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4,500 | Chapter 2. Surge capacity and infrastructure considerations for mass critical care | PURPOSE: To provide recommendations and standard operating procedures for intensive care unit (ICU) and hospital preparations for a mass disaster or influenza epidemic with a specific focus on surge capacity and infrastructure considerations. METHODS: Based on a literature review and expert opinion, a Delphi process was used to define the essential topics including surge capacity and infrastructure considerations. RESULTS: Key recommendations include: (1) hospitals should increase their ICU beds to the maximal extent by expanding ICU capacity and expanding ICUs into other areas; (2) hospitals should have appropriate beds and monitors for these expansion areas; hospitals should develop contingency plans at the facility and government (local, state, provincial, national) levels to provide additional ventilators; (3) hospitals should develop a phased staffing plan (nursing and physician) for ICUs that provides sufficient patient care supervision during contingency and crisis situations; (4) hospitals should provide expert input to the emergency management personnel at the hospital both during planning for surge capacity as well as during response; (5) hospitals should assure that adequate infrastructure support is present to support critical care activities; (6) hospitals should prioritize locations for expansion by expanding existing ICUs, using postanesthesia care units and emergency departments to capacity, then step-down units, large procedure suites, telemetry units and finally hospital wards. CONCLUSIONS: Judicious planning and adoption of protocols for surge capacity and infrastructure considerations are necessary to optimize outcomes during a pandemic. |
4,501 | Public-Health-Ethik: Bedarf und Diskurs in Deutschland | The international discourse about public health ethics is becoming more intensive and complex. The starting point is bioethics. The debate about public health ethics is simultaneously a debate about an adequate identity of public health, its goals, tasks and standards. In Germany there is a tremendous need to take part in this discourse. German experiences within the traditions of social medicine, social hygiene and medical ethics could significantly contribute to the international discussion. Unfortunately the German speaking public health community has hardly acknowledged the topic of ethics. The reasons for this are not explicitly known. The Angloamerican discourse is much more developed, but the concepts, terms and paradigms should not simply be transferred. They should critically be proven. |
4,502 | The synthetic and therapeutic expedition of isoxazole and its analogs | Isoxazole, constituting an important family of five-membered heterocycles with one oxygen atom and one nitrogen atom at adjacent positions is of immense importance because of its wide spectrum of biological activities and therapeutic potential. It is, therefore, of prime importance that the development of new synthetic strategies and designing of new isoxazole derivatives should be based on the most recent knowledge emerging from the latest research. This review is an endeavor to highlight the progress in the chemistry and biological activity of isoxazole derivatives which could provide a low-height flying bird’s eye view of isoxazole derivatives to the medicinal chemists for the development of clinically viable drugs using this information. |
4,503 | Die telefonische infektionsepidemiologische Bund-Länder-Lagekonferenz in Deutschland: Eine Zwischenbilanz nach drei Quartalen 2009 | Public health threats are increasingly triggered by events which span across international, national and state level jurisdictions. Innovative surveillance methods are needed to ensure adequate and timely response to such threats. In January 2009 the Department of Infectious Disease Epidemiology at the Robert Koch Institute (RKI) established a system of weekly telephone conferences with all competent authorities of the German federal states to identify, discuss and respond to infectious disease events in real-time. A regular and structured platform was developed for use between participants from state level public health authorities, the military and the RKI. During the first three quarters, 46 infectious diseases were covered, including mandatory reports of measles and meningococcal meningitis and outbreaks of cowpox, which does not have to be notified in Germany. Results of a targeted evaluation and a consistently high attendance rate both indicate that the teleconference has met additional needs for supplemental information exchange among participants. The telephone conference has proven to be a useful resource for rapid and direct communication, coordination and evaluation of signals for public health events in Germany. |
4,504 | Ausbildungsprogramme für angewandte Epidemiologie in Deutschland und Europa: Eine lohnende Investition für die Zukunft | Outbreaks of infectious diseases such as SARS and influenza can have a profound impact on society. Therefore, training epidemiologists in infectious diseases control is of crucial importance. The German Postgraduate training in Applied Epidemiology (PAE) at the Robert Koch Institute (RKI) and the European Programme for Intervention Epidemiology Training (EPIET) are striving to meet these challenges. Currently, 27 and 12 persons of German origin have joined PAE and EPIET, respectively. A total of 17 out of the 36 alumni started working at the RKI, regional or local German health authorities after completing their training. Since 2006, the number of yearly admitted fellows increased from 3 to 6 in PAE, and 9 to 19 in EPIET and 5 state health departments have been added as training sites. The collaboration between EPIET and PAE has been strengthened and diversified in recent years. Alumni of these programs will play a key role in the control of infectious diseases in Germany and Europe. |
4,505 | Infektionskrankheiten und ihre Codierung: Was kann sich durch die ICD-11 verbessern? | The revision of the International Classification of Diseases (ICD) could change morbidity and mortality statistics significantly, which also affects the area of infectious diseases. Infectious diseases are classified according to their etiology, affected body system or the life period during which the episode occurs. Specific challenges arise from emerging pathogens and the respective necessary adaptation. For epidemiologic analysis ICD-10 does not always offer enough additional information. ICD provides the basis for international comparison of infectious disease morbidity and mortality statistics, but it is also used to collect data for surveillance and research purposes, e. g. the notification system for infectious diseases, syndromic surveillance systems and the evaluation of data quality by using secondary data sources. ICD-11 offers the chance to better represent epidemiological concepts of infectious diseases by adding more relevant information as affected body system or manifestation. Due to the complexity of coding, ensuring continuity of morbidity and mortality statistics could be challenging. |
4,506 | Epidemien und Pandemien in der hausärztlichen Praxis: Was können wir aus dem Schweinegrippe (H1N1)- und EHEC-Ausbruch lernen? | BACKGROUND: As primary care givers with a coordinating function, general practitioners (GP) play a key role in dealing with epidemics and pandemics. As of yet, there are no studies in Germany describing the difficulties experienced by GPs in patient care during epidemics/pandemics. OBJECTIVES: This study aimed at identifying the problem areas in GPs’ patient care during the H1N1 and EHEC (enterohemorrhagic strain of Escherichia coli) outbreaks. With this information, recommendations for guaranteeing proper patient care during future epidemics/pandemics can be derived. MATERIALS AND METHODS: In all, 12 qualitative, semi-structured, open guideline interviews with GPs in Hamburg and Lübeck were conducted, transcribed, and evaluated with qualitative content analysis. RESULTS: Five areas in ambulatory patient care were identified in which changes are needed from the primary care perspective: provision of information for GPs, workload, financing of epidemic-related measures, organization of the practices, care of those taken ill. CONCLUSIONS: The workload of GPs in particular can and should be reduced through successful, centralized information distribution during epidemics/pandemics. The GP’s function as a coordinator should be supported and consolidated, in order to relieve the in-patient sector in cases of an epidemic/pandemic. Secured financing of epidemic-associated measures can help ensure patient care. |
4,507 | Strukturelle Erfordernisse für das Management von Patienten mit hochkontagiösen, lebensbedrohlichen Erkrankungen – Update 2015 | The care of highly contagious life-threatening infectious diseases (HLID) requires specialized treatment facilities that are capable of strict isolation measures and appropriate medical treatment. The German approach to the management of these diseases, which is maintained by the Permanent Working Group of Medical Competence and Treatment Centers for Highly Contagious and Life-Threatening Diseases (STAKOB) is adjusted in the present publication with regards to recent experiences and upcoming needs. Clear synergies in using infrastructures and bundling of resources have led to similar efforts at the European level. The German concept, therefore, has a pioneering role. This update is intended to improve professional patient care and also minimize the risk of disease spread and transmission. |
4,508 | Infektiöse Lungenerkrankungen | Infectious pulmonary diseases and pneumonias are important causes of death within the group of infectious diseases in Germany. Most cases are triggered by bacteria. The morphology of the inflammation is often determined by the agent involved but several histopathological types of reaction are possible. Histology alone is only rarely able to identify the causal agent; therefore additional microbiological diagnostics are necessary in most cases. Clinically cases are classified as community acquired and nosocomial pneumonia, pneumonia under immunosuppression and mycobacterial infections. Histologically, alveolar and interstitial as well as lobar and focal pneumonia can be differentiated. |
4,509 | Zoonotische Infektionen beim Menschen: Übersicht über die epidemiologische Situation in Deutschland | Zoonoses are infectious diseases that can be transmitted from vertebrate animals to humans. Their significance lies in the large number of cases that occur, the high case fatality ratio of certain zoonoses, and the potential for some pathogens as yet restricted to animal hosts to cross the species barrier and infect humans. Changing habits in food production (for example, intensive animal husbandry) and food consumption as well as demographic, climatic, and ecological factors contribute to the spread of zoonotic pathogens. Several zoonoses are notifiable in Germany according to the Protection Against Infection Act enacted 1 January 2001. The European Commission issued a new directive on the monitoring of zoonoses and zoonotic agents on 17 November 2003. There is ongoing need to develop further measures to prevent and control zoonotic diseases on a national as well as international basis. |
4,510 | Surveillance gemäß den Internationalen Gesundheitsvorschriften (2005) | The International Health Regulations (IHR 2005) are a legally binding agreement that was adopted by all WHO Member States and which entered into force in June 2007. While taking the challenges of a globalized world into consideration, the purpose of the IHR (2005) is to provide a framework for international efforts to contain or reduce the risk from public health threats that may spread between countries. To this end, the IHR (2005) contain rights and obligations for the States and for WHO concerning national and international surveillance, assessment and public health response. With respect to surveillance, States are required to notify WHO of all events “that may constitute a public health emergency of international concern” according to agreed criteria. This obligation applies to novel or evolving public health risks, taking into account the context in which the event occurs. The IHR (2005) also contain obligations regarding global preparedness to address public health threats which include the establishment of national capacity to both detect and respond to events by June 2012. |
4,511 | Kommunen, Länder, Bund und Europäische Gemeinschaft: Zuständigkeiten und Aufgaben bei Seuchennotfällen im Kontext der neuen Internationalen Gesundheitsvorschriften | Pandemic preparedness has become a catch phrase for politicians, government agencies and communities, both nationally and internationally. This is due to the increasing number of infectious diseases emergencies that are important challenges for health protection authorities, which was shown impressively when SARS emerged as the first pandemic in this millennium. In Germany, effective and efficient infection control is complex, with local health protection authorities having their own responsibilities. In the case of an emergency epidemic, regional health departments are responsible. Having authority over these are authorities on the federal state level as well as on the federal level. For the European Community, the European Centre for Disease Prevention and Control (ECDC) was established. The mission of this agency is to identify, assess and communicate current and emerging threats to human health posed by infectious diseases. |
4,512 | Evidence for a prokaryotic insertion-sequence contamination in eukaryotic sequences registered in different databases | An insertion-sequence of prokaryotic origin was detected in a genomic clone obtained from a Phaseolus vulgaris bacterial artificial chromosome (BAC) library. This BAC clone, characterized as part of a contig constructed near a virus resistance gene, exhibited restriction fragment length polymorphism with an overlapping clone of the contig. Restriction analysis of DNA obtained from individual colonies of the stock culture indicated the presence of a mixed population of wild-type and insertional mutants. Sequence analysis of both members of the population revealed the presence of IS10R, an insertion-sequence from Escherichia coli. A BLAST search for IS10-like sequences detected unexpected homologies with a large number of eukaryotic sequences from Homo sapiens, Arabidopsis thaliana, Drosophila melanogaster and Caenorhabditis elegans. Southern analysis of a random sample of BAC clones failed to detect IS10 in the BAC DNA. However, prolonged sub-culturing of a set of 15 clones resulted in transposition into the BAC DNA. Eventually, all cultures acquired a 2.3-kb fragment that hybridized strongly with IS10. Sequence analysis revealed the presence of a preferred site for transposition in the BAC vector. These results indicate that a large number, if not all, of the BAC libraries from different organisms are contaminated with IS10R. The source of this element has been identified as the DH10B strain of E. coli used as the host for BAC libraries. |
4,513 | Early diagnosis and treatment of steroid-induced osteonecrosis of the femoral head | OBJECTIVE: This study aims to investigate the early diagnosis and treatment of steroid-induced osteonecrosis of the femoral head. PATIENTS AND METHODS: From January 2010 to January 2014, a total of 350 patients, who required the use of large amounts of hormones, were enrolled into the study. These patients were followed up every three months after starting the hormone therapy. A total of 62 cases were screened, among which nine cases were asymptomatic. Furthermore, 38 patients were diagnosed as stage I and were given low-molecular weight heparin (LMWH) and vasodilator drugs. Moreover, 22 cases were diagnosed as stage IIa/b and underwent core decompression. In addition, two cases were diagnosed as stage IIc and underwent pedicled bone transplantation. During the follow-up period, ARCO staging was used for radiological evaluation, the HHS score was applied to evaluate for clinical efficacy, and SPSS 22.0 statistical software was used for the data analysis. RESULTS: A total of 60 patients were followed up for 24 months. Among these patients, 38 patients were diagnosed with ARCO stage I and underwent systematic therapy. No progress was found in 29 cases (76.3%). Furthermore, three cases progressed to stage IIb (7.8%), four cases progressed to stage IIc (10.5%), two cases progressed to stage III and IV, respectively (2.6%), and 16 cases (80%) did not progress after core decompression. In the 16 cases at stage IIa and four cases at stage IIb, and four cases (20%) progressed in stage III. The HHS score of stage I was 80.42 ± 3.25 before follow-up, while the HHS score was 86.46 ± 8.54 after follow-up, and the difference was statistically significant (P < 0.05). Furthermore, the HHS score of patients with stage IIa/b was 70.38 ± 4.62 before follow-up, while the HHS score was 80.28 ± 6.72 after follow-up, and the difference was statistically significant (P < 0.01). CONCLUSION: MRI remains as the most effective method for the non-invasive diagnosis of osteonecrosis, at present. Enhanced MRI may be able to detect early osteonecrosis, but further research is needed. Drug treatment and core decompression can achieve satisfactory results at the early stage. |
4,514 | Innovationen in der Leberchirurgie durch die Transplantation mit Lebendspende | Living-donor liver transplantation was introduced into clinical practice in the early 1990s. At first the results were unsatisfactory, but today's results after living donation are as good as those obtained after conventional liver transplantation with full-sized organs. With minimally invasive diagnostic methods, it is now possible to determine the quality of potential donor livers and exclude focal lesions and anatomical variants which influence the strategy of organ retrieval procedures. Donor liver resection is done without hilar occlusion after determining the anatomical variants of the bile system (especially for right lobes) and localizing of the course of the middle hepatic vein. Microsurgical techniques are used for reconstruction of the biliary system and hepatic vessels. Living-donor liver transplantation allows us to investigate the complex changes after liver resection. The surgical techniques and pathophysiological postoperative changes can be adapted unconventionally to complex oncological liver resections. Therapeutic optimization and better risk management are becoming possible for liver resections. |
