TRPV1-expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms

The mechanisms that generate itch are poorly understood at both the molecular and cellular levels despite its clinical importance. To explore the peripheral neuronal mechanisms underlying itch, we assessed the behavioral responses (scratching) produced by s.c. injection of various pruritogens in PLCβ3- or TRPV1-deficient mice. We provide evidence that at least 3 different molecular pathways contribute to the transduction of itch responses to different pruritogens: 1) histamine requires the function of both PLCβ3 and the TRPV1 channel; 2) serotonin, or a selective agonist, α-methyl-serotonin (α-Me-5-HT), requires the presence of PLCβ3 but not TRPV1, and 3) endothelin-1 (ET-1) does not require either PLCβ3 or TRPV1. To determine whether the activity of these molecules is represented in a particular subpopulation of sensory neurons, we examined the behavioral consequences of selectively eliminating 2 nonoverlapping subsets of nociceptors. The genetic ablation of MrgprD^+ neurons that represent ≈90% of cutaneous nonpeptidergic neurons did not affect the scratching responses to a number of pruritogens. In contrast, chemical ablation of the central branch of TRPV1+ nociceptors led to a significant behavioral deficit for pruritogens, including α-Me-5-HT and ET-1, that is, the TRPV1-expressing nociceptor was required, whether or not TRPV1 itself was essential. Thus, TRPV1 neurons are equipped with multiple signaling mechanisms that respond to different pruritogens. Some of these require TRPV1 function; others use alternate signal transduction pathways

Improving older people's care in one acute hospital setting: a realist evaluation of a KT intervention

Background: Older people make up an increasingly large group using acute care facilities yet the nature of the care is often not conducive to their personal needs, wellbeing and recovery. This research explored how a structured intervention (called the KT Toolkit) could help frontline clinical staff improve the care for older people going through one acute hospital setting in South Australia. Methods/Design: The case study approach used draws on the overarching framework of realist evaluation, a methodology designed to test, refine and explain what is happening in complex situations. Seven parallel teams within the organisation selected one discrete clinical area each for improvement through the introduction of evidence based practice guidelines. Each improvement team’s progress was recorded using multiple data sources including ethnographic observations, semi structured interviews, document reviews and other routinely collected data on nursing care. Each of the seven journeys was analysed and synthesised according to the principles of realist evaluation where the role of the researchers (and stakeholders) is to elucidate what things work for which teams in what particular circumstances thus arriving at a set of explanatory statements. Results: Four broad mechanisms appeared to be affecting the way improvements were being introduced into the clinical areas by the seven different teams: building on existing structures and support; optimising existing human potential; focus on the older person and on-going support through facilitation. Within these mechanisms a range of different actions and behaviours were noted but collectively the teams were able to show how these mechanisms enabled them to make progress in improving discrete aspects of care for their older patients. Conclusions: The use of realist evaluation as the overarching methodological framework enabled the research team to document and interpret the complex interactions happening at the level of everyday practice. Such interpretations enabled the research team to engage the clinical teams and work with them on on-going improvements. We found that even trying to improve the so-called simplest of aspects of care (e.g. weighing patients as part of nutritional care) was fraught with challenges. Also, our use of the realist method raised a number of theoretical and methodological questions that need further refining and in particular how realist evaluation relates to knowledge translation (KT) conceptual frameworks.Alison Kitson, Rick Wiechula, Kathryn Zeitz, Danni Marcoionni, Tammy Page and Heidi Silversto

BMJ Open Ophthalmol

Objective: Explore relationships between systemic exposure to intravitreal aflibercept injection (IAI) and systemic pharmacodynamic effects via post hoc analyses of clinical trials of IAI for neovascular age-related macular degeneration (nAMD) or diabetic macular oedema (DME). Methods and analysis: Adults from VGFT-OD-0702.PK (n=6), VGFT-OD-0512 (n= 5), VIEW 2 (n=1204) and VIVID-DME (n=404) studies were included. Validated ELISAs were used to measure concentrations of free and bound aflibercept (reported as adjusted bound) in plasma at predefined time points in each study. Non-compartmental analysis of concentration-time data was obtained with dense sampling in VGFT-OD-0702.PK and VGFT-OD-0512. Sparse sampling was used in VIEW 2 and VIVID-DME. Blood pressure or intrarenal function changes were also investigated. Results: Following intravitreal administration, free aflibercept plasma concentrations quickly decreased once maximum concentrations were achieved at 1-3 days postdose; pharmacologically inactive adjusted bound aflibercept concentrations increased over a longer period and reached plateau 7 days postdose. Ratios of free and adjusted bound aflibercept decreased over time. There were no meaningful changes in systolic/diastolic blood pressure over the duration of each study at all systemic aflibercept exposure levels. For all treatment arms in VIEW 2, there was no clinically relevant change in mean intrarenal function from baseline at week 52. Overall, incidence of systemic adverse events in VIEW 2 and VIVID-DME was low and consistent with the known safety profile of IAI. Conclusion: IAI administration was not associated with systemic effects in patients with nAMD or DME as measured by blood pressure or intrarenal function, two known pharmacologically relevant effects of anti-vascular endothelial growth factor

Cardiologists appropriately exclude resuscitated out-of-hospital cardiac arrests from emergency coronary angiography

Objective: Emergency coronary angiography after resuscitated out-of-hospital cardiac arrest as a selective or non-selective diagnostic procedurewith orwithout intervention continues to be the subject of debate. This study sought to determine if cardiologists reliably select patients using clinical judgement for emergency coronary angiography without missing acutely ischemic cases requiring revascularization. Methods: Presenting clinical details and ECGs (within 2 hours) from 52 consecutive out-of-hospital cardiac arrest patients who underwent non-selective coronary angiography were compiled retrospectively. Three out-of-hospital cardiac arrestexperienced interventional cardiologists, blinded to patient outcome, independently determined working diagnosis, and decision for emergency coronary angiography using clinical judgement. Sensitivity of the cardiologists’ decision was assessed with respect to the outcome of acute revascularization. Inter-rater differences, consensus in clinical assessment, and influence of working diagnosis were also investigated. Results: Sensitivity of individual cardiologist’s decision for emergency coronary angiography with respect to acute revascularization was very high (adjusted overall sensitivity = 95.8%, 95% CI = 89–100, cardiologist range = 93%–100%), and perfect for the consensus of 2 or more cardiologists (100%, 95% CI = 79.4–100). There was no statistical difference in the sensitivity of this decision between cardiologists (P < 0.05), and inter-rater agreement was moderate (78% overall agreement, Κ = 0.56). Conclusions: Experienced cardiologists recommend emergency coronary angiography in all resuscitated out-of-hospital cardiac arrest requiring acute revascularization and appropriately excluded one-third of patients. Rather than advocating a non-selective, or conversely, a restrictive strategy with respect to coronary angiography after out-of-hospital cardiac arrest, the findings support an individualized approach by a multidisciplinary emergency team that includes experienced cardiologists. The results should be confirmed in a larger prospective study.Melanie R.Wittwer, Chris Zeitz, Sunny Wu, Kumaril Mishra, Sharmalar Rajendran, John F. Beltrame, Margaret A. Arstal