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Abstract: Nociceptors with somata in dorsal root ganglia (DRGs) readily switch from an electrically silent state to a hyperactive state of tonic, nonaccommodating, low-frequency, irregular discharge of action potentials (APs). Spontaneous activity (SA) during this state is present in vivo in rats months after spinal cord injury (SCI) and has been causally linked to SCI pain. Intrinsically generated SA and, more generally, ongoing activity (OA) are induced by various neuropathic conditions in rats, mice, and humans and are retained in nociceptor somata after dissociation and culturing, providing a powerful tool for investigating its mechanisms and functions. The present study shows that long-lasting hyperexcitability that can generate OA during modest depolarization in probable nociceptors dissociated from DRGs of male and female rats is induced by plantar incision injury. OA occurred when the soma was artificially depolarized to a level within the normal range of membrane potentials where large, transient depolarizing spontaneous fluctuations (DSFs) can approach AP threshold. This hyperexcitability persisted for at least 3 weeks, whereas behavioral indicators of affective pain-hind paw guarding and increased avoidance of a noxious substrate in an operant conflict test-persisted for 1 week or less. The most consistent electrophysiological alteration associated with OA was enhancement of DSFs. An unexpected discovery after plantar incisions was hyperexcitability in neurons from thoracic DRGs that innervate dermatomes distant from the injured tissue. Potential in vivo functions of widespread, low-frequency nociceptor OA consistent with these and other findings are to contribute to hyperalgesic priming and to drive anxiety-related hypervigilance., (Copyright © 2024 International Association for the Study of Pain.)

Neuroimmune interactions are essential for the development of neuropathic pain, yet the contributions of distinct immune cell populations have not been fully unraveled. Here, we demonstrate the critical role of B cells in promoting mechanical hypersensitivity (allodynia) after peripheral nerve injury in male and female mice. Depletion of B cells with a single injection of anti-CD20 monoclonal antibody at the time of injury prevented the development of allodynia. B cell-deficient (muMT) mice were similarly spared from allodynia. Nerve injury was associated with increased immunoglobulin G (IgG) accumulation in ipsilateral lumbar dorsal root ganglia (DRGs) and dorsal spinal cords. IgG was colocalized with sensory neurons and macrophages in DRGs and microglia in spinal cords. IgG also accumulated in DRG samples from human donors with chronic pain, colocalizing with a marker for macrophages and satellite glia. RNA sequencing revealed a B cell population in naive mouse and human DRGs. A B cell transcriptional signature was enriched in DRGs from human donors with neuropathic pain. Passive transfer of IgG from injured mice induced allodynia in injured muMT recipient mice. The pronociceptive effects of IgG are likely mediated through immune complexes interacting with Fc gamma receptors (FcγRs) expressed by sensory neurons, microglia, and macrophages, given that both mechanical allodynia and hyperexcitability of dissociated DRG neurons were abolished in nerve-injured FcγR-deficient mice. Consistently, the pronociceptive effects of IgG passive transfer were lost in FcγR-deficient mice. These data reveal that a B cell-IgG-FcγR axis is required for the development of neuropathic pain in mice.

