Haemophilus influenzae and smoking-related obstructive airways disease

Background: Intralumenal bacteria play a critical role in the pathogenesis of acute infective episodes and airway inflammation. Antigens from colonizing bacteria such as nontypeable Haemophilus influenzae (NTHi) may contribute to chronic lung disease through an immediate hypersensitivity response. The objective of this study was to determine the presence of specific NTHi-IgE antibodies in subjects with chronic bronchitis (CB) and COPD who had smoked. Methods: Serum, sputum, and saliva samples were collected from subjects with CB and moderate–severe COPD and healthy aged-matched controls. Total IgE and specific NTHi IgE were measured by enzyme linked immmunosorbent assay. Throat swabs were examined for the presence of NTHi. Results: The results demonstrate that: i) specific NTHi IgE antibodies occur at a low level in healthy subjects; ii) those with both CB and moderate–severe COPD have elevated specific NTHi IgE antibody compared with healthy controls, with higher levels in those with most severe disease; iii) IgE levels are greater in those with moderate–severe COPD than in those with CB. They demonstrate specific NTHi IgE antibody is regularly found at higher than normal levels in COPD. Conclusion: The detection of IgE antibody to colonizing bacteria in all subjects with CB or moderate–severe COPD identifies a possible mechanism of bronchospasm in these subjects amenable to specific intervention therapy

Plasma TGF-β1 in pediatric cystic fibrosis: Potential biomarker of lung disease and response to therapy

Transforming growth factor beta-1 (TGF-β1) is an important genetic modifier of lung disease severity in cystic fibrosis (CF), yet the mechanism behind this disease association remains unknown. Initial steps in the investigation of the relationship between TGF-β1 and CF lung disease include determining the most appropriate available biospecimen for TGF-β1 protein measurement

A multiscale predictive digital twin for neurocardiac modulation

Cardiac function is tightly regulated by the autonomic nervous system (ANS). Activation of the sympathetic nervous system increases cardiac output by increasing heart rate and stroke volume, while parasympathetic nerve stimulation instantly slows heart rate. Importantly, imbalance in autonomic control of the heart has been implicated in the development of arrhythmias and heart failure. Understanding of the mechanisms and effects of autonomic stimulation is a major challenge because synapses in different regions of the heart result in multiple changes to heart function. For example, nerve synapses on the sinoatrial node (SAN) impact pacemaking, while synapses on contractile cells alter contraction and arrhythmia vulnerability. Here, we present a multiscale neurocardiac modelling and simulator tool that predicts the effect of efferent stimulation of the sympathetic and parasympathetic branches of the ANS on the cardiac SAN and ventricular myocardium. The model includes a layered representation of the ANS and reproduces firing properties measured experimentally. Model parameters are derived from experiments and atomistic simulations. The model is a first prototype of a digital twin that is applied to make predictions across all system scales, from subcellular signalling to pacemaker frequency to tissue level responses. We predict conditions under which autonomic imbalance induces proarrhythmia and can be modified to prevent or inhibit arrhythmia. In summary, the multiscale model constitutes a predictive digital twin framework to test and guide high-throughput prediction of novel neuromodulatory therapy. KEY POINTS: A multi-layered model representation of the autonomic nervous system that includes sympathetic and parasympathetic branches, each with sparse random intralayer connectivity, synaptic dynamics and conductance based integrate-and-fire neurons generates firing patterns in close agreement with experiment. A key feature of the neurocardiac computational model is the connection between the autonomic nervous system and both pacemaker and contractile cells, where modification to pacemaker frequency drives initiation of electrical signals in the contractile cells. We utilized atomic-scale molecular dynamics simulations to predict the association and dissociation rates of noradrenaline with the β-adrenergic receptor. Multiscale predictions demonstrate how autonomic imbalance may increase proclivity to arrhythmias or be used to terminate arrhythmias. The model serves as a first step towards a digital twin for predicting neuromodulation to prevent or reduce disease

Public health messages on arboviruses transmitted by Aedes aegypti in Brazil.

BACKGROUND: The outbreak of Zika virus in Brazil in 2015 followed the arrival of chikungunya in 2014 and a long history of dengue circulation. Vital to the response to these outbreaks of mosquito-borne pathogens has been the dissemination of public health messages, including those promoted through risk communication posters. This study explores the content of a sample of posters circulated in Brazil towards the end of the Zika epidemic in 2017 and analyses their potential effectiveness in inducing behaviour change. METHODS: A content analysis was performed on 37 posters produced in Brazil to address outbreaks of mosquito-borne pathogens. The six variables of the Health Belief Model were used to assess the potential effectiveness of the posters to induce behaviour change. RESULTS: Three overarching key messages emerged from the posters. These included (i) the arboviruses and their outcomes, (ii) a battle against the mosquito, and (iii) a responsibility to protect and prevent. Among the six variables utilised through the Health Belief Model, cues to action were most commonly featured, whilst the perceived benefits of engaging in behaviours to prevent arbovirus transmission were the least commonly featured. CONCLUSIONS: The posters largely focused on mosquito-borne transmission and the need to eliminate breeding sites, and neglected the risk of the sexual and congenital transmission of Zika and the importance of alternative preventive actions. This, we argue, may have limited the potential effectiveness of these posters to induce behaviour change

Explanation for the increase in high altitude water on Mars observed by NOMAD during the 2018 global dust storm

