent macrophytes were the principal sources of organic carbon supporting the local shredder communities. However, in developed reaches, course particulate organic matter and filamentous algae were the principal food sources. The C:N ratios of the food sources in developed reaches were higher than those of their consumers indicating a stoichiometric mismatch. This imbalanced consumer‐resource nutrient ratio in those developed reaches is likely to impose constraints on the growth and reproduction of their aquatic shredder communities with probable knock‐on effects to higher trophic levels.

Structure and environmental relationships of insectivorous bat assemblages in tropical Australian savannas

Abstract Patterns in the composition of assemblages of microbat species sampled during the late dry season (the ‘build‐up’) in north Australian savannas were assessed against a range of environmental factors as well as four a priori defined habitat types (riparian, escarpments, coastal and woodlands). Distinct species assemblages were most strongly associated with topographic and climatic variables. There were also limited associations with vegetation structure, fire and local roost potential but no associations with insects or water availability. Total species diversity at sample sites was associated with distance to rivers and rainfall. In general, species assemblages were not clearly defined and the number of significant environmental associations was relatively few. We compare these associations with those reported for bat assemblages elsewhere in Australia.

Relationship between species in the genus Rosa, section Pimpinellifoliae

The morphology of twelve species of Rosa is described and similarities between these species are assessed. Possible origins of the tetraploid species from diploid species are indicated on grounds of comparative morphology. The wild origins of living and herbarium specimens are given in order to supplement published data on geographical distribution. Meiosis in pollen mother cells, viability of pollen grains at anthesis and ability to set seed was studied in several F(1) hybrids: no indication of complete or even partial sterility was found. Reproductive isolation is therefore unlikely to be maintained by reduced fertility of interspecific hybrids. Three species are reduced to synonymy with three other species, being retained as subspecific taxa. Two species are transferred from section Pimpinellifoliae to section Cinnamomeae.

Study on Prediction Model of HIV Incidence Based on GRU Neural Network Optimized by MHPSO

Acquired Immune Deficiency Syndrome (AIDS) is still one of the most life-threatening diseases in the world. Moreover, new infections are still potentially increasing. This difficult problem must be solved. Early warning is the most effective way to solve this problem. Here, we aim to determine the best performing model to track the epidemic of AIDS, which will provide a methodological basis for testing the time characteristics of the disease. From January 2004 to January 2018, we built four computing methods based on AIDS dataset: BPNN model, RNN model, LSTM model and MHPSO-GRU model. Compare the final estimated performance to determine the preferred method. Result. Considering the root mean square error (RMSE), mean absolute error (MAE), mean error rate (MER) and mean absolute percentage error (MAPE) in the simulation and prediction subsets, the MHPSO-GRU model is determined as the best performance technology. Estimates for the period from May 2018 to December 2020 suggest that the event appears to continue to increase and remain high.

Next Generation Technology for Epidemic Prevention and Control: Data-Driven Contact Tracking

Contact tracking is one of the key technologies in prevention and control of infectious diseases. In the face of a sudden infectious disease outbreak, contact tracking systems can help medical professionals quickly locate and isolate infected persons and high-risk individuals, preventing further spread and a large-scale outbreak of infectious disease. Furthermore, the transmission networks of infectious diseases established using contact tracking technology can aid in the visualization of actual virus transmission paths, which enables simulations and predictions of the transmission process, assessment of the outbreak trend, and further development and deployment of more effective prevention and control strategies. Exploring effective contact tracking methods will be significant. Governments, academics, and industries have all given extensive attention to this goal. In this paper, we review the developments and challenges of current contact tracing technologies regarding individual and group contact from both static and dynamic perspectives, including static individual contact tracing, dynamic individual contact tracing, static group contact tracing, and dynamic group contact tracing. With the purpose of providing useful reference and inspiration for researchers and practitioners in related fields, directions in multi-view contact tracing, multi-scale contact tracing, and AI-based contact tracing are provided for next-generation technologies for epidemic prevention and control.