4,515 | Adaptive evolution of virus-sensing toll-like receptor 8 in bats | Recently, bats have gained attention as potential reservoir hosts for emerging zoonotic single-stranded (ssRNA) viruses that may prove fatal for humans and other mammals. It has been hypothesized that some features of their innate immune system may enable bats to trigger an efficient early immune response. Toll-like receptors (TLRs) represent a first line defense within the innate immune system and lie directly at the host–pathogen interface in targeting specific microbe-molecular patterns. However, the direction and strength of selection acting on TLRs are largely unknown for bats. Here, we studied the selection on viral ssRNA sensing TLR8 based on sequence data of 21 bat species. The major part (63 %) of the TLR8 gene evolved under purifying selection, likely due to functional constraints. We also found evidence for persistent positive selection acting on specific amino acid sites (7 %), especially when compared to viral TLR evolution of other mammals. All of these putatively positively selected codons were located in the ligand-binding ectodomain, some coincidenced or were in close proximity to functional sites, as suggested by the crystallographic structure of the human TLR8. This might contribute to the inter-species variation in the ability to recognize molecular patterns of viruses. TLR8 evolution within bats revealed that branches leading to ancestral and recent lineages evolved under episodic positive selection, indicating selective selection pressures in restricted bat lineages. Altogether, we found that the TLR8 displays extensive sequence variation within bats and that unique features separate them from humans and other mammals. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00251-016-0940-z) contains supplementary material, which is available to authorized users. |
4,516 | Microfluidics in macro-biomolecules analysis: macro inside in a nano world | Use of microfluidic devices in the life sciences and medicine has created the possibility of performing investigations at the molecular level. Moreover, microfluidic devices are also part of the technological framework that has enabled a new type of scientific information to be revealed, i.e. that based on intensive screening of complete sets of gene and protein sequences. A deeper bioanalytical perspective may provide quantitative and qualitative tools, enabling study of various diseases and, eventually, may offer support for the development of accurate and reliable methods for clinical assessment. This would open the way to molecule-based diagnostics, i.e. establish accurate diagnosis and disease prognosis based on identification and/or quantification of biomacromolecules, for example proteins or nucleic acids. Finally, the development of disposable and portable devices for molecule-based diagnosis would provide the perfect translation of the science behind life-science research into practical applications dedicated to patients and health practitioners. This review provides an analytical perspective of the impact of microfluidics on the detection and characterization of bio-macromolecules involved in pathological processes. The main features of molecule-based diagnostics and the specific requirements for the diagnostic devices are discussed. Further, the techniques currently used for testing bio-macromolecules for potential diagnostic purposes are identified, emphasizing the newest developments. Subsequently, the challenges of this type of application and the status of commercially available devices are highlighted, and future trends are noted. |
4,517 | Pandemic risk prevention in European countries: role of the ECDC in preparing for pandemics: Development and experience with a national self-assessment procedure, 2005–2008 | To be effective risk prevention work takes place well before pandemics through the three Ps: Planning, Preparedness and Practise. Between 2005 and 2008 the European Centre for Disease Prevention and Control (ECDC) worked with the European Commission (EC) and the WHO Regional Office for Europe (WHO-Euro) to assist European countries in preparing themselves for a future influenza pandemic. All eligible countries in the European Union and European Economic Area participated with energy and commitment. Indicators of preparedness were developed based on WHO planning guidance and these were set within a simple assessment which included a formal country visit. The procedure evolved considerably with field experience. As the complexity of pandemic preparedness was appreciated it changed from being a classical short external assessment to longer national self-assessments with demonstrable impact, especially when self-assessments were published. There were essential supporting activities undertaken including a series of pan-European pandemic preparedness workshops organised by EC, WHO-Euro, ECDC and countries holding the European Union Presidency. The self-assessments highlighted additional work and documentation that was needed by national authorities from the ECDC. This work was undertaken and the document produced. The benefits of the self-assessments were seen in the 2009 pandemic in that EU/EEA countries performed better than some others. A number of the guidance documents were updated to fit the specific features of the pandemic. However the pandemic revealed many weaknesses and brought new challenges for European countries, notably over communication and vaccines, the need to prepare for a variety of scenarios and to factor severity estimates into preparedness, to improve surveillance for severe disease and to deliver seroepidemiology. Any revised self-assessment procedure will need to respond to these challenges. |
4,518 | Chapter 1. Introduction | BACKGROUND: In December 2007, the European Society of Intensive Care Medicine established a Task Force to develop standard operating procedures (SOPs) for operating intensive care units (ICU) during an influenza epidemic or mass disaster. PURPOSE: To provide direction for health care professionals in the preparation and management of emergency ICU situations during an influenza epidemic or mass disaster, standardize activities, and promote coordination and communication among the medical teams. METHODS: Based on a literature review and contributions of content experts, a list of essential categories for managing emergency situations in the ICU were identified. Based on three cycles of a modified Delphi process, consensus was achieved regarding the categories. A primary author along with an expert group drafted SOPs for each category. RESULTS: Based on the Delphi cycles, the following key topics were found to be important for emergency preparedness: triage, infrastructure, essential equipment, manpower, protection of staff and patients, medical procedures, hospital policy, coordination and collaboration with interface units, registration and reporting, administrative policies and education. CONCLUSIONS: The draft SOPs serve as benchmarks for emergency preparedness and response of ICUs to emergencies or outbreak of pandemics. |
4,519 | Das Auftreten alter und neuer Seuchen als Konsequenz menschlichen Handelns | In the era of antibiotics and vaccines and prior to the appearance of AIDS, well-known infectious diseases received decreasing clinical attention. Occasionally, the opinion was also expressed that new types of infectious diseases could no longer be expected. However, a more detailed analysis of the state of infectious diseases yields quite a different picture. A variety of new infectious diseases has clinically been defined over the last few decades. New viruses, bacteria, and parasites with pathogenic potential for humans have been detected and well-known microorganisms have spread beyond their original geographic areas. Infectious agents, in particular viruses, permanently alter their genomes and may thus gain new clinical relevance. This article demonstrates that primarily the behavior of man influenced the nature and distribution of infectious diseases in the past and will affect the spread of infectious diseases in the future. |
4,520 | Das Renin–Angiotensin–Aldosteron–System – komplexer als bisher gedacht | BACKGROUND: Angiotensin II (ANG II) is an important factor for the progression of renal diseases. ANG II has many pleiotropic effects on the kidney such as pro–inflammatory and profibrotic actions besides the well–known blood pressure–increasing effect. NOVEL KNOWLEDGE: Organs have local ANG II–generating systems that work independently from their classic systemic counterpart. Renal proximal tubular cells could generate and secrete ANG II into the urine in concentrations that are 10,000 times higher than those found in serum. These local systems are only incompletely blocked by currently used doses of ACE inhibitors or AT(1) antagonists. There are other enzyme systems besides ACE that contribute to the formation of ANG II. Alternative pathways generate peptides such as angiotensin 1–7 that have antagonistic effect compared with ANG II. Degradation products of ANG II such as angiotensin IV bind at separate receptors and could mediate fibrosis. The discovery of AT(1) receptor dimers and agonistic antibodies against AT(1) receptors contributes to the complexity of the system. CLINICAL RELEVANCE: The complexity of the renin–angiotensin–aldosterone system (RAAS) implies that dual blockade with ACE inhibitors and AT(1) receptor antagonists makes sense for pathophysiological reasons. First clinical studies have shown that such as dual therapy reduces progression of chronic renal disease more efficiently that the respective monotherapies in certain risk populations. This shows that novel pathophysiological data could lead to innovative clinical treatment strategies. |
4,521 | Design and application of GB virus C (GBV-C) peptide microarrays for diagnosis of GBV-C/HIV-1 co-infection | The main objectives of the design of GB virus C (GBV-C) peptide microarrays are the miniaturisation of antigen–antibody interaction assays, the simultaneous analysis of several peptide sequences and the reduction in the volume of serum required from patients since this always represents a limiting factor in studies to develop new systems for diagnosing human diseases. We herein report the design of a microarray immunoassay based on synthetic peptides derived from the GBV-C E2 protein to evaluate their diagnostic value in detecting anti-E2 antibodies in HIV-1 patients. To this end, peptide microarrays were initially prepared to identify the most relevant epitopes in the GBV-C E2 protein. Thus, 124 peptides composed of 18 amino acids covering the whole E2-protein sequence, with 15 residue overlaps, were spotted in triplicate onto γ-aminopropyl silane-functionalised adsorbent binding slides. The procedure to select the E2 protein epitopes was carried out using serum samples from HIV-1-infected patients. The samples had previously been tested for the presence or absence of GBV-C anti-E2 antibodies by means of the Abbott test. Thus, 11 specific epitopes in the GBV-C E2 protein were identified. Subsequently, peptide antigen microarrays were constructed using the E2 epitopes identified to detect GBV-C anti-E2 antibodies in the serum of HIV-1-infected patients with no known GBV-C co-infection. The 11 peptides selected identified anti-E2 GBV-C antibodies among HIV-1-infected patients, and a reactivity of 47 % was established. The potential antigenic peptides selected could be considered a useful tool for designing a new diagnostic system based on peptide microarrays to determine anti-GBV-C E2 antibodies in the serum of HIV-1-infected patients. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00216-012-6585-3) contains supplementary material, which is available to authorized users. |
4,522 | Haben HIV-Positive eine besondere Verantwortung?: Ein Diskussionsbeitrag | In the 1980s, most Western countries decided to opt for a new public health approach based on learning strategies to fight HIV/AIDS. Within the new public health paradigm, every sexually active person protects him-/herself, whereas it is the infected people that bear the burden of prevention according to old public health. The paper begins with a clear statement for the new public health approach that includes self-protection and the protection of civil rights. It argues that this approach is still valid under the changing circumstances due to combination therapies and the developments related to them, such as the introduction of routine HIV screening in some countries. On this background, the paper examines from an ethical perspective to what extent people with HIV have a responsibility in HIV prevention. The paper argues that a person with HIV has a responsibility to protect his/her partner in the case of a relationship of love. On the other hand, in the case of "purely" sexual encounters, each person is responsible for his/her own security and should not rely on the other. This position also helps to clarify prevention messages. In conclusion, the paper shows how morality evolves into ethical positions and then translates into the law. It finally claims for stronger obligations for sex businesses to support HIV prevention. |
4,523 | Exact epidemic models on graphs using graph-automorphism driven lumping | The dynamics of disease transmission strongly depends on the properties of the population contact network. Pair-approximation models and individual-based network simulation have been used extensively to model contact networks with non-trivial properties. In this paper, using a continuous time Markov chain, we start from the exact formulation of a simple epidemic model on an arbitrary contact network and rigorously derive and prove some known results that were previously mainly justified based on some biological hypotheses. The main result of the paper is the illustration of the link between graph automorphisms and the process of lumping whereby the number of equations in a system of linear differential equations can be significantly reduced. The main advantage of lumping is that the simplified lumped system is not an approximation of the original system but rather an exact version of this. For a special class of graphs, we show how the lumped system can be obtained by using graph automorphisms. Finally, we discuss the advantages and possible applications of exact epidemic models and lumping. |
4,524 | Role of environmental persistence in pathogen transmission: a mathematical modeling approach | Although diseases such as influenza, tuberculosis and SARS are transmitted through an environmentally mediated mechanism, most modeling work on these topics is based on the concepts of infectious contact and direct transmission. In this paper we use a paradigm model to show that environmental transmission appears like direct transmission in the case where the pathogen persists little time in the environment. Furthermore, we formulate conditions for the validity of this modeling approximation and we illustrate them numerically for the cases of cholera and influenza. According to our results based on recently published parameter estimates, the direct transmission approximation fails for both cholera and influenza. While environmental transmission is typically chosen over direct transmission in modeling cholera, this is not the case for influenza. |
4,525 | Angst essen Impfbereitschaft auf?: Der Einfluss kognitiver und affektiver Faktoren auf die Risikowahrnehmung im Ausbruchsgeschehen | During the influenza pandemic in 2009 individuals had the choice of either receiving a vaccination or running the risk of becoming infected with the pandemic influenza virus A (H1N1). For many individuals knowledge of a likely infection and possibly serious health consequences stood in contrast to a vague fear of the vaccination itself. What has a stronger influence on the decision to be vaccinated: the cognitive estimation of risk or the feeling of risk? Based on data collected during the 2009 influenza A (H1N1) pandemic we tested the relative influence of the cognitive and affective aspects of risk on estimation of the individual willingness to be vaccinated. In doing so we also focused on fear. The results indicate that the feeling of risk had a significant effect on the willingness to be vaccinated. In contrast, the classic, cognitive estimation of a risk was no longer a significant predictor when the feeling of risk was also used to predict the willingness to be vaccinated. A highly felt risk to become infected with influenza A (H1N1) substantially increased the willingness to be vaccinated. A highly felt risk regarding the vaccination, on the other hand, decreased the willingness to be vaccinated. Fear of the vaccination significantly decreased the willingness to be vaccinated even when fear of the spreading disease was also very high. The implications of the results for crisis communications will also be discussed. |
