title: Association of Burnout with Emotional Coping Strategies, Friendship, and Institutional Support Among Internal Medicine Physicians

text: Physician burnout influences physician mental health, staff stress, safety events, and patient outcomes. The association of burnout with compassion satisfaction, secondary stress, emotional coping strategies and many psychosocial variables, such as institutional support, friendship, and spirituality, have not been well studied. A convenience sample of internal medicine physicians was emailed a survey using validated instruments to explore these associations. The response rate was 337/1021 (33%), with a burnout prevalence of 175/337 (52%). Grit, acceptance, active coping, positive reframing, and strategy planning were associated with lower burnout domains and greater compassion satisfaction. Certain emotional coping strategies such as denial, disengagement, self-blame, substance abuse, and venting were associated with greater burnout and lower compassion satisfaction. Greater institutional support was associated with lower burnout (r = − .35, p < .001), secondary stress (r = − .14, p < .05), and compassion satisfaction (r = .28, p < .0001). Friendship was associated with lower burnout (r = − .25, p < .0001) and greater compassion satisfaction (r = .28, p < .0001). This study suggests that amelioration of burnout requires both intrinsic strategies that emphasize physician coping skills as well as extrinsic strategies that address institutional support.


title: Multiple arboviral infections during a DENV-2 outbreak in Solomon Islands

text: BACKGROUND: Solomon Islands, a country made up of tropical islands, has suffered cyclic dengue fever (DF) outbreaks in the past three decades. An outbreak of dengue-like illness (DLI) that occurred in April 2016 prompted this study, which aimed to determine the population’s immunity status and identify the arboviruses circulating in the country. METHODS: A household survey, involving 188 participants in two urban areas (Honiara and Gizo), and a parallel hospital-based clinical survey were conducted in April 2016. The latter was repeated in December after a surge in DLI cases. Arbovirus IgG ELISA were performed on the household blood samples to determine the prevalence of arboviruses in the community, while qPCR testing of the clinical samples was used to identify the circulating arboviruses. Dengue virus (DENV)-positive samples were further characterized by amplifying and sequencing the envelope gene. RESULTS: The overall prevalence rates of DENV, Zika virus, and chikungunya virus were 83.4%, 7.6%, and 0.9%, respectively. The qPCR positivity rates of the clinical samples collected in April 2016 were as follows: DENV 39.6%, Zika virus 16.7%, and chikungunya virus 6.3%, which increased to 74%, 48%, and 20% respectively in December 2016. The displacement of the circulating serotype-3, genotype-1, with DENV serotype 2, genotype cosmopolitan was responsible for the outbreak in 2016. CONCLUSIONS: A DENV outbreak in Solomon Islands was caused by the introduction of a single serotype. The high prevalence of DENV provided transient cross-protection, which prevented the introduction of a new serotype from the hyperendemic region for at least 3 years. The severe outcomes seen in the recent outbreak probably resulted from changes in the causative viruses and the effects of population immunity and changes in the outbreak pattern. Solomon Islands needs to step up surveillance to include molecular tools, increase regional communication, and perform timely interventions.


title: P1′ Residue-Oriented Virtual Screening for Potent and Selective Phosphinic (Dehydro) Dipeptide Inhibitors of Metallo-Aminopeptidases

text: Designing side chain substituents complementary to enzyme binding pockets is of great importance in the construction of potent and selective phosphinic dipeptide inhibitors of metallo-aminopeptidases. Proper structure selection makes inhibitor construction more economic, as the development process typically consists of multiple iterative preparation/bioassay steps. On the basis of these principles, using noncomplex computation and modeling methodologies, we comprehensively screened 900 commercial precursors of the P1′ residues of phosphinic dipeptide and dehydrodipeptide analogs to identify the most promising ligands of 52 metallo-dependent aminopeptidases with known crystal structures. The results revealed several nonproteinogenic residues with an improved energy of binding compared with the best known inhibitors. The data are discussed taking into account the selectivity and stereochemical implications of the enzymes. Using this approach, we were able to identify nontrivial structural elements substituting the recognized phosphinic peptidomimetic scaffold of metallo-aminopeptidase inhibitors.


title: A High-Throughput Single-Clone Phage Fluorescence Microwell Immunoassay and Laser-Driven Clonal Retrieval System

text: Phage display is one of the most frequently used platform technologies utilized to screen and select therapeutic antibodies, and has contributed to the development of more than 10 therapeutic antibodies used in the clinic. Despite advantages like efficiency and low cost, it has intrinsic technical limitations, such as the asymmetrical amplification of the library after each round of biopanning, which is regarded as a reason for it yielding a very limited number of antigen binders. In this study, we developed a high-throughput single-clonal screening system comprised of fluorescence immunoassays and a laser-driven clonal DNA retrieval system using microchip technology. Using this system, from a single-chain variable fragment (scFv) library displayed on phages with a complexity of 5.21 × 10(5) harboring random mutations at five amino acid residues, more than 70,000 clones—corresponding to ~14% of the library complexity—were screened, resulting in 78 antigen-reactive scFv sequences with mutations restricted to the randomized residues. Our results demonstrate that this system can significantly reduce the number of biopanning rounds, or even eliminate the need for this process for libraries with lower complexity, providing an opportunity to obtain more diverse clones from the library.


title: Novel Abs targeting the N‐terminus of fibroblast growth factor 19 inhibit hepatocellular carcinoma growth without bile‐acid‐related side‐effects

text: Hepatocellular carcinoma (HCC) is a common and particularly fatal form of cancer for which very few drugs are effective. The fibroblast growth factor 19 (FGF19) has been viewed as a driver of HCC development and a potential Ab target for developing novel HCC therapy. However, a previously developed anti‐FGF19 Ab disrupted FGF19’s normal regulatory function and caused severe bile‐acid‐related side‐effects despite of having potent antitumor effects in preclinical models. Here, we developed novel human Abs (G1A8 and HS29) that specifically target the N‐terminus of FGF19. Both Abs inhibited FGF19‐induced HCC cell proliferation in vitro and significantly suppressed HCC tumor growth in mouse models. Importantly, no bile‐acid‐related side effects were observed in preclinical cynomolgus monkeys. Fundamentally, our study demonstrates that it is possible to target FGF19 for anti‐HCC therapies without adversely affecting its normal bile acid regulatory function, and highlights the exciting promise of G1A8 or HS29 as potential therapy for HCC.


title: Fully Human Antibodies for Malignant Pleural Mesothelioma Targeting

text: Immunotherapy is the most promising therapeutic approach against malignant pleural mesothelioma (MPM). Despite technological progress, the number of targetable antigens or specific antibodies is limited, thus hindering the full potential of recent therapeutic interventions. All possibilities of finding new targeting molecules must be exploited. The specificity of targeting is guaranteed by the use of monoclonal antibodies, while fully human antibodies are preferred, as they are functional and generate no neutralizing antibodies. The aim of this review is to appraise the latest advances in screening methods dedicated to the identification and harnessing of fully human antibodies. The scope of identifying useful molecules proceeds along two avenues, i.e., through the antigen-first or binding-first approaches. The first relies on screening human antibody libraries or plasma from immunized transgenic mice or humans to isolate binders to specific antigens. The latter takes advantage of specific binding to tumor cells of antibodies present in phage display libraries or in responders’ plasma samples without prior knowledge of the antigens. Additionally, next-generation sequencing analysis of B-cell receptor repertoire pre- and post-therapy in memory B-cells from responders allows for the identification of clones expanded and matured upon treatment. Human antibodies identified can be subsequently reformatted to generate a plethora of therapeutics like antibody-drug conjugates, immunotoxins, and advanced cell-therapeutics such as chimeric antigen receptor-transduced T-cells.


title: Gastrointestinal dysfunction in the critically ill: a systematic scoping review and research agenda proposed by the Section of Metabolism, Endocrinology and Nutrition of the European Society of Intensive Care Medicine

text: BACKGROUND: Gastrointestinal (GI) dysfunction is frequent in the critically ill but can be overlooked as a result of the lack of standardization of the diagnostic and therapeutic approaches. We aimed to develop a research agenda for GI dysfunction for future research. We systematically reviewed the current knowledge on a broad range of subtopics from a specific viewpoint of GI dysfunction, highlighting the remaining areas of uncertainty and suggesting future studies. METHODS: This systematic scoping review and research agenda was conducted following successive steps: (1) identify clinically important subtopics within the field of GI function which warrant further research; (2) systematically review the literature for each subtopic using PubMed, CENTRAL and Cochrane Database of Systematic Reviews; (3) summarize evidence for each subtopic; (4) identify areas of uncertainty; (5) formulate and refine study proposals that address these subtopics; and (6) prioritize study proposals via sequential voting rounds. RESULTS: Five major themes were identified: (1) monitoring, (2) associations between GI function and outcome, (3) GI function and nutrition, (4) management of GI dysfunction and (5) pathophysiological mechanisms. Searches on 17 subtopics were performed and evidence summarized. Several areas of uncertainty were identified, six of them needing consensus process. Study proposals ranked among the first ten included: prevention and management of diarrhoea; management of upper and lower feeding intolerance, including indications for post-pyloric feeding and opioid antagonists; acute gastrointestinal injury grading as a bedside tool; the role of intra-abdominal hypertension in the development and monitoring of GI dysfunction and in the development of non-occlusive mesenteric ischaemia; and the effect of proton pump inhibitors on the microbiome in critical illness. CONCLUSIONS: Current evidence on GI dysfunction is scarce, partially due to the lack of precise definitions. The use of core sets of monitoring and outcomes are required to improve the consistency of future studies. We propose several areas for consensus process and outline future study projects.