Modeling Behavioral Response to Vaccination Using Public Goods Game

Epidemics of infectious disease can be traced back to the early days of mankind. Only in the last two centuries vaccination has become a viable strategy to prevent such epidemics. In addition to the clinical efficacy of this strategy, the behavior and public attitudes affect the success of vaccines. This paper describes modeling the efficacy of vaccination considering the cost and benefit of vaccination to individual players. The model is based on the public goods game and is presented as a spatial game on a lattice. Using this model, individuals can contribute to the public health by paying the cost of vaccination or choose to be protected by the public who is vaccinated rather than pay the cost and share the risk of vaccination. Thus, in this model individuals can choose to stay susceptible, can become infected, or choose to vaccinate once in each episode. This paper presents the behavioral changes of the population and the cost to the society as a function of the cost of vaccines, cost of being infected, and the “fear factor” created by the public media.

Uncertainty Assisted Robust Tuberculosis Identification With Bayesian Convolutional Neural Networks

Tuberculosis (TB) is an infectious disease that can lead towards death if left untreated. TB detection involves extraction of complex TB manifestation features such as lung cavity, air space consolidation, endobronchial spread, and pleural effusions from chest x-rays (CXRs). Deep learning based approach named convolutional neural network (CNN) has the ability to learn complex features from CXR images. The main problem is that CNN does not consider uncertainty to classify CXRs using softmax layer. It lacks in presenting the true probability of CXRs by differentiating confusing cases during TB detection. This paper presents the solution for TB identification by using Bayesian-based convolutional neural network (B-CNN). It deals with the uncertain cases that have low discernibility among the TB and non-TB manifested CXRs. The proposed TB identification methodology based on B-CNN is evaluated on two TB benchmark datasets, i.e., Montgomery and Shenzhen. For training and testing of proposed scheme we have utilized Google Colab platform which provides NVidia Tesla K80 with 12 GB of VRAM, single core of 2.3 GHz Xeon Processor, 12 GB RAM and 320 GB of disk. B-CNN achieves 96.42% and 86.46% accuracy on both dataset, respectively as compared to the state-of-the-art machine learning and CNN approaches. Moreover, B-CNN validates its results by filtering the CXRs as confusion cases where the variance of B-CNN predicted outputs is more than a certain threshold. Results prove the supremacy of B-CNN for the identification of TB and non-TB sample CXRs as compared to counterparts in terms of accuracy, variance in the predicted probabilities and model uncertainty.

Variable-Gain Control for Respiratory Systems

In this paper, we introduce a variable-gain control strategy for mechanical ventilators in the respiratory systems. Respiratory systems assist the patients who have difficulty breathing on their own. For the comfort of the patient, fast pressure buildup (and release) and a stable flow response are desired. However, linear controllers typically need to balance between these conflicting objectives. In order to balance this tradeoff in a more desirable manner, a variable-gain controller is proposed, which switches the controller gain based on the magnitude of the patient flow. The effectiveness of the control strategy is demonstrated in experiments on different test lungs.

Information Diffusion on Social Media During Natural Disasters

Social media analytics has drawn new quantitative insights of human activity patterns. Many applications of social media analytics, from pandemic prediction to earthquake response, require an in-depth understanding of how these patterns change when human encounter unfamiliar conditions. In this paper, we select two earthquakes in China as the social context in Sina-Weibo (or Weibo for short), the largest Chinese microblog site. After proposing a formalized Weibo information flow model to represent the information spread on Weibo, we study the information spread from three main perspectives: individual characteristics, the types of social relationships between interactive participants, and the topology of real interaction networks. The quantitative analyses draw the following conclusions. First, the shadow of Dunbar’s number is evident in the “declared friends/followers” distributions, and the number of each participant’s friends/followers who also participated in the earthquake information dissemination show the typical power-law distribution, indicating a rich-gets-richer phenomenon. Second, an individual’s number of followers is the most critical factor in user influence. Strangers are very important forces for disseminating real-time news after an earthquake. Third, two types of real interaction networks share the scale-free and small-world property, but with a looser organizational structure. In addition, correlations between different influence groups indicate that when compared with other online social media, the discussion on Weibo is mainly dominated and influenced by verified users.