4,526 | Evolutionary dynamics of HIV at multiple spatial and temporal scales | Infectious diseases remain a formidable challenge to human health, and understanding pathogen evolution is crucial to designing effective therapeutics and control strategies. Here, we review important evolutionary aspects of HIV infection, highlighting the concept of selection at multiple spatial and temporal scales. At the smallest scale, a single cell may be infected by multiple virions competing for intracellular resources. Recombination and phenotypic mixing introduce novel evolutionary dynamics. As the virus spreads between cells in an infected individual, it continually evolves to circumvent the immune system. We discuss evolutionary mechanisms of HIV pathogenesis and progression to AIDS. Viral spread throughout the human population can lead to changes in virulence and the transmission of immune-evading variation. HIV emerged as a human pathogen due to selection occurring between different species, adapting from related viruses of primates. HIV also evolves resistance to antiretroviral drugs within a single infected host, and we explore the possibility for the spread of these strains between hosts, leading to a drug-resistant epidemic. We investigate the role of latency, drug-protected compartments, and direct cell-to-cell transmission on viral evolution. The introduction of an HIV vaccine may select for viral variants that escape vaccine control, both within an individual and throughout the population. Due to the strong selective pressure exerted by HIV-induced morbidity and mortality in many parts of the world, the human population itself may be co-evolving in response to the HIV pandemic. Throughout the paper, we focus on trade-offs between costs and benefits that constrain viral evolution and accentuate how selection pressures differ at different levels of selection. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00109-012-0892-1) contains supplementary material, which is available to authorized users. |
4,527 | Infektionsprävention durch Hygiene zu Hause und in der Öffentlichkeit: Die Notwendigkeit für eine familienzentrierte Strategie | Over the past 20 years, infectious disease has moved back up the health agenda, prompting new emphasis on developing strategies for prevention and control, including reduction of spread of infection within the family at home and in their social and work lives outside the home. This paper reviews the various issues that have contributed to this trend. In response to the need for a science-based approach to home hygiene, the International Scientific Forum on Home Hygiene has developed an approach based on risk management which involves identifying the critical control points for preventing the spread of infectious diseases in the home. If we are to be successful in achieving behaviour change in the community, we need to develop a family-centred approach which ensures an understanding of infectious disease agents and their mechanism of spread. |
4,528 | Erster Erfahrungsaustausch zur H1N1-Pandemie in Deutschland 2009/2010: Bericht über einen Workshop am 22. und 23. März 2010 in Berlin | In April 2009 the first pandemic of the 21st century developed within a few weeks starting from Mexico. Its first wave reached Germany in autumn 2009 and was responsible for 1.8–3.5 million additional medical consultations. For the public health sector, this pandemic was one of the largest challenges of the last few decades. As a contribution to broader evaluations on national and international level, the Robert Koch Institute invited representatives from different professions involved in the pandemic response to participate in a workshop on 22–23 March 2010. This workshop was structured in short presentations, group work, and plenary discussions. Main experiences were that (a) pandemic preparedness was helpful, (b) the early warning systems were reliable, (c) vaccines were available within a few months, however, in limited amounts. Need for improvement was discussed for (a) effectiveness of vaccination logistics, (b) mechanisms for the reimbursement of the cost of vaccination, (c) availability of surveillance and monitoring systems, (d) integration of physicians in decision-making processes and health education, and (e) proactive communication strategies. Investments in the above mentioned areas can help to improve public health protection in the future. |
4,529 | Lage – Krise – Katastrophe. Eine Konzeptualisierung biologischer Gefahrenlagen | Unusual biological threats demand adequate preparedness efforts, as demonstrated, for example, by the Ebola virus disease outbreak in West Africa in 2014/2015 and pandemic influenza in 2009/2010. In Germany, responsibilities for such efforts are located in different governmental authorities and differ from state to state. As a result, there are many different preparedness approaches using divergent core terminology. In this article a common definition for the term “unusual biological incident” is proposed. To do so, a literature review as well as semi-structured expert interviews with representatives of central actors in Germany were conducted. The understanding of “unusual biological incident” was not consistent among experts; four approaches to qualify a biological incident as “unusual” were identified. These were merged in a comprehensive system-oriented approach that focuses on the health system’s resilience and on shortages of knowledge and material resources during incidents. Based on this approach, we suggest a stage model for the categorization of biological threats as “incident,” “crisis,” “severe crisis,” or “disaster.” The need for central coordination is a defining characteristic to qualify a biological incident as “unusual.” Based on the identified shortages, the necessary response strategies can be derived. |
4,530 | Bacterial survival in evaporating deposited droplets on a teflon-coated surface | Understanding of bacterial survival in aerosols is crucial for controlling infection transmission via airborne aerosols and/or large droplets routes. The cell viability changes of four bacteria species (Escherichia coli K12 JM109; Acinetobacter sp. 5A5; Pseudomonas oleovorans X5; and Staphylococcus aureus X8), three Gram-negative and one Gram-positive, in a large evaporating droplet of size 1,800 μm in diameter on teflon-coated slides were measured using the LIVE/DEAD BacLight solution and a microscope. Droplets of three levels of salinity (0, 0.9, and 36% w/v) were tested. All four species survived well during the droplet evaporation process, but died mostly at the time when droplets were dried out at 40–45 min. The final bacteria survival rate after droplets were completely dried was dependent on bacteria species and the salinity of the suspension solution. Droplet evaporation over the first 35–40 min had no adverse effect on bacterial survival for the droplets tested. The lethal effect of desiccation was found to be the most important death mechanism. |
4,531 | Systemische Infektionen in der Geburtshilfe | The importance of systemic infections in pregnancy is often underestimated. This is primarily due to the fact that pregnant women, in the majority of cases, do not notice any complaints or only have unspecific flu-like symptoms (e.g. toxoplasmosis). Serological screening within the framework of German maternity care is often insufficient to diagnose existing or emerging infections in time. However, the long-term consequences for the affected children and their parents can be immense. A serological TORCH analysis should be performed if a pregnant woman complains about any typical or unspecific symptoms on suspicion of an infection. |
4,532 | Seroprävalenz von Antikörpern gegen schwangerschaftsrelevante virale Infektionserreger bei Mitarbeiterinnen im Gesundheitswesen | Healthcare workers (HCWs) are exposed to infectious diseases throughout the course of their work. The concerns of pregnant HCWs are considerable because certain otherwise mild infections may affect fetal development. We studied 424 pregnant HCWs at the University Hospital Frankfurt between March 2007 and July 2011. Serological tests were carried out for varicella zoster virus (VZV), measles, mumps, rubella (MMR), cytomegalovirus (CMV) and parvovirus B19. Our overall seroprevalence data with regard to VZV, MMR, CMV and parvovirus B 19 corresponded to the general population. However, physicians demonstrated lower seroprevalence towards the two non-vaccine-preventable diseases (CMV: 37.5% [KI 27.4–48.5]; parvovirus B19: 69.3% [KI 58.6–78.7]) compared with nurses (CMV: 53.4% [KI 46.1–60.6], parvovirus B19: 75.1% [68.4–81.1]). It was striking that, only one in five of the study population showed IgG antibodies against all of the six pregnant-relevant viral diseases tested, of the physicians as few as one in six. A routine exclusion from the workplace due to non-immunity would mean that it would not be possible to employ the majority of pregnant staff in healthcare and childcare. |
4,533 | SUMO fusion system facilitates soluble expression and high production of bioactive human fibroblast growth factor 23 (FGF23) | As a key humoral regulator of phosphate homeostasis and its involvement in the pathogenesis of human disease, human fibroblast growth factor 23 (hFGF23) has become a particularly attractive therapeutic target. To prepare soluble and bioactive recombinant human FGF23 to meet the increasing demand in its pharmacological application, small ubiquitin-related modifier (SUMO)-FGF23 fusion gene and FGF23 non-fusion gene were amplified by standard PCR methods and cloned into vector pET-22b and pET-3c, then transformed into Escherichia coli Rosetta (DE3) and BL21 (DE3). The best combination of plasmid and host strain was screened, and only Rosetta (DE3)/pET-SUMO-FGF23 was screened for rhFGF23 protein expressed. The average bacterial yield and the soluble expression level of recombinant hFGF23 of three batches attained 687 ± 18 g and 30 ± 1.5%, respectively, after treatment with 0.4 mM isopropyl-thio-β-galactopyranoside for 19 h at 16 °C in a 30-L fermentor, after which it was purified by DEAE Sepharose FF and nickel nitrilotriacetic acid affinity chromatography. Once cleaved by the SUMO protease, the recombinant human FGF23 was released from the fusion protein. The purity of rFGF23 was shown by high performance liquid chromatography to be greater than 90% and the yield was 60 ± 1.5 mg/L. In vitro data showed that the purified rFGF23 can induce the phosphorylation of mitogen-activated protein kinases in the glioma U251 cell. The results of in vivo animal experiments also showed that rFGF23 could decrease the concentration in the plasma of normal rats fed with a fixed formula diet. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00253-011-3864-4) contains supplementary material, which is available to authorized users. |
4,534 | Fünf Jahre Empfehlungen der Kommission für Krankenhaushygiene zur Aufbereitung flexibler Endoskope: Blick zurück und Blick nach vorn(1) | In a short review the national and international reception of the German guidelines for reprocessing flexible endoscopes is presented. The recommendations of the guidelines are discussed in view of recent knowledge on old problems such as prion inactivation and new infectious diseases and new microorganisms such as SARS, avian influenza and C. difficile. New disinfectants and new methods for endoscope disinfection are mentioned, the importance of careful cleaning is underlined. The German guidelines of the Robert Koch Institute and the US Multi-Society guidelines, published in 2003, are compared. The discrepancies concerning recommendations for water quality for final rinsing and need of microbiological controls of endoscope reprocessing are stressed. Aspects not mentioned in the German guidelines, e.g. duration of storage after reprocessing and risk of infection transmission by the endo-washer, are discussed. |
4,535 | The role of the WHO Regional Office for Europe in response to seasonal, avian, and pandemic influenza | Between 2005 and 2011, the WHO Regional Office for Europe assisted the member states of the WHO European Region to prepare and respond to outbreaks of avian influenza H5N1, the 2009 pandemic, and to enhance their capacities for the prevention and control of seasonal influenza. It did this through conducting a combination of regional and subregional meetings and trainings, establishing a regional network for influenza surveillance, providing operational guidance for implementing influenza surveillance and strengthening the capacities of National Influenza Centers, and through assistance at the country-level where needed. In all, close to 60 country-missions or country-level activities were conducted. These activities were conducted in close coordination with WHO headquarters, WHO European Region Country Offices, the European Commission, the European Centre for Disease Prevention and Control, and with other partner organizations, and were in line with the implementation of the International Health Regulations (2005). The results of activities as well as guidance documents were disseminated to a wide audience through publication on the WHO Regional Office for Europe Influenza website, on the EuroFlu website, and through peer-reviewed publications. |
4,536 | Diagnosis of severe respiratory infections in immunocompromised patients | An increasing number of critically ill patients are immunocompromised. Acute hypoxemic respiratory failure (ARF), chiefly due to pulmonary infection, is the leading reason for ICU admission. Identifying the cause of ARF increases the chances of survival, but may be extremely challenging, as the underlying disease, treatments, and infection combine to create complex clinical pictures. In addition, there may be more than one infectious agent, and the pulmonary manifestations may be related to both infectious and non-infectious insults. Clinically or microbiologically documented bacterial pneumonia accounts for one-third of cases of ARF in immunocompromised patients. Early antibiotic therapy is recommended but decreases the chances of identifying the causative organism(s) to about 50%. Viruses are the second most common cause of severe respiratory infections. Positive tests for a virus in respiratory samples do not necessarily indicate a role for the virus in the current acute illness. Invasive fungal infections (Aspergillus, Mucorales, and Pneumocystis jirovecii) account for about 15% of severe respiratory infections, whereas parasites rarely cause severe acute infections in immunocompromised patients. This review focuses on the diagnosis of severe respiratory infections in immunocompromised patients. Special attention is given to newly validated diagnostic tests designed to be used on non-invasive samples or bronchoalveolar lavage fluid and capable of increasing the likelihood of an early etiological diagnosis. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00134-019-05906-5) contains supplementary material, which is available to authorized users. |
4,537 | Wie groß sind die Differenzen zwischen den europäischen Pandemieplänen, sind sie relevant und woher stammen sie? | The coordination of influenza pandemic preparedness planning within Europe is especially important for Germany with 10 out of 16 Länder (regions) bordering neighbouring countries. The language barrier presents only one of the challenges to overcome. Creating a European early warning system by linking national surveillance structures and the development of a communication network are important initial achievements. Several instruments have been designed and the European Centre for Disease Prevention and Control has already played a major role in the coordination of this process. It has also led the assessment of preparedness and planning by Member States. The speed of the European Member States in preparing for and the foci they have chosen when dealing with an influenza outbreak are heterogeneous. The simultaneous analysis presented here from European, national and regional points of view aims to identify both opportunities and risks of this diversity in Europe for coping with a new pandemic. Regional and local initiatives for cross-border measures and crisis management will play a central role in achieving successful influenza pandemic preparedness in Europe. |
4,538 | Recent advances and safety issues of transgenic plant-derived vaccines | Transgenic plant-derived vaccines comprise a new type of bioreactor that combines plant genetic engineering technology with an organism's immunological response. This combination can be considered as a bioreactor that is produced by introducing foreign genes into plants that elicit special immunogenicity when introduced into animals or human beings. In comparison with traditional vaccines, plant vaccines have some significant advantages, such as low cost, greater safety, and greater effectiveness. In a number of recent studies, antigen-specific proteins have been successfully expressed in various plant tissues and have even been tested in animals and human beings. Therefore, edible vaccines of transgenic plants have a bright future. This review begins with a discussion of the immune mechanism and expression systems for transgenic plant vaccines. Then, current advances in different transgenic plant vaccines will be analyzed, including vaccines against pathogenic viruses, bacteria, and eukaryotic parasites. In view of the low expression levels for antigens in plants, high-level expression strategies of foreign protein in transgenic plants are recommended. Finally, the existing safety problems in transgenic plant vaccines were put forward will be discussed along with a number of appropriate solutions that will hopefully lead to future clinical application of edible plant vaccines. |
4,539 | Infektionsprävention bei der Narkosebeatmung durch Einsatz von Atemsystemfiltern: Gemeinsame Empfehlung der Deutschen Gesellschaft für Krankenhaushygiene e.V. (DGKH) und der Deutschen Gesellschaft für Anästhesiologie und Intensivmedizin e.V. (DGAI) | An interdisciplinary working group from the German Society of Hospital Hygiene (DGKH) and the German Society for Anesthesiology and Intensive Care (DGAI) worked out the following recommendations for infection prevention during anesthesia by using breathing system filters (BSF). The BSF shall be changed after each patient. The filter retention efficiency for airborne particles is recommended to be >99% (II). The retention performance of BSF for liquids is recommended to be at pressures of at least 60 hPa (=60 mbar) or 20 hPa above the selected maximum ventilation pressure in the anesthetic system. The anesthesia breathing system may be used for a period of up to 7 days provided that the functional requirements of the system remain unchanged and the manufacturer states this in the instructions for use. The breathing system and the manual ventilation bag are changed immediately after the respective anesthesia if the following situation has occurred or it is suspected to have occurred: Notifiable infectious disease involving the risk of transmission via the breathing system and the manual bag, e.g. tuberculosis, acute viral hepatitis, measles, influenza virus, infection and/or colonization with a multi-resistant pathogen or upper or lower respiratory tract infections. In case of visible contamination e.g. by blood or in case of defect, it is required that the BSF and also the anesthesia breathing system is changed and the breathing gas conducting parts of the anesthesia ventilator are hygienically reprocessed. Observing of the appropriate hand disinfection is very important. All surfaces of the anesthesia equipment exposed to hand contact must be disinfected after each case. |
