Mirtazapine for chronic breathlessness? A review of mechanistic insights and therapeutic potential

Introduction: Chronic breathlessness is a common and distressing symptom of advanced disease with few effective treatments. Central nervous system mechanisms are important in respiratory sensation and control. Consequently, drugs which may modify processing and perception of afferent information in the brain, may have a role. Antidepressants have been proposed, however current evidence is limited. Of potentially suitable antidepressants, mirtazapine is an attractive option given its tolerability profile, low cost and wide availability, along with additional potential benefits.Areas covered: The paper provides an overview of the physiology of breathlessness, with an emphasis on central mechanisms, particularly the role of fear circuits and the associated neurotransmitters. It provides a potential rationale for how mirtazapine may improve chronic breathlessness and quality of life in patients with advanced disease. The evidence was identified by a literature search performed in PubMed through to October 2018.Expert commentary: Currently, there is insufficient evidence to support the routine use of antidepressants for chronic breathlessness in advanced disease. Mirtazapine is a promising candidate to pursue, with definitive randomised controlled trials required to determine its efficacy and safety in this setting

A chromosomally integrated bacteriophage in invasive meningococci

Cerebrospinal meningitis is a feared disease that can cause the death of a previously healthy individual within hours. Paradoxically, the causative agent, Neisseria meningitidis, is a common inhabitant of the human nasopharynx, and as such, may be considered a normal, commensal organism. Only in a small proportion of colonized people do the bacteria invade the bloodstream, from where they can cross the blood–brain barrier to cause meningitis. Furthermore, most meningococcal disease is caused by bacteria belonging to only a few of the phylogenetic groups among the large number that constitute the population structure of this genetically variable organism. However, the genetic basis for the differences in pathogenic potential remains elusive. By performing whole genome comparisons of a large collection of meningococcal isolates of defined pathogenic potential we brought to light a meningococcal prophage present in disease-causing bacteria. The phage, of the filamentous family, excises from the chromosome and is secreted from the bacteria via the type IV pilin secretin. Therefore, this element, by spreading among the population, may promote the development of new epidemic clones of N. meningitidis that are capable of breaking the normal commensal relationship with humans and causing invasive disease

Frequent capsule switching in 'ultra-virulent' meningococci - Are we ready for a serogroup B ST-11 complex outbreak?

The meningococcal ST-11 complex (cc11) causes large invasive disease outbreaks with high case fatality rates, such as serogroup C (MenC) epidemics in industrialised nations in the 1990s and the serogroup W epidemic currently expanding globally. Glycoconjugate vaccines are available for serogroups A, C, W and Y. Broad coverage protein-based vaccines have recently been licensed against serogroup B meningococci (MenB), however, these do not afford universal MenB protection. Capsular switching from MenC to MenB among cc11 organisms is concerning because a large MenB cc11 (B:cc11) outbreak has the potential to cause significant morbidity and mortality. This study aimed to assess the potential for licensed and developmental non-capsular meningococcal vaccines to protect against B:cc11. The population structure and vaccine antigen distribution was determined for a panel of >800 geo-temporally diverse, predominantly MenC cc11 and B:cc11 genomes. The two licensed vaccines potentially protect against many but not all B:cc11 meningococci. Furthermore, strain coverage by these vaccines is often due to a single vaccine antigen and both vaccines are highly susceptible to vaccine escape owing to the apparent dispensability of key proteins used as vaccine antigens. cc11 strains with MenB and MenC capsules warrant special consideration when formulating future non-capsular meningococcal vaccines

Disease-associated genotypes of the commensal skin bacterium Staphylococcus epidermidis

Some of the most common infectious diseases are caused by bacteria that naturally colonise humans asymptomatically. Combating these opportunistic pathogens requires an understanding of the traits that differentiate infecting strains from harmless relatives. Staphylococcus epidermidis is carried asymptomatically on the skin and mucous membranes of virtually all humans but is a major cause of nosocomial infection associated with invasive procedures. Here we address the underlying evolutionary mechanisms of opportunistic pathogenicity by combining pangenome-wide association studies and laboratory microbiology to compare S. epidermidis from bloodstream and wound infections and asymptomatic carriage. We identify 61 genes containing infection-associated genetic elements (k-mers) that correlate with in vitro variation in known pathogenicity traits (biofilm formation, cell toxicity, interleukin-8 production, methicillin resistance). Horizontal gene transfer spreads these elements, allowing divergent clones to cause infection. Finally, Random Forest model prediction of disease status (carriage vs. infection) identifies pathogenicity elements in 415 S. epidermidis isolates with 80% accuracy, demonstrating the potential for identifying risk genotypes pre-operatively.Peer reviewe

The global meningitis genome partnership.

