title: Medical Students’ Clinical Reasoning During a Simulated Viral Pandemic: Evidence of Cognitive Integration and Insights on Novices’ Approach to Diagnostic Reasoning

text: INTRODUCTION: Cognitive integration from multiple disciplines is essential to clinical problem-solving. Because it is not directly observable, demonstrating evidence of learners’ cognitive integration remains a challenge. In addition, little is known about preclinical medical students’ approach to diagnostic reasoning despite widespread implementation of clinical reasoning curricula for these early learners. The objectives of this study were to characterize how first-year medical students integrated knowledge to problem-solve during a simulated viral pandemic and to characterize students’ diagnostic reasoning approach to this clinical scenario. MATERIALS AND METHODS: Student teams analyzed clinical data to formulate hypotheses for the pandemic’s source and submitted reports justifying their hypotheses and treatment recommendations. A content analysis on students’ reports identified codes and themes characterizing the learning content integrated and students’ approaches to diagnostic reasoning tasks. RESULTS: Sixteen problem-solving codes were identified, demonstrating integration of new and previously encountered content from multiple disciplines. A compare-contrast analytical approach was the most commonly employed diagnostic reasoning approach (100%), with a smaller subset of teams also using a causal approach (20%). DISCUSSION: Content analysis of preclinical students’ diagnostic justification tasks provided insights into their approach to diagnostic reasoning, which was most consistent with the search-inference framework rather than a causal approach, likely due to limited pathophysiological knowledge at that point in training. CONCLUSIONS: Evidence of cognitive integration can be made explicit through learners’ narrative justification of diagnostic reasoning tasks. Preclinical students’ diagnostic reasoning development has implications for curricular design and implementation for this learner group.


title: In-silico identification of the vaccine candidate epitopes against the Lassa virus hemorrhagic fever

text: Lassa virus (LASV), a member of the Arenaviridae, is an ambisense RNA virus that causes severe hemorrhagic fever with a high fatality rate in humans in West and Central Africa. Currently, no FDA approved drugs or vaccines are available for the treatment of LASV fever. The LASV glycoprotein complex (GP) is a promising target for vaccine or drug development. It is situated on the virion envelope and plays key roles in LASV growth, cell tropism, host range, and pathogenicity. In an effort to discover new LASV vaccines, we employ several sequence-based computational prediction tools to identify LASV GP major histocompatibility complex (MHC) class I and II T-cell epitopes. In addition, many sequence- and structure-based computational prediction tools were used to identify LASV GP B-cell epitopes. The predicted T- and B-cell epitopes were further filtered based on the consensus approach that resulted in the identification of thirty new epitopes that have not been previously tested experimentally. Epitope-allele complexes were obtained for selected strongly binding alleles to the MHC-I T-cell epitopes using molecular docking and the complexes were relaxed with molecular dynamics simulations to investigate the interaction and dynamics of the epitope-allele complexes. These predictions provide guidance to the experimental investigations and validation of the epitopes with the potential for stimulating T-cell responses and B-cell antibodies against LASV and allow the design and development of LASV vaccines.


title: Strain-specific transcriptional and posttranscriptional regulation of heat-labile toxin expression by enterotoxigenic Escherichia coli

text: Enterotoxigenic Escherichia coli (ETEC) represents one of the most important etiological agents of diarrhea in developing countries and characteristically produces at least one of two enterotoxins: heat-labile toxin (LT) and heat-stable toxin (ST). It has been previously shown that the production and release of LT by human-derived ETEC strains are variable. Although the natural genetic polymorphisms of regulatory sequences of LT-encoding (eltAB) genes may explain the variable production of LT, the knowledge of the transcriptional and posttranscriptional aspects affecting LT expression among ETEC strains is not clear. To further understand the factors affecting LT expression, we evaluated the impact of the natural polymorphism in noncoding regulatory sequences of eltAB among clinically derived ETEC strains. Sequence analyses of seven clinically derived strains and the reference strain H10407 revealed polymorphic sites at both the promoter and upstream regions of the eltAB operon. Operon fusion assays with GFP revealed that specific nucleotide changes in the Pribnow box reduce eltAB transcription. Nonetheless, the total amounts of LT produced by the tested ETEC strains did not strictly correspond to the detected LT-specific mRNA levels. Indeed, the stability of LT varied according to the tested strain, indicating the presence of posttranscriptional mechanisms affecting LT expression. Taken together, our results indicate that the production of LT is a strain-specific process and involves transcriptional and posttranscriptional mechanisms that regulate the final amount of toxin produced and released by specific strains. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s42770-020-00231-2) contains supplementary material, which is available to authorized users.


title: Tracheostomy in patients with acute respiratory distress syndrome is not related to quality of life, symptoms of psychiatric disorders or return-to-work: the prospective DACAPO cohort study

text: BACKGROUND: Acute respiratory distress syndrome (ARDS) is a life-threatening condition that often requires prolonged mechanical ventilation. Tracheostomy is a common procedure with some risks, on the other hand with potential advantages over orotracheal intubation in critically ill patients. This study investigated the association of tracheostomy with health-related quality of life (HRQoL), symptoms of psychiatric disorders and return-to-work of ARDS survivors. METHODS: Data were collected in the context of the prospective observational German-wide DACAPO study. Clinical and demographic patient data and treatment characteristics were obtained from the participating intensive care units (ICU). HRQoL and return-to-work were assessed using patient-reported questionnaires 3, 6 and 12 months after ICU discharge. HRQoL was measured with the Physical and Mental Component Scale of the Short-Form 12 Questionnaire (PCS-12, MCS-12). The prevalence of psychiatric symptoms (depression and post-traumatic stress disorder [PTSD]) was assessed using the Patient Health Questionnaire-9 and the Post-Traumatic Stress Syndrome-14. Physician-diagnosed anxiety and obsessive–compulsive disorder were recorded by patient self-report in the follow-up questionnaires. The associations of tracheostomy with HRQoL, psychiatric symptoms and return-to-work after 12 months were investigated by means of multivariable linear and logistic regression models. RESULTS: Primary 877 ARDS patients (mean ± standard deviation: 54 ± 16 years, 68% male) survived and were discharged from ICU. Out of these patients, 478 (54.5%) were tracheotomised during ICU treatment. After 12 months, patient-reported outcomes could be analysed of 388 (44.2%) respondents, 205 with tracheostomy and 183 without. One year after ICU discharge, tracheostomy showed no significant association with physical or mental health-related quality of life (PCS-12: − 0.73 [− 3.96, 2.51]; MCS-12: − 0.71 [− 4.92, 3.49]), symptoms of psychiatric disorders (depression: 0.10 [− 1.43, 1.64]; PTSD: 3.31 [− 1.81, 8.43]; anxiety: 1.26 [0.41, 3.86]; obsessive–compulsive disorder: 0.59 [0.05, 6.68]) or return-to-work (0.71 [0.31, 1.64]) in the multivariable analysis (OR [95%-CI]). CONCLUSIONS: Up to 1 year after ICU discharge, neither HRQoL nor symptoms of psychiatric disorders nor return-to-work was affected by tracheostomy. Trial registration NCT02637011 (ClinicalTrials.gov, Registered 15 December 2015, retrospectively registered)


title: Physiology in Medicine: Understanding dynamic alveolar physiology to minimize ventilator-induced lung injury

text: Acute respiratory distress syndrome (ARDS) remains a serious clinical problem with the main treatment being supportive in the form of mechanical ventilation. However, mechanical ventilation can be a double-edged sword: if set improperly, it can exacerbate the tissue damage caused by ARDS; this is known as ventilator-induced lung injury (VILI). To minimize VILI, we must understand the pathophysiologic mechanisms of tissue damage at the alveolar level. In this Physiology in Medicine paper, the dynamic physiology of alveolar inflation and deflation during mechanical ventilation will be reviewed. In addition, the pathophysiologic mechanisms of VILI will be reviewed, and this knowledge will be used to suggest an optimal mechanical breath profile (MB(P): all airway pressures, volumes, flows, rates, and the duration that they are applied at both inspiration and expiration) necessary to minimize VILI. Our review suggests that the current protective ventilation strategy, known as the “open lung strategy,” would be the optimal lung-protective approach. However, the viscoelastic behavior of dynamic alveolar inflation and deflation has not yet been incorporated into protective mechanical ventilation strategies. Using our knowledge of dynamic alveolar mechanics (i.e., the dynamic change in alveolar and alveolar duct size and shape during tidal ventilation) to modify the MB(P) so as to minimize VILI will reduce the morbidity and mortality associated with ARDS.


title: Lung Parenchymal Mechanics in Health and Disease

text: The mechanical properties of lung tissue are important determinants of lung physiological functions. The connective tissue is composed mainly of cells and extracellular matrix, where collagen and elastic fibers are the main determinants of lung tissue mechanical properties. These fibers have essentially different elastic properties, form a continuous network along the lungs, and are responsible for passive expiration. In the last decade, many studies analyzed the relationship between tissue composition, microstructure, and macrophysiology, showing that the lung physiological behavior reflects both the mechanical properties of tissue individual components and its complex structural organization. Different lung pathologies such as acute respiratory distress syndrome, fibrosis, inflammation, and emphysema can affect the extracellular matrix. This review focuses on the mechanical properties of lung tissue and how the stress-bearing elements of lung parenchyma can influence its behavior.


title: A case report of fatal disseminated fungal sepsis in a patient with ARDS and extracorporeal membrane oxygenation

text: BACKGROUND: With the following report we want to present an unusual case of a patient suffering from acute respiratory distress syndrome with early discovery of bacterial pathogens in bronchoalveolar liquid samples that developed a fatal undiscovered disseminated fungal infection. CASE PRESENTATION: A 67-year-old man was admitted to our university hospital with dyspnea. Progressive respiratory failure developed leading to admission to the intensive care unit, intubation and prone positioning was necessary. To ensure adequate oxygenation and lung protective ventilation veno-venous extracorporeal membrane oxygenation was established. Despite maximal therapy and adequate antiinfective therapy of all discovered pathogens the condition of the patient declined further and he deceased. Postmortem autopsy revealed Mucor and Aspergillus mycelium in multiple organs such as lung, heart and pancreas as the underlying cause of his deterioration and death. CONCLUSION: Routine screening re-evaluation of every infection is essential for adequate initiation and discontinuation of every antiinfective therapy. In cases with unexplained deterioration and unsuccessful sampling the possibility for diagnostic biopsies should be considered.