Persistent hyperactivity of nociceptors is known to contribute significantly to long-lasting sensitization and ongoing pain in many clinical conditions. It is often assumed that nociceptor hyperactivity is mainly driven by continuing stimulation from inflammatory mediators. We have tested an additional possibility: that persistent increases in excitability promoting hyperactivity can be induced by a prototypical cellular signaling pathway long known to induce late-phase long-term potentiation (LTP) of synapses in brain regions involved in memory formation. This cAMP-PKA-CREB-gene transcription-protein synthesis pathway was tested using whole-cell current clamp methods on small dissociated sensory neurons (primarily nociceptors) from dorsal root ganglia (DRGs) excised from previously uninjured ("naïve") male rats. Six-hour treatment with the specific Gαs-coupled 5-HT4 receptor agonist, prucalopride, or with the adenylyl cyclase activator forskolin induced long-term hyperexcitability (LTH) in DRG neurons that manifested 12-24 h later as action potential (AP) discharge (ongoing activity, OA) during artificial depolarization to -45 mV, a membrane potential that is normally subthreshold for AP generation. Prucalopride treatment also induced significant long-lasting depolarization of resting membrane potential (from -69 to -66 mV), enhanced depolarizing spontaneous fluctuations (DSFs) of membrane potential, and produced trends for reduced AP threshold and rheobase. LTH was prevented by co-treatment of prucalopride with inhibitors of PKA, CREB, gene transcription, or protein synthesis. As in the induction of synaptic memory, many other cellular signals are likely to be involved. However, the discovery that this prototypical memory induction pathway can induce nociceptor LTH, along with reports that cAMP signaling and CREB activity in DRGs can induce hyperalgesic priming, suggest that early, temporary, cAMP-induced transcriptional and translational mechanisms can induce nociceptor LTH that might last for long periods. The present results also raise the question of whether reactivation of primed signaling mechanisms by re-exposure to inflammatory mediators linked to cAMP synthesis during subsequent challenges to bodily integrity can "reconsolidate" nociceptor memory, extending the duration of persistent hyperexcitability., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Over half of spinal cord injury (SCI) patients develop opioid-resistant chronic neuropathic pain. Safer alternatives to opioids for treatment of neuropathic pain are gabapentinoids (e.g., pregabalin and gabapentin). Clinically, gabapentinoids appear to amplify opioid effects, increasing analgesia and overdose-related adverse outcomes, but in vitro proof of this amplification and its mechanism are lacking. We previously showed that after SCI, sensitivity to opioids is reduced by fourfold to sixfold in rat sensory neurons. Here, we demonstrate that after injury, gabapentinoids restore normal sensitivity of opioid inhibition of cyclic AMP (cAMP) generation, while reducing nociceptor hyperexcitability by inhibiting voltage-gated calcium channels (VGCCs). Increasing intracellular Ca 2+ or activation of L-type VGCCs (L-VGCCs) suffices to mimic SCI effects on opioid sensitivity, in a manner dependent on the activity of the Raf1 proto-oncogene, serine/threonine-protein kinase C-Raf, but independent of neuronal depolarization. Together, our results provide a mechanism for potentiation of opioid effects by gabapentinoids after injury, via reduction of calcium influx through L-VGCCs, and suggest that other inhibitors targeting these channels may similarly enhance opioid treatment of neuropathic pain., Competing Interests: Competing interests statement:The authors declare no competing interest.

Abstract: Nociceptor cell bodies generate "spontaneous" discharge that can promote ongoing pain in persistent pain conditions. Little is known about the underlying mechanisms. Recordings from nociceptor cell bodies (somata) dissociated from rodent and human dorsal root ganglia have shown that previous pain in vivo is associated with low-frequency discharge controlled by irregular depolarizing spontaneous fluctuations of membrane potential (DSFs), likely produced by transient inward currents across the somal input resistance. Using mouse nociceptors, we show that DSFs are associated with high somal input resistance over a wide range of membrane potentials, including depolarized levels where DSFs approach action potential (AP) threshold. Input resistance and both the amplitude and frequency of DSFs were increased in neurons exhibiting spontaneous activity. Ion substitution experiments indicated that the depolarizing phase of DSFs is generated by spontaneous opening of channels permeable to Na + or Ca 2+ and that Ca 2+ -permeable channels are especially important for larger DSFs. Partial reduction of the amplitude or frequency of DSFs by perfusion of pharmacological inhibitors indicated small but significant contributions from Nav1.7, Nav1.8, TRPV1, TRPA1, TRPM4, and N-type Ca 2+ channels. Less specific blockers suggested a contribution from NALCN channels, and global knockout suggested a role for Nav1.9. The combination of high somal input resistance plus background activity of diverse ion channels permeable to Na + or Ca 2+ produces DSFs that are poised to reach AP threshold if resting membrane potential depolarizes, AP threshold decreases, or DSFs become enhanced-all of which can occur under painful neuropathic and inflammatory conditions., (Copyright © 2023 International Association for the Study of Pain.)