4,540 | Wirksamkeit von Pflanzenprodukten gegen Herpesinfektionen | Essential oils from various aromatic medicinal plants are highly active against some viral infections, e.g. labial herpes caused by herpes simplex virus type 1. Balm oil, tea tree oil and peppermint oil demonstrate in vitro a significant antiherpetic activity, mainly related to a direct drug-virus particle interaction, some essential oils also act directly virucidal. Interestingly, these essential oils are also highly active against acyclovir-resistant herpes simplex virus strains. In clinical studies, tea tree oil has been shown to possess antiherpetic, anti-inflammatory and pain-relieving properties, as well as to accelerate the healing process of herpes labialis. Applying diluted essential oils three to four times daily for the antiherpetic treatment of affected areas is recommended. Some companies have marketed plant products, e.g. from Melissa, for the treatment of recurrent herpetic infections. |
4,541 | HIV-Infektion – Grenzen der Präventionskonzepte: Überlegungen zur Verantwortung der Betroffenen, der Politik und der Gesellschaft* | Despite the introduction of campaigns to prevent the continued spread of HIV/AIDS in Germany, the number of annual firsttime HIV-diagnoses is continuing steadily. The concepts behind the current campaigns are largely based on models of New Public Health, of which social learning strategies are an essential element. The established personal and individual rights should be unimpeachable but the right not to know the status of HIV infection should be questioned for those people who spread their HIV infection intentionally and wilfully. Confronted with more than 10,000 people in Germany unconscious of their HIV infection, easy access to HIV testing and access of opportune therapy should be offered with the goal of reducing the number of new infections. Expanded strategies on the responsibility to one’s personal health and that of the partner, understandable and adapted to special groups of the society, should be established and maintained at a high level of awareness. All measures must be performed voluntarily. |
4,542 | Automated analytical microarrays: a critical review | Microarrays provide a powerful analytical tool for the simultaneous detection of multiple analytes in a single experiment. The specific affinity reaction of nucleic acids (hybridization) and antibodies towards antigens is the most common bioanalytical method for generating multiplexed quantitative results. Nucleic acid-based analysis is restricted to the detection of cells and viruses. Antibodies are more universal biomolecular receptors that selectively bind small molecules such as pesticides, small toxins, and pharmaceuticals and to biopolymers (e.g. toxins, allergens) and complex biological structures like bacterial cells and viruses. By producing an appropriate antibody, the corresponding antigenic analyte can be detected on a multiplexed immunoanalytical microarray. Food and water analysis along with clinical diagnostics constitute potential application fields for multiplexed analysis. Diverse fluorescence, chemiluminescence, electrochemical, and label-free microarray readout systems have been developed in the last decade. Some of them are constructed as flow-through microarrays by combination with a fluidic system. Microarrays have the potential to become widely accepted as a system for analytical applications, provided that robust and validated results on fully automated platforms are successfully generated. This review gives an overview of the current research on microarrays with the focus on automated systems and quantitative multiplexed applications. [Figure: see text] |
4,543 | Behandlungseinrichtungen für hochkontagiöse, lebensbedrohliche Erkrankungen: Deutschland im Vergleich zu 15 europäischen Staaten | BACKGROUND: Patients suffering from highly contagious, life-threatening infections should be treated in specialized clinical facilities that follow the highest infection control standards. Consensus statements defining technical equipment and operational procedures have been published in recent years, but the level of adherence to these has not been evaluated. METHODS: Data summarized here comparing German and European isolation facilities are the partial results of a cross-sectional analysis conducted by the “European Network for Highly Infectious Diseases” that included 48 clinical care facilities in 16 European nations. Data collection was conducted using questionnaires and on-site visits, focussing on aspects of infrastructure, technical equipment, and the availability of trained personnel. RESULTS: Although all centres enrolled were listed as “isolation units”, all aspects evaluated differed broadly. Eighteen facilities fulfilled the definition of a ‘High Level Isolation Unit’, as 6/8 enrolled German facilities did. In contrast, 24 facilities could not operate independently from their co-located hospital. DISCUSSION: Within and between nations contributing data disparities regarding the fulfilment of guidelines published were seen. German isolation facilities mostly fulfilled all criteria evaluated and performed on a high technical level. However, data presented do not reflect the current situation in Germany due to the time that has elapsed since the study was conducted. Hence, longitudinal data collection and harmonisation of terminology at least on national level needs to be implemented. |
4,544 | Epidemiological implications of mobility between a large urban centre and smaller satellite cities | An SIR infectious disease propagation model is considered that incorporates mobility of individuals between a large urban centre and smaller satellite cities. Because of the difference in population sizes, the urban centre has standard incidence and satellite cities have mass action incidence. It is shown that the general basic reproduction number [Formula: see text] acts as a threshold between global asymptotic stability of the disease free equilibrium and disease persistence. The case of Winnipeg (MB, Canada) and some neighbouring satellite communities is then considered numerically to complement the mathematical analysis, highlighting the importance of taking into account not only [Formula: see text] but also other measures of disease severity. It is found that the large urban centre governs most of the behaviour of the general system and control of the spread is better achieved by targeting it rather than reducing movement between the units. Also, the capacity of a satellite city to affect the general system depends on its population size and its connectivity to the main urban centre. |
4,545 | Current trends in targeted therapy for drug-resistant infections | Escalating antibiotic resistance is now a serious menace to global public health. It may be led to the emergence of “postantibiotic age” in which most of infections are untreatable. At present, there is an essential need to explore novel therapeutic strategies as a strong and sustainable pipeline to combat antibiotic-resistant infections. This review focuses on recent advances in this area including therapeutic antibodies, antimicrobial peptides, vaccines, gene therapy, genome editing, and phage therapy for tackling drug-resistant infections. |
4,546 | Studying the recovery procedure for the time-dependent transmission rate(s) in epidemic models | Determining the time-dependent transmission function that exactly reproduces disease incidence data can yield useful information about disease outbreaks, including a range potential values for the recovery rate of the disease and could offer a method to test the “school year” hypothesis (seasonality) for disease transmission. Recently two procedures have been developed to recover the time-dependent transmission function, β(t), for classical disease models given the disease incidence data. We first review the β(t) recovery procedures and give the resulting formulas, using both methods, for the susceptible-infected-recovered (SIR) and susceptible-exposed-infected-recovered (SEIR) models. We present a modification of one procedure, which is then shown to be identical to the other. Second, we explore several technical issues that appear when implementing the procedure for the SIR model; these are important when generating the time-dependent transmission function for real-world disease data. Third, we extend the recovery method to heterogeneous populations modeled with a certain SIR-type model with multiple time-dependent transmission functions. Finally, we apply the β(t) recovery procedure to data from the 2002–2003 influenza season and for the six seasons from 2002–2003 through 2007–2008, for both one population class and for two age classes. We discuss the consequences of the technical conditions of the procedure applied to the influenza data. We show that the method is robust in the heterogeneous cases, producing comparable results under two different hypotheses. We perform a frequency analysis, which shows a dominant 1-year period for the multi-year influenza transmission function(s). |
4,547 | Diagnostic workup for ARDS patients | Acute respiratory distress syndrome (ARDS) is defined by the association of bilateral infiltrates and hypoxaemia following an initial insult. Although a new definition has been recently proposed (Berlin definition), there are various forms of ARDS with potential differences regarding their management (ventilator settings, prone positioning use, corticosteroids). ARDS can be caused by various aetiologies, and the adequate treatment of the responsible cause is crucial to improve the outcome. It is of paramount importance to characterize the mechanisms causing lung injury to optimize both the aetiological treatment and the symptomatic treatment. If there is no obvious cause of ARDS or if a direct lung injury is suspected, bronchoalveolar lavage (BAL) should be strongly considered to identify microorganisms responsible for pneumonia. Blood samples can also help to identify microorganisms and to evaluate biomarkers of infection. If there is no infectious cause of ARDS or no other apparent aetiology is found, second-line examinations should include markers of immunologic diseases. In selected cases, open lung biopsy remains useful to identify the cause of ARDS when all other examinations remain inconclusive. CT scan is fundamental when there is a suspicion of intra-abdominal sepsis and in some cases of pneumonia. Ultrasonography is important not only in evaluating biventricular function but also in identifying pleural effusions and pneumothorax. The definition of ARDS remains clinical and the main objective of the diagnostic workup should be to be focused on identification of its aetiology, especially a treatable infection. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00134-016-4324-5) contains supplementary material, which is available to authorized users. |
4,548 | Recent advances in technology supporting biopharmaceutical production from mammalian cells | The demand for production of glycoproteins from mammalian cell culture continues with an increased number of approvals as biopharmaceuticals for the treatment of unmet medical needs. This is particularly the case for humanized monoclonal antibodies which are the largest and fastest growing class of therapeutic pharmaceuticals. This demand has fostered efforts to improve the efficiency of production as well as to address the quality of the final product. Chinese hamster ovary cells are the predominant hosts for stable transfection and high efficiency production on a large scale. Specific productivity of recombinant glycoproteins from these cells can be expected to be above 50 pg/cell/day giving rise to culture systems with titers of around 5 g/L if appropriate fed-batch systems are employed. Cell engineering can delay the onset of programmed cell death to ensure prolonged maintenance of productive viable cells. The clinical efficacy and quality of the final product can be improved by strategic metabolic engineering. The best example of this is the targeted production of afucosylated antibodies with enhanced antibody-dependent cell cytotoxicity, an important function for use in cancer therapies. The development of culture media from non-animal sources continues and is important to ensure products of consistent quality and without the potential danger of contamination. Process efficiencies may also be improved by employing disposable bioreactors with the associated minimization of downtime. Finally, advances in downstream processing are needed to handle the increased supply of product from the bioreactor but maintaining the high purity demanded of these biopharmaceuticals. |
4,549 | Prävention von Infektionskrankheiten in Industrieländern | Prevention of infectious diseases is targeted at individuals, specific risk groups or communities. Vaccines are one of the most cost-effective medical interventions and protect the individual and the community against vaccine preventable diseases. Immunization programs aim to control, eliminate or eradicate infectious pathogens. In industrialized countries several vaccine preventable diseases are almost eliminated. Strict implementation of recommendations for influenza and pneumococcal immunization is crucial to reduce morbidity and mortality. Hence, uptake of recommended immunization among adults and elderly people is often low. Internal specialists are demanded to improve vaccine coverage in those age groups. |
4,550 | Recent developments in optical detection methods for microchip separations | This paper summarizes the features and performances of optical detection systems currently applied in order to monitor separations on microchip devices. Fluorescence detection, which delivers very high sensitivity and selectivity, is still the most widely applied method of detection. Instruments utilizing laser-induced fluorescence (LIF) and lamp-based fluorescence along with recent applications of light-emitting diodes (LED) as excitation sources are also covered in this paper. Since chemiluminescence detection can be achieved using extremely simple devices which no longer require light sources and optical components for focusing and collimation, interesting approaches based on this technique are presented, too. Although UV/vis absorbance is a detection method that is commonly used in standard desktop electrophoresis and liquid chromatography instruments, it has not yet reached the same level of popularity for microchip applications. Current applications of UV/vis absorbance detection to microchip separations and innovative approaches that increase sensitivity are described. This article, which contains 85 references, focuses on developments and applications published within the last three years, points out exciting new approaches, and provides future perspectives on this field. |
4,551 | A branching model for the spread of infectious animal diseases in varying environments | This paper is concerned with a stochastic model, describing outbreaks of infectious diseases that have potentially great animal or human health consequences, and which can result in such severe economic losses that immediate sets of measures need to be taken to curb the spread. During an outbreak of such a disease, the environment that the infectious agent experiences is therefore changing due to the subsequent control measures taken. In our model, we introduce a general branching process in a changing (but not random) environment. With this branching process, we estimate the probability of extinction and the expected number of infected individuals for different control measures. We also use this branching process to calculate the generating function of the number of infected individuals at any given moment. The model and methods are designed using important infections of farmed animals, such as classical swine fever, foot-and-mouth disease and avian influenza as motivating examples, but have a wider application, for example to emerging human infections that lead to strict quarantine of cases and suspected cases (e.g. SARS) and contact and movement restrictions. |
4,552 | Risiken von Infektionskrankheiten und der Nutzen von Impfungen | Significant progress regarding hygiene, nutrition, and antimicrobial treatment as well as immunizations have lead to a significant decline of morbidity and mortality of infectious diseases in the recent past. Furthermore, immunizations are one of the most cost-effective tools for prevention. However, lack of perception of the substantial risks of complications associated with infectious diseases cause doubts about the necessity of immunizations today. This development is highly worrisome and needs to be adequately addressed by informing physicians and the public about the risks of vaccine-preventable diseases, efficiency, safety and benefits of available vaccines, as well as providing convincing arguments justifying current immunization recommendations. These activities are indispensable for successful implementation and continuation of current immunization programs. |