Development and validation of a portable, point-of-care canine distemper virus qPCR test

Canine distemper virus (CDV) is a multi-host pathogen that can cause significant mortality in domestic, wild terrestrial and marine mammals. It is a major conservation threat in some endangered species. Infection can result in severe respiratory disease and fatal encephalitis. Diagnosis and disease monitoring in wildlife, and differentiation of CDV from rabies (a life-threatening zoonotic disease that can produce similar neurologic signs), would benefit from the availability of a portable, point-of-care (POC) diagnostic test. We therefore developed a quantitative RT-PCR assay for CDV using shelf-stable, lyophilized reagents and target-specific primers and probes for use with the handheld Biomeme two3(™) qPCR thermocycler. Biomeme’s extraction methodology, lyophilized reagents, and thermocycler were compared to our standard laboratory-based methods to assess sensitivity, efficiency and overall test performance. Results using a positive control plasmid for CDV showed comparable sensitivity (detection of 50 copies) and PCR efficiency between the two platforms, and CDV detection was similar between platforms when tested using a modified live CDV vaccine. Significantly higher Ct values (average Ct = 5.1 cycles) were observed using the Biomeme platform on known CDV positive animal samples. CDV detection using the Biomeme platform was similar in 25 of 26 samples from suspect CDV cases when compared to standard virology laboratory testing. One false positive was observed that was negative upon retest. The Biomeme methodology can be adapted for detection of specific targets, and this portable technology saves time by eliminating the need for local or international sample transport for laboratory-based diagnostics. However, results of our testing suggest that decreased diagnostic sensitivity (higher Ct values) relative to laboratory-based methods was observed using animal samples, so careful validation and optimization are essential. Portable qPCR platforms can empower biologists and wildlife health professionals in remote and low-resource settings, which will greatly improve our understanding of CDV disease ecology and associated conservation threats in wildlife.

Protecting Medical Trainees on the Coronavirus Disease 2019 (COVID-19) Frontlines Saves Us All

The fight against stroke must go on

Obesity-related stigma—hiding in plain sight

A Unified Approach for EIT Imaging of Regional Overdistension and Atelectasis in Acute Lung Injury

Patients with acute lung injury or acute respiratory distress syndrome (ALI/ARDS) are vulnerable to ventilator-induced lung injury. Although this syndrome affects the lung heterogeneously, mechanical ventilation is not guided by regional indicators of potential lung injury. We used electrical impedance tomography (EIT) to estimate the extent of regional lung overdistension and atelectasis during mechanical ventilation. Techniques for tidal breath detection, lung identification, and regional compliance estimation were combined with the Graz consensus on EIT lung imaging (GREIT) algorithm. Nine ALI/ARDS patients were monitored during stepwise increases and decreases in airway pressure. Our method detected individual breaths with 96.0% sensitivity and 97.6% specificity. The duration and volume of tidal breaths erred on average by 0.2 s and 5%, respectively. Respiratory system compliance from EIT and ventilator measurements had a correlation coefficient of 0.80. Stepwise increases in pressure could reverse atelectasis in 17% of the lung. At the highest pressures, 73% of the lung became overdistended. During stepwise decreases in pressure, previously-atelectatic regions remained open at sub-baseline pressures. We recommend that the proposed approach be used in collaborative research of EIT-guided ventilation strategies for ALI/ARDS.

Impact of Model Shape Mismatch on Reconstruction Quality in Electrical Impedance Tomography

Electrical impedance tomography (EIT) is a low-cost, noninvasive and radiation free medical imaging modality for monitoring ventilation distribution in the lung. Although such information could be invaluable in preventing ventilator-induced lung injury in mechanically ventilated patients, clinical application of EIT is hindered by difficulties in interpreting the resulting images. One source of this difficulty is the frequent use of simple shapes which do not correspond to the anatomy to reconstruct EIT images. The mismatch between the true body shape and the one used for reconstruction is known to introduce errors, which to date have not been properly characterized. In the present study we, therefore, seek to 1) characterize and quantify the errors resulting from a reconstruction shape mismatch for a number of popular EIT reconstruction algorithms and 2) develop recommendations on the tolerated amount of mismatch for each algorithm. Using real and simulated data, we analyze the performance of four EIT reconstruction algorithms under different degrees of shape mismatch. Results suggest that while slight shape mismatch is well tolerated by all algorithms, using a circular shape severely degrades their performance.

