Within minutes of a traumatic impact, a robust inflammatory response is elicited in the injured brain. The complexity of this post-traumatic squeal involves a cellular component, comprising the ...activation of resident glial cells, microglia, and astrocytes, and the infiltration of blood leukocytes. The second component regards the secretion immune mediators, which can be divided into the following sub-groups: the archetypal pro-inflammatory cytokines (Interleukin-1, Tumor Necrosis Factor, Interleukin-6), the anti-inflammatory cytokines (IL-4, Interleukin-10, and TGF-beta), and the chemotactic cytokines or chemokines, which specifically drive the accumulation of parenchymal and peripheral immune cells in the injured brain region. Such mechanisms have been demonstrated in animal models, mostly in rodents, as well as in human brain. Whilst the humoral immune response is particularly pronounced in the acute phase following Traumatic brain injury (TBI), the activation of glial cells seems to be a rather prolonged effect lasting for several months. The complex interaction of cytokines and cell types installs a network of events, which subsequently intersect with adjacent pathological cascades including oxidative stress, excitotoxicity, or reparative events including angiogenesis, scarring, and neurogenesis. It is well accepted that neuroinflammation is responsible of beneficial and detrimental effects, contributing to secondary brain damage but also facilitating neurorepair. Although such mediators are clear markers of immune activation, to what extent cytokines can be defined as diagnostic factors reflecting brain injury or as predictors of long term outcome needs to be further substantiated. In clinical studies some groups reported a proportional cytokine production in either the cerebrospinal fluid or intraparenchymal tissue with initial brain damage, mortality, or poor outcome scores. However, the validity of cytokines as biomarkers is not broadly accepted. This review article will discuss the evidence from both clinical and laboratory studies exploring the validity of immune markers as a correlate to classification and outcome following TBI.
This book is essential reading for medical or veterinary practitioners who need to understand the new fluid physiology and to apply it to the safe care of patients. The Starling principle is one of ...medicine's most important concepts and originates from Ernest Starling's laboratory research 120 years ago. However, inappropriate fluid therapy is now recognised as harming and even killing thousands of patients every year. In 2004, a landmark study was published which confirmed the hypotheses put forward by Sheldon Weinbaum and Charles Michel, among other physiologists, that, in most tissues and in most situations, capillaries filter fluid to the interstitium, but do not reabsorb it. This book draws together for the first time the evolving science of the steady-state Starling principle and the clinical evidence that reveals its applicability to safer patient care. It is a thorough re-appraisal of the basics of fluid therapy. The mantra of colloid boluses for plasma volume resuscitation and colloid-free isotonic salt solution for extracellular fluid volume does not explain observations from blinded clinical trials, and the expectation of benefit for resuscitation with colloids, particularly in respect of oedema, has not materialised. Now that there is consensus that colloid volume therapy should not be used in critically-ill patients, there is a pressing need for a new paradigm for fluid therapy. This book proposes an improved paradigm that takes into consideration the Starling principle, which has been neglected by clinicians and revised by physiologists in recent years. It retires the view of colloids as preferred plasma substitutes, and focuses instead on the central volume of distribution of an infused fluid, its rate of distribution to a peripheral volume, and its rate of excretion. In short, it emphasises volume kinetics.
Improvement (defined broadly as purposive efforts to secure positive change) has become an increasingly important activity and field of inquiry within healthcare. This article offers an overview of ...possible methods for the study of improvement interventions. The choice of available designs is wide, but debates continue about how far improvement efforts can be simultaneously practical (aimed at producing change) and scientific (aimed at producing new knowledge), and whether the distinction between the practical and the scientific is a real and useful one. Quality improvement projects tend to be applied and, in some senses, self-evaluating. They are not necessarily directed at generating new knowledge, but reports of such projects if well conducted and cautious in their inferences may be of considerable value. They can be distinguished heuristically from research studies, which are motivated by and set out explicitly to test a hypothesis, or otherwise generate new knowledge, and from formal evaluations of improvement projects. We discuss variants of trial designs, quasi-experimental designs, systematic reviews, programme evaluations, process evaluations, qualitative studies, and economic evaluations. We note that designs that are better suited to the evaluation of clearly defined and static interventions may be adopted without giving sufficient attention to the challenges associated with the dynamic nature of improvement interventions and their interactions with contextual factors. Reconciling pragmatism and research rigour is highly desirable in the study of improvement. Trade-offs need to be made wisely, taking into account the objectives involved and inferences to be made.