Objective: Split-thickness skin grafting (STSG) is commonly used for wound closure in diabetic foot ulcers (DFUs). In many cases, patients with diabetes present on long-term anticoagulation therapy. The complications associated with anticoagulants can be discouraging to surgeons considering STSG. The goal of this study was to evaluate STSG outcomes in the setting of chronic anticoagulation across a large, multicenter database., Methods: The authors queried the TriNetX Network, which provides access to electronic medical records for more than 75 million patients, to search for patients with a history of DFUs treated with STSG. They divided those found into two groups: long-term anticoagulant use prior to grafting and no long-term anticoagulant use. After matching, the researchers evaluated outcomes following STSG after 1 month and 5 years., Results: The authors identified 722 patients on chronic anticoagulation with DFUs who were treated with STSG; 446 of these patients were matched to 446 patients with no prior anticoagulation. One month following STSG, the anticoagulated group showed no significant increase in death, graft failure, or regrafting. At 5 years, there was no significant increase in mortality, graft failure, regrafting, or lower extremity amputation rates., Conclusions: Chronic anticoagulation therapy does not lead to increased short- or long-term postoperative complications such as graft failure, regrafting, or increased amputation rates following STSG for wound closure. Negative outcomes following STSG for DFUs in chronically anticoagulated individuals are minimal, and grafting should be performed without hesitation., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Multiple studies have shown the SARS-CoV-2 virus (COVID-19) to be associated with deleterious outcomes in a wide range of patients. The impact of COVID-19 has not been well investigated among burned patients. We suspect that patients will have worsened respiratory and thrombotic complications, ultimately leading to increased mortality. The objective of this study is to determine the impact a concurrent infection of COVID-19 has on clinical outcomes after a burn injury., Methods: This is a retrospective, propensity matched, cohort study. We examined a de-identified database of electronic medical records of over 75 million patients across 75 health care associations in the United States for patients treated for thermal burns from 1 January 2020, to 31 July 2021, and those who also were diagnosed with COVID-19 infection within one day before or after injury based on International Classification of Disease, tenth revision (ICD-10) codes. Study participants included adults who were treated for a burn injury during the study period., Results: We included 736 patients with burn injury and concomitant COVID-19 infection matched to 736 patients with burn injury and no concurrent COVID-19 infection (total 1472 patients, mean age 36.3 ± 24.3). We found no significant increase in mortality observed for patients with concurrent COVID-19 (OR 1.203, 95% CI 0.517-2.803; p  = 0.6675). We did observe significant increase in infections (OR 3.537, 95% CI 2.798-4.471; p  = 0.0001), thrombotic complications (OR 2.342, 95% CI 1.351-4.058; p  = 0.0018), as was the incidence of hypertrophic scarring (OR 3.368, 95% CI 2.326-4.877; p  = 0.0001)., Conclusions: We observed that concurrent COVID-19 infection was associated with an increase in infections, thrombosis and hypertrophic scarring but no increase in mortality in our cohort of burn patients., Competing Interests: The authors report no disclosures relevant to the manuscript., (© The Author(s) 2023. Published by Oxford University Press.)