title: Improvement cues of lesion absorption using the adjuvant therapy of traditional Chinese medicine Qinbudan tablet for retreatment pulmonary tuberculosis with standard anti-tuberculosis regimen

text: BACKGROUND: China is the second highest pulmonary tuberculosis (PTB) burden country worldwide. However, retreatment of PTB has often developed resistance to at least one of the four first-line anti-TB drugs. The cure rate (approximately 50.0–73.3%) and management of retreatment of PTB in China needs to be improved. Qinbudan decoction has been widely used to treat PTB in China since the 1960s. Previously clinical studies have shown that the Qinbudan tablet (QBDT) promoted sputum-culture negative conversion and lesion absorption. However, powerful evidence from a randomized controlled clinical trial is lacking. Therefore, the aim of this study was to compare the efficacy and safety of QBDT as an adjunct therapy for retreatment of PTB. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled clinical trial in China. People diagnosed with PTB were enrolled who received previous anti-TB treatment from April 2011 to March 2013. The treatment group received an anti-TB regimen and QBDT, and the control group was administered an anti-TB regimen plus placebo. Anti-TB treatment options included isoniazid, rifampicin, pyrazinamide, ethambutol, streptomycin for 2 months (2HRZES), followed by isoniazid, rifampicin, ethambutol for 6 months (6HRE), daily for 8 months. Primary outcome was sputum-culture conversion using the MGIT 960 liquid medium method. Secondary outcomes included lung lesion absorption and cavity closure. Adverse events and reactions were observed after treatment. A structured questionnaire was used to record demographic information and clinical symptoms of all subjects. Data analysis was performed by SPSS 25.0 software in the full analysis set (FAS) population. RESULTS: One hundred eighty-one cases of retreatment PTB were randomly divided into two groups: the placebo group (88 cases) and the QBDT group (93 cases). A total of 166 patients completed the trial and 15 patients lost to follow-up. The culture conversion rate of the QBDT group and placebo group did not show a noticeable improvement by using the covariate sites to correct the rate differences (79.6% vs 69.3%; rate difference = 0.10, 95% confidence interval (CI): - 0.02–0.23; F = 2.48, P = 0.12) after treatment. A significant 16.6% increase in lesion absorption was observed in the QBDT group when compared with the placebo group (67.7% vs 51.1%; rate difference = 0.17, 95% CI: 0.02–0.31; χ(2) = 5.56, P = 0.02). The intervention and placebo group did not differ in terms of cavity closure (25.5% vs 21.1%; rate difference = 0.04, 95% CI: - 0.21–0.12; χ(2) = 0.27, P = 0.60). Two patients who received chemotherapy and combined QBDT reported pruritus/nausea and vomiting. CONCLUSIONS: No significant improvement in culture conversion was observed for retreatment PTB with traditional Chinese medicine plus standard anti-TB regimen. However, QBDT as an adjunct therapy significantly promoted lesion absorption, thereby reducing lung injury due to Mycobacterium tuberculosis infection. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov, NCT02313610.


title: Live-attenuated Salmonella enterica serotype Choleraesuis vaccine with regulated delayed fur mutation confer protection against Streptococcus suis in mice

text: BACKGROUND: Recombinant Salmonella enterica serotype Choleraesuis (S. Choleraesuis) vaccine vector could be used to deliver heterologous antigens to prevent and control pig diseases. We have previously shown that a live-attenuated S. Choleraesuis vaccine candidate strain rSC0011 (ΔP(crp527)::TT araC P(BAD)crp Δpmi-2426 ΔrelA199::araC P(BAD)lacI TT ΔasdA33, Δ, deletion, TT, terminator) delivering SaoA, a conserved surface protein in most of S. suis serotypes, provided excellent protection against S. suis challenge, but occasionally lead to morbidity (enteritidis) in vaccinated mice (approximately 1 in every 10 mice). Thus, alternated attenuation method was sought to reduce the reactogenicity of strain rSC0011. Herein, we described another recombinant attenuated S. Choleraesuis vector, rSC0012 (ΔP(fur88):: TT araC P(BAD)fur Δpmi-2426 ΔrelA199:: araC P(BAD)lacI TT ΔasdA33) with regulated delayed fur mutation to avoid inducing disease symptoms while exhibiting a high degree of immunogenicity. RESULTS: The strain rSC0012 strain with the ΔP(fur88)::TT araC P(BAD)fur mutation induced less production of inflammatory cytokines than strain rSC0011 with the ΔP(crp527)::TT araC P(BAD)crp mutation in mice. When delivering the same pS-SaoA plasmid, the intraperitoneal LD(50) of rSC0012 was 18.2 times higher than that of rSC0011 in 3-week-old BALB/C mice. rSC0012 with either pS-SaoA or pYA3493 was cleared from spleen and liver tissues 7 days earlier than rSC0011 with same vectors after oral inoculation. The strain rSC0012 synthesizing SaoA induced high titers of anti-SaoA antibodies in both systemic (IgG in serum) and mucosal (IgA in vaginal washes) sites, as well as increased level of IL-4, the facilitator of Th2-type T cell immune response in mice. The recombinant vaccine rSC0012(pS-SaoA) conferred high percentage of protection against S. suis or S. Choleraesuis challenge in BALB/C mice. CONCLUSIONS: The live-attenuated Salmonella enterica serotype Choleraesuis vaccine rSC0012(pS-SaoA) with regulated delayed fur mutation provides a foundation for the development of a safe and effective vaccine against S. Choleraesuis and S. suis.


title: Zebrafish as an alternative animal model in human and animal vaccination research

text: Much of medical research relies on animal models to deepen knowledge of the causes of animal and human diseases, as well as to enable the development of innovative therapies. Despite rodents being the most widely used research model worldwide, in recent decades, the use of the zebrafish (Danio rerio) model has exponentially been adopted among the scientific community. This is because such a small tropical freshwater teleost fish has crucial genetic, anatomical and physiological homology with mammals. Therefore, zebrafish constitutes an excellent experimental model for behavioral, genetic and toxicological studies which unravels the mechanism of various human diseases. Furthermore, it serves well to test new therapeutic agents, such as the safety of new vaccines. The aim of this review was to provide a systematic literature review on the most recent studies carried out on the topic. It presents numerous advantages of this type of animal model in tests of efficacy and safety of both animal and human vaccines, thus highlighting gains in time and cost reduction of research and analyzes.


title: The immune response to influenza in older humans: beyond immune senescence

text: Despite widespread influenza vaccination programs, influenza remains a major cause of morbidity and mortality in older adults. Age-related changes in multiple aspects of the adaptive immune response to influenza have been well-documented including a decline in antibody responses to influenza vaccination and changes in the cell-mediated response associated with immune senescence. This review will focus on T cell responses to influenza and influenza vaccination in older adults, and how increasing frailty or coexistence of multiple (≥2) chronic conditions contributes to the loss of vaccine effectiveness for the prevention of hospitalization. Further, dysregulation of the production of pro- and anti-inflammatory mediators contributes to a decline in the generation of an effective CD8 T cell response needed to clear influenza virus from the lungs. Current influenza vaccines provide only a weak stimulus to this arm of the adaptive immune response and rely on re-stimulation of CD8 T cell memory related to prior exposure to influenza virus. Efforts to improve vaccine effectiveness in older adults will be fruitless until CD8 responses take center stage.


title: Congenital diaphragmatic hernia presenting with symptoms within the first day of life; outcomes from a non-ECMO centre in Denmark

text: BACKGROUND: Between 1998 and 2015, we report on the survival of congenital diaphragmatic hernia (CDH)-infants presenting with symptoms within the first 24 h of life, treated at Odense University Hospital (OUH), a tertiary referral non-extracorporeal membrane oxygenation (ECMO) hospital for paediatric surgery. METHODS: We performed a retrospective cohort study of prospectively identified CDH-infants at our centre. Data from medical records and critical information systems were obtained. Baseline data included mode of delivery and infant condition. Outcome data included 24-h, 28-day, and 1 year mortality rates and management data included intensive care treatment, length of stay in the intensive care unit, time of discharge from hospital, and surgical intervention. Descriptive analyses were performed for all variables. Survivors and non-survivors were compared for baseline and treatment data. RESULTS: Ninety-five infants were identified (44% female). Of these, 77% were left-sided hernias, 52% were diagnosed prenatally, and 6.4% had concurrent malformations. The 28-day mortality rate was 21.1%, and the 1 year mortality rate was 22.1%. Of the 21 non-survivors, nine died within the first 24 h, and 10 were sufficiently stabilised to undergo surgery. A statistically significant difference was observed between survivors and non-survivors regarding APGAR score at 1 and 5 min., prenatal diagnosis, body length at birth, and delivery at OUH. CONCLUSIONS: Our outcome results were comparable to published data from other centres, including centres using ECMO.


Modern diagnostics in emergency medicine


title: A Spontaneous Lower Motor Neuron Disease Apparently Caused by Indigenous Type-C RNA Virus in Wild Mice

text: A high incidence of spontaneous lower-limb paralysis occurred in a population of wild mice (Mus musculus) which had a high incidence of naturally occurring lymphoma and elevated indigenous type-C virus activity. Experimental transmission evidence indicated that both the neurologic and lymphomatous disorders almost certainly were caused by the indigenous type-C virus. The virus appeared to have a direct neurotropic effect on anterior horn neurons in the lower spinal cord.


title: Type C Virus Expression in Lymphoma-Paralysis-Prone Wild Mice

text: Wild mice trapped near Lake Casitas (LC) in southern California showed a high prevalence of infectious type C virus in the liver, spleen, and thymus within the first few weeks of life. By young adulthood about 80% of LC mice (including their genital tissues) were infected. Virus isolates from these mice cause lymphoma and lower limb paralysis under both natural and experimental conditions. Mice destined to develop paralysis showed higher levels of serum gs antigen early in life, whereas mice destined to develop lymphoma or remain free of these diseases could not be distinguished by this test. The individual variation in virus expression suggested that differences in virus type or in the immune or other host defense mechanisms greatly influenced susceptibility or resistance to indigenous type C virus-caused disease in LC wild mice.


