Haem oxygenase-1 induction and activity in astrocytes and possible interactions with nitric oxide

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A Retrospective Critical Analysis and Risk Stratification of Penicillin Allergy De-labelling in a UK Specialist Regional Allergy Service.

BACKGROUND A spurious label of penicillin allergy (Pen-A) negatively impacts on antibiotic stewardship and healthcare costs. Recent studies have proposed a guideline-steered direct penicillin challenge without undertaking allergy tests when 'true allergy' is unlikely. OBJECTIVE Critically analyse Pen-A clinical presentation, perform risk stratification and determine clinical predictors for 'true allergy'. METHOD Retrospective data extraction from clinical and electronic patient records. RESULTS 231 patients (M= 82; F=149; mean age 51.22 (SD ± 18.07 years) were analysed. Based on clinical history, patients were categorised as likely type I hypersensitivity [HSR] (n=27), likely type IV HSR (n=65), indeterminate (n=111) and HSR unlikely (n=28). Based on index reaction and co-morbidities, patients were classified into 'low risk' (n=143) and 'high risk' (n=78). Pen-A was excluded in 74% of patients assessed having likely type I HSR, 91% with likely type IV HSR, 93% of indeterminate and 100% of HSR unlikely patients. Negative predictive value for successful de-labelling in the 'low risk' group was 94% (odds ratio [OR] - 2.9; p= 0.02). Predictors for 'true Pen-A' were history of anaphylaxis (OR - 30.6; p < 0.001), hospitalization (OR - 7; p<0.001), ≤5 years since index reaction (OR - 3; p= 0.04). CONCLUSION Systematic clinical characterisation and risk stratification has an important role in Pen-A de-labelling. These data provide proof of concept for a guideline-based selection of patients labelled with Pen-A for a direct penicillin challenge. Patients in the 'low risk' group seem suitable for this intervention, although a rigorous prospective evaluation is needed in a multi-centre study

Calibrating the classifier: siamese neural network architecture for end-to-end arousal recognition from ECG

Affective analysis of physiological signals enables emotion recognition in mobile wearable devices. In this paper, we present a deep learning framework for arousal recognition from ECG (electrocardio- gram) signals. Specifically, we design an end-to-end convolutional and recurrent neural network architecture to (i) extract features from ECG; (ii) analyse time-domain variation patterns; and (iii) non-linearly relate those to the user's arousal level. The key novelty is our use of a shared- parameter siamese architecture to implement user-specific feature cali- bration. At each forward and backward pass, we concatenate to the input a user-dependent template that is processed by an identical copy of the network. The siamese architecture makes feature calibration an integral part of the training process, allowing modelling of general dependencies between the user's ECG at rest and those during emotion elicitation. On leave-one-user-out cross validation, the proposed architecture obtains +21:5% score increase compared to state-of-the-art techniques. Compari- son with alternative network architectures demonstrates the effectiveness of the siamese network in achieving user-specific feature calibration

Active elite rugby participation is associated with altered precentral cortical thickness

There is growing concern that elite rugby participation may negatively influence brain health, but the underlying mechanisms are unclear. Cortical thickness is a widely applied biomarker of grey matter structure, but there is limited research into how it may be altered in active professional rugby players. Cross-sectional MRI data from 44 active elite rugby players, including 21 assessed within 1 week of head injury, and 47 healthy controls were analysed. We investigated how active elite rugby participation with and without sub-acute traumatic brain injury influenced grey matter structure using whole cortex and region of interest cortical thickness analyses. Relationships between cortical thickness and biomarkers of traumatic brain injury, including fractional anisotropy, plasma neurofilament light and glial fibrillary acidic protein, were also examined. In whole-cortex analyses, precentral cortical thickness in the right hemisphere was lower in rugby players compared with controls, which was due to reductions in non-injured players. Post hoc region of interest analyses showed non-injured rugby players had reduced cortical thickness in the inferior precentral sulcal thickness bilaterally ( P = 0.005) and the left central sulcus ( P = 0.037) relative to controls. In contrast, players in the sub-acute phase of mild traumatic brain injury had higher inferior precentral sulcal cortical thickness in the right hemisphere ( P = 0.015). Plasma glial fibrillary acidic protein, a marker of astrocyte activation, was positively associated with right inferior precentral sulcal cortical thickness in injured rugby players ( P = 0.0012). Elite rugby participation is associated with localized alterations in cortical thickness, specifically in sulcal motor regions. Sub-acute changes after mild traumatic brain injury are associated with evidence of astrocytic activation. The combination of cortical thickness and glial fibrillary acidic protein may be useful in understanding the pathophysiological relationship between sporting head injury and brain health. </p