Objective: This study aims to identify and analyze implications of COVID-19 positivity on AVF occlusion, subsequent treatment patterns, and ESRD patient outcomes. Our aim is to provide a quantitative context for vascular access surgeons in order to optimize surgical decision making and minimize patient morbidity. Methods: The de-identified national TriNetX database was queried to extracted all adult patients who had a known AVF between January 1, 2020 and December 31, 2021. From this cohort individuals who also were diagnosed with COVID-19 prior to creation of their AVF were identified. Cohorts were propensity score matched according to age at AVF surgery, gender, ethnicity, diabetes mellitus, nicotine dependence, tobacco use, use of anticoagulant medications, and use of platelet aggregation inhibitors, hypertensive diseases, hyperlipidemia, and prothrombotic states. Results: After propensity score matching there were 5170 patients; 2585 patients in each group. The total patient population had 3023 (58.5%) males and 2147 (41.5%) females. The overall rate of thrombosis of AV fistulas was 300 (11.6%) in the cohort with COVID-19 and 256 (9.9%) in the control group (OR 1.199, CI 1.005-1.43, P =.0453). Open revisions of AVF with thrombectomy were significantly higher in the COVID-19 cohort compared to the non-COVID-19 group (1.5% vs .5% P = .0002, OR 3.199, CI 1.668-6.136). Regarding the time from AVF creation to intervention, the median days for open thrombectomy in COVID-19 patients was 72 vs 105 days in controls. For endovascular thrombectomy, the median was 175 vs 168 days for the COVID-19 and control cohorts respectively. Conclusion: As for this study, there were significant differences in rates of thrombosis and open revisions of recent created AVF, however endovascular interventions remained remarkably low. As noted in this study, the persistent prothrombotic state of patients with a history of COVID-19 may persist beyond the acute infectious period of the disease.

Background: Burn patients continue to have a high opioid requirement, despite current national trends to decrease opioid prescribing. While effective, long-term opioid use results in opioid dependence and possibly other mental health comorbidities. This retrospective cohort study seeks to evaluate implications of diagnosed opioid use disorder in the development of subsequent psychiatric, behavioral and substance abuse patterns., Methods: The TriNetX database was queried for patients 18 years and older with a diagnosis of thermal or chemical burn who developed opioid use disorder after their burn injury. Two matched cohorts were studied, opioid use disorder versus non-opioid use disorder, to evaluate risk of developing subsequent mental health and behavioral conditions, use of psychiatric health services, and future substance abuse., Results: A total of 2020 patients were identified in each cohort, matched for demographics, external trauma, and burn size. Patients in the opioid use disorder group had a significantly higher incidence of mental health diagnoses (79.7 % versus 57.7 %, OR 1.973, CI 1.741-2.236, p < 0.0001), including major depressive disorder, generalized anxiety disorder, and post-traumatic stress disorder. This group was also more likely to utilize psychiatric services (16.0 % versus 10.3 %, OR 1.926, CI 1.595-2.326, p < 0.0001) and psychotherapy (12.6 % versus 7.2 %, OR 2.046, CI 1.650-2.536, p<0.0001). Furthermore, the opioid use disorder group had higher rates of polysubstance abuse (29.9 % versus 12.3 %, OR 3.048, CI 2.588-3.589, p<0.0001), suicidal / homicidal ideations (8.2 % versus 3.2 %, OR 3.057, CI 2.274-4.109, p<0.0001), and suicide attempts (2.0 % versus 0.7 %, OR 2.971, CI 1.611-5.478, p = 0.003)., Conclusions: Burn patients who develop opioid use disorder have significantly higher rates of future psychiatric diagnoses, behavioral disturbances, and polysubstance abuse. A multidisciplinary team approach, including early involvement of pain and mental health services, could potentially reduce the development of opioid use disorder and its consequences., (Copyright © 2022 Elsevier Ltd and International Society of Burns Injuries. All rights reserved.)

