Summary Primary nociceptors relay painful touch information from the periphery to the spinal cord. While it is established that signals generated by the receptor tyrosine kinases TrkA and Ret coordinate the development of distinct nociceptive circuits, mechanisms modulating TrkA or Ret pathways in developing nociceptors are unknown. We have identified tumor necrosis factor receptor 1 (TNFR1) as a critical modifier of TrkA and Ret signaling in peptidergic and non-peptidergic nociceptors. In particular, TrkA+ peptidergic nociceptors require TNFα-TNFR1 forward signaling to suppress NGF-mediated neurite growth, survival, excitability, and differentiation. Conversely, TNFR1-TNFα reverse signaling augments the neurite growth and excitability of Ret+ non-peptidergic nociceptors. The developmental and functional nociceptive defects associated with loss of TNFR1 signaling manifest behaviorally as lower pain thresholds caused by increased sensitivity to NGF. Thus, TNFR1 exerts a dual role in nociceptor information processing by suppressing TrkA and enhancing Ret signaling in peptidergic and non-peptidergic nociceptors, respectively.

Background and Purpose-The outcomes of patients remaining at a community spoke hospital after tissue-type plasminogen activator treatment via telemedicine are unclear. Our aim was to compare medical outcomes between these patients and those treated at a hub stroke center. Methods-We retrospectively examined patient medical records from 2006 to 2014 of 272 consecutive patients treated with intravenous tissue-type plasminogen activator at University of Pittsburgh Medical Center (UPMC) Presbyterian Hospital, a telestroke hub, and 134 consecutive patients treated after telemedicine consultation at 5 UPMC spoke hospitals, who then remained at these hospitals (drip-and-stay). Complications included mortality, length of stay, and common poststroke medical complications. We performed multivariate analysis to identify complications that are independently increased or decreased in the drip-and-stay population. We also performed a Cox proportional hazards regression to compare longterm survival. Results-The drip-and-stay patients had less severe strokes (National Institutes of Health Stroke Scale score, 9.5±5.9 versus 12.7±7.1; P<0.001) and fewer large vessel occlusions (11.9% versus 36%; P<0.001). After controlling for all variables with multivariate analysis, we found that the drip-and-stay patients had an increased risk of adjusted in-hospital mortality (adjusted odds ratio, 11.046; 95% confidence interval, 2.785-43.810) and having a length of stay >6 days (adjusted odds ratio, 4.696, 95% confidence interval, 2.428-9.083). Furthermore, the drip-and-stay patients had significantly decreased long-term survival compared with the hub patients (P<0.001). Conclusions-Despite having less severe strokes, the drip-and-stay patients had an increased adjusted risk of in-hospital mortality, longer length of stay, and lower long-term survival than hub hospital patients. Further studies are needed to confirm the findings and address differences in post-tissue-type plasminogen activator medical care.

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