The design and execution of measurement in quality improvement (QI) initiatives is often poor. Better guidance on "what good looks like" might help to mitigate some of the problems. We report a ...consensus-building process that sought to identify which features are important to include in QI measurement plans.
We conducted a three-stage consensus-building approach: (1) identifying the list of features of measurement plans that were potential candidates for inclusion based on literature review and the study team's experience; (2) a two-round modified Delphi exercise with a panel of experts to establish consensus on the importance of these features; and (3) a small in-person consensus group meeting to finalise the list of features.
A list of 104 candidate questions was generated. A panel of 19 experts in the Delphi reviewed these questions and produced consensus on retaining 46 questions in the first round and on a further 22 in the second round. Thematic analysis of open text responses from the panellists suggested a number of areas of debate that were explicitly considered by the consensus group. The exercise yielded 74 questions (71% of 104) on which there was consensus in five categories of measurement relating to: design, data collection and management, analysis, action, and embedding.
This study offers a consensus-based view on the features of a good measurement plan for a QI project in healthcare. The results may be of use to QI teams, funders and evaluators, but are likely to require further development and testing to ensure feasibility and usefulness.
Background Polypharmacy, prescription of multiple medications to a patient, is a major challenge for health systems. There have been no peer-reviewed studies of polypharmacy prevalence and medication ...cost at a population level in England. Aims To determine prevalence and medication cost of polypharmacy, by patient characteristics. Design and setting: Retrospective cohort study of North West London electronic health records Method We quantified prevalence and direct cost of polypharmacy (five or more regular medications), stratified by demographics and frailty. We fitted a mixed-effects logistic regression for polypharmacy. Results Of 1.7 million adults, 167,665 (9.4%) were on polypharmacy. Age and socio-economic deprivation were associated with polypharmacy (OR 9.24 95% CI 8.99 to 9.50, age 65-74 compared with 18-44; OR 0.68 95% CI 0.65 to 0.71, least deprived compared with most). Polypharmacy prevalence increased with frailty (OR 1.53 95% CI 1.53 to 1.54 per frailty component, for White women). Men had higher odds of polypharmacy than women at average frailty (OR 1.26 95% CI 1.24 to 1.28) and with additional frailty components (OR 1.10 95% CI 1.09 to 1.10). Black people had lower odds of polypharmacy at average frailty (OR 0.82 95% CI 0.79 to 0.85, compared with White), but along with other ethnicities, saw greater odds increases with increasing frailty (OR 1.02 95% CI 1.01 to 1.03). Annual medication cost 8.2 times more for those on polypharmacy compared with not (£370.89 and £45.31). Conclusion Demographic characteristics are associated with polypharmacy, after adjusting for frailty. Further research should explore why, to reduce health inequities and optimise cost associated with polypharmacy.
The atypical chemokine receptor ACKR2 promotes resolution of acute inflammation by operating as a scavenger receptor for inflammatory CC chemokines in several experimental models of inflammatory ...disorders, however its role in the brain remains unclear. Based on our previous reports of increased expression of inflammatory chemokines and their corresponding receptors following traumatic brain injury (TBI), we hypothesised that ACKR2 modulates neuroinflammation following brain trauma and that its deletion exacerbates cellular inflammation and chemokine production. We demonstrate increased CCL2 and ACKR2 mRNA expression in post-mortem human brain, whereby ACKR2 mRNA levels correlated with later times post-TBI. This data is consistent with the transient upregulation of ACKR2 observed in mouse brain after closed head injury (CHI). As compared to WT animals, ACKR2-/- mice showed a higher mortality rate after CHI, while the neurological outcome in surviving mice was similar. At day 1 post-injury, ACKR2-/- mice displayed aggravated lesion volume and no differences in CCL2 expression and macrophage recruitment relative to WT mice. Reciprocal regulation of ACKR2 and CCL2 expression was explored in cultured astrocytes, which are recognized as the major source of CCL2 and also express ACKR2. ACKR2 mRNA increased as early as 2 hours after an inflammatory challenge in WT astrocytes. As expected, CCL2 expression also dramatically increased at 4 hours in WT astrocytes but was significantly lower in ACKR2-/- astrocytes, possibly indicating a co-regulation of CCL2 and ACKR2 in these cells. Conversely, in vivo, CCL2 mRNA/protein levels were increased similarly in ACKR2-/- and WT brains at 4 and 12 hours after CHI, in line with the lack of differences in cerebral macrophage recruitment and neurological recovery. In conclusion, ACKR2 is induced after TBI and has a significant impact on mortality and lesion development acutely following CHI, while its role in chemokine expression, macrophage activation, brain pathology, and neurological recovery at later time-points is minor. Concordant to evidence in multiple sclerosis experimental models, our data corroborate a distinct role for ACKR2 in cerebral inflammatory processes compared to its reported functions in peripheral tissues.