Empty mast cell syndrome: fallacy or fact?

Post-anaphylaxis mast cell anergy (PAMA), commonly referred to as 'empty mast cell (MC) syndrome', is a state of temporary loss of cutaneous MC reactivity in the immediate aftermath of anaphylaxis. Data relating to this condition are sparse and the incidence rate is currently unknown. PAMA has been described only in a few published case reports in the context of hymenoptera venom allergy and perioperative anaphylaxis. Best practice guidelines regarding optimal timing for performing skin tests postanaphylaxis are largely based on expert opinion, and allergy work-up has been recommended after 4-6 weeks postanaphylaxis to avoid false-negative results.This article provides a review of clinical literature surrounding PAMA, critically evaluates intracellular events in MCs from in vitro data and hypothesises regarding plausible immune mechanisms. There are no published data to directly explain molecular mechanisms underlying this phenomenon. Although not evidence based, PAMA has been attributed to depletion of MC granules following anaphylaxis. It is also plausible that exposure to high allergen concentrations in anaphylaxis can induce a temporary shift in MCs towards dominance of inhibitory signalling pathways, thus contributing to a state of transient hyporesponsiveness observed in some patients. Other potential contributory factors for reduced MC reactivity include downregulation of FcεRI expression, cross-linking of FcεRI to the inhibitory, low-affinity IgG receptors and administration of pharmacotherapeutic agents for anaphylaxis treatment. It is likely that this interesting phenomenon can be explained by a combination of these proposed mechanisms in addition to other genetic/host factors that have not yet been identified

Axonal marker neurofilament light predicts long-term outcomes and progressive neurodegeneration after traumatic brain injury

Axonal injury is a key determinant of long-term outcomes after traumatic brain injury (TBI) but has been difficult to measure clinically. Fluid biomarker assays can now sensitively quantify neuronal proteins in blood. Axonal components such as neurofilament light (NfL) potentially provide a diagnostic measure of injury. In the multicenter BIO-AX-TBI study of moderate-severe TBI, we investigated relationships between fluid biomarkers, advanced neuroimaging, and clinical outcomes. Cerebral microdialysis was used to assess biomarker concentrations in brain extracellular fluid aligned with plasma measurement. An experimental injury model was used to validate biomarkers against histopathology. Plasma NfL increased after TBI, peaking at 10 days to 6 weeks but remaining abnormal at 1 year. Concentrations were around 10 times higher early after TBI than in controls (patients with extracranial injuries). NfL concentrations correlated with diffusion MRI measures of axonal injury and predicted white matter neurodegeneration. Plasma TAU predicted early gray matter atrophy. NfL was the strongest predictor of functional outcomes at 1 year. Cerebral microdialysis showed that NfL concentrations in plasma and brain extracellular fluid were highly correlated. An experimental injury model confirmed a dose-response relationship of histopathologically defined axonal injury to plasma NfL. In conclusion, plasma NfL provides a sensitive and clinically meaningful measure of axonal injury produced by TBI. This reflects the extent of underlying damage, validated using advanced MRI, cerebral microdialysis, and an experimental model. The results support the incorporation of NfL sampling subacutely after injury into clinical practice to assist with the diagnosis of axonal injury and to improve prognostication.</p