4,553 | IDX-184 is a superior HCV direct-acting antiviral drug: a QSAR study | ABSTRACT: Quantitative structure–activity relationship (QSAR) parameters are good indicators for the reactivity of direct-acting antiviral drugs. Since molecular structure is related to molecular function, careful selection of molecular substitutions will result in more drugs that are potent. In this work, QSAR parameters are selected in order to compare the four drugs used as nucleotide inhibitors (NIs) for non-structural 5B (NS5B) RNA-dependent RNA polymerase (RdRp) of hepatitis C virus (HCV). These drugs are: ribavirin (widely used over the last 20 years), sofosbuvir (approved on December 2013 by FDA), and finally IDX-184 and R7128 (phase IIb of clinical trial drugs). The nucleotide analogues uracil (U), guanine (G), and cytosine (C) from which these drugs are fabricated are also compared to that group of drugs. QSAR parameters suggested that the drug IDX-184 is the best among all of the studied NIs. It also shows that NIs are always more reactive than their parent nucleotide. GRAPHICAL ABSTRACT: The active site environment of 12 amino acids coordinated with IDX-184 through two Mg(2+). The interaction with HCV subtypes 1a, 2b, and 3b is better than 4a subtype. [Image: see text] |
4,554 | Denning behaviour of the European badger (Meles meles) correlates with bovine tuberculosis infection status | Heterogeneities in behaviours of individuals may underpin important processes in evolutionary biology and ecology, including the spread of disease. Modelling approaches can sometimes fail to predict disease spread, which may partly be due to the number of unknown sources of variation in host behaviour. The European badger is a wildlife reservoir for bovine tuberculosis (bTB) in Britain and Ireland, and individual behaviour has been demonstrated to be an important factor in the spread of bTB among badgers and to cattle. Radio-telemetry devices were deployed on 40 badgers from eight groups to investigate patterns of den (sett) use in a high-density population, where each group had one or two main and three to eight outlier setts in their territory. Badgers were located at their setts for 28 days per season for 1 year to investigate how patterns differed between individuals. Denning behaviour may have a strong influence on contact patterns and the transmission of disease. We found significant heterogeneity, influenced by season, sex and age. Also, when controlling for these, bTB infection status interacting with season was highly correlated with sett use. Test-positive badgers spent more time away from their main sett than those that tested negative. We speculate that wider-ranging behaviour of test-positive animals may result in them contacting sources of infection more frequently and/or that their behaviour may be influenced by their disease status. Measures to control infectious diseases might be improved by targeting functional groups, specific areas or times of year that may contribute disproportionately to disease spread. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00265-012-1467-4) contains supplementary material, which is available to authorized users. |
4,555 | Infektionen bei Organtransplantationen | Infections play a crucial role in organ transplantations as possible complications. Viruses, bacteria, fungi and parasites are potential agents. The relevance of individual diseases depends on the organ transplanted. Morphology of the inflammatory reaction is given by the agent involved, but often several reactions can be caused by the same agent and different agents can also lead to the same reaction. Histology therefore provides concrete identification of the causal agent only in some cases, such that additional microbiological diagnostics are necessary. Results from these investigations should be transferred to the pathologist to distinguish between infection-associated changes and transplant rejection. |
4,556 | SIR dynamics in random networks with heterogeneous connectivity | Random networks with specified degree distributions have been proposed as realistic models of population structure, yet the problem of dynamically modeling SIR-type epidemics in random networks remains complex. I resolve this dilemma by showing how the SIR dynamics can be modeled with a system of three nonlinear ODE’s. The method makes use of the probability generating function (PGF) formalism for representing the degree distribution of a random network and makes use of network-centric quantities such as the number of edges in a well-defined category rather than node-centric quantities such as the number of infecteds or susceptibles. The PGF provides a simple means of translating between network and node-centric variables and determining the epidemic incidence at any time. The theory also provides a simple means of tracking the evolution of the degree distribution among susceptibles or infecteds. The equations are used to demonstrate the dramatic effects that the degree distribution plays on the final size of an epidemic as well as the speed with which it spreads through the population. Power law degree distributions are observed to generate an almost immediate expansion phase yet have a smaller final size compared to homogeneous degree distributions such as the Poisson. The equations are compared to stochastic simulations, which show good agreement with the theory. Finally, the dynamic equations provide an alternative way of determining the epidemic threshold where large-scale epidemics are expected to occur, and below which epidemic behavior is limited to finite-sized outbreaks. |
4,557 | Characterization of the major histocompatibility complex class II DOB, DPB1, and DQB1 alleles in cynomolgus macaques of Vietnamese origin | Major histocompatibility complex (MHC) molecules play an important role in the susceptibility and/or resistance to many diseases. To gain an insight into the MHC background and to facilitate the experimental use of cynomolgus macaques, the second exon of the MhcMafa-DOB, -DPB1, and -DQB1 genes from 143 cynomolgus macaques were characterized by cloning to sequencing. A total of 16 Mafa-DOB, 16 Mafa-DPB1, and 34 Mafa-DQB1 alleles were identified, which revealed limited, moderate, and marked allelic polymorphism at DOB, DPB1, and DQB1, respectively, in a cohort of cynomolgus macaques of Vietnamese origin. In addition, 16 Mafa-DOB, 5 Mafa-DPB1, and 8 Mafa-DQB1 alleles represented novel sequences that had not been reported in earlier studies. Almost of the sequences detected at the DOB and DQB1 locus in the present study belonged to DOB*01 (100%) and DQB1*06 (62%) lineages, respectively. Interestingly, four, three, and one high-frequency alleles were detected at Mafa-DOB, -DPB1, and -DQB1, respectively, in this monkeys. The alleles with the highest frequency among these monkeys were Mafa-DOB*010102, Mafa-DPB1*13, and Mafa-DQB1*0616, and these were found in 33 (25.6%) of 129 monkeys, 32 (31.37%) of 102 monkeys, and 30 (31%) of 143 monkeys, respectively. The high-frequency alleles may represent high priority targets for additional characterization of immune function. We also carried out evolutionary and population analyses using these sequences to reveal population-specific alleles. This information will not only promote the understanding of MHC diversity and polymorphism in the cynomolgus macaque but will also increase the value of this species as a model for biomedical research. |
4,558 | The influence of organizational jurisdiction, organizational attributes, and training measures on perceptions of public health preparedness in Alberta | OBJECTIVES: Recent international events including the H1N1 influenza pandemic and the rising incidence of West Nile Virus throughout North America have brought critical attention to the Canadian public health system and how prepared the system is to respond to various types of contemporary public health threats. The current work assessed the association of organizational jurisdiction, organizational attributes, and training opportunities with three different measures of public health preparedness in the province of Alberta, Canada. METHODS: Organizational representatives involved in the delivery of public health systems completed an online questionnaire that asked about organizational attributes and training opportunities available to employees, their perception of organizational preparedness, and their connections to other organizations in Alberta. RESULTS: Findings revealed that (1) perceived human and material resources preparedness was associated with training opportunities, (2) perceived informational needs was associated with organizational size, and (3) whether an organization exercised their written preparedness plan in 2006 was associated with organizational jurisdiction. CONCLUSIONS: These findings help fill a gap in the literature with respect to identifying how organizational characteristics are associated with different aspects of preparedness. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00038-011-0261-9) contains supplementary material, which is available to authorized users. |
4,559 | Antibiotikatherapie in der Hals-Nasen-Ohren-Heilkunde | First, the general principles for an antibiotic therapy are stated. The indications have to be well thought through. Frequent viral ENT infections, as well as numerous bacterial infections, should not be treated with antibiotics. Due to the current antibiotic sensitivity of the main ENT pathogens, the antibiotic choice for an empiric therapy is emphasized, and also the advantage of an optimized therapy based on the results of Gram stain (supercalculated empiric therapy) and an antibiogram (specific therapy). Pus characteristics may be the first step in diagnosing the pathogens. The degree of severity of an infection determines the oral or parenteral route of administration. As a rule, antibiotic therapy has to be checked after 2–3 days. The grouping of the different ENT infections with a similar spectrum of pathogens gives a better view of the therapeutic principles and reduces repetitions. The current recommendations for antibiotic treatment of numerous ENT infections with different degrees of severity are indicated. After the presentation of the appropriate antibiotics with their current spectrum of efficacy, the initial therapy, treatment in case of penicillin allergy, and of severe cases and complications or therapeutic failure are mentioned. |
4,560 | Chaos in a seasonally perturbed SIR model: avian influenza in a seabird colony as a paradigm | Seasonality is a complex force in nature that affects multiple processes in wild animal populations. In particular, seasonal variations in demographic processes may considerably affect the persistence of a pathogen in these populations. Furthermore, it has been long observed in computer simulations that under seasonal perturbations, a host–pathogen system can exhibit complex dynamics, including the transition to chaos, as the magnitude of the seasonal perturbation increases. In this paper, we develop a seasonally perturbed Susceptible-Infected-Recovered model of avian influenza in a seabird colony. Numerical simulations of the model give rise to chaotic recurrent epidemics for parameters that reflect the ecology of avian influenza in a seabird population, thereby providing a case study for chaos in a host– pathogen system. We give a computer-assisted exposition of the existence of chaos in the model using methods that are based on the concept of topological hyperbolicity. Our approach elucidates the geometry of the chaos in the phase space of the model, thereby offering a mechanism for the persistence of the infection. Finally, the methods described in this paper may be immediately extended to other infections and hosts, including humans. |
4,561 | Gedanken zur Differentialdiagnostik* | Referring to H. E. Bock’s famous lectures on differential diagnostics, some recent developments are discussed. Topical remarks are given concerning modern differential diagnostics. In general, they have changed from the diagnostic of the phenotype to the detection of the pathogenesis. |
4,562 | Prinzipien und Aspekte der Seuchenalarmplanung am Beispiel der Influenzapandemieplanung | Despite significant medical progress, recent events have shown that infectious diseases have not lost significance. Indeed, the threat of worldwide epidemics has increased. Due to their high infectious ness and rapid person-to-person transmissibility, the emergence of new influenza viruses with pandemic potential poses an especially alarming situation in this regard. The world population would be “immunologically naïve” to a new pandemic virus, permitting explosive spread of the disease. During the last century, three influenza pandemics have demonstrated that this is not merely a hypothetical risk. Currently it is feared that the possible human adaptation of avian influenza viruses that have recently become endemic in birds in Southeast Asia could result in a new pandemic strain. With the publication of the German Influenza Pandemic Preparedness Plan, preparation for this potential threat has reached an important stage in Germany. The implementation of the plan, which includes measures that go beyond the scope of public health, must now proceed swiftly. The long-term goal of pandemic preparedness planning is to be better equipped to deal with potential health threats in general, in particular those ensuing from the emergence of new infectious diseases under conditions of a growing global network. |
4,563 | Was ist gute Wissenschaftliche Politikberatung?: Akademievorlesung bei der Berlin-Brandenburgischen Akademie der Wissenschaften | Scientific advice to politics is a primary function of governmental research. The advisory process is, in the ideal situation, a collective duty of science and politics. The final decision rests ultimately with politicians. An understanding of the differences between science and politics is necessary for successfully providing advice to politicians. The requirements necessary to allow politics to substantially follow the advice of scientists are multifarious. The first of these is trust from the side of politics and the public and from the side of science competitive research, respect and communication skills, neutrality and integrity. From these requireberatung ments it is possible to derive criteria for quality assurance in advice to politics. The maintenance of scientific expertise at the competitive international level demands independent, qualified and adequately financed research. Governmental institutes have an antenna function: they have to recognize in good time whether risks are increasing, whether the government has to be informed and whether there is a need for action. The continuing maintenance of excellence requires measures of quality assurance at all levels. Evidence for the quality of advice to politics can, for example, be found in the good reputation of an institution and its prominent representatives. Success in research is an indirect quality criterion that can be and should be measured to a certain extent. The influence of advisory activities on political decisions is direct evidence for the quality of the advice. A classic example of highly successful policy advice is the development of the German AIDS policy. |
4,564 | End-tidal carbon dioxide levels during resuscitation and carbon dioxide levels in the immediate neonatal period and intraventricular haemorrhage | Abnormal levels of end-tidal carbon dioxide (EtCO(2)) during resuscitation in the delivery suite are associated with intraventricular haemorrhage (IVH) development. Our aim was to determine whether carbon dioxide (CO(2)) levels in the first 3 days after birth reflected abnormal EtCO(2) levels in the delivery suite, and hence, a prolonged rather than an early insult resulted in IVH. In addition, we determined if greater EtCO(2)level fluctuations during resuscitation occurred in infants who developed IVH. EtCO(2) levels during delivery suite resuscitation and CO(2) levels on the neonatal unit were evaluated in 58 infants (median gestational age 27.3 weeks). Delta EtCO(2) was the difference between the highest and lowest level of EtCO(2). Thirteen infants developed a grade 3–4 IVH (severe group). There were no significant differences in CO(2) levels between those who did and did not develop an IVH (or severe IVH) on the NICU. The delta EtCO(2) during resuscitation differed between infants with any IVH (6.2 (5.4–7.5) kPa) or no IVH (3.8 (2.7–4.3) kPA) (p < 0.001) after adjusting for differences in gestational age. Delta EtCO(2) levels gave an area under the ROC curve of 0.940 for prediction of IVH. Conclusion: The results emphasize the importance of monitoring EtCO(2) levels in the delivery suite. |
4,565 | 600-ns pulsed electric fields affect inactivation and antibiotic susceptibilities of Escherichia coli and Lactobacillus acidophilus | Cell suspensions of Escherichia coli and Lactobacillus acidophilus were exposed to 600-ns pulsed electric fields (nsPEFs) at varying amplitudes (Low-13.5, Mid-18.5 or High-23.5 kV cm(−1)) and pulse numbers (0 (sham), 1, 5, 10, 100 or 1000) at a 1 hertz (Hz) repetition rate. The induced temperature rise generated at these exposure parameters, hereafter termed thermal gradient, was measured and applied independently to cell suspensions in order to differentiate inactivation triggered by electric field (E-field) from heating. Treated cell suspensions were plated and cellular inactivation was quantified by colony counts after a 24-hour (h) incubation period. Additionally, cells from both exposure conditions were incubated with various antibiotic-soaked discs to determine if nsPEF exposure would induce changes in antibiotic susceptibility. Results indicate that, for both species, the total delivered energy (amplitude, pulse number and pulse duration) determined the magnitude of cell inactivation. Specifically, for 18.5 and 23.5 kV cm(−1) exposures, L. acidophilus was more sensitive to the inactivation effects of nsPEF than E. coli, however, for the 13.5 kV cm(−1) exposures E. coli was more sensitive, suggesting that L. acidophilus may need to meet an E-field threshold before significant inactivation can occur. Results also indicate that antibiotic susceptibility was enhanced by multiple nsPEF exposures, as observed by increased zones of growth inhibition. Moreover, for both species, a temperature increase of ≤ 20 °C (89% of exposures) was not sufficient to significantly alter cell inactivation, whereas none of the thermal equivalent exposures were sufficient to change antibiotic susceptibility categories. |