title: Differential Distribution of Mouse Mammary Tumor Virus-Related Sequences in the DNA’s of Rats

text: Radioactively labeled mouse mammary tumor virus (MuMTV) 60-70S RNA, obtained from virions grown In both murine and feline cells, was employed In molecular hybridization experiments to detect MuMTV-related sequences In the DNA’s of rats (Rattus norveglcus). With the use of relaxed conditions of hybridization and assay for RNA-DNA duplexes, all strains of laboratory rats and feral rats examined were shown to possess endogenous MuMTV-related DNA sequences In the low repetitive range. These sequences were related to approximately 20% of the MuMTV genome and exhibited a melting temperature (Tm) approximately 5° C lower than MuMTV-specific proviral sequences In murine (Mus musculus) DNA’s. Certain colonies of the F344 strain of rat (Fischer) contained animals whose DNA’s possessed additional MuMTV-related sequences. These sequences were related to the non-germ-line-transmitted, tumorassociated (TA) sequences of the highly oncogenic MuMTV (C3H). They were found In the DNA of some F344 rats and a cloned established F344 rat embryo cell line at a frequency of approximately one copy per haploid genome and exhibited a Tm 9° C lower than that of hybrid duplexes formed between radioactive MuMTV TA-sequence RNA and C3H mouse mammary tumor DNA. The DNA’s of rats, therefore, contained two sets of sequences that were related to sequences of the MuMTV genome: One set was germ-line transmitted, whereas the other set appeared to be transmitted in some rats via a non-germ line or infectious process.


docid: lqkcvpza

title: Determinants of Susceptibility and Resistance to Feline Leukemia Virus Infection. I. Role of Macrophages

text: The role of autochthonous peritoneal feline macrophages (Mθ) in the age-related resistance of cats to feline leukemia virus (FeLV) was investigated by a study of the functional properties and FeLV susceptibility of Mθ from kittens and adult cats and the effect of hydrocortisone (HC) and silica on Mθ-FeLV interactions. Although the phagocytic functions of isolated Mθ from kittens and adults were equivalent, the mean FeLV susceptibility of Mθ from kittens was five times that of Mθ from adult cats, thus establishing a direct correlation between the age-related susceptibility of cats and Mθ from cats to FeLV. Mθ of viremic cats were found to be infected with FeLV in vivo; virus titers were slightly higher than those obtained after in vitro infection of Mθ. Mθ from cats that had experienced regressive FeLV infection were not significantly more resistant to FeLV infection in vitro than were Mθ from naive adult specific-pathogen-free cats. HC, which has been shown to enhance the in vivo FeLV susceptibility of cats, also enhanced the permissiveness of Mθ from cats to FeLV in vitro (600-fold for Mθ from adult cats and 200-fold for Mθ) from kittens. Mθ permissiveness to FeLV was highly sensitive to HC and occurred in Mθ infected in vivo or in vitro. In parallel with the effect of HC on the natural resistance of cats to FeLV, administration of silica before virus inoculation also markedly enhanced the FeLV susceptibility of adult cats. Silica was toxic for isolated Mθ but not for lymphocytes in vitro, and silica produced monocytopenia and neutrophilia, delayed skin allograft rejection, and augmented feline oncovirus-associated cell membrane antigen antibody responses in vivo. These experiments indicate that Mθ were linked to the natural resistance of cats to FeLV and that the temporary elimination of Mθ functions (e.g., by silica) and/or the conversion of the Mθ-FeLV relationship from a nonpermissive to a permissive state (e.g., by corticosteroids) resulted in failure of early virus containment, in persistent virus amplification in hemolymphatic tissues, and in subsequent FeLV-related proliferative or antiproliferative disease.


title: Pathogenesis of Lesions Induced in Rat Lung by Chronic Tobacco Smoke Inhalation

text: Lesions were induced in the lungs of specific-pathogen-free F344 rats by chronic tobacco smoke exposure. Animals exposed to 7 cigarettes/day were killed after 1, 1.5, or 2 years of exposure. Parallel lifetime exposures induced pulmonary tumors in 9% of the animals. In serially killed animals, four types of lesions were found: 1) perivascular or peribronchiolar accumulation of lymphoreticular cells, 2) fibrotic and cellular enlargement of peribronchiolar septa, 3) type II cell hyperplasia with septal fibrosis, and 4) air-space enlargement (emphysema). However, emphysema occurred only in animals exposed to a higher (10 cigarettes) dose of tobacco smoke. Ultrastructural studies showed all of the focal lesions to be infiltrated by cells typical of the inflammatory response. The type II hyperplastic and peribronchiolar alveolar lesions involved larger portions of the parenchyma in fibrotic changes but differed in structure, location, and frequency. The incidence of the peribronchiolar alveolar lesions was temporally related to tumor incidence.


title: Coronavirus disease: challenges for psychiatry

text: Coronavirus disease (COVID-19) presents two urgent health problems: the illness caused by the virus itself and the anxiety, panic and psychological problems associated with the pandemic. Both problems present substantial challenges for our patients, their families, our multidisciplinary teams and our psychiatrist colleagues. We need good psychiatry, now more than ever.


title: Triple combination therapy of favipiravir plus two monoclonal antibodies eradicates influenza virus from nude mice

text: Prolonged treatment of immunocompromised influenza patients with viral neuraminidase (NA) inhibitors is required, because the immune system of such patients fails to eradicate the viruses. Here, we attempted to eradicate influenza virus from the respiratory organs of nude mice, which is a model of immunocompromised hosts, by using combination therapy of the viral polymerase inhibitor favipiravir and monoclonal antibodies (mAbs) against the receptor-binding site (RBS) and stem of viral hemagglutinin (HA). Although monotherapy or combination therapy of two antivirals (two mAbs or favipiravir plus a mAb) suppressed virus replication, they failed to eradicate viruses from nude mice. In contrast, the triple combination therapy of favipiravir plus anti-Stem and anti-RBS mAbs completely stopped virus replication in nude mice, resulting in virus clearance. Triple combination approaches should be considered for the treatment of human immunocompromised patients with severe influenza.


Protecting Clinicians from Civil Liability During a Public Health Crisis: Legislative & Professional Organizational Efforts


title: The structure–activity relationship review of the main bioactive constituents of Morus genus plants

text: ABSTRACT: Morus genus plants are mainly distributed in the temperate to tropical areas over the world and include 17 species and two subspecies. Due to their excellent pharmacological activity, security in food additives and high value in the national economy, Morus genus plants have drawn more and more attention in recent years. In the light of the references published over the last few decades, flavonoids, benzofurans, stilbenes, and Diels–Alder adducts have been reported to be the main bioactive constituents of Morus genus plants. This review summarizes the compounds with excellent bioactivities isolated from Morus genus plants as well as their structure–activity relationships (SARs), which might be useful for the further research and development of Morus genus plants. GRAPHIC ABSTRACT: [Image: see text] The aromatic heterocycles with excellent bioactivities isolated from Morus genus plants as well as their structure–activity relationships (SARs) were summarized.


title: Advances in cytomegalovirus (CMV) biology and its relationship to health, diseases, and aging

text: Cytomegalovirus (CMV) is one of the largest and most ubiquitous latent persistent viruses. Most humans are infected with CMV early in life, and all immunocompetent humans spend several decades living with CMV. In the vast majority of the hosts, CMV does not cause manifest disease, and CMV therefore can be considered part of normal aging for 50–90% of the human population worldwide. Experimental, clinical, and epidemiological studies suggest that CMV carriage can have nuanced outcomes, including both potentially harmful and potentially beneficial impacts on the host. We here present a summary of the 7th International Workshop on CMV and Immunosenescence, covering various aspects of the interplay between CMV and its mammalian hosts in the context of virus spread, immune evasion, antiviral immunity, as well as the impact on health span and aging.


title: The dynamic change of serum S100B levels from day 1 to day 3 is more associated with sepsis-associated encephalopathy

text: We investigated the role of dynamic changes of serum levels S100B protein in brain injury and poor outcome of sepsis. This is a prospective cohort study designed to include 104 adult patients with sepsis who are admitted to ICU from Jan 2015 to Aug 2016. Sepsis was defined as sepsis 3.0. Patients with a GCS score of <15, or at least one positive CAM-ICU score were thought to have brain dysfunction. 59 patients were diagnosed with SAE and the rest 45 patients were diagnosed with non-SAE. Serum S100B was measured on day 1 and 3 after ICU admission. Primary outcomes included brain dysfunction and 28-day/180-day mortality. The SAE group showed a significantly higher APACHE II score, SOFA scores, length of ICU stay, 28-day and 180-day mortality, serum S100B levels on day 1 and day 3. S100B levels on day 1 of 0.226 μg/L were diagnostic for SAE with 80.0% specificity and 66.1% sensitivity, and the area under (AUC) the curve was 0.728, S100B levels on day 3 of 0.144 μg/L were diagnostic for SAE with 84.44% specificity and 69.49% sensitivity, and the AUC was 0.819. In addition, the AUC for S100B on day 3 for predicting 180-day mortality was larger than for S100B on day 1 (0.731 vs. 0.611). Multiple logistic regression analysis showed that S100B3 (p = 0.001) but not S100B1 (p = 0.927) were independently correlated with SAE. Kaplan-Meier survival analysis showed that patients with S100B levels higher than 0.144 μg/L had a lower probability of survival at day 180. There were more patients with encephalopathy and a higher 28-day or 180-day mortality in the ΔS100B + group than in the ΔS100B- group. Multiple logistic regression analysis showed that SAE and IL-6 on day 3 were independently correlated with S100B dynamic increase. These findings suggest that elevated serum S100B levels on day 3 and the dynamic changes of serum S100B levels from day three to one were more associated with brain dysfunction and mortality than that on day 1 in patients with sepsis.


title: Whose crisis? Pandemic flu, ‘communication disasters’ and the struggle for hegemony

text: Public health authorities in Germany regard communication as a crucial part of infectious disease prevention and control strategies. Communication becomes even more important during public health crises such as pandemics. Drawing on Briggs and Hallin’s concept of biocommunicability, we analysed the German National Pandemic Plan and key informant interviews with public health experts, critical infrastructure providers and ambulance services. We examined the projected expectations towards the behaviour of the audiences and the projected ways of information circulation informing public health communication strategies during a pandemic. Participants shared the expectation that the population would react towards an influenza pandemic with panic and fear due to a lack of information or a sensationalist media coverage. They associated the information uptake of their target audience with trust in their expertise. While our informants from public health conceptualised trust in terms of a face-to-face interaction, they sought to gain trust through transparency in their respective institutional settings. Our analysis suggests that this moved health information into a political register where their medical authority was open to debate. In response to this, they perceived the field of communication as a struggle for hegemony.