The Nadir and Occultation for MArs Discovery (NOMAD) instrument on board ExoMars Trace Gas Orbiter (TGO) measured a large increase in water vapor at altitudes in the range of 40‐100 km during the 2018 global dust storm on Mars. Using a three‐dimensional general circulation model, we examine the mechanism responsible for the enhancement of water vapor in the upper atmosphere. Experiments with different prescribed vertical profiles of dust show that when more dust is present higher in the atmosphere the temperature increases and the amount of water ascending over the tropics is not limited by saturation until reaching heights of 70‐100 km. The warmer temperatures allow more water to ascend to the mesosphere. Photochemical simulations show a strong increase in high‐altitude atomic hydrogen following the high‐altitude water vapor increase by a few days

Practice Management Guidelines for the Diagnosis and Management of Injury in the Pregnant Patient: The EAST Practice Management Guidelines Work Group

Trauma during pregnancy has presented very unique challenges over the centuries. From the first report of Ambrose Pare of a gunshot wound to the uterus in the 1600s to the present, there have existed controversies and inconsistencies in diagnosis, management, prognostics, and outcome. Anxiety is heightened by the addition of another, smaller patient. Trauma affects 7% of all pregnancies and requires admission in 4 of 1000 pregnancies. The incidence increases with advancing gestational age. Just over half of trauma during pregnancy occurs in the third trimester. Motor vehicle crashes comprise 50% of these traumas, and falls and assaults account for 22% each. These data were considered to be underestimates because many injured pregnant patients are not seen at trauma centers. Trauma during pregnancy is the leading cause of nonobstetric death and has an overall 6% to 7% maternal mortality. Fetal mortality has been quoted as high as 61% in major trauma and 80% if maternal shock is present. The anatomy and physiology of pregnancy make diagnosis and treatment difficult

A Novel and Lethal De Novo LQT-3 Mutation in a Newborn with Distinct Molecular Pharmacology and Therapeutic Response

SCN5A encodes the alpha-subunit (Na(v)1.5) of the principle Na(+) channel in the human heart. Genetic lesions in SCN5A can cause congenital long QT syndrome (LQTS) variant 3 (LQT-3) in adults by disrupting inactivation of the Na(v)1.5 channel. Pharmacological targeting of mutation-altered Na(+) channels has proven promising in developing a gene-specific therapeutic strategy to manage specifically this LQTS variant. SCN5A mutations that cause similar channel dysfunction may also contribute to sudden infant death syndrome (SIDS) and other arrhythmias in newborns, but the prevalence, impact, and therapeutic management of SCN5A mutations may be distinct in infants compared with adults.Here, in a multidisciplinary approach, we report a de novo SCN5A mutation (F1473C) discovered in a newborn presenting with extreme QT prolongation and differential responses to the Na(+) channel blockers flecainide and mexiletine. Our goal was to determine the Na(+) channel phenotype caused by this severe mutation and to determine whether distinct effects of different Na(+) channel blockers on mutant channel activity provide a mechanistic understanding of the distinct therapeutic responsiveness of the mutation carrier. Sequence analysis of the proband revealed the novel missense SCN5A mutation (F1473C) and a common variant in KCNH2 (K897T). Patch clamp analysis of HEK 293 cells transiently transfected with wild-type or mutant Na(+) channels revealed significant changes in channel biophysics, all contributing to the proband's phenotype as predicted by in silico modeling. Furthermore, subtle differences in drug action were detected in correcting mutant channel activity that, together with both the known genetic background and age of the patient, contribute to the distinct therapeutic responses observed clinically.The results of our study provide further evidence of the grave vulnerability of newborns to Na(+) channel defects and suggest that both genetic background and age are particularly important in developing a mutation-specific therapeutic personalized approach to manage disorders in the young

A Universal Next-Generation Sequencing Protocol To Generate Noninfectious Barcoded cDNA Libraries from High-Containment RNA Viruses

ABSTRACT Several biosafety level 3 and/or 4 (BSL-3/4) pathogens are high-consequence, single-stranded RNA viruses, and their genomes, when introduced into permissive cells, are infectious. Moreover, many of these viruses are select agents (SAs), and their genomes are also considered SAs. For this reason, cDNAs and/or their derivatives must be tested to ensure the absence of infectious virus and/or viral RNA before transfer out of the BSL-3/4 and/or SA laboratory. This tremendously limits the capacity to conduct viral genomic research, particularly the application of next-generation sequencing (NGS). Here, we present a sequence-independent method to rapidly amplify viral genomic RNA while simultaneously abolishing both viral and genomic RNA infectivity across multiple single-stranded positive-sense RNA (ssRNA+) virus families. The process generates barcoded DNA amplicons that range in length from 300 to 1,000 bp, which cannot be used to rescue a virus and are stable to transport at room temperature. Our barcoding approach allows for up to 288 barcoded samples to be pooled into a single library and run across various NGS platforms without potential reconstitution of the viral genome. Our data demonstrate that this approach provides full-length genomic sequence information not only from high-titer virion preparations but it can also recover specific viral sequence from samples with limited starting material in the background of cellular RNA, and it can be used to identify pathogens from unknown samples. In summary, we describe a rapid, universal standard operating procedure that generates high-quality NGS libraries free of infectious virus and infectious viral RNA. IMPORTANCE This report establishes and validates a standard operating procedure (SOP) for select agents (SAs) and other biosafety level 3 and/or 4 (BSL-3/4) RNA viruses to rapidly generate noninfectious, barcoded cDNA amenable for next-generation sequencing (NGS). This eliminates the burden of testing all processed samples derived from high-consequence pathogens prior to transfer from high-containment laboratories to lower-containment facilities for sequencing. Our established protocol can be scaled up for high-throughput sequencing of hundreds of samples simultaneously, which can dramatically reduce the cost and effort required for NGS library construction. NGS data from this SOP can provide complete genome coverage from viral stocks and can also detect virus-specific reads from limited starting material. Our data suggest that the procedure can be implemented and easily validated by institutional biosafety committees across research laboratories