Skin serves as a protective barrier against infection, prevents excessive fluid and electrolyte losses, performs crucial thermoregulation, and provides tactile feedback of surroundings. The skin also plays an essential role in human perception of body image, personal appearance, and self-confidence. With these many diverse functions, understanding normal anatomic composition of skin is pivotal to evaluating the extent of its disruption from burn injury. This article discusses the pathophysiology, initial evaluation, subsequent progression, and healing of burn wounds. By delineating the various microcellular and macrocellular alterations of burn injury, this review also augments providers' capacity to deliver patient-centered, evidence-based burn care., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Chronic, often intractable, pain is caused by neuropathic conditions such as traumatic peripheral nerve injury (PNI) and spinal cord injury (SCI). These conditions are associated with alterations in gene and protein expression correlated with functional changes in somatosensory neurons having cell bodies in dorsal root ganglia (DRGs). Most studies of DRG transcriptional alterations have utilized PNI models where axotomy-induced changes important for neural regeneration may overshadow changes that drive neuropathic pain. Both PNI and SCI produce DRG neuron hyperexcitability linked to pain, but contusive SCI produces little peripheral axotomy or peripheral nerve inflammation. Thus, comparison of transcriptional signatures of DRGs across PNI and SCI models may highlight pain-associated transcriptional alterations in sensory ganglia that do not depend on peripheral axotomy or associated effects such as peripheral Wallerian degeneration. Data from our rat thoracic SCI experiments were combined with meta-analysis of published whole-DRG RNA-seq datasets from prominent rat PNI models. Striking differences were found between transcriptional responses to PNI and SCI, especially in regeneration-associated genes (RAGs) and long noncoding RNAs (lncRNAs). Many transcriptomic changes after SCI also were found after corresponding sham surgery, indicating they were caused by injury to surrounding tissue, including bone and muscle, rather than to the spinal cord itself. Another unexpected finding was of few transcriptomic similarities between rat neuropathic pain models and the only reported transcriptional analysis of human DRGs linked to neuropathic pain. These findings show that DRGs exhibit complex transcriptional responses to central and peripheral neural injury and associated tissue damage. Although only a few genes in DRG cells exhibited similar changes in expression across all the painful conditions examined here, these genes may represent a core set whose transcription in various DRG cell types is sensitive to significant bodily injury, and which may play a fundamental role in promoting neuropathic pain.

Chronic pain caused by injury or disease of the nervous system (neuropathic pain) has been linked to persistent electrical hyperactivity of the sensory neurons (nociceptors) specialized to detect damaging stimuli and/or inflammation. This pain and hyperactivity are considered maladaptive because both can persist long after injured tissues have healed and inflammation has resolved. While the assumption of maladaptiveness is appropriate in many diseases, accumulating evidence from diverse species, including humans, challenges the assumption that neuropathic pain and persistent nociceptor hyperactivity are always maladaptive. We review studies indicating that persistent nociceptor hyperactivity has undergone evolutionary selection in widespread, albeit selected, animal groups as a physiological response that can increase survival long after bodily injury, using both highly conserved and divergent underlying mechanisms., Competing Interests: Declaration of interests T.J.P. is a co-founder of 4E Therapeutics, Doloromics, PARMedics, and NuvoNuro; he serves on the Board of Directors of 4E Therapeutics and Doloromics; he is an inventor on patents related to MNK inhibition for the treatment of pain. E.S.S. receives funding from AstraZeneca and GlaxoSmithKline. E.T.W., R.J.C., and G.G.N. declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Risk factors for opioid dependence amongst burn patients have not been well-explored compared to other surgical fields., Methods: The TrinetX database was queried for patients diagnosed with opioid use disorder (OUD) after thermal or chemical burn. Propensity score matching was performed. Opioid and non-opioid analgesia use, ICU care, surgery, and comparative risks among common opiates were examined using descriptive and univariate regression models, including odds ratios. Subgroup analysis evaluated the impact of multimodal analgesia., Results: Odds of receiving IV opioids for acute analgesia (p = <0.0001, OR = 1.80, CI = 1.45-2.25), undergoing surgery (p = <0.0001, OR = 1.58, CI = 1.26-1.98), and ICU care (p = <0.0001, OR = 3.60, CI = 2.00-3.83) after burn injury were higher in patients who developed OUD. Patients receiving multimodal therapy within 24 hours of admission had lower odds of developing OUD (OR = 0.74, CI = 2.76-4.68, p = 0.0001) and chronic pain (OR = 0.89, CI = 0.78-1.00, p = 0.05) regardless of TBSA., Conclusion: Patients who developed opioid use disorder following burn injury had higher odds of receiving opioid exclusive pain management, more frequent surgery, ICU care., (Published by Elsevier Inc.)