title: Independent risk factors and the long-term outcomes for postoperative continuous renal replacement treatment in patients who underwent emergency surgery for type a acute aortic dissection

text: OBJECTIVE: The study objective was to investigate the incidence and risk factors of continuous renal replacement therapy (CRRT) in patients undergoing emergency surgery for type A acute aortic dissection (TA-AAD) and evaluate the perioperative and long-term outcomes. METHODS: From January 2014 to December 2018, 712 consecutive patients were enrolled in the study. These patients were divided into two groups according to whether or not needed postoperative CRRT: the CRRT group vs the control group. Univariate analysis and binary logistic regression analysis were used to analyze the risk factors of CRRT. To avoid the selection bias and confounders, baseline characteristics were matched for propensity scores. Kaplan-Meier curves were generated to provide survival estimates at postoperative points in time. RESULTS: Before propensity score matching, univariate analysis showed that there were significant differences in age, preoperative hypertension, pericardial effusion, preoperative serum creatinine (sCr), intraoperative need for combined coronary artery bypass grafting (CABG) or mitral valve or tricuspid valve surgery, cardiopulmonary bypass (CPB) time, extracorporeal circulation assistant time, aortic cross-clamp time, drainage volume 24 h after surgery and ventilator time between two groups. All were higher in the CRRT group (P < 0.05). These risk factors were included in binary logistic regression. It showed that preoperative sCr and CPB time were independent risk factors for CRRT patients undergoing surgery for TA-AAD. And there were significant differences regarding 30-day mortality (P < 0.001) and long-term overall cumulative survival (P < 0.001) with up to a 6-year follow-up. After propensity scoring, 29 pairs (58 patients) were successfully matched. Among these patients, the analysis showed that CPB time was still significantly longer in the CRRT group (P = 0.004), and the 30-day mortality rate was also higher in this group (44.8% vs 10.3%; P = 0.003). CONCLUSION: CRRT after TA-AAD is common and worsened short- and long- term mortality. The preoperative sCr and CPB time are independent risk factors for postoperative CRRT patients. Shorten the CPB time as much as possible is recommended to reduce the risk of CRRT after the operation.


title: Epidemiological analysis of the Kaohsiung city strategy for dengue fever quarantine and epidemic prevention

text: BACKGROUND: Dengue is endemic in over 100 countries and is an important public health problem worldwide. Dengue fever is not endemic in Taiwan; the importation of dengue viruses from neighboring countries via close commercial links and air travel is considered to be the cause of local outbreaks. Therefore, efforts toward disease control have focused on preventing the importation of dengue into Taiwan. In this study, we investigated the relationships between the numbers of imported and indigenous dengue cases to test the validity of this strategy. METHODS: Data on cases of dengue fever that occurred between 2013 and 2018 were obtained from the surveillance systems of the Taiwan Center for Disease Control and Kaohsiung City Health Department. Standard epidemiological data, including the monthly numbers of indigenous and imported cases of dengue, were calculated. Potential associations between the numbers of indigenous and imported cases were investigated using correlation analyses. RESULTS: We identified a possible relationship between the period of disease concealment and the number of imported dengue cases, which resulted in epidemics of indigenous dengue fever within local communities. Further analysis of confirmed cases during previous epidemics in Kaohsiung City found that the risk of indigenous dengue fever may be related to the likelihood that patients with imported dengue fever will stay within local communities. CONCLUSION: Given the correlations found between imported and indigenous cases of dengue fever, as well as the relationship between the disease concealment period and the risk of indigenous dengue fever, prevention of disease importation and efficient identification of dengue cases within high-risk communities remain the major priorities for disease control.


title: M1 macrophage features in severe Plasmodium falciparum malaria patients with pulmonary oedema

text: BACKGROUND: Pulmonary oedema (PE) is a serious complication of Plasmodium falciparum malaria which can lead to acute lung injury in severe cases. Lung macrophages are activated during malaria infection due to a complex host-immune response. The molecular basis for macrophage polarization is still unclear but understanding the predominant subtypes could lead to new therapeutic strategies where the diseases present with lung involvement. The present study was designed to study the polarization of lung macrophages, as M1 or M2 macrophages, in the lungs of severe P. falciparum malaria patients, with and without evidence of PE. METHODS: Lung tissue samples, taken from patients who died from severe P. falciparum malaria, were categorized into severe malaria with PE and without PE (non-PE). Expression of surface markers (CD68+, all macrophages; CD40+, M1 macrophage; and CD163+, M2 macrophage) on activated lung macrophages was used to quantify M1/M2 macrophage subtypes. RESULTS: Lung injury was demonstrated in malaria patients with PE. The expression of CD40 (M1 macrophage) was prominent in the group of severe P. falciparum malaria patients with PE (63.44 ± 1.98%), compared to non-PE group (53.22 ± 3.85%, p < 0.05), whereas there was no difference observed for CD163 (M2 macrophage) between PE and non-PE groups. CONCLUSIONS: The study demonstrates M1 polarization in lung tissues from severe P. falciparum malaria infections with PE. Understanding the nature of macrophage characterization in malaria infection may provide new insights into therapeutic approaches that could be deployed to reduce lung damage in severe P. falciparum malaria.


title: Trauma complications and in-hospital mortality: failure-to-rescue

text: BACKGROUND: Reducing medical errors and minimizing complications have become the focus of quality improvement in medicine. Failure-to-rescue (FTR) is defined as death after a surgical complication, which is an institution-level surgical safety and quality metric that is an important variable affecting mortality rates in hospitals. This study aims to examine whether complication and FTR are different across low- and high-mortality hospitals for trauma care. METHODS: This was a retrospective cohort study performed at trauma care hospitals registered at Japan Trauma Data Bank (JTDB) from 2004 to 2017. Trauma patients aged ≥ 15 years with injury severity score (ISS) of ≥ 3 and those who survived for > 48 h after hospital admission were included. The hospitals in JTDB were categorized into three groups by standardized mortality rate. We compared trauma complications, FTR, and in-hospital mortality by a standardized mortality rate (divided by the institute-level quartile). RESULTS: Among 184,214 patients that were enrolled, the rate of any complication was 12.7%. The overall mortality rate was 3.7%, and the mortality rate among trauma patients without complications was only 2.8% (non-precedented deaths). However, the mortality rate among trauma patients with any complications was 10.2% (FTR). Hospitals were categorized into high- (40 facilities with 44,773 patients), average- (72 facilities with 102,368 patients), and low- (39 facilities with 37,073 patients) mortality hospitals, using the hospital ranking of a standardized mortality rate. High-mortality hospitals showed lower ISS than low-mortality hospitals [10 (IQR, 9–18) vs. 11 (IQR, 9–20), P < 0.01]. Patients in high-mortality hospitals showed more complications (14.2% vs. 11.2%, P < 0.01), in-hospital mortality (5.1% vs. 2.5%, P < 0.01), FTR (13.6% vs. 7.4%, P < 0.01), and non-precedented deaths (3.6% vs. 1.9%, P < 0.01) than those in low-mortality hospitals. CONCLUSIONS: Unlike reports of elective surgery, complication rates and FTR are associated with in-hospital mortality rates at the center level in trauma care.


docid: xqvpvebr

title: Stochastic epidemic dynamics on extremely heterogeneous networks

text: Networks of contacts capable of spreading infectious diseases are often observed to be highly heterogeneous, with the majority of individuals having fewer contacts than the mean, and a significant minority having relatively very many contacts. We derive a two-dimensional diffusion model for the full temporal behavior of the stochastic susceptible-infectious-recovered (SIR) model on such a network, by making use of a time-scale separation in the deterministic limit of the dynamics. This low-dimensional process is an accurate approximation to the full model in the limit of large populations, even for cases when the time-scale separation is not too pronounced, provided the maximum degree is not of the order of the population size.


title: Network Reconstruction and Community Detection from Dynamics

text: We present a scalable nonparametric Bayesian method to perform network reconstruction from observed functional behavior that at the same time infers the communities present in the network. We show that the joint reconstruction with community detection has a synergistic effect, where the edge correlations used to inform the existence of communities are also inherently used to improve the accuracy of the reconstruction which, in turn, can better inform the uncovering of communities. We illustrate the use of our method with observations arising from epidemic models and the Ising model, both on synthetic and empirical networks, as well as on data containing only functional information.


De Profundis II


Restructuring the surgical service during the COVID-19 pandemic: Experience from a tertiary institution in Singapore


À l’occasion de la journée mondiale 2020 de sensibilisation à l’autisme, message et recommandations de l’Académie nationale de médecine


title: Synthetic nucleic acid antibody prophylaxis confers rapid and durable protective immunity against Zika virus challenge

text: Significant concerns have arisen over the past 3 y from the increased global spread of the mosquito-borne flavivirus, Zika. Accompanying this spread has been an increase in cases of the devastating birth defect microcephaly as well as of Guillain–Barré syndrome in adults in many affected countries. Currently there is no vaccine or therapy for this infection; however, we sought to develop a combination approach that provides more rapid and durable protection than traditional vaccination alone. A novel immune-based prophylaxis/therapy strategy entailing the facilitated delivery of a synthetic DNA consensus prME vaccine along with DNA-encoded anti-ZIKV envelope monoclonal antibodies (dMAb) were developed and evaluated for antiviral efficacy. This immediate and persistent protection strategy confers the ability to overcome shortcomings inherent with conventional active vaccination or passive immunotherapy. A collection of novel dMAbs were developed which were potent against ZIKV and could be expressed in serum within 24–48 h of in vivo administration. The DNA vaccine, from a previous development, was potent after adaptive immunity was developed, protecting against infection, brain and testes pathology in relevant mouse challenge models and in an NHP challenge. Delivery of potent dMAbs protected mice from the same murine viral challenge within days of delivery. Combined injection of dMAb and the DNA vaccine afforded rapid and long-lived protection in this challenge model, providing an important demonstration of the advantage of this synergistic approach to pandemic outbreaks.