A SARS Method for Reliable Spectrum Sensing in Multiband Communication Systems

This paper introduces a novel method of spectrum sensing in communication systems that utilizes nonuniform sampling in conjunction with a suitable spectral analysis tool. It is referred to here as spectral analysis for randomized sampling (SARS). Owing to the deployment of nonuniform sampling, the proposed technique can accomplish the sensing task by using sampling rates well below the ones demanded by uniform-sampling-based digital signal processing (DSP). The effect of the cyclostationary nature of the incoming digital communication signal on the adequacy of the adopted periodogram-type estimator for the spectrum sensing operation is addressed. The statistical characteristics of the estimator are presented. General reliability conditions on the length of the required signal observation window, i.e., sensing time, for a chosen sampling rate or vice versa are provided amid a sought system performance. The impact of the presence of noise and processing transmissions with various power levels on the derived dependability recommendations is given. The analytical results are illustrated by numerical examples. This paper establishes a new framework for efficient spectrum sensing where considerable savings on the sampling rate and number of processed samples can be attained.

Absolute Electrical Impedance Tomography (aEIT) Guided Ventilation Therapy in Critical Care Patients: Simulations and Future Trends

Thoracic electrical impedance tomography (EIT) is a noninvasive, radiation-free monitoring technique whose aim is to reconstruct a cross-sectional image of the internal spatial distribution of conductivity from electrical measurements made by injecting small alternating currents via an electrode array placed on the surface of the thorax. The purpose of this paper is to discuss the fundamentals of EIT and demonstrate the principles of mechanical ventilation, lung recruitment, and EIT imaging on a comprehensive physiological model, which combines a model of respiratory mechanics, a model of the human lung absolute resistivity as a function of air content, and a 2-D finite-element mesh of the thorax to simulate EIT image reconstruction during mechanical ventilation. The overall model gives a good understanding of respiratory physiology and EIT monitoring techniques in mechanically ventilated patients. The model proposed here was able to reproduce consistent images of ventilation distribution in simulated acutely injured and collapsed lung conditions. A new advisory system architecture integrating a previously developed data-driven physiological model for continuous and noninvasive predictions of blood gas parameters with the regional lung function data/information generated from absolute EIT (aEIT) is proposed for monitoring and ventilator therapy management of critical care patients.

Computational Study of Interdependence Between Hemagglutinin and Neuraminidase of Pandemic 2009 H1N1

Influenza type A viruses are classified into subtypes based on their two surface proteins, hemagglutinin (HA) and neuraminidase (NA). The HA protein facilitates the viral binding and entering a host cell and the NA protein helps the release of viral progeny from the infected cell. The complementary roles of HA and NA entail their collaboration, which has important implications for viral replication and fitness. The HA protein from early strains of pandemic 2009 H1N1 of swine origin preferentially binds to human type receptors with a weak binding to avian type receptors. This virus caused several human deaths in December 2013 in Texas, USA, which motivated us to investigate the changes of genetic features that might contribute to the surged virulence of the virus. Our time series analysis on the strains of this virus collected from 2009 to 2013 implied that the HA binding preference of this virus in USA, Europe, and Asia has been the characteristic of swine H1N1 virus since 2009. However, its characteristic of seasonal human H1N1 and its binding avidity for avian type receptors both were on steady rise and had a clear increase in 2013 with American strains having the sharpest surge. The first change could enhance the viral transmission and replication in humans and the second could increase its ability to cause infection deep in lungs, which might account for the recent human deaths in Texas. In light of HA and NA coadaptation and evolutionary interactions, we also explored the NA activity of this virus to reveal the functional balance between HA and NA during the course of virus evolution. Finally we identified amino acid substitutions in HA and NA of the virus that were critical for the observed evolution.

Pandemic Influenza Detection by Electrically Active Magnetic Nanoparticles and Surface Plasmon Resonance

Influenza A virus (FLUAV), the causative agent of influenza infection, has received extensive attention due to the recent swine-origin H1N1 pandemic. FLUAV has long been the cause of annual epidemics as well as less frequent but more severe global pandemics. Here, we describe a biosensor utilizing electrically active magnetic (EAM) polyaniline-coated nanoparticles as the transducer in an electrochemical biosensor for rapidly identifying FLUAV strains based on receptor specificity, which will be useful to monitor animal influenza infections and to characterize pandemic potential of strains that have transmitted from animals to humans. Pandemic potential requires human-to-human transmissibility, which is dependent upon FLUAV hemagglutinin (HA) specificity for host glycan receptors. Avian FLUAV preferentially bind to α2,3-linked receptors, while human FLUAV bind to α2,6-linked receptors. EAM nanoparticles were prepared by synthesizing aniline monomer around gamma iron (III) oxide (γ-Fe(2)O(3)) cores, yielding 25–100-nm diameter nanoparticles that were structurally characterized by transmission electron microscopy and electron diffraction. The EAM nanoparticles were coated with monoclonal antibodies specific to H5N1 (A/Vietnam/1203/04). Specificity of binding between glycans and H5 was demonstrated. The biosensor results were correlative to supporting data from a surface plasmon resonance assay that characterized HA/glycan binding and α-H5 antibody activity. This novel study applies EAM nanoparticles as the transducer in a specific, portable, easy-to-use biosensor with great potential for disease monitoring and biosecurity applications.

