Maturation of the infant respiratory microbiota, environmental drivers and health consequences: a prospective cohort study

Rationale: Perinatal and postnatal influences are presumed important drivers of the early-life respiratory microbiota composition. We hypothesized that the respiratory microbiota composition and development in infancy is affecting microbiota stability and thereby resistance against respiratory tract infections (RTIs) over time. Objectives: To investigate common environmental drivers, including birth mode, feeding type, antibiotic exposure, and crowding conditions, in relation to respiratory tract microbiota maturation and stability, and consecutive risk of RTIs over the first year of life. Methods: In a prospectively followed cohort of 112 infants, we characterized the nasopharyngeal microbiota longitudinally from birth on (11 consecutive sample moments and the maximum three RTI samples per subject; in total, n = 1,121 samples) by 16S-rRNA gene amplicon sequencing. Measurements and Main Results: Using a microbiota-based machine-learning algorithm, we found that children experiencing a higher number of RTIs in the first year of life already demonstrate an aberrant microbial developmental trajectory from the first month of life on as compared with the reference group (0-2 RTIs/yr). The altered microbiota maturation process coincided with decreased microbial community stability, prolonged reduction of Corynebacterium and Dolosigranulum, enrichment of Moraxella very early in life, followed by later enrichment of Neisseria and Prevotella spp. Independent drivers of these aberrant developmental trajectories of respiratory microbiota members were mode of delivery, infant feeding, crowding, and recent antibiotic use. Conclusions: Our results suggest that environmental drivers impact microbiota development and, consequently, resistance against development of RTIs. This supports the idea that microbiota form the mediator between early-life environmental risk factors for and susceptibility to RTIs over the first year of life

The use of opioids at the end of life: the knowledge level of Dutch physicians as a potential barrier to effective pain management

<p>Abstract</p> <p>Background</p> <p>Pain is still one of the most frequently occurring symptoms at the end of life, although it can be treated satisfactorily in most cases if the physician has adequate knowledge. In the Netherlands, almost 60% of the patients with non-acute illnesses die at home where end of life care is coordinated by the general practitioner (GP); about 30% die in hospitals (cared for by clinical specialists), and about 10% in nursing homes (cared for by elderly care physicians).</p> <p>The research question of this study is: what is the level of knowledge of Dutch physicians concerning pain management and the use of opioids at the end of life?</p> <p>Methods</p> <p>A written questionnaire was sent to a random sample of physicians of specialties most often involved in end of life care in the Netherlands. The questionnaire was completed by 406 physicians, response rate 41%.</p> <p>Results</p> <p>Almost all physicians were aware of the most basal knowledge about opioids, e.g. that it is important for treatment purposes to distinguish nociceptive from neuropathic pain (97%). Approximately half of the physicians (46%) did not know that decreased renal function raises plasma concentration of morphine(-metabolites) and 34% of the clinical specialists erroneously thought opioids are the favoured drug for palliative sedation.</p> <p>Although 91% knew that opioids titrated against pain do not shorten life, 10% sometimes or often gave higher dosages than needed with the explicit aim to hasten death. About half felt sometimes or often pressured by relatives to hasten death by increasing opioiddosage.</p> <p>The large majority (83%) of physicians was interested in additional education about subjects related to the end of life, the most popular subject was opioid rotation (46%).</p> <p>Conclusions</p> <p>Although the basic knowledge of physicians was adequate, there seemed to be a lack of knowledge in several areas, which can be a barrier for good pain management at the end of life. From this study four areas emerge, in which it seems likely that an improvement can improve the quality of pain management at the end of life for many patients in the Netherlands: 1)palliative sedation; 2)expected effect of opioids on survival; and 3) opioid rotation.</p

Modelling Jets, Tori and Flares in Pulsar Wind Nebulae

In this contribution we review the recent progress in the modelling of Pulsar Wind Nebulae (PWN). We start with a brief overview of the relevant physical processes in the magnetosphere, the wind-zone and the inflated nebula bubble. Radiative signatures and particle transport processes obtained from 3D simulations of PWN are discussed in the context of optical and X-ray observations. We then proceed to consider particle acceleration in PWN and elaborate on what can be learned about the particle acceleration from the dynamical structures called GwispsG observed in the Crab nebula. We also discuss recent observational and theoretical results of gamma-ray flares and the inner knot of the Crab nebula, which had been proposed as the emission site of the flares. We extend the discussion to GeV flares from binary systems in which the pulsar wind interacts with the stellar wind from a companion star. The chapter concludes with a discussion of solved and unsolved problems posed by PWN

Bacterial–bacterial interactions.

<p>The composition of nasopharyngeal microbiota is constantly subject to interactions between species. Bacterial species can interact with other bacterial species by competition and synergism. Synergism can be characterized by, for instance, the production of components that favors another species, as shown for the production of outer membrane vesicles. These may contain factors that are able to inactivate complement factor C3, thereby allowing another species to escape the immune system. Production of substances by one species, for example hydrogen peroxide (H₂O₂), may eliminate its competitor. The immune system may also be involved in competition, as one bacterium has fewer escape mechanisms to evade the immune system than another and therefore may use co-inhabitants to survive, whereas the reverse phenomenon (i.e., one species may trigger the immune system to combat the other species) may also occur. In addition, since PhC (phosphorylcholine) is shown to be immunogenic and some species may be able to switch off PhC expression whereas others cannot, there might be a selective advantage. Another form of competition involves competition for the same host receptor, as demonstrated for PhC and its receptor platelet activating factor receptor (PAFr). Moreover, one species may use neuraminidase to cut off the sialic acids (SA) that other bacteria may require for attachment to host receptors, therefore inhibiting adherence of the other bacterial species. H₂O₂, hydrogen peroxide; PAFr, platelet activating factor receptor; PhC, phosphorylcholine; NA, neuraminidase; SA, sialic acid (SA); rSA, receptor for sialic acids; Ab, antibodies.</p

Viral–bacterial interaction based on data available from human, animal, and in vitro studies.