Pandemics and People


Leading the Compassionate Charge


Science in the Time of Coronavirus


title: Antigenic drift of hemagglutinin and neuraminidase in seasonal H1N1 influenza viruses from Saudi Arabia in 2014 to 2015

text: Antigenic drift of the hemagglutinin (HA) and neuraminidase (NA) proteins of the influenza virus cause a decrease in vaccine efficacy. Since the information about the evolution of these viruses in Saudi is deficient so we investigated the genetic diversity of circulating H1N1 viruses. Nasopharyngeal aspirates/swabs collected from 149 patients hospitalized with flu‐like symptoms during 2014 and 2015 were analyzed. Viral RNA extraction was followed by a reverse transcription‐polymerase chain reaction and genetic sequencing. We analyzed complete gene sequences of HA and NA from 80 positive isolates. Phylogenetic analysis of HA and NA genes of 80 isolates showed similar topologies and co‐circulation of clades 6b. Genetic diversity was observed among circulating viruses belonging to clade 6B.1A. The amino acid residues in the HA epitope domain were under purifying selection. Amino acid changes at key antigenic sites, such as position S101N, S179N (antigenic site‐Sa), I233T (antigenic site‐Sb) in the head domain might have resulted in antigenic drift and emergence of variant viruses. For NA protein, 36% isolates showed the presence of amino acid changes such as V13I (n = 29), I314M (n = 29) and 12% had I34V (n = 10). However, H257Y mutation responsible for resistance to neuraminidase inhibitors was missing. The presence of amino acid changes at key antigenic sites and their topologies with structural mapping of residues under purifying selection highlights the importance of antigenic drift and warrants further characterization of recently circulating viruses in view of vaccine effectiveness. The co‐circulation of several clades and the predominance of clade 6B.1 suggest multiple introductions in Saudi.


title: Defence in Depth Against Human Extinction: Prevention, Response, Resilience, and Why They All Matter

text: We look at classifying extinction risks in three different ways, which affect how we can intervene to reduce risk. First, how does it start causing damage? Second, how does it reach the scale of a global catastrophe? Third, how does it reach everyone? In all of these three phases there is a defence layer that blocks most risks: First, we can prevent catastrophes from occurring. Second, we can respond to catastrophes before they reach a global scale. Third, humanity is resilient against extinction even in the face of global catastrophes. The largest probability of extinction is posed when all of these defences are weak, that is, by risks we are unlikely to prevent, unlikely to successfully respond to, and unlikely to be resilient against. We find that it’s usually best to invest significantly into strengthening all three defence layers. We also suggest ways to do so tailored to the classes of risk we identify. Lastly, we discuss the importance of underlying risk factors – events or structural conditions that may weaken the defence layers even without posing a risk of immediate extinction themselves.


title: Electronic cigarettes: Tumultuous times

text: See related https://onlinelibrary.wiley.com/doi/10.1111/resp.13696


title: Human papillomavirus E6: Host cell receptor, GRP78, binding site prediction

text: Human papillomavirus (HPV) is the main cervical cancer‐promoting element that is transmitted through sexual routes. Anal, head, and throat cancers are also reported to be accompanied by HPV infection. E6 is one of the HPV nonstructural proteins, which is responsible for cell differentiation by targeting tumor suppressor genes, p105Rb and p53. E6 was reported to be stabilized by two chaperone proteins; glucose‐regulated protein 78 (GRP78) and heat shock protein 90. GRP78 is responsible for the unfolded protein response of the cells, and it was reported to be upregulated in many cancers, including cervical cancer. It was reported that knocking out GRP78 destabilizes E6 leading to faster degradation of E6 in vivo. The current work predicts the possible binding mode between E6 and GRP78 based on sequence and structural similarities.


title: MASS SPECTROMETRY IN VIROLOGICAL SCIENCES

text: Virology, as a branch of the life sciences, discovered mass spectrometry (MS) to be the pivotal tool around two decades ago. The technique unveiled the complex network of interactions between the living world of pro‐ and eukaryotes and viruses, which delivered “a piece of bad news wrapped in protein” as defined by Peter Medawar, Nobel Prize Laureate, in 1960. However, MS is constantly evolving, and novel approaches allow for a better understanding of interactions in this micro‐ and nanoworld. Currently, we can investigate the interplay between the virus and the cell by analyzing proteomes, interactomes, virus‐cell interactions, and search for the compounds that build viral structures. In addition, by using MS, it is possible to look at the cell from the broader perspective and determine the role of viral infection on the scale of the organism, for example, monitoring the crosstalk between infected tissues and the immune system. In such a way, MS became one of the major tools for the modern virology, allowing us to see the infection in the context of the whole cell or the organism. © 2019 Wiley Periodicals, Inc. Mass Spec Rev


title: Mycoplasma bovis and viral agents associated with the development of bovine respiratory disease in adult dairy cows

text: The etiology and pathologic findings of bovine respiratory disease (BRD) in adult dairy cows (n = 35) from a commercial dairy herd in Southern Brazil were investigated. Pulmonary samples were examined for histopathologic patterns and specific features within these patterns, while immunohistochemical (IHC) assays were designed to detect the intralesional antigens of viral infectious disease agents and Mycoplasma bovis. Pneumonia was diagnosed in 91.4% (32/35) of these cases; neither pneumonia nor any of the infectious disease pathogens evaluated occurred in three cows. The presence of multiple respiratory pathogens in 75% (24/32) of these cases indicated the complex origin of pneumonia in cattle. Interstitial pneumonia, necrosuppurative bronchopneumonia and suppurative bronchopneumonia were the principal patterns of pulmonary disease identified by histopathology. The most frequent pathogens identified by IHC were bovine viral diarrhea virus (BVDV; n = 18), M. bovis (n = 16) and bovine alphaherpesvirus type 1 (BoHV‐1; n = 14), followed by bovine respiratory syncytial virus (BRSV; n = 11) and bovine parainfluenza virus type 3 (BPIV‐3; n = 5). Obliterative bronchiolitis and peribronchial lymphocytic cuffings were the characteristic histopathologic features associated with M. bovis. Necrohemorrhagic bronchitis with bronchial angiogenesis was associated with BoHV‐1. Necrotizing bronchitis and bronchiolitis were associated with BVDV, BoHV‐1 and BRSV. Ballooning degeneration of the bronchial and bronchiolar epithelia was associated with BRSV and BoHV‐1. This is the first report from Brazil that correlated the histopathologic findings of BRD with the associated infectious disease agents by immunohistochemistry. M. bovis was frequently detected in the tissues of cows with fatal pulmonary disease during this study and may be a possible primary disease pathogen associated with the development of BRD in dairy cows. Additionally, the histopathologic features identified within patterns of pulmonary disease during this investigation may be an efficient diagnostic tool to associate histopathologic findings with specific agents of BRD in dairy cows.


title: The effects of inequality on total factor productivity across districts in South Africa: a spatial econometric analysis

text: This study builds on the fundamentals of the new economic geography and the skill-biased technological change argument, to empirically investigate whether increasing income/earning inequality enhances total factor productivity in South Africa. In so doing, panel data of district-municipalities and spatial econometric techniques are used for the period between 1995 and 2015, to gain a better understanding of the role of location and distance in the effects of income inequality on total factor productivity. The results from the analysis and empirical estimations indicate that: (1) there is strong support for the existence of positive spatial interactions in the effects of income inequality on total factor productivity; (2) the estimated direct effect of income inequality on TFP in local district-municipalities is negative and statistically significant, while the indirect effect is positive and statistically significant as well. These findings suggest that district-municipalities with moderate levels of inequality and high economic opportunities, attract more businesses, investments and important stocks of skilled labour from district-municipalities with high inequality. Furthermore, the finding of negative effects supports previous research suggesting that high levels of inequality set the stage for the adoption of distortionary policies which adversely influence the investment climate and produce political instability, thereby stifling the level of productivity and growth.


title: Inter-domain dynamics drive cholesterol transport by NPC1 and NPC1L1 proteins

text: Transport of LDL-derived cholesterol from lysosomes into the cytoplasm requires NPC1 protein; NPC1L1 mediates uptake of dietary cholesterol. We introduced single disulfide bonds into NPC1 and NPC1L1 to explore the importance of inter-domain dynamics in cholesterol transport. Using a sensitive method to monitor lysosomal cholesterol efflux, we found that NPC1’s N-terminal domain need not release from the rest of the protein for efficient cholesterol export. Either introducing single disulfide bonds to constrain lumenal/extracellular domains or shortening a cytoplasmic loop abolishes transport activity by both NPC1 and NPC1L1. The widely prescribed cholesterol uptake inhibitor, ezetimibe, blocks NPC1L1; we show that residues that lie at the interface between NPC1L1's three extracellular domains comprise the drug’s binding site. These data support a model in which cholesterol passes through the cores of NPC1/NPC1L1 proteins; concerted movement of various domains is needed for transfer and ezetimibe blocks transport by binding to multiple domains simultaneously.


title: Updates on Gene Therapy for Diabetic Retinopathy

text: PURPOSE OF REVIEW: Diabetic retinopathy (DR), a leading cause of visual impairment in the developed country, is characterized by vascular lesions and neuronal damage of the retina. Treatment options for this condition are currently limited. The advent of therapy targeting vascular endothelial growth factor (VEGF) demonstrated significant benefits to patients with DR. However, this treatment is limited by its short half-life and requirement for frequent invasive intravitreal injections. In addition, many patients failed to achieve clinically significant improvement in visual function. Gene therapy has the potential to provide an alternative treatment for DR with distinct advantages, such as longer therapeutic effect, less injection frequency, ability to intervene at disease onset, and potentially fewer side effects. RECENT FINDINGS: Strategies for gene therapy in DR, stemming from the current understanding of the disease pathogenesis, focus on the inhibition of neovascularization and protection of neurovascular degeneration in the retina. Studies with promising results have mainly focussed on animal models due to efficacy and safety concerns, despite a number of successful preclinical studies using adeno-associated virus-mediated transduction to treat both vascular dysfunction and neuronal degeneration. With the optimization of delivery vectors, transgene regulation, and outcome measure, gene therapy will potentially become available for patients with DR. SUMMARY: This review provides an update on the current strategies utilized in DR gene therapy research. Several barriers to the clinical application of gene therapy for DR are highlighted, and future directions for this research are proposed.


docid: ewxxytko

title: A modified live bat influenza A virus-based vaccine prototype provides full protection against HPAIV H5N1

text: Highly pathogenic avian influenza viruses (HPAIVs) of subtype H5 are a major threat for poultry holdings worldwide, here especially the zoonotic Asian H5N1 viruses. These HPAIVs have caused more than 500 fatal spillover infections from poultry to humans, with a looming danger of a new pandemic by establishing human-to-human transmissions. Besides culling measures in infected farms in endemic areas, vaccination is the major tool against HPAIV. However, the mainly used inactivated preparations have several limitations, like application to the individual animal by injection and a reduced efficiency. Here we present a modified live influenza vaccine prototype, which is based on the H17N10 bat influenza virus. The new chimeric vaccine strain R65(mono)/H17N10 was able to provide full protection against a lethal challenge infection with HPAIV H5N1 of juvenile and subadult chickens, as well as ferrets after oronasal immunization. In addition, the H5 vaccine prototype cannot reassort with avian influenza viruses and therefore is a promising tool against HPAIV H5 infection, allowing new vaccination strategies for efficient disease control.