Understanding and extending the Starling principle Michel, C. Charles; Woodcock, Thomas E.; Curry, Fitz‐Roy E.
Acta anaesthesiologica Scandinavica,
September 2020, Letnik:
64, Številka:
8
Journal Article
Recenzirano
Odprti dostop
The Starling Principle states that fluid movements between blood and tissues are determined by differences in hydrostatic and colloid osmotic (oncotic) pressures between plasma inside microvessels ...and fluid outside them. The Revised Starling Principle recognizes that, because microvessels are permeable to macromolecules, a balance of pressures cannot halt fluid exchange. In most tissues, steady oncotic pressure differences between plasma and interstitial fluid depend on low levels of steady filtration from plasma to tissues for which the Revised Principle provides the theory. Plasma volume is normally maintained by fluid losses from filtration being matched by fluid gains from lymph. Steady state fluid uptake into plasma only occurs in tissues such as intestinal mucosa and renal peri‐tubular capillaries where a protein‐free secretion of adjacent epithelia contributes significantly to interstitial fluid volume and keeps interstitial oncotic pressure low. Steady filtration rates in different tissues are disturbed locally by reflex changes in capillary pressure and perfusion. The rapid overall decline in capillary pressure after acute blood loss initiates rapid fluid uptake from tissue to plasma, that is, autotransfusion. Fluid uptake is transient, being rapid at first then attenuating but low levels may continue for more than an hour. The Revised Principle highlights the role of oncotic pressure of small volumes of interstitial fluid within a sub‐compartment surrounding the microvessels rather than the tissue's mean interstitial fluid oncotic pressure. This maximizes oncotic pressure differences when capillary pressure are high and enhances initial absorption rates when pressures are low, accelerating short‐term regulation of plasma volume.
We quantify and explain the effects of both anti-phase boundaries and twin defects in as-transformed τ-MnAl by carrying out micromagnetic simulations based closely on the results of microstructural ...characterization. We demonstrate that magnetic domain walls nucleate readily at anti-phase boundaries and are strongly pinned by them, due to anti-ferromagnetic coupling. Likewise, twin boundaries reduce the external field required to nucleate domain walls and provide strong pinning potentials, with the pinning strength dependent on the twinning angle. The relative strengths of the known twin defect types are quantified based on the anisotropy angles across their boundaries. Samples that have undergone heat treatment are imaged using electron back-scatter diffraction. The precise crystallographic orientation is mapped spatially and converted into a number of realistic finite element models, which are used to compute the effects of large concentrations of twin domains in a realistic morphology. This is shown to have a negative effect on the remanence coercivity and squareness. The maximum energy product (BH)max is therefore significantly lower than the theoretical limit of the material and much lower than MnAl permanent magnets that have been further processed to remove twin defects. The knowledge gained in this study will allow the optimization of processing routes in order to develop permanent magnets with enhanced magnetic properties.
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To determine whether the frequency of diagnostic codes for long-term conditions (LTCs) in primary care electronic healthcare records (EHRs) is associated with (1) disease coding incentives, (2) ...General Practice (GP), (3) patient sociodemographic characteristics and (4) calendar year of diagnosis.
Retrospective cohort study.
GPs in England from 2015 to 2022 contributing to the Clinical Practice Research Datalink Aurum dataset.
All patients registered to a GP with at least one incident LTC diagnosed between 1 January 2015 and 31 December 2019.
The number of diagnostic codes for an LTC in (1) the first and (2) the second year following diagnosis, stratified by inclusion in the Quality and Outcomes Framework (QOF) financial incentive programme.
3 113 724 patients were included, with 7 723 365 incident LTCs. Conditions included in QOF had higher rates of annual coding than conditions not included in QOF (1.03 vs 0.32 per year, p<0.0001). There was significant variation in code frequency by GP which was not explained by patient sociodemographics. We found significant associations with patient sociodemographics, with a trend towards higher coding rates in people living in areas of higher deprivation for both QOF and non-QOF conditions. Code frequency was lower for conditions with follow-up time in 2020, associated with the onset of the COVID-19 pandemic.
The frequency of diagnostic codes for newly diagnosed LTCs is influenced by factors including patient sociodemographics, disease inclusion in QOF, GP practice and the impact of the COVID-19 pandemic. Natural language processing or other methods using temporally ordered code sequences should account for these factors to minimise potential bias.
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