<p>Virus (column one) and respective bacterium (column two) for which interactions were observed (column three), and source of evidence: from human studies (column four), animal studies (column five), or in vitro studies (column six) showing type of epithelium tested.</p><p>NA, data not available from literature.</p

Viral–bacterial interactions.

<p>(A) Viral–bacterial interaction on the respiratory epithelial surface. Viral presence is thought to predispose the respiratory niche to bacterial colonization by different mechanisms. First, viruses may render the epithelium more susceptible to bacterial colonization by altering the mucosal surfaces. Ciliae may be damaged, leading to decreased mucociliar function of the respiratory epithelium. Additionally, due to viral-induced damage and loss of integrity of the epithelium layer, bacterial colonization may be enhanced and translocation may be increased. Virus-infected cells may decrease the expression of antimicrobial peptides, as shown for β-defensins, thereby affecting the natural defense of the host epithelium. Viral neuraminidase (NA) activity is able to cleave sialic acids residues, thereby giving access to bacterial receptors that were covered by these residues. Finally, viruses may induce bacterial colonization and replication both directly and indirectly, the latter by inducing upregulation of various receptors required for bacterial adherence, including PAFr, CAECAM-1, P5F, ICAM-1, and G-protein. PAFr, platelet activating factor receptor; ICAM-1, intracellular adhesion molecule 1; P5 fimbriae, outer membrane protein P5-homologous fimbriae; CAECAM-1, carcinoembryonic adhesion molecule-1; PhC, phosphorylcholine; SA, sialic acids; rSA, receptor for sialic acids; NA, neuraminidase; mRNA, messenger RNA, AMPs, antimicrobial peptides. (B) Viral–bacterial interaction in relation to the host immune system. Viruses may also induce changes in immune function favorable to bacterial invasion: fewer NK cells may be recruited into the tissue and their functionality may be suboptimal as a consequence of viral infection. Virus-induced IFN-α and IFN-β may impair recruitment and functionality of neutrophils, and subsequently induce apoptosis of neutrophils recruited to combat the viral invader. Furthermore, IFN-γ seems to negatively affect the activity of macrophages. Viral-infected monocytes appear less effective in ingesting and killing bacteria, predisposing them to bacterial overgrowth and invasion. Viral infection seems to impair TLR pathways, induce production of the anti-inflammatory cytokine IL-10, and decrease the concentration of the pro-inflammatory cytokine TNF-α, generally affecting adequate immune responses to bacterial infections. Black arrows indicate increased (↑) or decreased (↓) activity or functionality of a cytokine. IFN, interferon; TNF, tumor necrosis factor; TLR, toll like receptor; IL, interleukin; NK cell, natural killer cell.</p

Viral detection in respiratory samples in asymptomatic children.

a<p>Related to geographical area.</p>b<p>Number of samples tested.</p>c<p>Stratified for season.</p>d<p>Picornavirus general.</p><p>M, months of age; Y, years of age; HRV, human rhinoviruses; EV, entero viruses; AdV, adeno viruses; HBoV, human bocavirus; RSV, respiratory syncytial virus; hMPV, human metapneumovirus; CoV, corona viruses; IV, influenza viruses; PIV, para-influenza viruses; NS, not specified.</p

Nasopharyngeal carriage of Streptococcus pneumoniae and other bacteria in the 7th year after implementation of the pneumococcal conjugate vaccine in the Netherlands

After introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in the infant national immunization program (NIP) in the Netherlands in 2006, Streptococcus pneumoniae strains of the non-vaccine serotype 19A emerged and became the dominant serotype in carriage in children and their parents. Similar patterns were observed in other European countries and the United States. Increases in carriage rates of Staphylococcus aureus and non-typeable (NT) Haemophilus influenzae were also observed. After switching of PCV7 to 10-valent vaccine (PCV10) in 2011, a new carriage surveillance study was performed in the winter of 2012/2013. Nasopharyngeal carriage of S. pneumoniae, H. influenzae, S. aureus, and Moraxella catarrhalis was determined by conventional culture in 330 PCV10-vaccinated 11-month-old children, 330 PCV7-vaccinated 24-month-old children, and their parents. Carriage prevalence was compared with similar carriage studies conducted in 2005, 2009, and 2010/2011. Although serotype 19A remained the most frequently carried pneumococcal serotype in children, prevalence of 19A significantly declined in PCV7-vaccinated 24-month-old children (14% to 8%, p= 0.01), but less in PCV10-vaccinated 11-month-old children (12% to 9%, p= 0.31). Carriage of H. influenzae remained stable at an elevated level (65% in 11-month-olds and 69% in 24-month-olds), while the carriage of S. aureus returned to pre-PCV7 levels in 11-month-old children (14% in 2010/2011 to 7% in 2012/2013), but not in 24-month-olds (remained at 7%). Our results might indicate a new balance between replacing non-vaccine pneumococcal serotypes and other potential pathogenic bacteria in nasopharyngeal carriage. Carriage studies are valuable tools in assessing vaccine effects on pathogens circulating in the population, for evaluation of PCV impact, and in predicting changes in respiratory and invasive disease