title: The epidemiology of invasive meningococcal disease and the utility of vaccination in Malta

text: Invasive meningococcal disease (IMD) is a vaccine-preventable devastating infection that mainly affects infants, children and adolescents. We describe the population epidemiology of IMD in Malta in order to assess the potential utility of a meningococcal vaccination programme. All cases of microbiologically confirmed IMD in the Maltese population from 2000 to 2017 were analysed to quantify the overall and capsular-specific disease burden. Mean overall crude and age-specific meningococcal incidence rates were calculated to identify the target age groups that would benefit from vaccination. Over the 18-year study period, 111 out of the 245 eligible notified cases were confirmed microbiologically of which 70.3% had septicaemia, 21.6% had meningitis, and 6.3% had both. The mean overall crude incidence rate was 1.49/100,000 population with an overall case fatality rate of 12.6%. Meningococcal capsular groups (Men) B followed by C were the most prevalent with W and Y appearing over the last 6 years. Infants had the highest meningococcal incidence rate of 18.9/100,000 followed by 6.1/100,000 in 1–5 year olds and 3.6/100,000 in 11–15 year old adolescents. The introduction of MenACWY and MenB vaccines on the national immunization schedule in Malta would be expected to reduce the disease burden of meningococcal disease in children and adolescents in Malta.


title: The ICU Liberation Bundle and Strategies for Implementation in Pediatrics

text: PURPOSE OF REVIEW: We briefly review post-intensive care syndrome (PICS) and the morbidities associated with critical illness that led to the intensive care unit (ICU) liberation movement. We review each element of the ICU liberation bundle, including pediatric support data, as well as tips and strategies for implementation in a pediatric ICU (PICU) setting. RECENT FINDINGS: Numerous studies have found children have cognitive, physical, and psychiatric deficits after a PICU stay. The effects of the full ICU liberation bundle in children have not been published, but in adults, bundle implementation (even partial) resulted in significant improvement in survival, mechanical ventilation use, coma, delirium, restraint-free care, ICU readmissions, and post-ICU discharge disposition. SUMMARY: Although initially described in adults, children also suffer from PICS. The ICU liberation bundle is feasible in children and may ameliorate the effects of a PICU stay. Further studies are needed to characterize the benefits of the ICU liberation bundle in children.


title: Effects of larval exposure to sublethal doses of Bacillus thuringiensis var. israelensis on body size, oviposition and survival of adult Anopheles coluzzii mosquitoes

text: BACKGROUND: Application of the larvicide Bacillus thuringiensis var. israelensis (Bti) is a viable complementary strategy for malaria control. Efficacy of Bti is dose-dependent. There is a knowledge gap on the effects of larval exposure to sublethal Bti doses on emerging adult mosquitoes. The present study examined the effect of larval exposure to sublethal doses of Bti on the survival, body size and oviposition rate in adult Anopheles coluzzii. METHODS: Third-instar An. coluzzii larvae were exposed to control and sublethal Bti concentrations at LC(20), LC(50) and LC(70) for 48 h. Surviving larvae were reared to adults under standard colony conditions. Thirty randomly selected females from each treatment were placed in separate cages and allowed to blood feed. Twenty-five gravid females from the blood-feeding cages were randomly selected and transferred into new cages where they were provided with oviposition cups. Numbers of eggs laid in each cage and mortality of all adult mosquitoes were recorded daily. Wing lengths were measured of 570 mosquitoes as a proxy for body size. RESULTS: Exposure to LC(70)Bti doses for 48 h as third-instar larvae reduced longevity of adult An. coluzzii mosquitoes. Time to death was 2.58 times shorter in females exposed to LC(70)Bti when compared to the control females. Estimated mortality hazard rates were also higher in females exposed to the LC(50) and LC(20) treatments, but these differences were not statistically significant. The females exposed to LC(70) concentrations had 12% longer wings than the control group (P < 0.01). No differences in oviposition rate of the gravid females were observed between the treatments. CONCLUSIONS: Exposure of An. coluzzii larvae to sublethal Bti doses reduces longevity of resultant adults and is associated with larger adult size and unclear effect on oviposition. These findings suggest that anopheline larval exposure to sublethal Bti doses, though not recommended, could reduce vectorial capacity for malaria vector populations by increasing mortality of resultant adults. [Image: see text]


Response to “Visualization of Putative Coronavirus in Kidney”


The American Venous Forum Joins International Panel To Prioritize Venous Care In Crisis


Mechanisms of neurological injury in COVID -19


title: A Multicenter Study into Burnout, Perceived Stress, Job Satisfaction, Coping Strategies, and General Health among Emergency Department Nursing Staff

text: Burnout is a major problem among nurses working in emergency departments and is closely related to a high turnover of personnel, nursing errors, and patient dissatisfaction. The aims of this study were to estimate burnout, perceived stress, job satisfaction, coping and general health levels experienced by nurses working in emergency departments in Spain and to analyze the relationships between sociodemographic, occupational, and psychological variables and the occurrence of burnout syndrome among these professionals. A cross-sectional study was conducted in four emergency departments in Andalusia (Spain) from March to December 2016. The study sample was composed of n = 171 nurses. An ad hoc questionnaire was prepared to collect sociodemographic and work data, and the Maslach Burnout Inventory, the Perceived Stress Scale, the Font–Roja Questionnaire, the Brief Cope Orientation to Problem Experience and the General Health Questionnaire were used. The prevalence of high burnout was 8.19%. The levels of perceived stress and job satisfaction were moderate. The most frequent clinical manifestations were social dysfunction and somatic symptoms, and problem-focused coping was the strategy most used by nurses. Lack of physical exercise, gender, years worked at an emergency department, anxiety, social dysfunction, and avoidance coping were significant predictors of the dimensions of burnout.


title: Oral-Health-Related Quality of Life in Adult Patients with Rheumatic Diseases—A Systematic Review

text: Objectives: The aim of this systematic review was to assess the oral-health-related quality of life (OHRQoL) of adult patients with rheumatic diseases. Material and Methods: A systematic literature search was performed, including clinical studies on adults (aged at least 18 years) with a verified diagnosis of rheumatic disease. Results: 26 out of 41 clinical studies including rheumatoid arthritis (RA, seven studies), systemic sclerosis (SSc, five), Sjögren syndrome (SS, eight), Behcet disease (BD, four), systemic lupus erythematosus (SLE, one) and ankylosing spondylitis (AS, one) were found. In 15 studies, a healthy control group was recruited. The short form of the Oral Health Impact Profile (OHIP 14) was most frequently applied. The majority of studies (14/15) reported worse OHRQoL in patients with rheumatic disease compared to healthy individuals. In particular, patients with SS (salivary flow and composition) or BD (oral ulcers) showed a relation between OHRQoL and disease-specific oral manifestations. Most studies investigating subscales of OHRQoL (5/6) found the subscale physical disability to be predominantly affected in patients with rheumatic diseases. About half of the studies reported impaired psychosocial aspects. Conclusion: Patients with rheumatic diseases exhibit reduced OHRQoL, especially in diseases with oral manifestations like SS and BD. Physical affections due to oral diseases and psychosocial impairments caused by disease-related parameters must be recognized within patient-centered dental care.


PLASTA National Webinar Series: A developing model for remote surgical education


title: Leveraging the social network for treatment of social anxiety: Pilot study of a youth-specific digital intervention with a focus on engagement of young men

text: OBJECTIVE: The primary objective was to determine the acceptability, feasibility and safety of a novel digital intervention (Entourage) for young people with prominent social anxiety symptoms, with a particular focus on the engagement of young men. The secondary aim was to explore whether the intervention was associated with clinically significant improvements to clinical and social variables known to co-occur with social anxiety. METHOD: A multidisciplinary team comprising of mental health clinicians, researchers, young adult fiction writers, a comic artist and young people with a lived experience of social anxiety developed the Entourage platform in collaboration. Entourage combines evidence-based therapeutic techniques for social anxiety with an engaging, social-media-based interface that allows users to build social connections, while also receiving expert clinical moderation and support from peer workers. Acceptability, feasibility and safety outcomes of Entourage were tested in a 12-week pilot study with 89 young people (48.3% male; age M = 19.8 years, SD = 3.3 years). Eligible participants were recruited via liaison with four headspace early-intervention centres in north-western Melbourne. RESULTS: 56.8% of the sample reported social anxiety symptoms in the severe or very severe range at baseline. Results demonstrated the Entourage intervention was feasible, safe, and potentially acceptable, with 98.6% of participants reporting they would recommend Entourage to another young person experiencing social anxiety. Usage results were also comparable across male and non-male participants. Results showed that young people reliably and significantly improved on clinical and social variables. In particular, young males showed a clinically significant improvement on social anxiety symptoms (d = 0.79, p < .001), depression (d = 0.71, p < .001), belongingness (d = 0.58, p = .001), increased feelings of social connectedness (d = 0.46, p = .004) and decreased loneliness (d = 0.46, p = .006). Non-male participants also experienced a significant increase in social connectedness (d = 0.76, p < .001), alongside reduced social anxiety (d = 0.78, p < .001) and experiential avoidance (d = 0.81, p < .001). CONCLUSIONS: Entourage is a highly engaging and potentially effective intervention that represents a novel combination of features designed both to reduce social anxiety symptoms and improve social connection among young people. Entourage demonstrated some acceptability, feasibility and safety, with encouraging benefits to clinical and social variables. Entourage also showed favorable results for the engagement and support of young men with social anxiety symptoms.


title: Next-Generation Sequencing Analysis of Cellular Response to Influenza B Virus Infection

text: Influenza B virus (IBV) is a respiratory pathogen that infects humans and causes seasonal influenza epidemics. However, cellular response to IBV infection in humans and mechanisms of host-mediated restriction of IBV replication are not thoroughly understood. In this study, we used next-generation sequencing (NGS) to perform transcriptome profiling of IBV-infected human lung epithelial A549 cells at 0, 6, 12, and 24 h post infection (hpi) and characterized the cellular gene expression dynamics. We observed that more than 4000 host genes were differentially regulated during the study period, which included up regulation of genes encoding proteins, having a role in the innate antiviral immune responses, immune activation, cellular metabolism, autophagy, and apoptosis, as well as down regulation of genes involved in mitosis and cell proliferation. Further analysis of RNA-Seq data coupled with RT-qPCR validation collectively showed that double-strand RNA recognition pathways, including retinoic acid-inducible gene I (RIG-I) and Toll-like receptor 3 (TLR3), were substantially activated following IBV infection. Taken together, these results provide important initial insights into the intimate interaction between IBV and lung epithelial cells, which can be further explored towards elucidation of the cellular mechanisms in restriction or elimination of IBV infections in humans.