title: Early signs of right ventricular systolic and diastolic dysfunction in acute severe respiratory failure: the importance of diastolic restrictive pattern

text: BACKGROUND: The incidence and pathophysiology of right ventricular failure in patients with severe respiratory insufficiency has been largely investigated. However, there is a lack of early signs suggesting right ventricular systolic and diastolic dysfunction prior to acute cor pulmonale development. METHODS: We conducted a retrospective analytical cohort study of patients for acute respiratory distress syndrome undertaking an echocardiography during admission in the cardiothoracic intensive care unit. Patients were divided according to treatment: conventional protective ventilation (38 patients, 38%); interventional lung assist (23 patients, 23%); veno-venous extracorporeal membrane oxygenation (37 patients, 37%). Systolic and diastolic function was studied assessing, respectively: right ventricular systolic longitudinal function (tricuspid annular plane systolic excursion) and systolic contraction duration (tricuspid annular plane systolic excursion length); right ventricular diastolic filling time and right ventricular diastolic restrictive pattern (presence of pulmonary valve presystolic ejection wave). Correlation between the respiratory mechanics and systo-diastolic parameters were analysed. RESULTS: In 98 patients studied, systolic dysfunction (tricuspid annular plane systolic excursion <16 mm) was present in 33.6% while diastolic restrictive pattern was present in 64%. A negative correlation was found between tricuspid annular plane systolic excursion and tricuspid annular plane systolic excursion length (P<0.0001; r −0.42). Tricuspid annular plane systolic excursion and tricuspid annular plane systolic excursion length correlated with right ventricular diastolic filling time (P<0.001; r −0.39). Pulmonary valve presystolic ejection wave was associated with tricuspid annular plane systolic excursion (P<0.0001), tricuspid annular plane systolic excursion length (P<0.0001), right ventricular diastolic filling time (P<0.0001), positive end-expiratory pressure (P<0.0001) and peak inspiratory pressure (P<0.0001). CONCLUSION: Diastolic restrictive pattern is present in a remarkable percentage of patients with respiratory distress syndrome. Bedside echocardiography allows a mechanistic evaluation of systolic and diastolic interaction of the right ventricle.


title: FluA-p score: a novel prediction rule for mortality in influenza A-related pneumonia patients

text: BACKGROUND: The pneumonia severity index (PSI) and the CURB-65 (confusion, urea, respiratory rate, blood pressure, age ≥ 65 years) score have been shown to predict mortality in community-acquired pneumonia. Their ability to predict influenza-related pneumonia, however, is less well-established. METHODS: A total of 693 laboratory-confirmed FluA-p patients diagnosed between Jan 2013 and Dec 2018 and recruited from five teaching hospitals in China were included in the study. The sample included 494 patients in the derivation cohort and 199 patients in the validation cohort. The prediction rule was established based on independent risk factors for 30-day mortality in FluA-p patients from the derivation cohort. RESULTS: The 30-day mortality of FluA-p patients was 19.6% (136/693). The FluA-p score was based on a multivariate logistic regression model designed to predict mortality. Results indicated the following significant predictors (regression statistics and point contributions toward total score in parentheses): blood urea nitrogen > 7 mmol/L (OR 1.604, 95% CI 1.150–4.492, p = 0.040; 1 points), pO(2)/F(i)O(2) ≤ 250 mmHg (OR 2.649, 95% CI 1.103–5.142, p = 0.022; 2 points), cardiovascular disease (OR 3.967, 95% CI 1.269–7.322, p < 0.001; 3 points), arterial PH < 7.35 (OR 3.959, 95% CI 1.393–7.332, p < 0.001; 3 points), smoking history (OR 5.176, 95% CI 2.604–11.838, p = 0.001; 4 points), lymphocytes < 0.8 × 10(9)/L (OR 8.391, 95% CI 3.271–16.212, p < 0.001; 5 points), and early neurominidase inhibitor therapy (OR 0.567, 95% CI 0.202–0.833, p = 0.005; − 2 points). Seven points was used as the cut-off value for mortality risk stratification. The model showed a sensitivity of 0.941, a specificity of 0.762, and overall better predictive performance than the PSI risk class (AUROC = 0.908 vs 0.560, p < 0.001) and the CURB-65 score (AUROC = 0.908 vs 0.777, p < 0.001). CONCLUSIONS: Our results showed that a FluA-p score was easy to derive and that it served as a reliable prediction rule for 30-day mortality in FluA-p patients. The score could also effectively stratify FluA-p patients into relevant risk categories and thereby help treatment providers to make more rational clinical decisions.


title: Prehospital reversal of profound respiratory acidosis and hypercapnic coma by non-invasive ventilation: a report of two cases

text: BACKGROUND: In chronic obstructive pulmonary disease (COPD) patients with acute respiratory failure (ARF), non-invasive ventilation (NIV) is generally recommended and has proven its benefits by reducing endotracheal intubation (ETI) rates, intensive care unit (ICU) admissions, complications, and mortality. Choosing between immediate ETI or NIV trial is often difficult when such patients present with an altered mental status. Some guidelines recommend avoiding NIV when consciousness is impaired given the risk of aspiration, and some authors suggest that a pH < 7.25 is highly predictive of NIV failure. Though clinical response to a well-adjusted NIV treatment can be both swift and spectacular, these contraindications probably encourage physicians to proceed to immediate ETI. Some studies indeed report that NIV was not even considered in as many as 60% of patients who might have benefited from this therapy, though ETI related complications might have been avoided had NIV been successfully applied. CASE PRESENTATION: We report two cases of ARF in COPD patients who were successfully treated by NIV in prehospital setting and avoided ETI despite contraindications (altered mental status with a Glasgow Coma Scale < 8) and failure risk factors (severe respiratory acidosis with pH < 7.25). CONCLUSION: In COPD patients presenting ARF, NIV trial could be considered even when relative contraindications such as an altered level of consciousness or a severe respiratory acidosis are present.


title: Phenotypic heterogeneity by site of infection in surgical sepsis: a prospective longitudinal study

text: BACKGROUND: The role of site of infection in sepsis has been poorly characterized. Additionally, sepsis epidemiology has evolved. Early mortality has decreased, but many survivors now progress into chronic critical illness (CCI). This study sought to determine if there were significant differences in the host response and current epidemiology of surgical sepsis categorized by site of infection. STUDY DESIGN: This is a longitudinal study of surgical sepsis patients characterized by baseline predisposition, insult characteristics, serial biomarkers, hospital outcomes, and long-term outcomes. Patients were categorized into five anatomic sites of infection. RESULTS: The 316 study patients were predominantly Caucasian; half were male, with a mean age of 62 years, high comorbidity burden, and low 30-day mortality (10%). The primary sites were abdominal (44%), pulmonary (19%), skin/soft tissue (S/ST, 17%), genitourinary (GU, 12%), and vascular (7%). Most abdominal infections were present on admission and required source control. Comparatively, they had more prolonged proinflammation, immunosuppression, and persistent organ dysfunction. Their long-term outcome was poor with 37% CCI (defined as > 14 in ICU with organ dysfunction), 49% poor discharge dispositions, and 30% 1-year mortality. Most pulmonary infections were hospital-acquired pneumonia. They had similar protracted proinflammation and organ dysfunction, but immunosuppression normalized. Long-term outcomes are similarly poor (54% CCI, 47% poor disposition, 32% 1-year mortality). S/ST and GU infections occurred in younger patients with fewer comorbidities, less perturbed immune responses, and faster resolution of organ dysfunction. Comparatively, S/ST had better long-term outcomes (23% CCI, 39% poor disposition, 13% 1-year mortality) and GU had the best (10% CCI, 20% poor disposition, 10% 1-year mortality). Vascular sepsis patients were older males, with more comorbidities. Proinflammation was blunted with baseline immunosuppression and organ dysfunction that persisted. They had the worst long-term outcomes (38% CCI, 67% poor disposition, 57% 1-year mortality). CONCLUSION: There are notable differences in baseline predisposition, host responses, and clinical outcomes by site of infection in surgical sepsis. While previous studies have focused on differences in hospital mortality, this study provides unique insights into the host response and long-term outcomes associated with different sites of infection.


title: Propofol versus placebo (with rescue with ketamine) before less invasive surfactant administration: study protocol for a multicenter, double-blind, placebo controlled trial (PROLISA)

text: BACKGROUND: One major limitation for less invasive surfactant administration (LISA) is the difficulty in providing sedation before this procedure and the competitive risk of respiratory depression versus avoidance of intubation for most sedative or analgesic drugs used in this context. The objective of this study is to compare the need for mechanical ventilation within 72 h of life following premedication with propofol, versus placebo (rescue with ketamine), for the LISA procedure in preterm neonates born before 32 weeks gestational age (wGA). METHODS: ProLISA is a phase III, non-inferiority, multicenter, double blind, randomized, placebo controlled trial designed according to the SPIRIT Statement. Neonates born before 32 wGA in 12 geographically dispersed Neonatal Intensive Care Units in France needing surfactant will be included from September 2019 to September 2022. A sample of 542 patients is needed. The neonate is randomized to the intervention (propofol) or control placebo group. Open label rescue treatment with ketamine is possible in both groups if FANS (Faceless Acute Neonatal pain Scale) is ≥6. To guide drug administration, FANS is scored before attempting laryngoscopy. Once an adequate score has been obtained, LISA is performed according to a standardized protocol. The primary outcome is the need for mechanical ventilation within 72 h of life. Secondary outcomes are tolerance of the procedure, pain evaluation, hemodynamic and neurologic parameters after the intervention, morbidities before discharge and neurodevelopmental assessment at 2 years of age. DISCUSSION: This paper describes the first multicenter, double-blind, randomized, placebo-controlled trial on this topic and will provide crucial information to support implementation of the LISA procedure. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04016246. Registered 06 June 2019, N°EUDRACT: 2018–002876-41.