4,566 | Vaccination coverage with the pneumococcal and influenza vaccine among persons with chronic diseases in Shanghai, China, 2017 | BACKGROUND: Adults with chronic conditions such as heart disease, diabetes, or lung disease are more likely to develop complications from a number of vaccine-preventable diseases, including influenza and pneumonia. In this study, we use the data from a chronic disease management information system in Shanghai to estimate vaccination coverage and characterize predictors of seasonal influenza and 23-valent pneumococcal polysaccharide vaccine (PPSV23) vaccination among people with chronic disease in Shanghai. METHODS: The Shanghai Centers for Disease Control and Prevention have information systems related to chronic disease management, hospital records, and immunizations. Data from individuals with hypertension, diabetes and chronic obstructive pulmonary disease (COPD) were abstracted during July 2017. The main outcome was coverage of pneumococcal and influenza vaccination. Vaccination coverage was calculated across demographic groups. Significance in bivariate associations was assessed through Pearson’s chi-square tests, and in multivariable models through logistic regression models with a forward stepwise method to select variables. RESULTS: In the sample of 2,531,227 individuals ≥15 years, 22.8% were vaccinated for pneumonia from January 2013 to July 2017, and the vaccination coverage of influenza in the 2016/17 influenza season was 0.4%. Vaccination coverage was highest in those 70–79 and lowest in those younger than 60. Compared to urban areas, uptake in rural areas was higher for pneumonia vaccination (OR: 2.43, 95% CI: 2.41, 2.45), but lower for influenza vaccination (OR: 0.55, 95% CI: 0.51, 0.59). Having a greater number of chronic diseases was associated with higher likelihood of pneumonia vaccination (3 vs 1: OR: 1.68, 95% CI: 1.64, 1.71), but this relationship was not statistically significant for influenza vaccination. CONCLUSIONS: We found low levels with of pneumococcal vaccination, and extremely low uptake of influenza vaccination among individuals with high risk conditions in Shanghai who should be priority groups targeted for vaccination. Interventions could be designed to target groups with low uptake – like younger adults, and individuals who have not yet retired. |
4,567 | Uganda’s experience in Ebola virus disease outbreak preparedness, 2018–2019 | BACKGROUND: Since the declaration of the 10th Ebola Virus Disease (EVD) outbreak in DRC on 1st Aug 2018, several neighboring countries have been developing and implementing preparedness efforts to prevent EVD cross-border transmission to enable timely detection, investigation, and response in the event of a confirmed EVD outbreak in the country. We describe Uganda’s experience in EVD preparedness. RESULTS: On 4 August 2018, the Uganda Ministry of Health (MoH) activated the Public Health Emergency Operations Centre (PHEOC) and the National Task Force (NTF) for public health emergencies to plan, guide, and coordinate EVD preparedness in the country. The NTF selected an Incident Management Team (IMT), constituting a National Rapid Response Team (NRRT) that supported activation of the District Task Forces (DTFs) and District Rapid Response Teams (DRRTs) that jointly assessed levels of preparedness in 30 designated high-risk districts representing category 1 (20 districts) and category 2 (10 districts). The MoH, with technical guidance from the World Health Organisation (WHO), led EVD preparedness activities and worked together with other ministries and partner organisations to enhance community-based surveillance systems, develop and disseminate risk communication messages, engage communities, reinforce EVD screening and infection prevention measures at Points of Entry (PoEs) and in high-risk health facilities, construct and equip EVD isolation and treatment units, and establish coordination and procurement mechanisms. CONCLUSION: As of 31 May 2019, there was no confirmed case of EVD as Uganda has continued to make significant and verifiable progress in EVD preparedness. There is a need to sustain these efforts, not only in EVD preparedness but also across the entire spectrum of a multi-hazard framework. These efforts strengthen country capacity and compel the country to avail resources for preparedness and management of incidents at the source while effectively cutting costs of using a “fire-fighting” approach during public health emergencies. |
4,568 | Quality of neonatal resuscitation in Ethiopia: implications for the survival of neonates | BACKGROUND: Birth asphyxia accounts for one-quarter newborn deaths. Providing quality care service of neonatal resuscitation reduces neonatal mortality. However, challenges to providing quality neonatal resuscitation are not well investigated in Ethiopia. Hence, this study is conducted to assess the quality provision of neonatal resuscitation in Ethiopia. METHOD: We used data from the Ethiopian 2016 Emergency Obstetric Newborn Care survey, conducted in 3804 health facilities providing maternal and newborn health services. We described the quality of neonatal resuscitation services according to the structure, process and outcome triad of quality dimension. Data from registers and birth records for the last 12 months prior to the survey were extracted. In each facility, the three last eligible charts of resuscitated neonates were reviewed and the highest frequency of chart of resuscitated baby was considered to the analysis. Thus, a total of 555 charts were assessed. Logistic regression model was used to assess the relationship between the neonatal resuscitation processes, provider, facility and newborn characteristics with neonatal outcome at the time of discharge. RESULTS: The finding suggested that, around two-third, 364(65.6%) of the asphyxiated babies resuscitated by bag and mask type of neonatal resuscitation. Of the babies who had got neonatal resuscitation 463 (83.4%) survived. Resuscitated neonates with a gestational age of greater than 37 weeks and above (Adjusted Odds Ratio (AOR) =1.82; 95% Confidence Interval (CI) (1.09–3.04)), availability of priority equipment in health facilities for neonatal resuscitation (AOR = 1.24, 95% CI (1.09, 1.54)) and women who had 12 h and less duration of labor (AOR = 1.76; 95% CI (1.23, 3.13)) were the independent factors of survival of the neonate. CONCLUSION: Only half of the health facilities were ready for neonatal resuscitation (NR) in terms of priority equipment’s. However, eight out of ten babies survived after NR in Ethiopia. Gestational age, priority equipment for NR and duration of labor were determinants of survival of resuscitated neonates in Ethiopia. Therefore, the availability of priority equipment and attentive care and follow-up for premature neonates and those face prolonged labor need to be improved in Ethiopia. |
4,569 | The role of mini-bronchoalveolar lavage fluid in the diagnosis of pulmonary tuberculosis in critically ill patients | BACKGROUND: The detection of Mycobacterium tuberculosis (MTB) in the intensive care unit (ICU) presents several challenges, mainly associated to the clinical state of the patient. The presence of HIV infection further aggravates this scenario, requiring a reliable collection method, with better performance in the microbiological/molecular techniques to be used. We evaluated the performance of two methods for sample collection, mini bronchoalveolar lavage (Mini-BAL) and endotracheal aspirate (ETA), for diagnosis of pulmonary tuberculosis (PTB) in critically ill patients. METHODS: This prospective study involved 26 HIV positive ICU internalized patients, with presumptive PTB who required mechanical ventilation. Two samples were obtained prospectively from 26 HIV ICU patients with presumptive PTB by Mini-BAL and ETA. The samples were processed for smear microscopy, Löwenstein-Jensen medium and the BACTEC Mycobacteria Growth Indicator Tube 960 system®. We define as confirmed PTB patients with positive MTB culture. Furthermore, all samples obtained through the Mini-BAL were analyzed by Xpert® MTB/RIF. RESULTS: Our results demonstrated that the respiratory samples obtained by Mini-BAL were able to increase MTB detection in critically ill patients with presumptive PTB. The Mini-BAL allowed 30% increased recovery and guaranteed enough sample volume for processing in all methods. In addition, the larger volume of the samples obtained with this technique enabled the Xpert® MTB/RIF molecular test for diagnosis of TB. CONCLUSIONS: The Mini-BAL showed be an acceptable alternative to ETA in this population, since these critically ill and often-immunocompromised patients are more likely to develop complications related to invasive procedures. |
4,570 | Virale Otitis media | Obwohl allgemein angenommen wird, daß die akute Otitis media bakteriell bedingt ist, gibt es auch Argumente dafür, daß Viren in ihrer Ätiologie und Pathogenese eine entscheidende Rolle spielen. Darüber hinaus werden Versager der Antibiotikatherapie den Viren angelastet. Wohl wurden verschiedene Viren in der Mittelohrflüssigkeit bei akuter Otitis media nachgewiesen, bis jetzt ist jedoch nicht bekannt, welche Viren die wichtigsten sind, wie häufig eine allein viral bedingte Mittelohrinfektion ist, welches Zusammenspiel es zwischen Viren und Bakterien gibt und inwieweit die akute Otitis media durch antivirale Impfstoffe verhindert werden könnte. Diese klinisch und theoretisch wichtigen Fragen wurden in einer soeben im NEW ENGLAND JOURNAL OF MEDICINE publizierten Arbeit von Heikkinen et al. angeschnitten und z. T. beantwortet [1]. |
4,571 | Unusual accumulation of a wide array of antimicrobial resistance mechanisms in a patient with cytomegalovirus-associated hemophagocytic lymphohistiocytosis: a case report | BACKGROUND: Infections with multidrug-resistant organisms (MDRO) pose a serious threat to patients with dysregulated immunity such as in hemophagocytic lymphohistiocytosis (HLH), but such infections have rarely been comprehensively characterized. Here, we present a fatal case of HLH secondary to cytomegalovirus (CMV) infection complicated by both anti-viral drug resistance and sepsis from multiple MDROs including pandrug-resistant superbug bacteria. CASE PRESENTATION: A previously healthy, six-year-old boy presented with a 45-day history of fever prior to a diagnosis of hemophagocytic lymphohistiocytosis and hemorrhagic colitis, both associated with CMV. On hospital admission, the patient was found to be colonized with multiple, multidrug-resistant (MDR) bacteria including vancomycin-resistant enterococci (VRE) and carbapenamase-producing organisms (CPO). He eventually developed respiratory, urine and bloodstream infections with highly drug-resistant, including pandrug-resistant bacteria, which could not be controlled by antibiotic treatment. Antiviral therapy also failed to contain his CMV infection and the patient succumbed to overwhelming bacterial and viral infection. Whole genome sequencing (WGS) of the MDR bacteria and metagenomic analysis of his blood sample revealed an unusual accumulation of a wide range of antimicrobial resistance mechanisms in a single patient, including antiviral resistance to ganciclovir, and resistance mechanisms to all currently available antibiotics. CONCLUSIONS: The case highlights both the risk of acquiring MDR superbugs and the severity of these infections in HLH patients. |
4,572 | Inhibition of Human Cytomegalovirus Entry into Host Cells through A Pleiotropic Small Molecule | Human cytomegalovirus (HCMV) infections are wide-spread among the general population with manifestations ranging from asymptomatic to severe developmental disabilities in newborns and life-threatening illnesses in individuals with a compromised immune system. Nearly all current drugs suffer from one or more limitations, which emphasizes the critical need to develop new approaches and new molecules. We reasoned that a ‘poly-pharmacy’ approach relying on simultaneous binding to multiple receptors involved in HCMV entry into host cells could pave the way to a more effective therapeutic outcome. This work presents the study of a synthetic, small molecule displaying pleiotropicity of interactions as a competitive antagonist of viral or cell surface receptors including heparan sulfate proteoglycans and heparan sulfate-binding proteins, which play important roles in HCMV entry and spread. Sulfated pentagalloylglucoside (SPGG), a functional mimetic of heparan sulfate, inhibits HCMV entry into human foreskin fibroblasts and neuroepithelioma cells with high potency. At the same time, SPGG exhibits no toxicity at levels as high as 50-fold more than its inhibition potency. Interestingly, cell-ELISA assays showed downregulation in HCMV immediate-early gene 1 and 2 (IE 1&2) expression in presence of SPGG further supporting inhibition of viral entry. Finally, HCMV foci were observed to decrease significantly in the presence of SPGG suggesting impact on viral spread too. Overall, this work offers the first evidence that pleiotropicity, such as demonstrated by SPGG, may offer a new poly-therapeutic approach toward effective inhibition of HCMV. |
4,573 | Influenza in the school-aged population in Mexico: burden of disease and cost-effectiveness of vaccination in children | BACKGROUND: The current national influenza vaccination schedule in Mexico does not recommend vaccination in the school-aged population (5–11 years). Currently, there are limited data from middle-income countries analysing the cost-effectiveness of influenza vaccination in this population. We explored the clinical effects and economic benefits of expanding the current national influenza vaccination schedule in Mexico to include the school-aged population. METHODS: A static 1-year model incorporating herd effect was used to assess the cost-effectiveness of expanding the current national influenza vaccination schedule of Mexico to include the school-aged population. We performed a cross-sectional epidemiological study using influenza records (2009–2018), death records (2010–2015), and discharge and hospitalisation records (2010–2016), from the databases of Mexico’s Influenza Surveillance System (SISVEFLU), the National Mortality Epidemiological and Statistical System (SEED), and the Automated Hospital Discharge System (SAEH), respectively. Cost estimates for influenza cases were based on 7 scenarios using data analysed from SISVEFLU; assumptions for clinical management of cases were defined according to Mexico’s national clinical guidelines. The primary health outcome for this study was the number of influenza cases avoided. A sensitivity analysis was performed using conservative and optimistic parameters (vaccination coverage: 30% / 70%, Vaccine effectiveness: 19% / 68%). RESULTS: It was estimated that expanding the influenza immunisation programme to cover school-aged population in Mexico over the 2018–2019 influenza season would result in 671,461 cases of influenza avoided (50% coverage and 50% effectiveness assumed). Associated with this were 262,800 fewer outpatient consultations; 154,100 fewer emergency room consultations; 97,600 fewer hospitalisations, and 15 fewer deaths. Analysis of cases avoided by age-group showed that 55.4% of them were in the school-aged population, and the decrease in outpatient consultations was largest in this population. There was an overall decrease in the economic burden for the Mexican health care system of 111.9 million US dollars; the immunization programme was determined to be cost-saving in the base, conservative and optimistic scenarios. CONCLUSIONS: Vaccinating school-aged population in Mexico would be cost-effective; expansion of the current national vaccination schedule to this age group is supported. |
4,574 | Adjunct low-dose ketamine infusion vs standard of care in mechanically ventilated critically ill patients at a Tertiary Saudi Hospital (ATTAINMENT Trial): study protocol for a randomized, prospective, pilot, feasibility trial | BACKGROUND: A noticeable interest in ketamine infusion for sedation management has developed among critical care physicians for critically ill patients. The 2018 Pain, Agitation/sedation, Delirium, Immobility, and Sleep disruption guideline suggested low-dose ketamine infusion as an adjunct to opioid therapy to reduce opioid requirements in post-surgical patients in the intensive care unit (ICU). This was, however, rated as conditional due to the very low quality of evidence. Ketamine has favorable characteristics, making it an especially viable alternative for patients with respiratory and hemodynamic instability. The Analgo-sedative adjuncT keTAmine Infusion iN Mechanically vENTilated ICU patients (ATTAINMENT) trial aims to assess the effect and safety of adjunct low-dose continuous infusion of ketamine as an analgo-sedative compared to standard of care in critically ill patients on mechanical ventilation (MV) for ≥ 24 h. METHODS/DESIGN: This trial is a prospective, randomized, active controlled, open-label, pilot, feasibility study of adult ICU patients (> 14 years old) on MV. The study will take place in the adult ICUs in the King Faisal Specialist Hospital and Research Center (KFSH&RC), Riyadh, Saudi Arabia, and will enroll 80 patients. Patients will be randomized post-intubation into two groups: the intervention group will receive an adjunct low-dose continuous infusion of ketamine plus standard of care. Ketamine will be administered over a period of 48 h at a fixed infusion rate of 2 μg/kg/min (0.12 mg/kg/h) in the first 24 h followed by 1 μg/kg/min (0.06 mg/kg/h) in the second 24 h. The control group will receive standard of care in the ICU (propofol and/or fentanyl and/or midazolam) according to the KFSH&RC sedation and analgesia protocol as clinically appropriate. The primary outcome is MV duration until ICU discharge, death, extubation, or 28 days post-randomization, whichever comes first. DISCUSSION: The first patient was enrolled on 1 September 2019. As of 10 October 2019, a total of 16 patients had been enrolled. We expect to complete the recruitment by 31 December 2020. The findings of this pilot trial will likely justify further investigation for the role of adjunct low-dose ketamine infusion as an analgo-sedative agent in a larger, multicenter, randomized controlled trial. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04075006. Registered on 30 August 2019. Current controlled trials: ISRCTN14730035. Registered on 3 February 2020. |