Background: Several evolutionary explanations have been proposed for why chronic pain is a major clinical problem. One is that some mechanisms important for driving chronic pain, while maladaptive for modern humans, were adaptive because they enhanced survival. Evidence is reviewed for persistent nociceptor hyperactivity (PNH), known to promote chronic pain in rodents and humans, being an evolutionarily adaptive response to significant bodily injury, and primitive molecular mechanisms related to cellular injury and stress being exapted (co-opted or repurposed) to drive PNH and consequent pain., Summary: PNH in a snail (Aplysia californica), squid (Doryteuthis pealeii), fruit fly (Drosophila melanogaster), mice, rats, and humans has been documented as long-lasting enhancement of action potential discharge evoked by peripheral stimuli, and in some of these species as persistent extrinsically driven ongoing activity and/or intrinsic spontaneous activity (OA and SA, respectively). In mammals, OA and SA are often initiated within the protected nociceptor soma long after an inducing injury. Generation of OA or SA in nociceptor somata may be very rare in invertebrates, but prolonged afterdischarge in nociceptor somata readily occurs in sensitized Aplysia. Evidence for the adaptiveness of injury-induced PNH has come from observations of decreased survival of injured squid exposed to predators when PNH is blocked, from plausible survival benefits of chronic sensitization after severe injuries such as amputation, and from the functional coherence and intricacy of mammalian PNH mechanisms. Major contributions of cAMP-PKA signaling (with associated calcium signaling) to the maintenance of PNH both in mammals and molluscs suggest that this ancient stress signaling system was exapted early during the evolution of nociceptors to drive hyperactivity following bodily injury. Vertebrates have retained core cAMP-PKA signaling modules for PNH while adding new extracellular modulators (e.g., opioids) and cAMP-regulated ion channels (e.g., TRPV1 and Nav1.8 channels)., Key Messages: Evidence from multiple phyla indicates that PNH is a physiological adaptation that decreases the risk of attacks on injured animals. Core cAMP-PKA signaling modules make major contributions to the maintenance of PNH in molluscs and mammals. This conserved signaling has been linked to ancient cellular responses to stress, which may have been exapted in early nociceptors to drive protective hyperactivity that can persist while bodily functions recover after significant injury., (© 2023 S. Karger AG, Basel.)