COVID-19 pandemic


title: Inhibition of complement pathway activation with Pozelimab, a fully human antibody to complement component C5

text: Complement is a key component of the innate immune system. Inappropriate complement activation underlies the pathophysiology of a variety of diseases. Complement component 5 (C5) is a validated therapeutic target for complement-mediated diseases, but the development of new therapeutics has been limited by a paucity of preclinical models to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) properties of candidate therapies. The present report describes a novel humanized C5 mouse and its utility in evaluating a panel of fully human anti-C5 antibodies. Surprisingly, humanized C5 mice revealed marked differences in clearance rates amongst a panel of anti-C5 antibodies. One antibody, pozelimab (REGN3918), bound C5 and C5 variants with high affinity and potently blocked complement-mediated hemolysis in vitro. In studies conducted in both humanized C5 mice and cynomolgus monkeys, pozelimab demonstrated prolonged PK and durable suppression of hemolytic activity ex vivo. In humanized C5 mice, a switch in dosing from in-house eculizumab to pozelimab was associated with normalization of serum C5 concentrations, sustained suppression of hemolytic activity ex vivo, and no overt toxicity. Our findings demonstrate the value of humanized C5 mice in identifying new therapeutic candidates and treatment options for complement-mediated diseases.


title: Changing care pathways and between-center practice variations in intensive care for traumatic brain injury across Europe: a CENTER-TBI analysis

text: PURPOSE: To describe ICU stay, selected management aspects, and outcome of Intensive Care Unit (ICU) patients with traumatic brain injury (TBI) in Europe, and to quantify variation across centers. METHODS: This is a prospective observational multicenter study conducted across 18 countries in Europe and Israel. Admission characteristics, clinical data, and outcome were described at patient- and center levels. Between-center variation in the total ICU population was quantified with the median odds ratio (MOR), with correction for case-mix and random variation between centers. RESULTS: A total of 2138 patients were admitted to the ICU, with median age of 49 years; 36% of which were mild TBI (Glasgow Coma Scale; GCS 13–15). Within, 72 h 636 (30%) were discharged and 128 (6%) died. Early deaths and long-stay patients (> 72 h) had more severe injuries based on the GCS and neuroimaging characteristics, compared with short-stay patients. Long-stay patients received more monitoring and were treated at higher intensity, and experienced worse 6-month outcome compared to short-stay patients. Between-center variations were prominent in the proportion of short-stay patients (MOR = 2.3, p < 0.001), use of intracranial pressure (ICP) monitoring (MOR = 2.5, p < 0.001) and aggressive treatments (MOR = 2.9, p < 0.001); and smaller in 6-month outcome (MOR = 1.2, p = 0.01). CONCLUSIONS: Half of contemporary TBI patients at the ICU have mild to moderate head injury. Substantial between-center variations exist in ICU stay and treatment policies, and less so in outcome. It remains unclear whether admission of short-stay patients represents appropriate prudence or inappropriate use of clinical resources. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00134-020-05965-z) contains supplementary material, which is available to authorized users.


title: A management algorithm for adult patients with both brain oxygen and intracranial pressure monitoring: the Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC)

text: BACKGROUND: Current guidelines for the treatment of adult severe traumatic brain injury (sTBI) consist of high-quality evidence reports, but they are no longer accompanied by management protocols, as these require expert opinion to bridge the gap between published evidence and patient care. We aimed to establish a modern sTBI protocol for adult patients with both intracranial pressure (ICP) and brain oxygen monitors in place. METHODS: Our consensus working group consisted of 42 experienced and actively practicing sTBI opinion leaders from six continents. Having previously established a protocol for the treatment of patients with ICP monitoring alone, we addressed patients who have a brain oxygen monitor in addition to an ICP monitor. The management protocols were developed through a Delphi-method-based consensus approach and were finalized at an in-person meeting. RESULTS: We established three distinct treatment protocols, each with three tiers whereby higher tiers involve therapies with higher risk. One protocol addresses the management of ICP elevation when brain oxygenation is normal. A second addresses management of brain hypoxia with normal ICP. The third protocol addresses the situation when both intracranial hypertension and brain hypoxia are present. The panel considered issues pertaining to blood transfusion and ventilator management when designing the different algorithms. CONCLUSIONS: These protocols are intended to assist clinicians in the management of patients with both ICP and brain oxygen monitors but they do not reflect either a standard-of-care or a substitute for thoughtful individualized management. These protocols should be used in conjunction with recommendations for basic care, management of critical neuroworsening and weaning treatment recently published in conjunction with the Seattle International Brain Injury Consensus Conference. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00134-019-05900-x) contains supplementary material, which is available to authorized users.


title: Sero-epidemiological study of the rotavirus VP8* protein from different P genotypes in Valencia, Spain

text: The aims of the present work were to determine the prevalence and titer of serum antibodies against several rotavirus VP8* proteins from different P genotypes in children and adults in Valencia, Spain; and to determine the role of the secretor status (FUT2(G428A) polymorphism) in the antibody response. The VP8* protein from the P[4], P[6], P[8], P[9], P[11], P[14] and P[25] genotypes were produced in E. coli. These proteins were tested with 88 serum samples from children (n = 41, 3.5 years old in average) and from adults (n = 47, 58 years old in average) by ELISA. A subset of 55 samples were genotyped for the FUT2(G428A) polymorphism and the antibody titers compared. The same subset of samples was also analysed by ELISA using whole rotavirus Wa particles (G1P[8]) as antigen. Ninety-three per cent of the samples were positive for at least one of the VP8* antigens. Differences in the IgG seroprevalence were found between children and adults for the P[4], P[8] and P[11] genotypes. Similarly, significant differences were found between adults and children in their antibody titers against the P[4], P[8], and P[11] VP8* genotypes, having the children higher antibody titers than adults. Interestingly, positive samples against rare genotypes such as P[11] (only in children), P[14] and P[25] were found. While no statistical differences in the antibody titers between secretors and non-secretors were found for any of the tested P genotypes studied, a higher statistic significant prevalence for the P[25] genotype was found in secretors compared to non-secretors. Significant differences in the antibody titers between secretors and non-secretors were found when the whole viral particles from the Wa rotavirus strain (G1P[8]) were used as the antigen.


title: Structural basis of transmembrane coupling of the HIV-1 envelope glycoprotein

text: The prefusion conformation of HIV-1 envelope protein (Env) is recognized by most broadly neutralizing antibodies (bnAbs). Studies showed that alterations of its membrane-related components, including the transmembrane domain (TMD) and cytoplasmic tail (CT), can reshape the antigenic structure of the Env ectodomain. Using nuclear magnetic resonance (NMR) spectroscopy, we determine the structure of an Env segment encompassing the TMD and a large portion of the CT in bicelles. The structure reveals that the CT folds into amphipathic helices that wrap around the C-terminal end of the TMD, thereby forming a support baseplate for the rest of Env. NMR dynamics measurements provide evidences of dynamic coupling across the TMD between the ectodomain and CT. Pseudovirus-based neutralization assays suggest that CT-TMD interaction preferentially affects antigenic structure near the apex of the Env trimer. These results explain why the CT can modulate the Env antigenic properties and may facilitate HIV-1 Env-based vaccine design.


Error in Discussion


title: Predicting the global mammalian viral sharing network using phylogeography

text: Understanding interspecific viral transmission is key to understanding viral ecology and evolution, disease spillover into humans, and the consequences of global change. Prior studies have uncovered macroecological drivers of viral sharing, but analyses have never attempted to predict viral sharing in a pan-mammalian context. Using a conservative modelling framework, we confirm that host phylogenetic similarity and geographic range overlap are strong, nonlinear predictors of viral sharing among species across the entire mammal class. Using these traits, we predict global viral sharing patterns of 4196 mammal species and show that our simulated network successfully predicts viral sharing and reservoir host status using internal validation and an external dataset. We predict high rates of mammalian viral sharing in the tropics, particularly among rodents and bats, and within- and between-order sharing differed geographically and taxonomically. Our results emphasize the importance of ecological and phylogenetic factors in shaping mammalian viral communities, and provide a robust, general model to predict viral host range and guide pathogen surveillance and conservation efforts.


title: Rapid colorimetric loop-mediated isothermal amplification for hypersensitive point-of-care Staphylococcus aureus enterotoxin A gene detection in milk and pork products

text: Staphylococcus aureus strains carrying enterotoxin A gene (sea) causes food poisoning and cannot be distinguished from non-pathogenic strains by the culture method. Here, we developed a rapid, specific and sensitive visual detection of sea using loop-mediated isothermal amplification (LAMP) combined with nanogold probe (AuNP) or styryl dye (STR). LAMP-AuNP and LAMP-STR can detect as low as 9.7 fg (3.2 sea copies) and 7.2 sea copies, respectively, which were lower than PCR (97 fg or 32 sea copies). The excellent performance of these new assays was demonstrated in food samples using crude DNA lysates. While the culture method detected 10(4) CFU/g in ground pork and 10 CFU/mL in milk in 5–7 days, LAMP-AuNP could detect down to 10 CFU/g for both samples in 27 minutes. Analyzing 80 pork and milk samples revealed that the LAMP-AuNP showed 100% sensitivity, 97–100% specificity and 97.5–100% accuracy, which were superior to the culture method, and comparable to PCR but without requirement of a thermal cycler. Furthermore, our LAMP-AuNP detect sea at a range below the food safety control (<100 CFU/g). The LAMP-STR quantitated sea in 10–1,000 CFU (7.2–720 copies). Our crude DNA lysis combined with LAMP-AuNP/STR present effective point-of-care detection and facilitate appropriate control strategies.


title: In Vivo Delivery of Nucleic Acid-Encoded Monoclonal Antibodies

text: Antibody immunotherapy is revolutionizing modern medicine. The field has advanced dramatically over the past 40 years, driven in part by major advances in isolation and manufacturing technologies that have brought these important biologics to the forefront of modern medicine. However, the global uptake of monoclonal antibody (mAb) biologics is impeded by biophysical and biochemical liabilities, production limitations, the need for cold-chain storage and transport, as well as high costs of manufacturing and distribution. Some of these hurdles may be overcome through transient in vivo gene delivery platforms, such as non-viral synthetic plasmid DNA and messenger RNA vectors that are engineered to encode optimized mAb genes. These approaches turn the body into a biological factory for antibody production, eliminating many of the steps involved in bioprocesses and providing several other significant advantages, and differ from traditional gene therapy (permanent delivery) approaches. In this review, we focus on nucleic acid delivery of antibody employing synthetic plasmid DNA vector platforms, and RNA delivery, these being important approaches that are advancing simple, rapid, in vivo expression and having an impact in animal models of infectious diseases and cancer, among others.


title: Cell-Free Protein Synthesis: A Promising Option for Future Drug Development

text: Proteins are the main source of drug targets and some of them possess therapeutic potential themselves. Among them, membrane proteins constitute approximately 50% of the major drug targets. In the drug discovery pipeline, rapid methods for producing different classes of proteins in a simple manner with high quality are important for structural and functional analysis. Cell-free systems are emerging as an attractive alternative for the production of proteins due to their flexible nature without any cell membrane constraints. In a bioproduction context, open systems based on cell lysates derived from different sources, and with batch-to-batch consistency, have acted as a catalyst for cell-free synthesis of target proteins. Most importantly, proteins can be processed for downstream applications like purification and functional analysis without the necessity of transfection, selection, and expansion of clones. In the last 5 years, there has been an increased availability of new cell-free lysates derived from multiple organisms, and their use for the synthesis of a diverse range of proteins. Despite this progress, major challenges still exist in terms of scalability, cost effectiveness, protein folding, and functionality. In this review, we present an overview of different cell-free systems derived from diverse sources and their application in the production of a wide spectrum of proteins. Further, this article discusses some recent progress in cell-free systems derived from Chinese hamster ovary and Sf21 lysates containing endogenous translocationally active microsomes for the synthesis of membrane proteins. We particularly highlight the usage of internal ribosomal entry site sequences for more efficient protein production, and also the significance of site-specific incorporation of non-canonical amino acids for labeling applications and creation of antibody drug conjugates using cell-free systems. We also discuss strategies to overcome the major challenges involved in commercializing cell-free platforms from a laboratory level for future drug development.