Identification of Adequate Neurally Adjusted Ventilatory Assist (NAVA) During Systematic Increases in the NAVA Level

Neurally adjusted ventilatory assist (NAVA) delivers airway pressure (P(aw)) in proportion to the electrical activity of the diaphragm (EAdi) using an adjustable proportionality constant (NAVA level, cm⋅H (2)O/ [Formula: see text] V). During systematic increases in the NAVA level, feedback-controlled down-regulation of the EAdi results in a characteristic two-phased response in P(aw) and tidal volume (Vt). The transition from the 1st to the 2nd response phase allows identification of adequate unloading of the respiratory muscles with NAVA (NAVA(AL)). We aimed to develop and validate a mathematical algorithm to identify NAVA(AL). P(aw), Vt, and EAdi were recorded while systematically increasing the NAVA level in 19 adult patients. In a multistep approach, inspiratory P(aw) peaks were first identified by dividing the EAdi into inspiratory portions using Gaussian mixture modeling. Two polynomials were then fitted onto the curves of both P(aw) peaks and Vt. The beginning of the P(aw) and Vt plateaus, and thus NAVA (AL), was identified at the minimum of squared polynomial derivative and polynomial fitting errors. A graphical user interface was developed in the Matlab computing environment. Median NAVA(AL) visually estimated by 18 independent physicians was 2.7 (range 0.4 to 5.8) cm⋅H (2)O/ [Formula: see text] V and identified by our model was 2.6 (range 0.6 to 5.0) cm⋅H (2)O/ [Formula: see text] V. NAVA(AL) identified by our model was below the range of visually estimated NAVA(AL) in two instances and was above in one instance. We conclude that our model identifies NAVA(AL) in most instances with acceptable accuracy for application in clinical routine and research.

Unobtrusive Sensing and Wearable Devices for Health Informatics

The aging population, prevalence of chronic diseases, and outbreaks of infectious diseases are some of the major challenges of our present-day society. To address these unmet healthcare needs, especially for the early prediction and treatment of major diseases, health informatics, which deals with the acquisition, transmission, processing, storage, retrieval, and use of health information, has emerged as an active area of interdisciplinary research. In particular, acquisition of health-related information by unobtrusive sensing and wearable technologies is considered as a cornerstone in health informatics. Sensors can be weaved or integrated into clothing, accessories, and the living environment, such that health information can be acquired seamlessly and pervasively in daily living. Sensors can even be designed as stick-on electronic tattoos or directly printed onto human skin to enable long-term health monitoring. This paper aims to provide an overview of four emerging unobtrusive and wearable technologies, which are essential to the realization of pervasive health information acquisition, including: 1) unobtrusive sensing methods, 2) smart textile technology, 3) flexible-stretchable-printable electronics, and 4) sensor fusion, and then to identify some future directions of research.

Ensuring Equitable Access to School Meals

Plasma Donors in the Southwestern United States Positively Contribute to the Diverse Therapeutic Antibody Profile of Immune Globulin Products

Human-plasma-derived immune globulin (IG) is used in augmentation therapy to provide protective levels of antibodies to patients with primary immune deficiency diseases (PIDD) and for prophylaxis against infectious diseases. To maintain the breadth of antibodies necessary for clinical protection, it is important to understand regional patterns of antibody seroprevalence in source plasma from which IG products are manufactured. In this study, source plasma from donation centers in various locations of the Southwestern quarter of the United States was surveyed for antibody titers to hepatitis A virus (HAV), measles virus (MeV), and cytomegalovirus (CMV). A broad range of anti-HAV Ig plasma titers was observed among these centers, with some centers exhibiting 3–5 times the titers of the others. Minor to no differences were observed for levels of anti-MeV and anti-CMV, respectively. Importantly, elevated anti-HAV Ig titers were broadly observed across plasma units obtained from the centers exhibiting high titers, indicative of a potential regional phenomenon among donors as opposed to few donors with singularly high titers. Plasma from these high-titer centers conferred significantly greater neutralization against HAV in vitro. The outcomes of this study give a glimpse of the antibody diversity inherent in human plasma used to manufacture IG products..