title: Isolation and Characterisation of Alongshan Virus in Russia

text: In recent decades, many new flavi-like viruses have been discovered predominantly in different invertebrates and, as was recently shown, some of them may cause disease in humans. The Jingmenvirus (JMV) group holds a special place among flaviviruses and flavi-like viruses because they have a segmented ssRNA(+) genome. We detected Alongshan virus (ALSV), which is a representative of the JMV group, in ten pools of adult Ixodes persulcatus ticks collected in two geographically-separated Russian regions. Three of the ten strains were isolated in the tick cell line IRE/CTVM19. One of the strains persisted in the IRE/CTVM19 cells without cytopathic effect for three years. Most ALSV virions purified from tick cells were spherical with a diameter of approximately 40.5 nm. In addition, we found smaller particles of approximately 13.1 nm in diameter. We obtained full genome sequences of all four segments of two of the isolated ALSV strains, and partial sequences of one segment from the third strain. Phylogenetic analysis on genome segment 2 of the JMV group clustered our novel strains with other ALSV strains. We found evidence for the existence of a novel upstream open reading frame in the glycoprotein-coding segment of ALSV and other members of the JMV group.


title: Broad Antiviral Activity of Ginkgolic Acid against Chikungunya, Mayaro, Una, and Zika Viruses

text: The alphaviruses Chikungunya (CHIKV), Mayaro (MAYV), Una (UNAV), and the flavivirus Zika (ZIKV) are emerging or re-emerging arboviruses which are responsible for frequent epidemic outbreaks. Despite the large impact of these arboviruses on health systems, there are no approved vaccines or treatments to fight these infections. As a consequence, there is an urgent need to discover new antiviral drugs. Natural products are a rich source of compounds with distinct biological activities, including antiviral properties. Thus, we aimed to explore the potential antiviral activity of Ginkgolic acid against the arboviruses CHIKV, MAYV, UNAV, and ZIKV. Viral progeny production in supernatants from cells treated or not treated with Ginkgolic acid was quantified by plaque-forming assay. Ginkgolic acid’s direct virucidal activity against these arboviruses was also determined. Additionally, viral protein expression was assessed using Western blot and immunofluorescence. Our results reveal that Ginkgolic acid promotes a dose-dependent decrease in viral titers in all tested viruses. Moreover, the compound demonstrated strong virucidal activity. Finally, we found that viral protein expression was affected by treatment with this drug. Collectively, these findings suggest that Ginkgolic acid could have broader antiviral activity.


title: The In Silico Prediction of Hotspot Residues that Contribute to the Structural Stability of Subunit Interfaces of a Picornavirus Capsid

text: The assembly of picornavirus capsids proceeds through the stepwise oligomerization of capsid protein subunits and depends on interactions between critical residues known as hotspots. Few studies have described the identification of hotspot residues at the protein subunit interfaces of the picornavirus capsid, some of which could represent novel drug targets. Using a combination of accessible web servers for hotspot prediction, we performed a comprehensive bioinformatic analysis of the hotspot residues at the intraprotomer, interprotomer and interpentamer interfaces of the Theiler’s murine encephalomyelitis virus (TMEV) capsid. Significantly, many of the predicted hotspot residues were found to be conserved in representative viruses from different genera, suggesting that the molecular determinants of capsid assembly are conserved across the family. The analysis presented here can be applied to any icosahedral structure and provides a platform for in vitro mutagenesis studies to further investigate the significance of these hotspots in critical stages of the virus life cycle with a view to identify potential targets for antiviral drug design.


title: Metabolomic Analysis of Cricket paralysis virus Infection in Drosophila S2 Cells Reveals Divergent Effects on Central Carbon Metabolism as Compared with Silkworm Bm5 Cells

text: High-throughput approaches have opened new opportunities for understanding biological processes such as persistent virus infections, which are widespread. However, the potential of persistent infections to develop towards pathogenesis remains to be investigated, particularly with respect to the role of host metabolism. To explore the interactions between cellular metabolism and persistent/pathogenic virus infection, we performed untargeted and targeted metabolomic analysis to examine the effects of Cricket paralysis virus (CrPV, Dicistroviridae) in persistently infected silkworm Bm5 cells and acutely infected Drosophila S2 cells. Our previous study (Viruses 2019, 11, 861) established that both glucose and glutamine levels significantly increased during the persistent period of CrPV infection of Bm5 cells, while they decreased steeply during the pathogenic stages. Strikingly, in this study, an almost opposite pattern in change of metabolites was observed during different stages of acute infection of S2 cells. More specifically, a significant decrease in amino acids and carbohydrates was observed prior to pathogenesis, while their abundance significantly increased again during pathogenesis. Our study illustrates the occurrence of diametrically opposite changes in central carbon mechanisms during CrPV infection of S2 and Bm5 cells that is possibly related to the type of infection (acute or persistent) that is triggered by the virus.


title: High Throughput Screening of FDA-Approved Drug Library Reveals the Compounds that Promote IRF3-Mediated Pro-Apoptotic Pathway Inhibit Virus Replication

text: Interferon (IFN) regulatory factor 3 (IRF3) is the key transcription factor for the induction of IFN and antiviral genes. The absence of antiviral genes in IRF3 deficiency leads to susceptibility to a wide range of viral infections. Previously, we uncovered a function for nontranscriptional IRF3 (nt-IRF3), RLR (RIG-I-like receptor)-induced IRF3-mediated pathway of apoptosis (RIPA), which triggers apoptotic killing of virus-infected cells. Using knock-in mice expressing a transcriptionally inactive, but RIPA-active, IRF3 mutant, we demonstrated the relative contribution of RIPA to host antiviral defense. Given that RIPA is a cellular antiviral pathway, we hypothesized that small molecules that promote RIPA in virus-infected cells would act as antiviral agents. To test this, we conducted a high throughput screen of a library of FDA-approved drugs to identify novel RIPA activators. Our screen identified doxorubicin as a potent RIPA-activating agent. In support of our hypothesis, doxorubicin inhibited the replication of vesicular stomatitis virus, a model rhabdovirus, and its antiviral activity depended on its ability to activate IRF3 in RIPA. Surprisingly, doxorubicin inhibited the transcriptional activity of IRF3. The antiviral activity of doxorubicin was expanded to flavivirus and herpesvirus that also activate IRF3. Mechanistically, doxorubicin promoted RIPA by activating the extracellular signal-regulated kinase (ERK) signaling pathway. Finally, we validated these results using another RIPA-activating compound, pyrvinium pamoate, which showed a similar antiviral effect without affecting the transcriptional activity of IRF3. Therefore, we demonstrate that the RIPA branch of IRF3 can be targeted therapeutically to prevent virus infection.


title: Interferon-λ Attenuates Rabies Virus Infection by Inducing Interferon-Stimulated Genes and Alleviating Neurological Inflammation

text: Rabies, caused by rabies virus (RABV), is a fatal neurological disease that still causes more than 59,000 human deaths each year. Type III interferon IFN-λs are cytokines with type I IFN-like antiviral activities. Although IFN-λ can restrict the infection for some viruses, especially intestinal viruses, the inhibitory effect against RABV infection remains undefined. In this study, the function of type III IFN against RABV infection was investigated. Initially, we found that IFN-λ2 and IFN-λ3 could inhibit RABV replication in cells. To characterize the role of IFN-λ in RABV infection in a mouse model, recombinant RABVs expressing murine IFN-λ2 or IFN-λ3, termed as rB2c-IFNλ2 or rB2c-IFNλ3, respectively, were constructed and rescued. It was found that expression of IFN-λ could reduce the pathogenicity of RABV and limit viral spread in the brains by different infection routes. Furthermore, expression of IFN-λ could induce the activation of the JAK-STAT pathway, resulting in the production of interferon-stimulated genes (ISGs). It was also found that rRABVs expressing IFN-λ could reduce the production of inflammatory cytokines in primary astrocytes and microgila cells, restrict the opening of the blood-brain barrier (BBB), and prevent excessive infiltration of inflammatory cells into the brain, which could be responsible for the neuronal damage caused by RABV. Consistently, IFN-λ was found to maintain the integrity of tight junction (TJ) protein ZO-1 of BBB to alleviate neuroinflammation in a transwell model. Our study underscores the role of IFN-λ in inhibiting RABV infection, which potentiates IFN-λ as a possible therapeutic agent for the treatment of RABV infection.


title: Vero Cells as a Mammalian Cell Substrate for Human Norovirus

text: Human norovirus (HuNoV) is a principal cause of acute gastroenteritis worldwide, particularly in developing countries. Its global prevalence is underscored by more serious morbidity and some mortality in the young (<5 years) and the elderly. To date, there are no licensed vaccines or approved therapeutics for HuNoV, mostly because there are limited cell culture systems and small animal models available. Recently described cell culture systems are not ideal substrates for HuNoV vaccine development because they are not clonal or only support a single strain. In this study, we show Vero cell-based replication of two pandemic GII.4 HuNoV strains and one GII.3 strain and confirm exosome-mediated HuNoV infection in Vero cells. Lastly, we show that trypsin addition to virus cultures or disruption of Vero cell host genes can modestly increase HuNoV replication. These data provide support for Vero cells as a cell culture model for HuNoV.


docid: imbpgsub

title: Host–Virus Interaction: How Host Cells Defend against Influenza A Virus Infection

text: Influenza A viruses (IAVs) are highly contagious pathogens infecting human and numerous animals. The viruses cause millions of infection cases and thousands of deaths every year, thus making IAVs a continual threat to global health. Upon IAV infection, host innate immune system is triggered and activated to restrict virus replication and clear pathogens. Subsequently, host adaptive immunity is involved in specific virus clearance. On the other hand, to achieve a successful infection, IAVs also apply multiple strategies to avoid be detected and eliminated by the host immunity. In the current review, we present a general description on recent work regarding different host cells and molecules facilitating antiviral defenses against IAV infection and how IAVs antagonize host immune responses.