Mitteilungen des BDI


title: Direct RNA Sequencing for the Study of Synthesis, Processing, and Degradation of Modified Transcripts

text: It has been known for a few decades that transcripts can be marked by dozens of different modifications. Yet, we are just at the beginning of charting these marks and understanding their functional impact. High-quality methods were developed for the profiling of some of these marks, and approaches to finely study their impact on specific phases of the RNA life-cycle are available, including RNA metabolic labeling. Thanks to these improvements, the most abundant marks, including N(6)-methyladenosine, are emerging as important determinants of the fate of marked RNAs. However, we still lack approaches to directly study how the set of marks for a given RNA molecule shape its fate. In this perspective, we first review current leading approaches in the field. Then, we propose an experimental and computational setup, based on direct RNA sequencing and mathematical modeling, to decipher the functional consequences of RNA modifications on the fate of individual RNA molecules and isoforms.


Editorial: Immunopathology of Chronic Bacterial and Viral Diseases Prevalent in Latin America


title: Practical Considerations When Performing Neurodiagnostic Studies on Patients with COVID-19 and Other Highly Virulent Diseases.

text: The coronavirus disease 2019, SARS-COV-2 (the cause of COVID-19), has led to a worldwide shortage of personal protective equipment (PPE) and an increased stress on hospital resources, which has resulted in a spike in the anxiety of the frontline healthcare workers. News reports and information about the virus are rapidly changing. We present a case of a patient with COVID-19 who had a seizure-like spell for which an EEG was performed. In early to mid-March, there were no clear guidelines or recommendations available from neurodiagnostic-related organizations or hospitals on how to adapt procedure workflow to those with COVID-19. When caring for COVID-19 patients, as when caring for any patient with an infectious disease, it is hospital protocol to follow contact, droplet/airborne precautions by wearing appropriate PPE. However, because we knew very little about the coronavirus, this case was different. In this article, we discuss our experience with our EEG workflow and concerns for staff exposure. We then discuss our adaptations and modifications to our standard procedures and protocols. A time analysis comparing our standard EEG protocol with our modified COVID-19 protocol revealed a significant decrease in technologist exposure time (99 minutes versus 51 minutes), which theoretically would reduce the chance of virus transmission to our technologist. At this critical moment in time, we hope such modifications will allow us to continue delivering high quality patient care while optimizing resource utilization and above all keeping our technologists safe.


docid: kvmjkknp

title: Diverse CD8 T Cell Responses to Viral Infection Revealed by the Collaborative Cross

text: Enhanced host protection against re-infection requires generation of memory T cells of sufficient quantity and functional quality. Unlike well-studied inbred mice, T cell responses of diverse size and quality are generated following infection of humans and outbred mice. Thus, additional models are needed that accurately reflect variation in immune outcomes in genetically diverse populations and to uncover underlying genetic causes. The Collaborative Cross (CC), a large recombinant inbred panel of mice, is an ideal model in this pursuit for the high degree of genetic variation present, because it allows for assessment of genetic factors underlying unique phenotypes. Here, we advance the utility of the CC as a tool to analyze the immune response to viral infection. We describe variability in resting immune cell composition and adaptive immune responses generated among CC strains following systemic virus infection and reveal quantitative trait loci responsible for generation of CD62L+ memory CD8 T cells.


Primum non nocere


title: Mesenchymal stem/stromal cells: the therapeutic effects in animal models of acute pulmonary diseases

text: The pulmonary diseases are one of the most important causes of death in the world. The successful therapies in the field of lung diseases are very limited and the medical treatments available are ineffective in many of the lung diseases. Many studies have evaluated the new therapies in the acute pulmonary diseases, and the transplantation of mesenchymal stem/stromal cells (MSCs), which is a branch of cell therapy, has a special place among the new medical techniques. The MSCs are present throughout the body and are thought to play a role in tissue regeneration and inflammation control. In the event of injury, the local MSCs traverse the shortest possible distance from the tissue or blood vessels to reach the affected site. But, there are few undifferentiated cells in the tissues. The exogenous MSCs are used to immunity modify or regenerative treatments in preclinical models of acute pulmonary diseases. Several studies have shown the positive effects of MSCs replacement in the acute lung disorders. The effection mechanism of the MSCs include the differentiation ability and the secretion of paracrine agents such as the anti-inflammatory mediators. Many studies suggest that this treatment method is safe and is probably to be widely used in future clinical trials. This review will describe the therapeutic effects of the MSCs in the experimental models of the acute pulmonary diseases for use as a method of treatment in clinical trials in future.


From severe acute respiratory syndrome-associated coronavirus to 2019 novel coronavirus outbreak: similarities in the early epidemics and prediction of future trends


title: Synthetic strategies, SAR studies, and computer modeling of indole 2 and 3-carboxamides as the strong enzyme inhibitors: a review

text: ABSTRACT: Indole derivatives have been the focus of many researchers in the study of pharmaceutical compounds for many years. Researchers have investigated the effect of carboxamide moiety at positions 2 and 3, giving unique inhibitory properties to these compounds. The presence of carboxamide moiety in indole derivatives causes hydrogen bonds with a variety of enzymes and proteins, which in many cases, inhibits their activity. In this review, synthetic strategies of indole 2 and 3-carboxamide derivatives, the type, and mode of interaction of these derivatives against HLGP, HIV-1, renin enzyme, and structure–activity studies of these compounds were investigated. It is hoped that indole scaffolds will be tested in the future for maximum activity in pharmacological compounds. GRAPHIC ABSTRACT: [Image: see text]


title: Association between risk factors of metabolic syndrome with lung function

text: BACKGROUND/OBJECTIVES: Increased evidence suggests that metabolic syndrome (MetS) is correlated with lung function impairment. This study aimed to explore the associations between MetS risk factors and the lung function. SUBJECTS/METHODS: The cross-sectional study included 6945 participants attending health examination between 2010 and 2012 in Taiwan. MetS was assessed according to the criteria of National Cholesterol Education Program III. Spirometric parameters were measured to define lung function. The relationships were tested using multiple linear regression and logistic regression analyses. RESULTS: The prevalence of MetS was significantly higher in males (16.2%) than females (3.8%). Although the prevalence of restrictive lung disease (RLD) was comparable between genders (20.7 and 21.0%), males with co-existent MetS had a higher prevalence of RLD than females (27.4 vs. 18.0%). Abdominal obesity, indicated by waist circumference (WC) and weight-to-height ratio (WHtR), was the most significant factor associated with lung function decline. Other components of MetS also showed statistically significant relationships, but very weak, with lung function. There was a trend toward an increased prevalence of RLD with the increasing number of MetS scores in males, independent of age, smoking, and body mass index. CONCLUSIONS: Abdominal obesity was the key component of MetS associated with mechanical effect on lung function impairment in a prime-age adult population. Although RLD was not associated with increased probability of having MetS, the participants with more MetS scores were at a higher risk of losing lung function.


docid: eltzjhgq

title: Sans-abri, sans-papiers et confinés ?


title: A deubiquitylase with an unusually high-affinity ubiquitin-binding domain from the scrub typhus pathogen Orientia tsutsugamushi

text: Ubiquitin mediated signaling contributes critically to host cell defenses during pathogen infection. Many pathogens manipulate the ubiquitin system to evade these defenses. Here we characterize a likely effector protein bearing a deubiquitylase (DUB) domain from the obligate intracellular bacterium Orientia tsutsugamushi, the causative agent of scrub typhus. The Ulp1-like DUB prefers ubiquitin substrates over ubiquitin-like proteins and efficiently cleaves polyubiquitin chains of three or more ubiquitins. The co-crystal structure of the DUB (OtDUB) domain with ubiquitin revealed three bound ubiquitins: one engages the S1 site, the second binds an S2 site contributing to chain specificity and the third binds a unique ubiquitin-binding domain (UBD). The UBD modulates OtDUB activity, undergoes a pronounced structural transition upon binding ubiquitin, and binds monoubiquitin with an unprecedented ~5 nM dissociation constant. The characterization and high-resolution structure determination of this enzyme should aid in its development as a drug target to counter Orientia infections.


title: NLRP6 Plays an Important Role in Early Hepatic Immunopathology Caused by Schistosoma mansoni Infection

text: Schistosomiasis is a debilitating parasitic disease that affects more than 200 million people worldwide and causes approximately 280,000 deaths per year. Inside the definitive host, eggs released by Schistosoma mansoni lodge in the intestine and especially in the liver where they induce a granulomatous inflammatory process, which can lead to fibrosis. The molecular mechanisms initiating or promoting hepatic granuloma formation remain poorly understood. Inflammasome activation has been described as an important pathway to induce pathology mediated by NLRP3 receptor. Recently, other components of the inflammasome pathway, such as NLRP6, have been related to liver diseases and fibrotic processes. Nevertheless, the contribution of these components in schistosomiasis-associated pathology is still unknown. In the present study, using dendritic cells, we demonstrated that NLRP6 sensor is important for IL-1β production and caspase-1 activation in response to soluble egg antigens (SEA). Furthermore, the lack of NLRP6 has been shown to significantly reduce periovular inflammation, collagen deposition in hepatic granulomas and mRNA levels of α-SMA and IL-13. Livers of Nlrp6(–/–) mice showed reduced levels of CXCL1/KC, CCL2, CCL3, IL-5, and IL-10 as well as Myeloperoxidase (MPO) and Eosinophilic Peroxidase (EPO) enzymatic activity. Consistently, the frequency of macrophage and neutrophil populations were lower in the liver of NLRP6 knockout mice, after 6 weeks of infection. Finally, it was further demonstrated that the onset of hepatic granuloma and collagen deposition were also compromised in Caspase-1(–/–), IL-1R(–/–) and Gsdmd(–/–) mice. Our findings suggest that the NLRP6 inflammasome is an important component for schistosomiasis-associated pathology.