Genomic surveillance of bacterial meningitis pathogens is essential for effective disease control globally, enabling identification of emerging and expanding strains and consequent public health interventions. While there has been a rise in the use of whole genome sequencing, this has been driven predominately by a subset of countries with adequate capacity and resources. Global capacity to participate in surveillance needs to be expanded, particularly in low and middle-income countries with high disease burdens. In light of this, the WHO-led collaboration, Defeating Meningitis by 2030 Global Roadmap, has called for the establishment of a Global Meningitis Genome Partnership that links resources for: N. meningitidis (Nm), S. pneumoniae (Sp), H. influenzae (Hi) and S. agalactiae (Sa) to improve worldwide co-ordination of strain identification and tracking. Existing platforms containing relevant genomes include: PubMLST: Nm (31,622), Sp (15,132), Hi (1935), Sa (9026); The Wellcome Sanger Institute: Nm (13,711), Sp (> 24,000), Sa (6200), Hi (1738); and BMGAP: Nm (8785), Hi (2030). A steering group is being established to coordinate the initiative and encourage high-quality data curation. Next steps include: developing guidelines on open-access sharing of genomic data; defining a core set of metadata; and facilitating development of user-friendly interfaces that represent publicly available data

A logic of behaviour in context

AbstractWe present a novel temporal logic for expressing properties of behaviour in context. The logic is applied to models of continuous processes, specifically using the continuous π-calculus as a modelling language for biochemical systems.The logic allows the expression of the temporal behaviour of a system when placed in the context of another system. Here we study this in terms of biochemical reactions and the expression of temporal behaviour in the context of other biochemical processes. We present the syntax and semantics of the logic and study the model-checking problem over continuous time and continuous state-space process models, using the continuous π-calculus.We present a succinct, but naive, model-checking algorithm and then show how this can be improved. We investigate the complexity of model-checking, where repeated ODE solving emerges as a particular cost; assess some limitations of the technique; and identify potential routes to overcome these

Black Hole Spin via Continuum Fitting and the Role of Spin in Powering Transient Jets

The spins of ten stellar black holes have been measured using the continuum-fitting method. These black holes are located in two distinct classes of X-ray binary systems, one that is persistently X-ray bright and another that is transient. Both the persistent and transient black holes remain for long periods in a state where their spectra are dominated by a thermal accretion disk component. The spin of a black hole of known mass and distance can be measured by fitting this thermal continuum spectrum to the thin-disk model of Novikov and Thorne; the key fit parameter is the radius of the inner edge of the black hole's accretion disk. Strong observational and theoretical evidence links the inner-disk radius to the radius of the innermost stable circular orbit, which is trivially related to the dimensionless spin parameter a_* of the black hole (|a_*| < 1). The ten spins that have so far been measured by this continuum-fitting method range widely from a_* \approx 0 to a_* > 0.95. The robustness of the method is demonstrated by the dozens or hundreds of independent and consistent measurements of spin that have been obtained for several black holes, and through careful consideration of many sources of systematic error. Among the results discussed is a dichotomy between the transient and persistent black holes; the latter have higher spins and larger masses. Also discussed is recently discovered evidence in the transient sources for a correlation between the power of ballistic jets and black hole spin.Comment: 30 pages. Accepted for publication in Space Science Reviews. Also to appear in hard cover in the Space Sciences Series of ISSI "The Physics of Accretion onto Black Holes" (Springer Publisher). Changes to Sections 5.2, 6.1 and 7.4. Section 7.4 responds to Russell et al. 2013 (MNRAS, 431, 405) who find no evidence for a correlation between the power of ballistic jets and black hole spi

Pharyngeal carriage of Neisseria species in the African meningitis belt.

OBJECTIVES: Neisseria meningitidis, together with the non-pathogenic Neisseria species (NPNs), are members of the complex microbiota of the human pharynx. This paper investigates the influence of NPNs on the epidemiology of meningococcal infection. METHODS: Neisseria isolates were collected during 18 surveys conducted in six countries in the African meningitis belt between 2010 and 2012 and characterized at the rplF locus to determine species and at the variable region of the fetA antigen gene. Prevalence and risk factors for carriage were analyzed. RESULTS: A total of 4694 isolates of Neisseria were obtained from 46,034 pharyngeal swabs, a carriage prevalence of 10.2% (95% CI, 9.8-10.5). Five Neisseria species were identified, the most prevalent NPN being Neisseria lactamica. Six hundred and thirty-six combinations of rplF/fetA_VR alleles were identified, each defined as a Neisseria strain type. There was an inverse relationship between carriage of N. meningitidis and of NPNs by age group, gender and season, whereas carriage of both N. meningitidis and NPNs was negatively associated with a recent history of meningococcal vaccination. CONCLUSION: Variations in the prevalence of NPNs by time, place and genetic type may contribute to the particular epidemiology of meningococcal disease in the African meningitis belt.MenAfriCar was funded by the Wellcome Trust (086546/Z/08/Z) and the Bill and Melinda Gates Foundation (51251). Kanny Diallo holds a Wellcome Trust Training Fellowship in Public Health and Tropical Medicine.This is the final version of the article. It first appeared from Elsevier via https://doi.org/10.1016/j.jinf.2016.03.01