docid: eojeofum

title: A Humanized Monoclonal Antibody Cocktail to Prevent Pulmonary Ricin Intoxication

text: PB10 IgG(1), a monoclonal antibody (MAb) directed against an immunodominant epitope on the enzymatic subunit (RTA) of ricin toxin (RT), has been shown to passively protect mice and non-human primates from an aerosolized lethal-dose RT challenge. However, it was recently demonstrated that the therapeutic efficacy of PB10 IgG1 is significantly improved when co-administered with a second MAb, SylH3, targeting RT’s binding subunit (RTB). Here we report that the PB10/SylH3 cocktail is also superior to PB10 alone when used as a pre-exposure prophylactic (PrEP) in a mouse model of intranasal RT challenge. The benefit of the PB10/SylH3 cocktail prompted us to engineer a humanized IgG1 version of SylH3 (huSylH3). The huPB10/huSylH3 cocktail proved highly efficacious in the mouse model, thereby opening the door to future testing in non-human primates.


title: Development of a real-time loop-mediated isothermal amplification method for the detection of severe fever with thrombocytopenia syndrome virus.

text: Severe fever with thrombocytopenia syndrome (SFTS) is being reported annually in South Korea since its first detection there in 2010. The causal agent is a negative-strand RNA virus 80-100 nm in diameter. It causes fever, thrombocytopenia, leukocytopenia, gastrointestinal symptoms, and neural symptoms. The mortality rate of SFTS was 32.6% among 172 cases reported from 2012 to 2015 in South Korea. Thus, is necessary to develop an effective diagnostic method that selectively identifies the isolates circulating in South Korea. The real-time reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay is a simple, rapid, and sensitive approach for molecular diagnosis. Here, we designed novel primers for this assay and found that the technique had very high specificity, sensitivity, and efficiency. This real-time RT-LAMP approach using the novel primers developed herein can be applied for early diagnosis of SFTSV strains in South Korea to reduce the mortality rate of SFTS.


Stages or phenotypes? A critical look at COVID-19 pathophysiology.


title: Association of the bleeding time test with aspects of traumatic brain injury in patients with alcohol use disorder

text: BACKGROUND—AIM: Traumatic brain injury (TBI) and alcohol use disorder (AUD) can occur concomitantly and be associated with coagulopathy that influences TBI outcome. The use of bleeding time tests in TBI management is controversial. We hypothesized that in TBI patients with AUD, a prolonged bleeding time is associated with more severe injury and poor outcome. MATERIAL AND METHODS: Moderate and severe TBI patients with evidence of AUD were examined with bleeding time according to IVY bleeding time on admission during neurointensive care. Baseline clinical and radiological characteristics were recorded. A standardized IVY bleeding time test was determined by staff trained in the procedure. Bleeding time test results were divided into normal (≤ 600 s), prolonged (> 600 s), and markedly prolonged (≥ 900 s). Normal platelet count (PLT) was defined as > 150,000/μL. This cohort was compared with another group of TBI patients without evidence of AUD. RESULTS: Fifty-two patients with TBI and AUD were identified, and 121 TBI patients without any history of AUD were used as controls. PLT was low in 44.2% and bleeding time was prolonged in 69.2% of patients. Bleeding time values negatively correlated with PLT (p < 0.05). TBI patients with markedly prolonged values (≥ 900 s) had significantly increased hematoma size, and more frequently required intracranial pressure measurement and mechanical ventilation compared with those with bleeding times < 900 s (p < 0.05). Most patients (88%) with low platelet count had prolonged bleeding time. No difference in 6-month outcome between the bleeding time groups was observed (p > 0.05). Subjects with TBI and no evidence for AUD had lower bleeding time values and higher platelet count compared with those with TBI and history of AUD (p < 0.05). CONCLUSIONS: Although differences in the bleeding time values between TBI cohorts exist and prolonged values may be seen even in patients with normal platelet count, the bleeding test is a marker of primary hemostasis and platelet function with low specificity. However, it may provide an additional assessment in the interpretation of the overall status of TBI patients with AUD. Therefore, the bleeding time test should only be used in combination with the patient’s bleeding history and careful assessment of other hematologic parameters.


docid: dtwmnnqu

title: Contrast-enhanced ultrasound (CEUS) of the lung reveals multiple areas of microthrombi in a COVID-19 patient.


title: Solving an ethical issue involved in experimentation with animals in a brazilian teaching laboratory

text: Changes are occurring within Brazilian institutes of higher education; currently several universities are reviewing their course offerings and teaching approaches to determine if they meet the needs of today's undergraduate students. When changes are made to the curriculum of experimental courses, there should be an understood guarantee that all efforts to avoid ethical and biosafety issues have been diligently considered. Ethical considerations lead us to create an alternative experimental session to be conducted that eliminated the use of rats, the conventional in vivo model employed for learning metabolism of glycogen in our university. To avoid possible biosafety issues, we prepared an alternative sample to simulate human urine, which we called guarurine. Using our new method, it is possible to verify positive results imitating a diabetic and starving people samples for detection of glucose and ketone. The alternative tool described herein is not only particularly suited to bypass the ethics of using animals for teaching, but also permits the discussion of significant aspects of pathological and physiological situations such as diabetics and starvation in a simple, safe, and interesting way.


title: Locked nucleic acid containing antisense oligonucleotides enhance inhibition of HIV‐1 genome dimerization and inhibit virus replication

text: We have evaluated antisense design and efficacy of locked nucleic acid (LNA) and DNA oligonucleotide (ON) mix‐mers targeting the conserved HIV‐1 dimerization initiation site (DIS). LNA is a high affinity nucleotide analog, nuclease resistant and elicits minimal toxicity. We show that inclusion of LNA bases in antisense ONs augments the interference of HIV‐1 genome dimerization. We also demonstrate the concomitant RNase H activation by six consecutive DNA bases in an LNA/DNA mix‐mer. We show ON uptake via receptor‐mediated transfection of a human T‐cell line in which the mix‐mers subsequently inhibit replication of a clinical HIV‐1 isolate. Thus, the technique of LNA/DNA mix‐mer antisense ONs targeting the conserved HIV‐1 DIS region may provide a strategy to prevent HIV‐1 assembly in the clinic.


Peering through the portal: COVID-19 and the future of agriculture


Upcoming Events in Pediatric Cardiology Pediatric Cardiology 41–4


Lessons of dislocation


Optimal sleep health among frontline healthcare workers during the COVID-19 pandemic.


title: Synthesis and biological evaluation of a new series of 1-aryl-3-[4-(pyridin-2-ylmethoxy)phenyl]urea derivatives as new anticancer agents

text: The diaryl ureas are very important fragments in medicinal chemistry. By means of computer-aided design, 1-aryl-3-[4-(pyridin-2-ylmethoxy)phenyl]urea derivatives were designed and synthesized, and evaluated for their antiproliferative activity against A549, HCT-116, PC-3 cancer cell lines, and HL7702 human normal liver cell lines in vitro by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric assay. Most of the target compounds demonstrate significant antiproliferative effects on all the selective cancer cell lines. The calculated IC(50) values were reported. The target compound 1-(4-chlorophenyl)-3-{4-{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methoxy}phenyl}urea (7u) demonstrated the most potent inhibitory activity (IC(50) = 2.39 ± 0.10 μM for A549 and IC(50) = 3.90 ± 0.33 μM for HCT-116), comparable to the positive-control sorafenib (IC(50) = 2.12 ± 0.18 μM for A549 and IC(50) = 2.25 ± 0.71 μM for HCT-116). Conclusively, 1-aryl-3-[4-(pyridin-2-ylmethoxy)phenyl]urea derivatives as the new anticancer agents were discovered, and could be used as the potential BRAF inhibitors for further research.


docid: nkkmzymu

title: Letter to the Editor: Is COVID-19 the Cause of Delayed Surgical Treatment of Spine Trauma in Latin America?


COVID-19: Long-term Planning for Procedure-based Specialties During Extended Mitigation and Suppression Strategies


docid: vzzqjbpd

title: JMIG During the COVID-19 Crisis: Drawing on our International Expertise


Letter to the editor regarding "Challenges of Neurosurgery Education During the Coronavirus Disease 2019 (COVID-19) Pandemic: A U.S. Perspective" and a Virtual Neurosurgery Clerkship for Medical Students


We Must Remain Resolute


What can psychiatrists learn from SARS and MERS outbreaks?


docid: illrdtko

title: The uncertainty of tuberculosis diagnosis


The synchronized gene expression of retrotransposons and type I interferon in dermatomyositis


docid: nnunjora

title: “Considerable unreimbursed medical care is delivered through electronic patient portals: a retrospective review”


Editorial ECTES Abstracts 2020


title: Genetic and antigenic characterization of H5 and H7 avian influenza viruses isolated from migratory waterfowl in Mongolia from 2017 to 2019

text: The circulation of highly pathogenic avian influenza viruses (HPAIVs) of various subtypes (e.g., H5N1, H5N6, H5N8, and H7N9) in poultry remains a global concern for animal and public health. Migratory waterfowls play important roles in the transmission of these viruses across countries. To monitor virus spread by wild birds, active surveillance for avian influenza in migratory waterfowl was conducted in Mongolia from 2015 to 2019. In total, 5000 fecal samples were collected from lakesides in central Mongolia, and 167 influenza A viruses were isolated. Two H5N3, four H7N3, and two H7N7 viruses were characterized in this study. The amino acid sequence at hemagglutinin (HA) cleavage site of those isolates suggested low pathogenicity in chickens. Phylogenetic analysis revealed that all H5 and H7 viruses were closely related to recent H5 and H7 low pathogenic avian influenza viruses (LPAIVs) isolated from wild birds in Asia and Europe. Antigenicity of H7Nx was similar to those of typical non-pathogenic avian influenza viruses (AIVs). While HPAIVs or A/Anhui/1/2013 (H7N9)-related LPAIVs were not detected in migratory waterfowl in Mongolia, sporadic introductions of AIVs including H5 and H7 viruses into Mongolia through the wild bird migration were identified. Thus, continued monitoring of H5 and H7 AIVs in both domestic and wild birds is needed for the early detection of HPAIVs spread into the country. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11262-020-01764-2) contains supplementary material, which is available to authorized users.