title: The Impact of Non-optimum Ambient Temperature on Years of Life Lost: A Multi-county Observational Study in Hunan, China

text: The ambient temperature–health relationship is of growing interest as the climate changes. Previous studies have examined the association between ambient temperature and mortality or morbidity, however, there is little literature available on the ambient temperature effects on year of life lost (YLL). Thus, we aimed to quantify the YLL attributable to non-optimum ambient temperature. We obtained data from 1 January 2013 to 31 December 2017 of 70 counties in Hunan, China. In order to combine the effects of each county, we used YLL rate as a health outcome indicator. The YLL rate was equal to the total YLL divided by the population of each county, and multiplied by 100,000. We estimated the associations between ambient temperature and YLL with a distributed lag non-linear model (DNLM) in a single county, and then pooled them in a multivariate meta-regression. The daily mean YLL rates were 22.62 y/(p·100,000), 10.14 y/(p·100,000) and 2.33 y/(p·100,000) within the study period for non-accidental, cardiovascular, and respiratory disease death. Ambient temperature was responsible for advancing a substantial fraction of YLL, with attributable fractions of 10.73% (4.36–17.09%) and 16.44% (9.09–23.79%) for non-accidental and cardiovascular disease death, respectively. However, the ambient temperature effect was not significantly for respiratory disease death, corresponding to 5.47% (−2.65–13.60%). Most of the YLL burden was caused by a cold temperature than the optimum temperature, with an overall estimate of 10.27% (4.52–16.03%) and 15.94% (8.82–23.05%) for non-accidental and cardiovascular disease death, respectively. Cold and heat temperature-related YLLs were higher in the elderly and females than the young and males. Extreme cold temperature had an effect on all age groups in different kinds of disease-caused death. This study highlights that general preventative measures could be important for moderate temperatures, whereas quick and effective measures should be provided for extreme temperatures.


title: The burden of laboratory-confirmed influenza infection in Lebanon between 2008 and 2016: a single tertiary care center experience

text: BACKGROUND: Influenza is a major cause of morbidity and mortality worldwide. Following the 2009 pandemic, there was widened interest in studying influenza burden in all regions. However, since data from the World Health Organization (WHO) Middle East and North Africa (MENA) region remain limited, we aimed to contribute to the understanding of influenza burden in Lebanon. METHODS: A retrospective chart review extending over a period of 8 seasons from Jan 1st, 2008 till June 30th, 2016 at a tertiary care center in Beirut was performed. All cases confirmed to have influenza based on rapid antigen detection or/and polymerase chain reaction on a respiratory sample were included for analysis. Data on epidemiology, clinical presentation, complications, antiviral use and mortality were collected for analysis. RESULTS: A total of 1829 cases of laboratory-confirmed influenza were identified. Average annual positivity rate was 14% (positive tests over total requested). Both influenza A and B co-circulated in each season with predominance of influenza A. Influenza virus started circulating in December and peaked in January and February. The age group of 19–50 years accounted for the largest proportion of cases (22.5%) followed by the age group of 5–19 years (18%). Pneumonia was the most common complication reported in 33% of cases. Mortality reached 3.8%. The two extremes of age (< 2 years and ≥ 65 years) were associated with a more severe course of disease, hospitalization, intensive care unit (ICU) admission, complications, and mortality rate. Of all the identified cases, 26% were hospitalized. Moderate-to-severe disease was more likely in influenza B cases but no difference in mortality was reported between the two types. Antivirals were prescribed in 68.8% and antibiotics in 41% of cases. There seemed to be an increasing trend in the number of diagnosed and hospitalized cases over the years of the study. CONCLUSION: Patients with laboratory-confirmed influenza at our center had a high rate of hospitalization and mortality. A population based prospective surveillance study is needed to better estimate the burden of Influenza in Lebanon that would help formulate a policy on influenza control.


title: First Molecular Identification of Canine Parvovirus Type 2 (CPV2) in Chile Reveals High Occurrence of CPV2c Antigenic Variant

text: Canine parvovirus type 2 (CPV2) is one of the most important intestinal pathogens in dogs and puppies. CPV2 has been evolved into three genetic and antigenic variants (2a, 2b, and 2c), which are distributed worldwide. We reported the first study of genetic diversity of CPV2 in Chile. Sixty-five samples were collected from puppies presenting with severe gastroenteritis and different vaccination statuses. PCR, restriction fragment length polymorphism (RFLP), and partial sequencing of the coding region of the structural viral protein VP2 was performed. Thirty of a total of 65 samples tested positive by PCR out of which 19 were further classified as CPV2c and one as CPV2a using RFLP and Sanger sequencing. The phylogeny was in concordance with the RFLP analysis. This is the first report of the genetic characterization of CPV2 in Chile and reveals a high occurrence of CPV2c.


title: Pulmonary complications associated with veno-arterial extra-corporeal membrane oxygenation: a comprehensive review

text: Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a life-saving technology that provides transient respiratory and circulatory support for patients with profound cardiogenic shock or refractory cardiac arrest. Among its potential complications, VA-ECMO may adversely affect lung function through various pathophysiological mechanisms. The interaction of blood components with the biomaterials of the extracorporeal membrane elicits a systemic inflammatory response which may increase pulmonary vascular permeability and promote the sequestration of polymorphonuclear neutrophils within the lung parenchyma. Also, VA-ECMO increases the afterload of the left ventricle (LV) through reverse flow within the thoracic aorta, resulting in increased LV filling pressure and pulmonary congestion. Furthermore, VA-ECMO may result in long-standing pulmonary hypoxia, due to partial shunting of the pulmonary circulation and to reduced pulsatile blood flow within the bronchial circulation. Ultimately, these different abnormalities may result in a state of persisting lung inflammation and fibrotic changes with concomitant functional impairment, which may compromise weaning from VA-ECMO and could possibly result in long-term lung dysfunction. This review presents the mechanisms of lung damage and dysfunction under VA-ECMO and discusses potential strategies to prevent and treat such alterations.


title: Multi-task learning sparse group lasso: a method for quantifying antigenicity of influenza A(H1N1) virus using mutations and variations in glycosylation of Hemagglutinin

text: BACKGROUND: In addition to causing the pandemic influenza outbreaks of 1918 and 2009, subtype H1N1 influenza A viruses (IAVs) have caused seasonal epidemics since 1977. Antigenic property of influenza viruses are determined by both protein sequence and N-linked glycosylation of influenza glycoproteins, especially hemagglutinin (HA). The currently available computational methods are only considered features in protein sequence but not N-linked glycosylation. RESULTS: A multi-task learning sparse group least absolute shrinkage and selection operator (LASSO) (MTL-SGL) regression method was developed and applied to derive two types of predominant features including protein sequence and N-linked glycosylation in hemagglutinin (HA) affecting variations in serologic data for human and swine H1N1 IAVs. Results suggested that mutations and changes in N-linked glycosylation sites are associated with the rise of antigenic variants of H1N1 IAVs. Furthermore, the implicated mutations are predominantly located at five reported antibody-binding sites, and within or close to the HA receptor binding site. All of the three N-linked glycosylation sites (i.e. sequons NCSV at HA 54, NHTV at HA 125, and NLSK at HA 160) identified by MTL-SGL to determine antigenic changes were experimentally validated in the H1N1 antigenic variants using mass spectrometry analyses. Compared with conventional sparse learning methods, MTL-SGL achieved a lower prediction error and higher accuracy, indicating that grouped features and MTL in the MTL-SGL method are not only able to handle serologic data generated from multiple reagents, supplies, and protocols, but also perform better in genetic sequence-based antigenic quantification. CONCLUSIONS: In summary, the results of this study suggest that mutations and variations in N-glycosylation in HA caused antigenic variations in H1N1 IAVs and that the sequence-based antigenicity predictive model will be useful in understanding antigenic evolution of IAVs.


title: Cervical and oral human papillomavirus infection in women living with human immunodeficiency virus (HIV) and matched HIV-negative controls in Brazil

text: BACKGROUND: Despite the demonstrated role of human Papillomavirus (HPV) in the etiology of cervical cancer and the strong evidence suggesting the importance of HPV in the development of oropharyngeal cancer, several aspects of the interrelationship between HPV infection in both body sites remain unknown, specifically in female human immunodeficiency virus (HIV)-positive (HIV+) patients. We aimed to assess the prevalence, distribution, and concordance of cervical and oral HPV in HIV+ women and matched HIV-negative (HIV-) controls in Brazil. MATERIAL AND METHODS: Cervical and endocervical samples for cytological screening and HPV detection and oral samples were collected from 115 HIV+ women using highly active antiretroviral therapy (HAART) and 139 HIV-matched controls (HIV-) in Maringá City, Brazil. Risk factors were assessed using a standardized questionnaire, and the data regarding HIV infection were obtained from the patients’ medical records. HPV detection and typing were performed using the Kit Multiplex XGEN Multi HPV Chip HS12. RESULTS: HIV infection was well controlled in this cohort, but women who exhibited detectable HIV loads were significantly associated with HPV-positive status overall (P = 0.03) and in cervical mucosa (P = 0.01). HIV+ women had significantly more abnormal cytological findings (P = 0.04) than HIV- women. Of the 115 HIV+ women, 48.7% were positive for cervical and/or oral HPV DNA; of the 139 HIV- women, 41% were positive for cervical and/or oral HPV (P = 0.25). Both HIV+ and HIV- women had a statistically higher prevalence of cervical HPV infection than oral infection. The concurrent HPV infection in two anatomical sites was similar in HIV+ and HIV- women; however, HPV type concordance was not observed. HPV type distribution was different between the anatomical sites in both groups, and HIV+ women presented less common types, mainly in oral mucosa. CONCLUSION: Our data support the importance of testing HPV infection in HIV+ women, even when the HIV infection is well controlled. Prospective studies are required to better understand the natural history of HPV infection in both anatomical sites, specifically in HIV+ women.