Development of a Yeast Two-Hybrid Screen for Selection of Human Ras-Raf Protein Interaction Inhibitors

A yeast two-hybrid screening system was developed to screen for small molecules that inhibit the interaction of the Ras and the Raf proteins. Hyperpermeable yeast strains useful for high-throughput screening (HTS) for the two-hybrid system were created. Differential inhibition of the Ras-Raf vs the hsRPB4-hsRPB7 interaction allowed the identification of selective inhibitors.

Acute Hemorrhagic Rectal Ulcer Syndrome: A New Clinical Entity? Report of 19 Cases and Review of the Literature

PURPOSE: Acute hemorrhagic rectal ulcer syndrome is characterized by sudden onset, painless, and massive hemorrhage from rectal ulcer(s) in patients with serious underlying illnesses. It is a matter of controversy whether acute hemorrhagic rectal ulcer syndrome is a distinct clinical entity. This is the first Asian report on acute hemorrhagic rectal ulcer syndrome to be made outside Japan. METHODS: From January 1989 to December 1999, 8,085 patients underwent total colonoscopy at our institution. We retrospectively analyzed the medical records and colonoscopic files. The diagnosis of acute hemorrhagic rectal ulcer syndrome was made by means of the clinical, histologic, and colonoscopic findings. RESULTS: Among the 8,085 patients, 19 patients (11 males; mean age, 71.2 ± 10.1 years) were diagnosed with acute hemorrhagic rectal ulcer syndrome, which accounted for 2.8 percent of the patients with massive lower gastrointestinal bleeding. The duration from hospitalization to the onset of massive bleeding ranged from 3 to 14 (mean, 9 ± 3.3) days. Characteristics of colonoscopic appearance were solitary or multiple rectal ulcer(s), with round, circumferential, geographical, or Dieulafoy-like lesions located within a mean of 4.7 cm ± 1.5 cm from the dentate line. Histopathologically, the lesions appeared as necrosis with denudation of covering epithelium, hemorrhage, and multiple thrombi in the vessels of the mucosa and underlying stroma, which is considered to be similar to stress-related mucosa injury. Successful hemostasis was obtained in 74 percent (14/19) of patients with direct therapeutic maneuvers. Prognosis was largely dependent on accurate diagnosis and management of the underlying disorders. CONCLUSIONS: We assert that acute hemorrhagic rectal ulcer syndrome is a rare but important entity and stress that awareness of this clinical entity should lead to a high index of suspicion resulting in early detection, diagnosis, and appropriate therapy.

Culture, institutions and democratization*

We construct a model of revolution and transition to democracy under individualistic and collectivist cultures. The main result is that, despite facing potentially more challenging collective action problems, countries with individualistic cultures are more likely to end up adopting democracy earlier than countries with collectivist cultures. Our empirical analysis suggests a strong and robust association between individualistic cultures and average polity scores and durations of democracy, even after controlling for other determinants of democracy emphasized in the literature. We provide evidence that countries with collectivist cultures also are more likely to experience autocratic breakdowns and transitions from autocracy to autocracy.

Reply to the letter to the editor by Tuuminen et al. (2020), “Indoor air nontoxicity should be proven with special techniques prior claiming that it may cause a variety of mental disorders.”

Investigating the Strategies Adopted by Emergency Nurses to Address Uncertainty and Change in the Event of Emerging Infectious Diseases: A Grounded Theory Study

Emergency nurses frequently encounter uncertainty and changes during the management of emerging infectious diseases, which challenge their capability to perform their duties in a well-planned and systematic manner. To date, little is known about the coping strategies adopted by emergency nurses in addressing uncertainty and changes during an epidemic event. The present study explored emergency nurses’ behaviours and strategies in handling uncertainty and practice changes during an epidemic event. A qualitative study based on the Straussian grounded theory approach was established. Semi-structured, face-to-face, individual interviews were conducted with 26 emergency nurses for data collection. Adapting protocol to the evolving context of practice was revealed as the core category. Four interplaying subcategories were identified: (1) Completing a comprehensive assessment, (2) continuing education for emerging infectious disease management, (3) incorporating guideline updates and (4) navigating new duties and competencies. The nurses demonstrated the prudence to orientate themselves to an ambiguous work situation and displayed the ability to adapt and embrace changes in their practice and duties. These findings offer insights into the need for education and training schemes that allow emergency nurses to acquire and develop the necessary decision-making and problem-solving skills to handle a public health emergency.