Nursing in uncertain times


Arrigo Moglia (1947–2020)


title: Transcriptome Landscape of Intracellular Brucella ovis Surviving in RAW264.7 Macrophage Immune System

text: Brucella ovis infection results in genital damage and epididymitis in rams, placental inflammation and rare abortion in ewes, and neonatal mortality in lambs. However, the mechanism underlying B. ovis infection remains unclear. In the present study, we used prokaryotic transcriptome sequencing to identify the differentially expressed genes (DEGs) between wild-type B. ovis and intracellular B. ovis in RAW264.7 macrophages. Gene ontology (GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed, and quantitative reverse transcriptase PCR (qRT-PCR) was used to validate the top 10 upregulated and downregulated DEGs. The results showed that 212 genes were differentially expressed, including 68 upregulated and 144 downregulated genes, which were mainly enriched in 30 GO terms linked to biological process, cellular component, and molecular function. KEGG analysis showed that the DEGs were enriched in the hypoxia-inducible factor 1 (HIF-1) signaling pathway, mitogen-activated protein kinase (MAPK) signaling pathway, beta-alanine metabolism, and quorum sensing pathway. BME_RS01160, BME_RS04270, BME_RS08185, BME_RS12880, BME_RS25875, predicted_RNA865, and predicted_RNA953 were confirmed with the transcriptome sequencing data. Hence, our findings not only reveal the intracellular parasitism of B. ovis in the macrophage immune system, but also help to understand the mechanism of chronic B. ovis infection.


title: Generation and validation of a highly sensitive bioluminescent HIV-1 reporter vector that simplifies measurement of virus release

text: BACKGROUND: The continued persistence of HIV-1 as a public health concern due to the lack of a cure calls for the development of new tools for studying replication of the virus. Here, we used NanoLuc, a small and extremely bright luciferase protein, to develop an HIV-1 bioluminescent reporter virus that simplifies functional measurement of virus particle production. RESULTS: The reporter virus encodes a Gag protein containing NanoLuc inserted between the matrix (MA) and capsid (CA) domains of Gag, thereby generating virus particles that package high levels of the NanoLuc reporter. We observe that inserting the NanoLuc protein within HIV-1 Gag has minimal impact on Gag expression and virus particle release. We show that the reporter virus recapitulates inhibition of HIV-1 particle release by Gag mutations, the restriction factor tetherin, and the small-molecule inhibitor amphotericin-B methyl ester. CONCLUSION: These results demonstrate that this vector will provide a simple and rapid tool for functional studies of virus particle assembly and release and high-throughput screening for cellular factors and small molecules that promote or inhibit HIV-1 particle production.


title: Genetic polymorphism of merozoite surface protein-3 in Myanmar Plasmodium falciparum field isolates

text: BACKGROUND: Plasmodium falciparum merozoite surface protein-3 (PfMSP-3) is a target of naturally acquired immunity against P. falciparum infection and is a promising vaccine candidate because of its critical role in the erythrocyte invasion of the parasite. Understanding the genetic diversity of pfmsp-3 is important for recognizing genetic nature and evolutionary aspect of the gene in the natural P. falciparum population and for designing an effective vaccine based on the antigen. METHODS: Blood samples collected from P. falciparum-infected patients in Naung Cho and Pyin Oo Lwin, Myanmar, in 2015 were used in this study. The pfmsp-3 was amplified by polymerase chain reaction, cloned, and sequenced. Genetic polymorphism and natural selection of Myanmar pfmsp-3 were analysed using the programs DNASTAR, MEGA6, and DnaSP 5.10.00. Genetic diversity and natural selection of the global pfmsp-3 were also comparatively analysed. RESULTS: Myanmar pfmsp-3 displayed 2 different alleles, 3D7 and K1. The 3D7 allelic type was predominant in the population, but genetic polymorphism was less diverse than for the K1 allelic type. Polymorphic characters in both allelic types were caused by amino acid substitutions, insertions, and deletions. Amino acid substitutions were mainly occurred at the alanine heptad repeat domains, whereas most insertions and deletions were found at the glutamate rich domain. Overall patterns of amino acid polymorphisms detected in Myanmar pfmsp-3 were similar in the global pfmsp-3 population, but novel amino acid changes were observed in Myanmar pfmsp-3 with low frequencies. Complicated patterns of natural selection and recombination events were predicted in the global pfmsp-3, which may act as major driving forces to maintain and generate genetic diversity of the global pfmsp-3 population. CONCLUSION: Global pfmsp-3 revealed genetic polymorphisms, suggesting that the functional and structural consequences of the polymorphisms should be considered in designing a vaccine based on PfMSP-3. Further examination of genetic diversity of pfmsp-3 in the global P. falciparum population is necessary to gain in-depth insight for the population structure and evolutionary aspect of global pfmsp-3.


Mental health: why it still matters in the midst of a pandemic.


Corrigendum


title: Identification of 2-(4-(Phenylsulfonyl)piperazine-1-yl)pyrimidine Analogues as Novel Inhibitors of Chikungunya Virus

text: [Image: see text] The chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus, and it is the causative agent of chikungunya fever (CHIKF). Although it has re-emerged as an epidemic threat, so far there are neither vaccines nor pharmacotherapy available to prevent or treat an infection. Herein, we describe the synthesis and structure–activity relationship studies of a class of novel small molecule inhibitors against CHIKV and the discovery of a new potent inhibitor (compound 6a). The starting point of the optimization process was N-ethyl-6-methyl-2-(4-(4-fluorophenylsulfonyl)piperazine-1-yl)pyrimidine-4-amine (1) with an EC(50) of 8.68 μM, a CC(50) of 122 μM, and therefore a resulting selectivity index (SI) of 14.2. The optimized compound 6a, however, displays a much lower micromolar antiviral activity (EC(50) value of 3.95 μM), considerably better cytotoxic liability (CC(50) value of 260 μM) and consequently an improved SI of greater than 61. Therefore, we report the identification of a promising novel compound class that has the potential for further development of antiviral drugs against the CHIKV.


title: Supervised pulmonary hypertension exercise rehabilitation (SPHERe): study protocol for a multi-centre randomised controlled trial

text: BACKGROUND: Supervised cardio-pulmonary rehabilitation may be safe and beneficial for people with pulmonary hypertension (PH) in groups 1 (pulmonary arterial hypertension) and 4 (chronic thromboembolic disease), particularly as a hospital in-patient. It has not been tested in the most common PH groups; 2 (left heart disease), 3 (lung disease), or 5 (other disorders). Further it has not been evaluated in the UK National Health Service (NHS) out-patient setting, or with long-term follow-up. The aim of this randomised controlled trial (RCT) is to test the clinical and cost-effectiveness of a supervised exercise rehabilitation intervention with psychosocial support compared to best practice usual care for people with PH in the community/outpatient setting. METHODS: This multi-centre, pragmatic, two-arm RCT with embedded process evaluation aims to recruit 352 clinically stable adults with PH (groups 1–5) and WHO functional class II-IV. Participants will be randomised to either the Supervised Pulmonary Hypertension Exercise Rehabilitation (SPHERe) intervention or control. The SPHERe intervention consists of 1) individual assessment and familiarisation sessions; 2) 8-week, twice-weekly, supervised out-patient exercise training; 3) psychosocial/motivational support and education; 4) guided home exercise plan. The control intervention consists of best practice usual care with a single one-to-one practitioner appointment, and general advice on physical activity. Outcomes will be measured at baseline, 4 months (post-intervention) and 12 months by researchers blinded to treatment allocation. The primary outcome is the incremental shuttle walk test at 4 months. Secondary outcomes include health-related quality of life (HRQoL), time to clinical worsening and health and social care use. A purposive sample of participants (n = 20 intervention and n = 20 control) and practitioners (n = 20) will be interviewed to explore experiences of the trial, outcomes and interventions. DISCUSSION: The SPHERe study is the first multi-centre clinical RCT to assess the clinical and cost effectiveness of a supervised exercise rehabilitation intervention compared to usual care, delivered in the UK NHS, for people in all PH groups. Results will inform clinicians and commissioners as to whether or not supervised exercise rehabilitation is effective and should be routinely provided for people with PH. TRIAL REGISTRATION: ISRCTN no. 10608766, prospectively registered on 18th March 2019.


title: Morbidity and Mortality of Typhoid Intestinal Perforation Among Children in Sub-Saharan Africa 1995–2019: A Scoping Review

text: BACKGROUND: Typhoid fever incidence and complications, including intestinal perforation, have declined significantly in high-income countries, with mortality rates <1%. However, an estimated 10.9 million cases still occur annually, most in low- and middle-income countries. With the availability of a new typhoid conjugate vaccine licensed for children and recommended by the World Health Organization, understanding severe complications, including associated mortality rates, is essential to inform country-level decisions on introduction of this vaccine. This scoping review summarizes over 20 years of the literature on typhoid intestinal perforation in sub-Saharan Africa. METHODS: We searched EMBASE, PubMed, Medline, and Cochrane databases for studies reporting mortality rates due to typhoid intestinal perforation in children, under 18 years old, in sub-Saharan Africa published from January 1995 through June 2019. RESULTS: Twenty-four papers from six countries were included. Reported mortality rates ranged from 4.6–75%, with 16 of the 24 studies between 11 and 30%. Thirteen papers included postoperative morbidity rates, ranging from 16–100%. The most documented complications included surgical site infections, intra-abdominal abscesses, and enterocutaneous fistulas. High mortality rates can be attributed to late presentation to tertiary centers, sepsis and electrolyte abnormalities requiring preoperative resuscitation, prolonged perforation-to-surgery interval, and lack of access to critical care or an intensive care unit postoperatively. CONCLUSIONS: Current estimates of mortality related to typhoid intestinal perforation among children in sub-Saharan Africa remain unacceptably high. Prevention of typhoid fever is essential to reduce mortality, with the ultimate goal of a comprehensive approach that utilizes vaccination, improvements in water, sanitation, and hygiene, and greater access to surgical care. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00268-020-05567-2) contains supplementary material, which is available to authorized users.


Medical Licensure: It is time to eliminate practice borders within the United States


2020 Letter from the Editor-in-Chief


Aktuelles Studienergebnis unterstreicht zurückhaltende Kommentierung


What can the world learn from New Zealand on climate?


When does a major outbreak become a Public Health Emergency of International Concern?