Split-thickness skin grafts (STSG) are an effective modality for lower extremity wound coverage. Many patients in the highly comorbid chronic wound population present with cardiovascular disease requiring chronic antiplatelet or anticoagulant therapy, theoretically increasing risk for bleeding complications, donor site morbidity, and poor graft take. Some surgeons advocate temporary cessation of antithrombotic therapy, which may increase cardiovascular risk. The objective of this study was to examine the effects of anticoagulation use on STSG outcomes., Methods: All patients receiving STSGs for lower extremity wounds from 2014 to 2016 at a single institution were retrospectively reviewed. Successful grafts were defined as greater than 99.5% wound coverage. Patients were divided into two groups: anticoagulation/antiplatelet or no anticoagulation/antiplatelet. Continuous variables were described by means and SDs and analyzed using student's t -test. Categorical variables were described by frequencies and percentages and analyzed using Chi-square or Fisher exact tests as appropriate., Results: In total, 231 wounds were identified among 189 patients; 124 patients were receiving at least one antiplatelet/anticoagulant at time of grafting. Three hematomas were reported during 30 days of follow-up; there was no significant difference between groups ( P > 0.05). Anticoagulation/antiplatelet therapy in the perioperative period had no significant impact on STSG take and overall healing., Conclusions: The findings from this study demonstrate that administration of anticoagulant/antiplatelet agents in the perioperative period does not increase the risk of skin graft failure. Based on these findings, STSG can be performed without cessation of anticoagulation or antiplatelet therapy., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Neuropathic pain in rodents can be driven by ectopic spontaneous activity (SA) generated by sensory neurons in dorsal root ganglia (DRG). The recent demonstration that SA in dissociated human DRG neurons is associated with reported neuropathic pain in patients enables a detailed comparison of pain-linked electrophysiological alterations driving SA in human DRG neurons to alterations that distinguish SA in nociceptors from SA in low-threshold mechanoreceptors (LTMRs) in rodent neuropathy models. Analysis of recordings from dissociated somata of patient-derived DRG neurons showed that SA and corresponding pain in both sexes were significantly associated with the three functional electrophysiological alterations sufficient to generate SA in the absence of extrinsic depolarizing inputs. These include enhancement of depolarizing spontaneous fluctuations of membrane potential (DSFs), which were analyzed quantitatively for the first time in human DRG neurons. The functional alterations were indistinguishable from SA-driving alterations reported for nociceptors in rodent chronic pain models. Irregular, low-frequency DSFs in human DRG neurons closely resemble DSFs described in rodent nociceptors while differing substantially from the high-frequency sinusoidal oscillations described in rodent LTMRs. These findings suggest that conserved physiological mechanisms of SA in human nociceptor somata can drive neuropathic pain despite documented cellular differences between human and rodent DRG neurons. PERSPECTIVE: Electrophysiological alterations in human sensory neurons associated with patient-reported neuropathic pain include all three of the functional alterations that logically can promote spontaneous activity. The similarity of distinctively altered spontaneous depolarizations in human DRG neurons and rodent nociceptors suggests that spontaneously active human nociceptors can persistently promote neuropathic pain in patients., (Copyright © 2022 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Neuropathic pain is a major, inadequately treated challenge for people with spinal cord injury (SCI). While SCI pain mechanisms are often assumed to be in the CNS, rodent studies have revealed mechanistic contributions from primary nociceptors. These neurons become chronically hyperexcitable after SCI, generating ongoing electrical activity that promotes ongoing pain. A major question is whether extrinsic chemical signals help to drive ongoing electrical activity after SCI. People living with SCI exhibit acute and chronic elevation of circulating levels of macrophage migration inhibitory factor (MIF), a cytokine implicated in preclinical pain models. Probable nociceptors isolated from male rats and exposed to an MIF concentration reported in human plasma (1 ng/ml) showed hyperactivity similar to that induced by SCI, although, surprisingly, a 10-fold higher concentration failed to increase excitability. Conditioned behavioral aversion to a chamber associated with peripheral MIF injection suggested that MIF stimulates affective pain. A MIF inhibitor, Iso-1, reversed SCI-induced hyperexcitability. Unlike chronic SCI-induced hyperexcitability, acute MIF-induced hyperexcitability was only partially abrogated by inhibiting ERK signaling. Unexpectedly, MIF concentrations that induced hyperactivity in nociceptors from naive animals, after SCI induced a long-lasting conversion from a highly excitable nonaccommodating type to a rapidly accommodating, hypoexcitable type, possibly as a homeostatic response to prolonged depolarization. Treatment with conditioned medium from cultures of DRG cells obtained after SCI was sufficient to induce MIF-dependent hyperactivity in neurons from naive rats. Thus, changes in systemic and DRG levels of MIF may help to maintain SCI-induced nociceptor hyperactivity that persistently promotes pain. SIGNIFICANCE STATEMENT Chronic neuropathic pain is a major challenge for people with spinal cord injury (SCI). Pain can drastically impair quality of life, and produces substantial economic and social burdens. Available treatments, including opioids, remain inadequate. This study shows that the cytokine macrophage migration inhibitory factor (MIF) can induce pain-like behavior and plays an important role in driving persistent ongoing electrical activity in injury-detecting sensory neurons (nociceptors) in a rat SCI model. The results indicate that SCI produces an increase in MIF release within sensory ganglia. Low MIF levels potently excite nociceptors, but higher levels trigger a long-lasting hypoexcitable state. These findings suggest that therapeutic targeting of MIF in neuropathic pain states may reduce pain and sensory dysfunction by curbing nociceptor hyperactivity., (Copyright © 2022 the authors.)

