Every baby, child and adolescent will experience pain at times throughout their life. Despite its ubiquity, pain is a major challenge for individuals, families, healthcare professionals, and societies. Pain is often hidden and can go undiscussed or ignored. Undertreated, unrecognised, or poorly managed pain in childhood leads to important and long-lasting negative consequences that continue into adulthood. This undertreatment should not continue. We have the tools, expertise, and evidence to provide better treatment for childhood pain.In this Commission we present four transformative goals that will, if achieved, transform the lives of children with pain and their families. These goals, taken at face value, may seem simple and obvious. However, if the goals were easy to achieve there would be few, if any, young people reporting poorly managed acute pain, pain after surgery or procedures, or ongoing chronic pain. Pain is multifactorial, and influenced by biological, psychological and social factors, making it complex and difficult to treat effectively, especially in infants, children and adolescents. This Commission focusses on children from birth through to 24 years of age in developed countries.The first transformative goal is to 'make pain matter'. Here we argue that pain has not mattered enough, as evidenced by common failings in clinical practice, low levels of training and investment, and a lack of concern for issues of equity and equality. Despite some good examples of knowledge translation, we highlight that investment in a strong social science research base for paediatric pain will catapult us into a new era in which we can address the social and cultural context of pain.The second is to 'make pain understood' at a fundamental biological and psychological level. There has been excellent progress in mechanistic understandings of nociception and pain perception for both acute and chronic pain states but gaps in knowledge remain. Advances in developmental biology, in genetics, in psychology, and in nosology and classification will all help speed up the discovery in these areas. There is also a need for greater investment in larger international birth cohort studies that incorporate comprehensive pain-related measurement incorporated.The third is to 'make pain visible'. Pain can and should be assessed. We need to help improve understanding of optimal methods for pain assessment at throughout childhood and in all clinical scenarios. While subjective pain report is the primary and desirable method when this is possible, many of the methods and measures that are in common use can and should be improved. There has been development in understanding the biological correlates of pain, and in broader patient reported outcome variables that can expand our horizons. Finally, we should be more focussed on assessing outcomes that are important to patients, rather than those that are central to researchers and clinicians.The fourth is to 'make pain better' by advancing our knowledge of multiple treatment options in all a...
Summary Despite resulting in a similar overall outcome, unlike antibodies directed against the DNABII protein, integration host factor (IHF), which induce catastrophic structural collapse of biofilms formed by nontypeable Haemophilus influenzae (NTHI), those directed against a recombinant soluble form of PilA [the majority subunit of Type IV pili (Tfp) produced by NTHI], mediated gradual ‘top-down’ dispersal of NTHI from biofilms. This dispersal occurred via a mechanism that was dependent upon expression of both PilA (and by inference, Tfp) and production of AI-2 quorum signaling molecules by LuxS. The addition of rsPilA to a biofilm-targeted therapeutic vaccine formulation comprised of IHF plus the powerful adjuvant dmLT, and delivered via a non-invasive transcutaneous immunization route, induced an immune response that targeted two important determinants essential for biofilm formation by NTHI. This resulted in significantly earlier eradication of NTHI from both planktonic and adherent populations in the middle ear, disruption of mucosal biofilms already resident within middle ears prior to immunization, and rapid resolution of signs of disease in an animal model of experimental otitis media. These data support continued development of this novel combinatorial immunization approach for resolution and/or prevention of multiple diseases of the respiratory tract caused by NTHI.
Respiratory syncytial virus (RSV) is an important viral pathogen of otitis media, bronchiolitis, and pneumonia. As infection of the upper airways is a precondition for the development of these diseases, understanding RSV pathogenesis and the host response induced by RSV in this niche may enable the development of novel therapeutic strategies against this virus. We have used a microarray approach and showed that expression of the gene that encodes the antiviral protein viperin was significantly upregulated in the chinchilla nasopharynx up to 1 week after RSV challenge. Overexpression of human viperin in vitro diminished the ability of RSV to infect HeLa or A549 cells. Furthermore, transduction of the chinchilla airways with a recombinant adeno-associated virus vector that encodes viperin resulted in reduced titers of RSV in the nasopharyngeal lavage fluid. Collectively, these data indicated that viperin plays a significant role in the innate immune defense against RSV.
Density functional theory and ab initio multi-reference calculations are performed to examine the stability and electronic structure of boron complexes that host diffuse electrons in their periphery. Such complexes (solvated electron precursors or SEPs) have been experimentally identified and studied theoretically for several s- and d-block metals. For the first time, we demonstrate that a p-block metalloid element can form a stable SEP when appropriate ligands are chosen. We show that three ammonia and one methyl ligands can displace two of the three boron valence electrons to a peripheral 1s-type orbital. The shell model for these outer electrons is identical to previous SEP systems (1s, 1p, 1d, 2s). Further, we preformed the first examination of a molecular system consisting of two SEPs bridged by a hydrocarbon chain. The electronic structure of these dimers is very similar to that of traditional diatomic molecules forming bonding and anti-bonding σ and π orbitals. Their ground state electronic structure resembles that of two He atoms, and our results indicate that the excitation energies are nearly independent of the chain length for four carbon atoms or longer. These findings pave the way for the development of novel materials similar to expanded metals and electrides.
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