Obituary: Arnold Demain 1927–2020


Abstracts from the International Science Symposium on HIV and Infectious Diseases (ISSHID 2019): Infectious diseases: Chennai, India. 12-14 October 2019


title: In vitro Studies on The Inhibition of Replication of Zika and Chikungunya Viruses by Dolastane Isolated from Seaweed Canistrocarpus cervicornis

text: The lack of vaccines and antiviral treatment, along with the increasing number of cases of Zika virus (ZIKV) and Chikungunya virus (CHIKV) infections, emphasize the need for searching for new therapeutic strategies. In this context, the marine brown seaweed Canistrocarpus cervicornis has been proved to hold great antiviral potential. Hence, the aim of this work was to evaluate the anti-ZIKV and anti-CHIKV activity of a marine dolastane isolated from brown seaweed C. cervicornis and its crude extract. Vero cells were used in antiviral assays, submitted to ZIKV and CHIKV, and treated with different concentrations of C. cervicornis extract or dolastane. The crude extract of C. cervicornis showed inhibitory activities for both ZIKV and CHIKV, with EC(50) values of 3.3 μg/mL and 3.1 μg/mL, respectively. However, the isolated dolastane showed a more significant and promising inhibitory effect (EC(50) = 0.95 µM for ZIKV and 1.3 µM for CHIKV) when compared to both the crude extract and ribavirin, which was used as control. Also, the dolastane showed a very potent virucidal activity against CHIKV and was able to inhibit around 90% of the virus infectivity at 10 μM. For the ZIKV, the effects were somewhat lower, although interesting, at approximately 64% in this same concentration. Further, we observed that both the extract and the dolastane were able to inhibit the replication of ZIKV and CHIKV at different times of addition post-infection, remaining efficient even if added after 8 hours post-infection, but declining soon after. A synergistic effect using sub-doses of the extract and isolates was associated with ribavirin, inhibiting above 80% replication even at the lowest concentrations. Therefore, this work has unveiled the anti-ZIKV and CHIKV potential of C. cervicornis crude extract and an isolated dolastane, which, in turn, can be used as a preventive or therapeutic strategy in the future.


title: Derivation and validation of a prognostic score for neonatal mortality in Ethiopia: a case-control study

text: BACKGROUND: Early warning scores for neonatal mortality have not been designed for low income countries. We developed and validated a score to predict mortality upon admission to a NICU in Ethiopia. METHODS: We conducted a retrospective case-control study at the University of Gondar Hospital, Gondar, Ethiopia. Neonates hospitalized in the NICU between January 1, 2016 to June 31, 2017. Cases were neonates who died and controls were neonates who survived. RESULTS: Univariate logistic regression identified variables associated with mortality. The final model was developed with stepwise logistic regression. We created the Neonatal Mortality Score, which ranged from 0 to 52, from the model’s coefficients. Bootstrap analysis internally validated the model. The discrimination and calibration were calculated. In the derivation dataset, there were 207 cases and 605 controls. Variables associated with mortality were admission level of consciousness, admission respiratory distress, gestational age, and birthweight. The AUC for neonatal mortality using these variables in aggregate was 0.88 (95% CI 0.85–0.91). The model achieved excellent discrimination (bias-corrected AUC) under internal validation. Using a cut-off of 12, the sensitivity and specificity of the Neonatal Mortality Score was 81 and 80%, respectively. The AUC for the Neonatal Mortality Score was 0.88 (95% CI 0.85–0.91), with similar bias-corrected AUC. In the validation dataset, there were 124 cases and 122 controls, the final model and the Neonatal Mortality Score had similar discrimination and calibration. CONCLUSIONS: We developed, internally validated, and externally validated a score that predicts neonatal mortality upon NICU admission with excellent discrimination and calibration.


title: Factors affecting tracheostomy in critically ill paediatric patients in Japan: a data-based analysis

text: BACKGROUND: There has been an increasing number of children surviving with high medical needs, for whom tracheostomy and/or home ventilation is part of their chronic disease management. The purpose of this study was to describe the indications, epidemiology, frequency, and associated factors for tracheostomy in critically ill paediatric patients using the data available in the Japanese Registry of Paediatric Acute Care (JaRPAC). METHODS: This multicentre epidemiologic study collected data concerning paediatric tracheostomy from the JaRPAC database. Patients were divided into two groups: those with or without tracheostomies when they were discharged from the Intensive Care Unit (ICU) or Paediatric Intensive Care Unit (PICU). Consecutive patients aged ≤16 years who did not undergo tracheostomy when admitted to ICU or PICU between April 2014 and March 2017 were included. RESULTS: A total of 23 hospitals participated, involving 6199 paediatric patients registered in the JaRPAC database during the study period. Of the registered paediatric patients, 5769 (95%) patients were admitted to the ICUs or PICUs without tracheostomies. Among the patients, 181 patients (3.1%) had undergone tracheostomies. There were significant differences in chronic conditions (134, 74.0% versus 3096, 55.4%, p < 0.01), chromosomal anomalies (19, 10.5% versus 326, 5.8%, p < 0.01), urgent admission (151, 83.4% versus 3093, 55.4%, p < 0.01). More tracheostomies were performed on patients who were admitted for respiratory failure (61, 33.7% versus 926, 16.1%, p < 0.01) and for post-cardiac pulmonary arrest (CPA) resuscitation (40, 22.1% versus 71, 1.1%, p < 0.01). CONCLUSIONS: This is the first report to use a large-scale registry of critically ill paediatric patients in Japan to describe the interrelated factors of tracheostomies. Chronic conditions (especially for neuromuscular disease), chromosomal anomaly, admission due to respiratory failure, or treatment for post-CPA resuscitation all had the possibility to be risk factors for tracheostomy.


docid: dogmqsys

title: The Journal of Adolescent Health Editor-In-Chief Annual Reflection: A Year of Extraordinary Change


JAH Intersection: An Introduction and Invitation


Start Now


title: Cold Exposure-Induced Up-Regulation of Hsp70 Positively Regulates PEDV mRNA Synthesis and Protein Expression In Vitro

text: Porcine epidemic diarrhea (PED) is a highly contagious, intestinal infectious disease caused by porcine epidemic diarrhea virus (PEDV). PEDV as an emerging and re-emerging epizootic virus of swine causes substantial economic losses to the pig industry in China and other countries. In China, the occurrence of PED shows significant seasonal variations, usually outbreak during the winter season. The epidemic characteristics of PED may be highly correlated with the changes of ambient temperature. However, molecular mechanism on the seasonal occurrence of PED still remains unclear. It has been widely observed that low ambient temperature up-regulates the expression of host heat shock protein 70 (Hsp70). Here, we showed that nucleotide and protein levels of Hsp70 were up-regulated in the intestinal of cold exposed pig and cold exposed Vero E6 cells. We found that overexpression of Hsp70 could increase PEDV mRNA synthesis and protein expression in Vero E6 and IPEC-J2 cells, while the siRNAs mediated knockdown of Hsp70 and VER155008 mediated inhibition of Hsp70 resulted in inhibition of viral mRNA synthesis and protein expression in Vero E6 cells. These data suggested that Hsp70 positively regulated PEDV mRNA synthesis and protein expression, which being helpful for understanding the seasonality of PED epidemics and development of novel antiviral therapies in the future.


title: Novel Approaches Towards a Functional Cure of HIV/AIDS

text: Therapeutic approaches towards a functional cure or eradication of HIV have gained renewed momentum upon encouraging data emerging from studies in SIV monkey models and recent results from human clinical studies. However, a multitude of questions remain to be addressed, including how to deal with the latent viral reservoir, how to boost the host immune response to the virus and what the hurdles are to reach relevant viral compartments in the body. Advances have been made especially with regard to identifying agents that can reactivate the latent virus in vivo and boost the cellular and humoral immunity, but it remains largely unclear whether any of these strategies can awaken a sufficiently large fraction of the viral reservoir and whether the boosted immunity can prevent rapid viral replication once antiretroviral treatments are stopped.


title: Retrobulbar Sinus Injection of Doxorubicin is More Efficient Than Lateral Tail Vein Injection at Inducing Experimental Nephrotic Syndrome in Mice: A Pilot Study

text: Doxorubicin-induced nephropathy in mice is a model for studying experimental nephrotic syndrome. It corresponds to puromycin aminonucleoside nephrosis in rats. In this model, susceptible 129 S1/SvImJ mice are administered a rapid intravenous injection that can be accomplished via either the lateral tail vein or the retrobulbar sinus. Because doxorubicin is a highly toxic substance, extravasation must be avoided during the administration of the intravenous injection to prevent the development of large necrotizing lesions and exacerbation of the animals’ stress. In the present study, we compared the safety and stress of these two injection routes by using histopathological analyses of the animals’ orbital cavities or tails, respectively. The injection of 14.5 µg/g body weight doxorubicin into the mice’s lateral tail veins (n = 9) or retrobulbar sinuses (n = 19) caused no clinically detectable stress or impairment. Histopathologies of the specimens five days after doxorubicin injection revealed inflammatory lesions at the injection sites in both groups. In the orbital sinus specimens from the retrobulbar-injected group, fibrosis was evident 25 days after injection. Moreover, while all of the retrobulbar-injected mice (100%) developed nephrotic syndrome, tail vein-injected mice had a significantly lower response rate (66%, p = 0.047, Fisher’s exact test) and exhibited only attenuated features of nephrotic syndrome. It was therefore concluded that doxorubicin administration via either lateral tail vein or retrobulbar sinus injections led to a similar induction of histopathological changes with no effects on the clinical well-being of the mice. However, retrobulbar sinus injections were more efficient for inducing experimental nephrotic syndrome.


SPR 2020


Authors’ correction for Euro Surveill. 2020;25(17)


title: A guide to cancer immunotherapy: from T cell basic science to clinical practice

text: The T lymphocyte, especially its capacity for antigen-directed cytotoxicity, has become a central focus for engaging the immune system in the fight against cancer. Basic science discoveries elucidating the molecular and cellular biology of the T cell have led to new strategies in this fight, including checkpoint blockade, adoptive cellular therapy and cancer vaccinology. This area of immunological research has been highly active for the past 50 years and is now enjoying unprecedented bench-to-bedside clinical success. Here, we provide a comprehensive historical and biological perspective regarding the advent and clinical implementation of cancer immunotherapeutics, with an emphasis on the fundamental importance of T lymphocyte regulation. We highlight clinical trials that demonstrate therapeutic efficacy and toxicities associated with each class of drug. Finally, we summarize emerging therapies and emphasize the yet to be elucidated questions and future promise within the field of cancer immunotherapy.


Balancing Expediency and Scientific Rigor in Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine Development


Re: Reflections on the COVID-19 Pandemic