4,575 | Systematic review of statistical methods for safety data in malaria chemoprevention in pregnancy trials | BACKGROUND: Drug safety assessments in clinical trials present unique analytical challenges. Some of these include adjusting for individual follow-up time, repeated measurements of multiple outcomes and missing data among others. Furthermore, pre-specifying appropriate analysis becomes difficult as some safety endpoints are unexpected. Although existing guidelines such as CONSORT encourage thorough reporting of adverse events (AEs) in clinical trials, they provide limited details for safety data analysis. The limited guidelines may influence suboptimal analysis by failing to account for some analysis challenges above. A typical example where such challenges exist are trials of anti-malarial drugs for malaria prevention during pregnancy. Lack of proper standardized evaluation of the safety of antimalarial drugs has limited the ability to draw conclusions about safety. Therefore, a systematic review was conducted to establish the current practice in statistical analysis for preventive antimalarial drug safety in pregnancy. METHODS: The search included five databases (PubMed, Embase, Scopus, Malaria in Pregnancy Library and Cochrane Central Register of Controlled Trials) to identify original English articles reporting Phase III randomized controlled trials (RCTs) on anti-malarial drugs for malaria prevention in pregnancy published from January 2010 to July 2019. RESULTS: Eighteen trials were included in this review that collected multiple longitudinal safety outcomes including AEs. Statistical analysis and reporting of the safety outcomes in all the trials used descriptive statistics; proportions/counts (n = 18, 100%) and mean/median (n = 2, 11.1%). Results presentation included tabular (n = 16, 88.9%) and text description (n = 2, 11.1%). Univariate inferential methods were reported in most trials (n = 16, 88.9%); including Chi square/Fisher’s exact test (n = 12, 66.7%), t test (n = 2, 11.1%) and Mann–Whitney/Wilcoxon test (n = 1, 5.6%). Multivariable methods, including Poisson and negative binomial were reported in few trials (n = 3, 16.7%). Assessment of a potential link between missing efficacy data and safety outcomes was not reported in any of the trials that reported efficacy missing data (n = 7, 38.9%). CONCLUSION: The review demonstrated that statistical analysis of safety data in anti-malarial drugs for malarial chemoprevention in pregnancy RCTs is inadequate. The analyses insufficiently account for multiple safety outcomes potential dependence, follow-up time and informative missing data which can compromise anti-malarial drug safety evidence development, based on the available data. |
4,576 | ISCCM Guidelines for the Use of Non-invasive Ventilation in Acute Respiratory Failure in Adult ICUs | A. ACUTE HYPERCAPNIC RESPIRATORY FAILURE A1. Acute Exacerbation of COPD: Recommendations: NIV should be used in management of acute exacerbation of COPD in patients with acute or acute-on-chronic respiratory acidosis (pH = 7.25-7.35). (1A) NIV should be attempted in patients with acute exacerbation of COPD (pH <7.25 & PaCO2 ≥ 45) before initiating invasive mechanical ventilation (IMV) except in patients requiring immediate intubation. (2A). Lower the pH higher the chance of failure of NIV. (2B) NIV should not to be used routinely in normo- or mildly hyper-capneic patients with acute exacerbation of COPD, without acidosis (pH > 7.35). (2B) A2. NIV in ARF due to Chest wall deformities/Neuromuscular diseases: Recommendations: NIV may be used in patients of ARF due to chest wall deformity/Neuromuscular diseases. (PaCO2 ≥ 45) (UPP) A3. NIV in ARF due to Obesity hypoventilation syndrome (OHS): Recommendations: NIV may be used in AHRF in OHS patients when they present with acute hypercapnic or acute on chronic respiratory failure (pH 45). (3B) NIV/CPAP may be used in obese, hypercapnic patients with OHS and/or right heart failure in the absence of acidosis. (UPP) B. NIV IN ACUTE HYPOXEMIC RESPIRATORY FAILURE: B1. NIV in Acute Cardiogenic Pulmonary Oedema: Recommendations: NIV is recommended in hospital patients with ARF, due to Cardiogenic pulmonary edema. (1A). NIV should be used in patients with acute heart failure/ cardiogenic pulmonary edema, right from emergency department itself. (1B) Both CPAP and BiPAP modes are safe and effective in patients with cardiogenic pulmonary edema. (1A). However, BPAP (NIV-PS) should be preferred in cardiogenic pulmonary edema with hypercapnia. (3A) B2. NIV in acute hypoxemic respiratory failure: Recommendations: NIV may be used over conventional oxygen therapy in mild early acute hypoxemic respiratory failure (P/F ratio <300 and >200 mmHg), under close supervision. (2B) We strongly recommend against a trial of NIV in patients with acute hypoxemic failure with P/F ratio <150. (2A) B3. NIV in ARF due to Chest Trauma: Recommendations: NIV may be used in traumatic flail chest along with adequate pain relief. (3B) B4. NIV in Immunocompromised Host: Recommendations: In Immunocompromised patients with early ARF, we may consider NIV over conventional oxygen. (2B). B5. NIV in Palliative Care: Recommendations: We strongly recommend use of NIV for reducing dyspnea in palliative care setting. (2A) B6. NIV in post-operative cases: Recommendations: NIV should be used in patients with post-operative acute respiratory failure. (2A) B6a. NIV in abdominal surgery: Recommendations: NIV may be used in patients with ARF following abdominal surgeries. (2A) B6b. NIV in bariatric surgery: Recommendations: NIV may be used in post-bariatric surgery patients with pre-existent OSA or OHS. (3A) B6c. NIV in Thoracic surgery: Recommendations: In cardiothoracic surgeries, use of NIV is recommended post operatively for acute respiratory failure to improve oxygenation and reduce chance of reintubation. (2A) NIV should not be used in patients undergoing esophageal surgery. (UPP) B6d. NIV in post lung transplant: Recommendations: NIV may be used for shortening weaning time and to avoid re-intubation following lung transplantation. (2B) B7. NIV during Procedures (ETI/Bronchoscopy/TEE/Endoscopy): Recommendations: NIV may be used for pre-oxygenation before intubation. (2B) NIV with appropriate interface may be used in patients of ARF during Bronchoscopy/Endoscopy to improve oxygenation. (3B) B8. NIV in Viral Pneumonitis ARDS: Recommendations: NIV cannot be considered as a treatment of choice for patients with acute respiratory failure with H1N1 pneumonia. However, it may be reasonable to use NIV in selected patients with single organ involvement, in a strictly controlled environment with close monitoring. (2B) B9. NIV and Acute exacerbation of Pulmonary Tuberculosis: Recommendations: Careful use of NIV in patients with acute Tuberculosis may be considered, with effective infection control precautions to prevent air-borne transmission. (3B) B10. NIV after planned extubation in high risk patients: Recommendation: We recommend that NIV may be used to wean high risk patients from invasive mechanical ventilation as it reduces re-intubation rate. (2B) B11. NIV for respiratory distress post extubation: Recommendations: We recommend that NIV therapy should not be used to manage respiratory distress post-extubation in high risk patients. (2B) C. APPLICATION OF NIV: Recommendation: Choice of mode should be mainly decided by factors like disease etiology and severity, the breathing effort by the patient and the operator familiarity and experience. (UPP) We suggest using flow trigger over pressure triggering in assisted modes, as it provides better patient ventilator synchrony. Especially in COPD patients, flow triggering has been found to benefit auto PEEP. (3B) D. MANAGEMENT OF PATIENT ON NIV: D1. Sedation: Recommendations: A non-pharmacological approach to calm the patient (Reassuring the patient, proper environment) should always be tried before administrating sedatives. (UPP) In patients on NIV, sedation may be used with extremely close monitoring and only in an ICU setting with lookout for signs of NIV failure. (UPP) E. EQUIPMENT: Recommendations: We recommend that portable bilevel ventilators or specifically designed ICU ventilators with non-invasive mode should be used for delivering Non–invasive ventilation in critically ill patients. (UPP) Both critical care ventilators with leak compensation and bi-level ventilators have been equally effective in decreasing the WOB, RR, and PaCO2. (3B) Currently, Oronasal mask is the most preferred interface for non-invasive ventilation for acute respiratory failure. (3B) F. WEANING: Recommendations: We recommend that weaning from NIV may be done by a standardized protocol driven approach of the unit. (2B) How to cite this article: Chawla R, Dixit SB, Zirpe KG, Chaudhry D, Khilnani GC, Mehta Y, et al. ISCCM Guidelines for the Use of Non-invasive Ventilation in Acute Respiratory Failure in Adult ICUs. Indian J Crit Care Med 2020;24(Suppl 1):S61–S81. |
4,577 | New Semi-dominant Mutation in the Syrian Hamster | SEVERAL different mutations causing hypotrichosis are well known in both rats and mice(1,2) but none have so far been described in the hamster. |
4,578 | Australia Antigen as a Marker of Propagation of the Serum Hepatitis Virus in Liver Cultures | ATTEMPTS to isolate the human hepatitis viruses in tissue culture have resulted in a collection of “hepatitis-candidate” viruses, none of which has since been shown to be the causal agent of human hepatitis(1). The discovery of Australia antigen provided a specific serological marker of infection with or carriage of the serum hepatitis virus, although the nature of the antigen remains unsettled(2). |
4,579 | A Novel Substituted Guanidine with High Activity in vitro against Rhinoviruses | THE number and diversity of the viruses which infect the upper respiratory tract, and cause the common cold, virtually preclude the control of this disease by conventional vaccines. From this, apart from symptomatic therapy, the only hope for effective treatment of this most prevalent of diseases is in the development of broad spectrum antiviral drugs. We have developed a substituted guanidine, ICI 65,709 (ref. 1) (Fig. 1) which has good activity in vitro against all twenty-five rhinovirus serotypes tested in human embryonic lung cells, and also against certain other picornaviruses. |
4,580 | Human Intolerance to Bacteria as Food | DEMANDS for new means to solve man's nutritional needs when the pressure of population intensifies or when he attempts to travel in space have suggested the use of single cell organisms as food. Hydrogenomonas eutropha, a hydrogen-fixing bacterium, could effectively control the atmosphere of a space cabin as well as providing nourishment(1). The protein is of high biological value(2) and is well tolerated even in high concentrations in rat diets(3). Human feeding trials seemed warranted and were attempted. |
4,581 | Occurrence and Determination of Inositol in the Oviducts of Turkey and Hen | AT the junction of uterus and vagina of the turkey a few scattered tubular glands have been observed, Spermatozoa are stored there(2) and retain their fertilizing ability for about 45 days(2). Turkey semen collected for insemination, however, has to be used within an hour of ejaculation, because fertility decreases considerably after that time. |
4,582 | Presence of factor VIII-related antigen in blood platelets of patients with Von Willebrand's disease | VON WILLEBRAND'S disease (VWD) is an autosomally inherited disorder characterised by low factor VIII activity (antihaemophilic factor, AHF), prolonged bleeding time, reduced retention of platelets in a glass bead column and abnormal distocetin-induced platelet aggregation. The prolonged bleeding time in VWD has been attributed to the absence of a plasma factor, the von Willebrand factor (VWF), as shown by a correction of the bleeding time after infusion of normal and haemophilic plasmas(1). Addition of purified factor VIII in vitro specifically corrects the abnormal platelet retention and ristocetin aggregation in VWD(2–5), whereas transfusion of similar material into dogs with VWD also corrects the prolonged bleeding time (B.N.B., W. J. Dodds, J. A. van Mourik, J.J.S and W. P. Webster, unpublished). This led to the suggestion that factor VIII is closely related if not identical to VWF, although dissociation of factor VIII procoagulant activity from factor VIII-related antigen (F VIII-RA) is observed in certain conditions(6,7). The plasma concentration of F VIII-RA is usually reduced in VWD suggesting a reduced synthesis of factor VIII (VWF)(8). In contrast to this we now report the presence of normal concentrations of F VIII-RA in platelets of patients with VWD. This F VIII-RA supported aggregation induced by ristocetin in a washed platelet system(9), a property of factor VIII which has been attributed to VWF activity. |
4,583 | Segregation of RD-114 and FeLV-related sequences in crosses between domestic cat and leopard cat | TYPE C viruses of the RD-114 (ref. 1) group have been isolated, either spontaneously or after chemical induction, from cell cultures of the domestic cat (Felis catus)(2–4). Nucleic acid sequences related to the RD-114 genome are in the DNA of all domestic cats(5–8). Thus these viral genomes are transmitted vertically from parent to offspring as integral components of cat cellular DNA. Although the family Felidae consists of closely related animals, only four Felis species have been found to contain RD-114-related sequences. These include the domestic cat, the European wildcat (F. sylvestris), the sand cat (F. margarita), and the jungle cat (F. chaus); other members of the Felidae lack nucleic acid sequences related to RD-114 (ref. 9). The observation that RD-114 is partially related to the endogenous baboon type C viruses(10–12) and that sequences related to RD-114 are found in the cellular DNA of all Old World monkeys led to the postulate that this group of viruses originated from an endogenous primate type C virus(13) transmitted horizontally to the germ line of ancestors of certain Felis species during the Pliocene or early Pleistocene somewhere in the region of the Mediterranean basin(9). |
4,584 | Developmental Regulation of Angiotensinogen Gene Expression in Sheep | ABSTRACT: It has been suggested that the liver is not the main source of angiotensinogen during fetal life in rats, but that the kidney is an important site of fetal angiotensinogen synthesis. In an effort to determine if this phenomenon is specific to the rat or applicable to other species, we compared the ontogenic changes in hepatic and renal angiotensinogen mRNA expression in fetal (60, 90, 118, and 138 d of gestation, term being 145 d), newborn (7 d postnatal), and adult sheep. Total RNA was extracted, subjected to Northern blotting and hybridized using a full-length rat radiolabeled antisense RNA. Angiotensinogen mRNA sequences were detected in all fetal liver samples and appeared to increase 3-fold from 60 to 138 d gestation and then to decrease after birth. In contrast, angiotensiogen mRNA could not be detected in renal cortical tissue of 118 or 138 d fetuses, or newborn or adult sheep. We conclude that, unlike in the rat, liver angiotensinogen gene expression is detectable during the 2nd trimester of gestation in sheep and is developmentally regulated. Furthermore, in contrast to the fetal rat, angiotensinogen mRNA sequences were undetectable in fetal sheep kidney. |
4,585 | Prophylaxis of necrotizing enterocolitis by oral IgA-IgG: Review of a clinical study in low birth weight infants and discussion of the pathogenic role of infection | Necrotizing enterocolitis, a severe gastrointestinal disease in the neonatal period, affects primarily premature infants. Perinatal complications that predispose the neonate to systemic hypoxia are frequent in infants with necrotizing enterocolitis. Ischemia of the intestinal mucosa may facilitate the invasion of enteric microorganisms in stressed low birth weight infants. Geographical and temporal clustering of outbreaks of the disease and the termination of epidemics by standard infection control underline the importance of infectious agents in the development of this disease. Several studies have established the immunoprotective effect of orally administered antibodies against infection of the gastrointestinal mucosa in children and adults. Anecdotal evidence suggested that feeding of human immune globulin might have a positive effect on the incidence of necrotizing enterocolitis in premature infants. This paper reviews a prospective, randomized, controlled trial of the efficacy of an oral immune globulin preparation (published in detail in theNew England Journal of Medicine, Vol. 319, pp. 1–7, 1988) and discusses the pathogenic role of infection in necrotizing enterocolitis. |
4,586 | Demyelination in mice resulting from infection with a mutant of Semliki Forest virus | Twelve of 34 weanling mice (35%) developed lesions in the brain and spinal cord following i.p. infection with 10(2) p.f.u. of a mutant of Semliki Forest virus (SFV). Six of 12 mice examined 13 days post infection (p.i.) showed meningo-encephalomyelitis with focal spongiform lesions in the grey and white matter. The spongiform lesions were characterised by necrosis of putative oligodendrocytes, myelinic vacuolation and mononuclear cell infiltration. Only one of six mice examined 21 days p.i. and one of six mice examined 28 days p.i. showed lesions which comprised reactive and dystrophic changes in the white matter. Spongiform lesions and pycnotic nuclei were not seen at these times. Viral nucleocapsids were seen in the early stages of the disease in putative necrotic oligodendrocytes. Mature virus particles were not seen. This was in contrast to mice infected with virulent wild-type SFV when lesions were more severe and were accompanied by large numbers of immature and mature virus particles. It is suggested that the demyelination in mice infected with mutant SFV results primarily from selective destruction of oligodendrocytes by the mutant virus. |
