Accepted

The airways are densely innervated by sensory afferent nerves, whose activation regulates respiration and triggers defensive reflexes (e.g. cough, bronchospasm). Airway innervation is heterogeneous, and distinct afferent subsets have distinct functional responses. However, little is known of the innervation patterns of subsets within the lung. A neuroanatomical map is critical for understanding afferent activation under physiological and pathophysiological conditions. Here, we quantified the innervation of the mouse lung by vagal and dorsal root ganglion (DRG) sensory subsets defined by the expression of Pirt (all afferents), 5HT (vagal nodose afferents), Tac1 (tachykinergic afferents) and TRPV1 (defensive/nociceptive afferents) using Cre-mediated reporter expression. We found that vagal afferents innervate almost all conducting airways and project into the alveolar region, whereas DRG afferents only innervate large airways. Of the two vagal ganglia, only nodose afferents project into the alveolar region, but both nodose and jugular afferents innervate conducting airways throughout the lung. Many afferents that project into the alveolar region express TRPV1. Few DRG afferents expressed TRPV1. ∼25% of blood vessels were innervated by vagal afferents (many were Tac1+). ∼10% of blood vessels had DRG afferents (some were Tac1+), but this was restricted to large vessels. Lastly, innervation of neuroepithelial bodies correlated with the cell number within the bodies. In conclusion, functionally distinct sensory subsets have distinct innervation patterns within the conducting airways, alveoli and blood vessels. Physiological (e.g. stretch) and pathophysiological (e.g. inflammation, edema) stimuli likely vary throughout these regions. Our data provide a neuroanatomical basis for understanding afferent responses in vivo.Activation of airway sensory afferent nerves by physical and chemical stimuli evokes reflex changes in respiratory function. Multiple afferent subsets exist, including those activated by noxious stimuli (so-called "nociceptors"), which have distinct functions. The inappropriate activation of airway afferents, especially nociceptors, in inflammatory/infectious disease contributes to morbidity (e.g. bronchospasm, mucus secretion, cough). Despite extensive electrophysiological characterization of airway afferent subsets, little is known of their innervation patterns. To date, afferent subsets have been qualitatively identified in airway tissue, mostly using immunohistochemistry (which often lacks specificity and signal strength). Here, we have used Cre-dependent reporter expression to quantify genetically-defined afferent subsets. Thus, we provide a neuroanatomical map of the sensory innervation of conducting airways, alveoli and blood vessels throughout the lung.

The diagnosis of headache disorders relies on the correct classification of individual headache attacks. Currently, this is mainly done by clinicians in a clinical setting, which is dependent on subjective self-reported input from patients. Existing classification apps also rely on self-reported information and lack validation. Therefore, the exploratory mBrain study investigates moving to continuous, semi-autonomous and objective follow-up and classification based on both self-reported and objective physiological and contextual data.

Opioids are commonly used as analgesics to relieve chronic pain and have high abuse potential. Due to their strong potency and trace concentration in plasma, a robust analytical method is necessary for quantification in forensic and pharmacology fields. Hence, this study developed and validated a simple, rapid, and robust method for the simultaneous determination of 12 opioids and metabolites which were available legally by prescription or abused for non-medical purposes, in plasma samples by simple liquid extraction and high-performance liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). We compared the extraction recovery of our sample pre-treatment to two other sample pre-treatments (namely QuEChERS and simplified QuEChERS) and showed that the method used in our study gave the highest recoveries. The method validation followed the European Medicines Agency guidelines, including selectivity, carryover, accuracy and precision, dilution integrity, matrix effect and freeze/thaw stability. This method's accuracy ranged from 85% to 115% with a precision less than 15%, within the acceptable range of the validation protocol. The lower limit of quantification of the method ranged between 0.05 μg L and 0.38 μg L among 12 opioids/metabolites. Stability was assessed, with all opioids observed as relatively stable at 0.5 μg L and 5 μg L levels under -20 °C and 25 °C storage conditions. In summary, the developed method has the potential to achieve simultaneous analysis for monitoring opioids in forensic and pain management regimens using a simple sample pre-treatment.

Pain is a distressing, subjective and complex phenomenon that all nurses will encounter in their clinical practice. Effective pain management requires nurses to undertake a structured assessment to identify the probable causes of pain and guide management. Interventions used to reduce pain can be varied and multimodal. This article provides an overview of pain including its definition, classifications, assessment and management. It emphasises the importance of a person-centred approach to care which reflects Margo McCaffery's seminal quote that pain is 'whatever the experiencing person says it is'.

Migraine frequency increases after the cessation of successful preventive treatment with CGRP(-receptor) monoclonal antibodies (mAbs). In this study, we aimed to evaluate the course of migraine after treatment resumption.