title: Brain natriuretic peptide to predict successful liberation from mechanical ventilation in critically ill patients: a systematic review and meta-analysis

text: BACKGROUND: Predicting successful liberation from mechanical ventilation (MV) in critically ill patients is challenging. Brain natriuretic peptide (BNP) has been proposed to help guide decision-making for readiness to liberate from MV following a spontaneous breathing trial (SBT). METHODS: We performed a systematic review and meta-analysis of randomized and prospective observational studies that measured BNP levels at the time of SBT in patients receiving MV. The primary endpoint was successful liberation from MV (absence of reintubation or non-invasive ventilation at 48 h). Statistical analyses included bi-variate and Moses-Littenberg models and DerSimonian-Laird pooling of areas under ROC curve (AUROC). RESULTS: A total of 731 articles were screened. Eighteen adult and 2 pediatric studies were fulfilled pre-specified eligibility. The measure of the relative variation of BNP during SBT (ΔBNP%) after exclusion of SBT failure by clinical criteria in adults yielded a sensitivity and specificity of 0.889 [0.831–0.929] and 0.828 [0.730–0.896] for successful liberation from MV, respectively, with a pooled AUROC of 0.92 [0.88–0.97]. The pooled AUROC for any method of analysis for absolute variation of BNP (ΔBNP), pre-SBT BNP, and post-SBT BNP were 0.89 [0.83–0.95], 0.77 [0.63–0.91], and 0.85 [0.80–0.90], respectively. CONCLUSION: The relative change in BNP during a SBT has potential value as an incremental tool after successful SBT to predict successful liberation from MV in adults. There is insufficient data to support the use of BNP in children or as an alternate test to clinical indices of SBT, or the use of ΔBNP, BNP-pre, and BNP-post as an alternate or incremental test. TRIAL REGISTRATION: PROSPERO CRD42018087474 (6 February 2018)


title: Neue intensivmedizinische Herausforderungen durch Klimawandel und globale Erderwärmung

text: BACKGROUND: In the last five decades a continuous increase in the average global temperature has been recorded. Furthermore, natural disasters (e.g. heat waves, severe storms, floods and large forest fires) are becoming more frequent. The impact of global warming and climate change on health involves an increase in respiratory, cardiovascular, renal and cognitive mental diseases. Furthermore, a change in the frequency and patterns of infectious diseases can also be observed in Europe. MATERIAL AND METHODS: This article presents the most important studies that investigated diseases associated with the climate change, with special reference to those that represent a challenge for intensive care medicine. RESULTS: Currently available epidemiological data and statistical extrapolations indicate that diseases resulting from the climate change (acute infection-related respiratory and intestinal diseases, exacerbation of pre-existing pulmonary lesions, heat-related dehydration, cerebral insults and myocardial infarction) are relevant for intensive care medicine. Particular emphasis is placed on a significant increase in acute kidney damage during heat waves. A previously unknown pattern of infectious diseases necessitates new knowledge and targeted management. In some studies, persisting mental impairments were registered during heat waves and natural disasters, e.g. posttraumatic stress disorder. CONCLUSION: Intensive care medicine must be prepared for the challenges due to global warming and climate change. Slow but continuous changes (e.g. rise in temperature) as well as acute changes (e.g. heat waves and natural disasters) will induce an increased need for intensive medical care services (e.g. an increase in the need for renal replacement procedures). Intensive care physicians will need to be familiar with the diagnostics and management of diseases associated with the climate change. An initiative of the specialist societies involved would be welcomed.


Triaging Telehealth in Wound Care: Embracing the Regulations within Your Workflows


title: Inherited Thoracic Aortic Disease: New Insights and Translational Targets

text: Inherited thoracic aortopathies denote a group of congenital conditions that predispose to disease of the thoracic aorta. Aortic wall weakness and abnormal aortic hemodynamic profiles predispose these patients to dilatation of the thoracic aorta, which is generally silent but can precipitate aortic dissection or rupture with devastating and often fatal consequences. Current strategies to assess the future risk of aortic dissection or rupture are based primarily on monitoring aortic diameter. However, diameter alone is a poor predictor of risk, with many patients experiencing dissection or rupture below current intervention thresholds. Developing tools that improve the risk assessment of those with aortopathy is internationally regarded as a research priority. A robust understanding of the molecular pathways that lead to aortic wall weakness is required to identify biomarkers and therapeutic targets that could improve patient management. Here, we summarize the current understanding of the genetically determined mechanisms underlying inherited aortopathies and critically appraise the available blood biomarkers, imaging techniques, and therapeutic targets that have shown promise for improving the management of patients with these important and potentially fatal conditions.


title: Differential expression of interferon-lambda receptor 1 splice variants determines the magnitude of the antiviral response induced by interferon-lambda 3 in human immune cells

text: Type III interferons (IFN-lambdas(λ)) are important cytokines that inhibit viruses and modulate immune responses by acting through a unique IFN-λR1/IL-10RB heterodimeric receptor. Until now, the primary antiviral function of IFN-λs has been proposed to be at anatomical barrier sites. Here, we examine the regulation of IFN-λR1 expression and measure the downstream effects of IFN-λ3 stimulation in primary human blood immune cells, compared with lung or liver epithelial cells. IFN-λ3 directly bound and upregulated IFN-stimulated gene (ISG) expression in freshly purified human B cells and CD8(+) T cells, but not monocytes, neutrophils, natural killer cells, and CD4(+) T cells. Despite similar IFNLR1 transcript levels in B cells and lung epithelial cells, lung epithelial cells bound more IFN-λ3, which resulted in a 50-fold greater ISG induction when compared to B cells. The reduced response of B cells could be explained by higher expression of the soluble variant of IFN-λR1 (sIFN-λR1), which significantly reduced ISG induction when added with IFN-λ3 to peripheral blood mononuclear cells or liver epithelial cells. T-cell receptor stimulation potently, and specifically, upregulated membrane-bound IFNLR1 expression in CD4(+) T cells, leading to greater antiviral gene induction, and inhibition of human immunodeficiency virus type 1 infection. Collectively, our data demonstrate IFN-λ3 directly interacts with the human adaptive immune system, unlike what has been previously shown in published mouse models, and that type III IFNs could be potentially utilized to suppress both mucosal and blood-borne viral infections.


title: Dynamical correlations and pairwise theory for the symbiotic contact process on networks

text: The two-species symbiotic contact process (2SCP) is a stochastic process in which each vertex of a graph may be vacant or host at most one individual of each species. Vertices with both species have a reduced death rate, representing a symbiotic interaction, while the dynamics evolves according to the standard (single species) contact process rules otherwise. We investigate the role of dynamical correlations on the 2SCP on homogeneous and heterogeneous networks using pairwise mean-field theory. This approach is compared with the ordinary one-site theory and stochastic simulations. We show that our approach significantly outperforms the one-site theory. In particular, the stationary state of the 2SCP model on random regular networks is very accurately reproduced by the pairwise mean-field, even for relatively small values of vertex degree, where expressive deviations of the standard mean-field are observed. The pairwise approach is also able to capture the transition points accurately for heterogeneous networks and provides rich phase diagrams with transitions not predicted by the one-site method. Our theoretical results are corroborated by extensive numerical simulations.


title: Role of structural holes in containing spreading processes

text: Structural holes are channels or paths spanned by a group of indirectly connected nodes and their intermediary in a network. In this work we emphasize the interesting role of structural holes as brokers for information propagation. Based on the distribution of the structural hole numbers associated with each node, we propose a simple yet effective approach for choosing the most influential nodes to immunize in containing the spreading processes. Using a wide spectrum of large real-world networks, we demonstrate that the proposed approach outperforms conventional methods in a remarkable way. In particular, we find that the performance gains of our approach are particularly prominent for networks with high transitivity and assortativity, which verifies the vital role of structural holes in information diffusion on networked systems.


title: Collective versus hub activation of epidemic phases on networks

text: We consider a general criterion to discern the nature of the threshold in epidemic models on scale-free (SF) networks. Comparing the epidemic lifespan of the nodes with largest degrees with the infection time between them, we propose a general dual scenario, in which the epidemic transition is either ruled by a hub activation process, leading to a null threshold in the thermodynamic limit, or given by a collective activation process, corresponding to a standard phase transition with a finite threshold. We validate the proposed criterion applying it to different epidemic models, with waning immunity or heterogeneous infection rates in both synthetic and real SF networks. In particular, a waning immunity, irrespective of its strength, leads to collective activation with finite threshold in scale-free networks with large degree exponent, at odds with canonical theoretical approaches.


title: Intervention threshold for epidemic control in susceptible-infected-recovered metapopulation models

text: Metapopulation epidemic models describe epidemic dynamics in networks of spatially distant patches connected via pathways for migration of individuals. In the present study, we deal with a susceptible-infected-recovered (SIR) metapopulation model where the epidemic process in each patch is represented by an SIR model and the mobility of individuals is assumed to be a homogeneous diffusion. We consider two types of patches including high-risk and low-risk ones under the assumption that a local patch is changed from a high-risk one to a low-risk one by an intervention. We theoretically analyze the intervention threshold which indicates the critical fraction of low-risk patches for preventing a global epidemic outbreak. We show that an intervention targeted to high-degree patches is more effective for epidemic control than a random intervention. The theoretical results are validated by Monte Carlo simulations for synthetic and realistic scale-free patch networks. The theoretical results also reveal that the intervention threshold depends on the human mobility network and the mobility rate. Our approach is useful for exploring better local interventions aimed at containment of epidemics.


title: Traffic-driven epidemic spreading in multiplex networks

text: Recent progress on multiplex networks has provided a powerful way to abstract the diverse interaction of a network system with multiple layers. In this paper, we show that a multiplex structure can greatly affect the spread of an epidemic driven by traffic dynamics. One of the interesting findings is that the multiplex structure could suppress the outbreak of an epidemic, which is different from the typical finding of spread dynamics in multiplex networks. In particular, one layer with dense connections can attract more traffic flow and eventually suppress the epidemic outbreak in other layers. Therefore, the epidemic threshold will be larger than the minimal threshold of the layers. With a mean-field approximation, we provide explicit expressions for the epidemic threshold and for the onset of suppressing epidemic spreading in multiplex networks. We also provide the probability of obtaining a multiplex configuration that suppresses the epidemic spreading when the multiplex is composed of: (i) two Erdős-Rényi layers and (ii) two scale-free layers. Therefore, compared to the situation of an isolated network in which a disease may be able to propagate, a larger epidemic threshold can be found in multiplex structures.