4,587 | Reovirus Type 3 Infection in a Suckling Mouse: the Effects on Pancreatic Structure and Enzyme Content | Summary: Alterations in pancreatic function and structure were examined in suckling mice infected intraperitoneally with reovirus type 3. The results were compared to pancreatic zymogen enzyme activities and histology in adult mice infected with the same virus. No effect of the reovirus type 3 on the adult mice could be elicited. In contrast, the suckling mice infected by the reovirus type 3 revealed a definite change in pancreatic zymogen enzymes. However, the zymogen enzymes were affected in a nonparallel fashion and three groups of enzymes with different responses were noted. Amylase and lipase activities were significantly diminished (P < 0.001) at 6 days of viral infection. The endopeptidases, trypsin (P < 0.025) and chymotrypsin (P < 0.001) activities were increased significantly in the infected group. The exopeptidases, carboxypeptidase A and B in the infected animals were not changed significantly compared to the control. It seems reasonable that the reovirus type 3 infection in the suckling mouse causes diminished lipase and amylase activities that might contribute to the pathogenesis of viral enteritis. Speculation: Studies on viral enteritis in infants and young animals have primarily implicated changes in the small intestine as the cause of diarrhea. The viral invasion of the intestinal mucosa causes villous cell destruction and as a consequence, the mucosa generated is immature and incapable of handling normal salt and water absorption. In addition, changes in pancreatic function as a result of an extension of the viral infection to the pancreatic parenchyma might contribute to the pathophysiologic mechanisms operating in viral enteritis. In the infected suckling mice, only amylase and lipase activities are diminished to a large extent, while trypsin and chymotrypsin activities are elevated and carboxypeptidase A and B activities remain unaffected. The nonparallel change in pancreatic enzymes toward a viral insult can be explained by a separate effect of the virus on the biosynthesis of each of the zymogen pancreatic enzymes. It is conceivable that amylase and lipase while in a developing stage, are more affected by the virus than the other pancreatic enzymes which are already developed to a certain extent. Another explanation is that lipase and amylase activities are intrinsically more prone to be decreased in response to different disease states affecting the pancreas. Diminished lipolytic and amylolytic activities due to viral gastroenteritis is a possible contributing factor of the diarrhea in infants and children. |
4,588 | Marek's disease virus-induced transient paralysis in chickens: electron microscopic lesions | A study was made to determine the causative lesion of Marek's disease virus (MDV)-induced transient paralysis (TP) in chickens by comparing the ultrastructure of brain tissue from MDV-infected genetically susceptible and resistant birds. There were numerous intramyelinic vacuoles in the brains of TP-affected birds. Many of these vacuoles contained particulate material compatible with precipitated protein from edema. Astrocyte processes often were distended with similar particulate material. Most intrameylinic vacuoles were either adjacent to the axolemma or within inner myelin lamellae. Myelin sheaths of affected axons, while being displaced, were relatively normal with no vesiculation. Most affected axons were also otherwise normal. Cell processes adjacent to occasional affected axons were distended by degenerating mitochondria, vacuoles, and amorphous material. Some of these processes appeared to be inner loops of oligodendrocyte cytoplasm. The cell bodies of most oligodendrocytes were normal, but a few contained vacuoles similar to those seen in processes adjacent to axons. There were scattered necrotic cells. While most of these could not be specifically identified, some appeared to be oligodendrocytes. Mononuclear inflammatory cells were present both perivascularly and within the parenchyma. Although these cells occasionally contacted myelinated axons and there was myelin phagocytosis, there was no indication that they initiated demyelination. Brain tissue from virus-inoculated resistant birds had perivascular aggregates of mononuclear cells, but there were no intramyelinic vacuoles and few necrotic cells. These findings suggest that intramyelinic vacuolation contributes to the pathogenesis of transient paralysis. Potential pathophysiological mechanisms contributing to the vacuoles, including brain edema and oligodendrocyte injury, are discussed. |
4,589 | Ependymitis, leukoencephalitis, hydrocephalus, and thrombotic vasculitis following chronic infection by mouse hepatitis virus 3 (MHV 3) | Mouse hepatitis virus 3 (MHV 3) is either avirulent (resistant mice), hepatotropic (susceptible mice). or neurotropic (semisusceptible mice), depending on the strain of mice infected. In semisusceptible mice, infection led first to a transient meningitis, ependymitis, and leukoencephalitis, followed by a permanent communicating hydrocephalus and, later on, to a chronic thrombotic vasculitis affecting meningeal and parenchymal vessels at the brain stem level. Small foci of ischemic necrosis related to vascular occlusions were seen in the dorsal brain stem. Cyclophosphamide treatment of semisusceptible mice significantly reduced the meningeal infiltrates but did not prevent the development of hydrocephalus and other neuropathologic changes. Identical lesions occurred in fully susceptible mice infected with a low dose of virus, but no neurologic disorder could be induced in genetically resistant mice even following immunosuppression or intracranial inoculation. The leukoencephalitis differed from the demyelinating lesions observed with MHV4. Vascular lesions were of particular interest. More attention should be given to the possibifity of virus induced chronic cerebral vasculitis in man. |
4,590 | Long-lasting perivascular accumulation of major histocompatibility complex class II-positive lipophages in the spinal cord of stroke patients: possible relevance for the immune privilege of the brain | Six cases of middle cerebral artery occlusion are presented in which the cellular changes accompanying descending degeneration of the lateral corticospinal tract were studied at different time points (5 days–10 years) following the insult. Microglia and perivascular cells were found to ingest large amounts of myelin degradation products, while expressing high levels of major histocompatibility complex (MHC) class II molecules. Activation of perivascular macrophages, as indicated by increased class II expression, lasted for many years and appeared to follow down-regulation of both phagocytic activity and class II expression on parenchymal microglia. TUNEL labeling was absent from both microglia and perivascular cells at all time points investigated. Indirect evidence is presented that microglia may transfer myelin degradation products to the perivascular space. Perivascular cells which express MHC class II molecules constitutively do not appear to leave the perivascular compartment in large numbers and could release myelin degradation products into the cerebrospinal fluid. The possible immunological consequences of these findings are discussed with respect to their possible relevance for antigen presentation and autoimmune central nervous system disease. |
4,591 | Oligodendrocyte infection and demyelination produced in mice by the M9 mutant of Semliki Forest virus | Intraperitoneal inoculation with the M9 mutant of Semliki Forest virus caused focal demyelinating encephalomyelitis in weanling BALB/c and C57BL/6 mice. Demyelination was more severe in BALB/c than in C57BL/6 mice. Virus particles were seen in oligodendrocytes in areas of myelin vacuolation 5 and 7 days post inoculation (DPI). Oligodendrocytes containing virus in BALB/c mice showed hypertrophy and vacuolar degeneration. There was a mononuclear cell infiltrate and lymphocytes and necrotic cells were present in vacuoles in myelin sheaths. Demyelinating plaques containing macrophages laden with myelin debris were most prominent 14 DPI when virus was cleared from the brain. Remyelination of the central type occurred 28 DPI in BALB/c mice. These findings indicate that direct virus-induced injury to oligodendrocytes has a major role in the initiation of inflammation and demyelination in this model system. |
4,592 | Aberrant remyelination of axons after heat injury in the dorsal funiculus of rat spinal cord | We studied the course of demyelination and subsequent remyelination of nerve fibers after heat injury in the dorsal funiculus of the rat spinal cord. Four weeks after heat treatment, we observed, in addition to normally remyelinated axons, a few aberrantly remyelinated axons which had both CNS-and PNS-type myelin sheaths: the CNS-type myelin sheaths were always situated inside the PNS-type sheaths. This finding indicates that in some conditions Schwann cells can form myelin sheaths around those formed by oligodendrocytes. |
4,593 | Occurrence of Necrotizing Enterocolitis May Be Dependent on Patterns of Bacterial Adherence and Intestinal Colonization: Studies in Caco-2 Tissue Culture and Weanling Rabbit Models | ABSTRACT: Necrotizing enterocolitis (NEC) is one of the leading causes of death in neonatal intensive care units. The underlying pathophysiology of NEC is poorly defined, although there is a suggestion that bacterial agents play an important role in the process. In this study, we evaluated bacterial isolates from 17 NEC cases and matched asymptomatic control infants. Isolates from NEC patients were no more likely than control isolates to be adherent to enterocytes, as assessed by a Caco-2 cell tissue culture model. Adherent Escherichia coli isolates, from both NEC cases and controls, were able to cause pathologic changes typical of NEC in a weanling rabbit ileal loop model. Adherence of E. coli strains to Caco-2 cells, and subsequent production of disease in weanling rabbits, could be blocked by coinfection with Gram-positive isolates from control children. In contrast, in three of four instances, adherent E. coli from NEC cases retained their adherence and caused illness in rabbits when coinfected with Gram-positive isolates from the homologous child. Our data suggest that patterns of intestinal adherence, as influenced by the underlying intestinal microbial ecology, play a role in the pathophysiology of NEC. |
4,594 | Olfactory neural pathway in mouse hepatitis virus nasoencephalitis | The mechanism of brain infection with mouse hepatitis virus-JHM was studied in BALB/cByJ mice following intranasal inoculation, and found to be a consequence of direct viral spread along olfactory nerves into olfactory bulbs of the brain. Infection was followed sequentially from nose to brain, using microscopy, immunohistochemistry and virus quantification. Lesions, antigen and virus were observed in the olfactory bulb and anterior brain as early as 2 days and posterior brain by 4 days after inoculation. Viral antigen extended through nasal mucosa into submucosa, then coursed along the olfactory nerve perineurium and fibers, through the cribriform plate into the olfactory bulbs. On days 4 and 7, viral antigen was found in the antero-ventral brain, along ventral meninges, olfactory tracts and anterior ramifications of the lateral ventricles. Virus was cleared from nose by 10 days and anterior brain by 20 days, but persisted in posterior brain for 20 days after inoculation. Mice also developed disseminated infection, with viremia and hepatitis. Infection of brain did not correlate with presence of viremia. In contrast to intranasally inoculated mice, orally-inoculated mice did not develop encephalitis, despite evidence of disseminated infection. |
4,595 | Primary demyelination in experimental canine distemper virus induced encephalomyelitis in gnotobiotic dogs: Sequential immunologic and morphologic findings | Experimental infection of gnotobiotic Beagle dogs at 21 days of age with neurovirulent R252 strain of canine distemper virus (R252-CDV) resulted in a non-suppurative encephalomyelitis. Segmental internodal primary demyelination was found in almost 90% of the dogs from 27 days post inoculation (DPI). Ultrastructurally demyelination was initiated by the insertion of CDV-infected astrocytic processes at nodes of Ranvier with subsequent cleavage of well-preserved myelin from the axolemma. CDV-infected macrophages were consistently involved in myelin phagocytosis. Some remyelination of denuded axons occurred after 35 DPI. Persistent productive infection of the choroid plexus and ependyma in the fourth ventricle was consistently associated with subependymal foci of demyelination. Primary demyelination occurred without detectable CDV-specific virus-neutralizing (CDV-VN) antibody in either serum or cerebrospinal fluid (CSF). There were no immunoglobulin deposits or inflammatory cells within the lesions. These findings indicate that both direct CDV antibody-dependent and CDV antibody-dependent cell-mediated immune mechanisms of cytolysis or myelin destruction are not involved in the genesis of initial primary demyelination. The sequential morphologic and serologic findings in this model of demyelinating encephalomyelitis indicate that direct virus-induced injury has a major role in both the initiation and early progression of primary demyelination. |
4,596 | Structural and physiological properties of mengovirus: Avirulent, hemagglutination-defective mutants express altered alpha (1 D) proteins and are adsorption-defective | Structural and physiological properties of two mutants of mengovirus, 205 and 280, were compared to those of wild-type virus to understand the molecular basis of changes exhibited in their biological function. Two dimensional gel electrophoresis of wild-type and mutant structural proteins revealed alterations in the isoelectric character of the alpha (1 D) protein of both mutant 205 and 280. These data suggest that alterations in the alpha (1 D) protein may be responsible for the phenotypic changes by the mutants. A delay in detectable virus-specified protein synthesis was exhibited in mutant-infected cells in comparison to wild-type. The amount of RNA synthesized in mutant- and revertant-infected cells was less than that synthesized in wild-type infected cells. Changes in virus-specified macro-molecular synthesis in mutant and revertant-infected cells reflected a decrease in the ability of the viruses to attach to cells. |
4,597 | Membrane association of the C-terminal half of the open reading frame 1a protein of lactate dehydrogenase-elevating virus | ORF 1a of lactate dehydrogenase-elevating virus, strain P (LDV-P), encodes a protein of 2206 amino acids. Eisenberg hydrophobic moment analysis of the protein predicted the presence of eleven transmembrane segments in the C-terminal half of the molecule (amino acids 980–1852) that flank the serine protease domain. cDNAs encoding ORF 1a protein segments encompassing transmembrane segments 5 to 11 and its amphipathic C-terminal end as well as the N-terminal 80 amino acids of the downstream ORF 1b protein were transcribed and the transcripts in vitro translated in the absence and presence of microsomal membranes. The synthesis of the protein products with putative transmembrane segments was enhanced by the presence of the microsomal membranes and the proteins became membrane associated. When synthesized in the absence of membranes they were recovered in the supernatant upon ultracentrifugation of the translation reaction mixtures, whereas they were recovered in the membrane pellet when synthesized in the presence of membranes. Furthermore, the latter proteins were not released from the membranes by disruption of the membrane vesicles in carbonate buffer, pH 11.5, and large portions of the proteins were resistant to digestion by trypsin, chymotrypsin and proteinase K. No N-glycosylation was observed and only little, if any, processing of the protein by the putative serine protease. The results indicate that the C-terminal half of the ORF 1a protein represents a non-glycosylated integral membrane protein. Potential modes of synthesis and function of the protein are discussed. In addition, the results showed that the synthesis of the ORF 1a protein was generally terminated at its termination codon, but that read-through into the ORF 1b gene occurred with low frequency. |
4,598 | Fatty acid acylation of viral proteins in murine hepatitis virus-infected cells | The fatty acid acylation of the cell-associated virus-specific proteins of mouse hepatitis virus (A 59-strain) was studied.(3)H-palmitate label was associated with E 2, one of the two virion glycoproteins and its intracellular precursor gp 150. A 110 K protein, the unglycosylated apoprotein of gp 150, accumulated by tunicamycin treatment, also incorporated radiolabeled palmitic acid. The addition of fatty acid to the MHV-A 59 E 2 protein is therefore not dependent on glycosylation. |
4,599 | Canine distemper virus-induced glial cell changes in vitro | In vitro studies on glial cell changes in canine distemper virus (CDV) infection could be useful for the understanding of the pathogenesis of demyelination in vivo in this disease. Mixed glial cell cultures derived from neonatal mice and dogs were infected with CDV and examined using immunocytochemical techniques demonstrating specific oligodendroglial and astroglial cell markers. Astrocytic changes were similar in both murine and canine cultures and consisted of loss of processes, cell fusion, and cell necrosis. Marked oligodendroglial lesions were apparent in the canine brain cultures and were characterized by focal perikaryal protrusions, swelling and loss of cell processes, and cell necrosis. Fusion between oligodendrocytes was not observed. Fusion between astrocytes and oligodendrocytes could not be documented with double labeling techniques. In contrast to the canine cultures, murine oligodendrocytes remained relatively unaffected by the infection. These findings were discussed with respect to cell pathology and mechanisms of demyelination in vivo. The exact nature of the canine oligodendroglial lesions in vitro needs to be studied in further experiments. |
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