The Relationship Exploration between Public Migration Attention and Population Migration from a Perspective of Search Query

Rapid population migration has been viewed as a critical factor impacting urban network construction and regional sustainable development. The supervision and analysis of population migration are necessary for guiding the optimal allocation of urban resources and for attaining the high efficiency development of region. Currently, the explorations of population migration are often restricted by the limitation of data. In the information era, search engines widely collect public attention, implying potential individual actions, and freely provide open, timelier, and large-scope search query data for helping explore regional phenomena and problems. In this paper, we endeavor to explore the possibility of adopting such data to depict population migration. Based on the search query from Baidu search engine, three migration attention indexes (MAIs) are constructed to capture public migration attention in cyber space. Taking three major urban agglomerations in China as case study, we conduct the correlation analysis among the cyber MAIs and population migration in geographical space. Results have shown that external-MAI and local-MAI can positively reflect the population migration inner regions and across regions from a holistic lens and that intercity-MAI can be a helpful supplement for the delineation of specific population flow. Along with the accumulation of cyber search query data, its potential in exploring population migration can be further reinforced.

Validation of age, PaO(2)/FlO(2) and plateau pressure score in Korean patients with acute respiratory distress syndrome: a retrospective cohort study

BACKGROUND: A predictive scoring system for acute respiratory distress syndrome (ARDS) patients, which incorporates age, PaO(2)/FlO(2), and plateau pressure, APPS, was developed recently. It was validated externally in a Caucasian population but has not been studied in Asian populations. The aim of this study was to validate APPS in Korean ARDS patients. METHODS: We retrospectively reviewed the medical records of patients who were diagnosed with ARDS using the Berlin criteria and admitted to the medical ICU at Seoul National University Hospital from January 2015 to December 2016. The validation of the APPS was performed by evaluating its calibration and predictive accuracy. Its calibration was plotted and quantified using the Hosmer–Lemeshow test. Its predictive accuracy was assessed by calculating the area under the receiver operating characteristics (AUC–ROC) curve. RESULTS: A total of 116 patients were analyzed, 32 of whom survived. Of the 116 patients, 11 (9.5%) were classified as APPS grade 1 (score 3–4), 88 (75.9%) as grade 2 (score 5–7) and 17 (14.6%) as grade 3 (score 8–9). In-hospital mortality was 27.3% for grade 1, 73.9% for grade 2 and 94.1% for grade 3 (P for trend < 0.001). The APPS was well calibrated (Hosmer–Lemeshow test, P = 0.578) and its predictive accuracy was acceptable (AUC–ROC 0.704, 95% confidence interval 0.599–0.809). CONCLUSIONS: The APPS predicted in-hospital mortality in Korean patients with ARDS with similar power to its application in a Western population and with acceptable predictive accuracy. TRIAL REGISTRATION: Retrospectively registered.

H2 influenza A virus is not pathogenic in Tmprss2 knock-out mice

The host cell protease TMPRSS2 cleaves the influenza A virus (IAV) hemagglutinin (HA). Several reports have described resistance of Tmprss2(−/−) knock-out (KO) mice to IAV infection but IAV of the H2 subtype have not been examined yet. Here, we demonstrate that TMPRSS2 is able to cleave H2-HA in cell culture and that Tmprss2(−/−) mice are resistant to infection with a re-assorted PR8_HA(H2) virus. Infection of KO mice did not cause major body weight loss or death. Furthermore, no significant increase in lung weights and no virus replication were observed in Tmprss2(−/−) mice. Finally, only minor tissue damage and infiltration of immune cells were detected and no virus-positive cells were found in histological sections of Tmprss2(−/−) mice. In summary, our studies indicate that TMPRSS2 is required for H2 IAV spread and pathogenesis in mice. These findings extend previous results pointing towards a central role of TMPRSS2 in IAV infection and validate host proteases as a potential target for antiviral therapy.