Objective: To evaluate our institutional outcomes of surgical management of lower extremity (LE) wounds in the solid organ transplant recipient population. Approach: An 8-year retrospective review was conducted for all solid organ transplantation (SOT) recipients with LE wounds necessitating surgical management at our tertiary limb salvage center. Outcomes of interest included wound healing, surgical treatment, progression to amputation, and amputation level. Factors contributing to amputation progression were analyzed. The article adheres to the Strengthening the Reporting of Observational Studies in Epidemiology statement. Results: Sixty-four SOT recipients underwent surgical management for their LE wounds between 2010 and 2018. Median number of surgeries per patient was 5 (interquartile range = 2-8); 47 of 64 patients (73.4%) underwent amputation, and 17 of 64 patients (26.6%) underwent nonamputation surgical management. In the amputation group, the majority of primary amputations were minor (42/47, 89.4%); 24 of 42 (57.1%) patients progressed to a higher amputation level, 16 of 42 (38.1%) healed after their index procedure, and 2 of 42 (4.8%) were lost to follow-up (LTFU) after their primary minor amputation. Five of 47 (10.6%) patients undergoing amputations required primary below-knee amputations. In the nonamputation group, 15 of 17 (88.2%) healed, 1 of 17 (5.9%) expired, and 1 of 17 (5.9%) was LTFU. Innovation: To identify the outcomes of patients undergoing surgical management for LE wounds after SOT and elucidate clinical factors that impact the rate of limb salvage. Conclusions: This is the first comprehensive analysis of LE wounds in the transplant population. Our analysis indicates high rates of failed minor amputation, and frequent progression to major amputation in SOT patients. Preexisting comorbidities and immunosuppressive regimens complicate limb salvage; therefore, further research is warranted to optimize surgical LE wound management in this population.

Many surgeons use a single table of instruments for both excisional debridement and coverage/closure of infected wounds. This study investigates the effectiveness of a two-table set-up of sterile instruments, in addition to glove exchange, to reduce instrument cross-contamination during these procedures. This is a prospective, single-site, institutional review board-approved observational study of surgical debridements of infected wounds over a 17-month period. Two separate sterile surgical tables were used for each case: Table A for initial wound debridement (debridement set-up) and Table B for wound coverage/closure (clean set-up). Swabs of each table and its respective instruments were taken after debridement but prior to coverage/closure. The primary outcome of interest was bacterial growth at 48 hours. There were 72 surgical cases included in this study. Culture results of Table A demonstrated bacterial growth in 23 of 72 (32%) cases at 48 hours compared with 5of 72 (7%) from Table B (P = .001). These data suggest that there is significant bacterial contamination of surgical instruments used for debridement of infected wounds. Use of a two-table set-up reduced instrument cross-contamination by 78%, suggesting avoidable re-contamination of the wound., (© 2021 The Authors. International Wound Journal published by Medicalhelplines.com Inc (3M) and John Wiley & Sons Ltd.)

Objective: Porcine-derived xenograft biological dressings (PXBDs) are occasionally used to prepare chronic wound beds for definitive closure before split-thickness skin grafts (STSGs). We sought to determine whether PXBD influences rate of STSG take in lower-extremity wounds., Methods: Lower-extremity wounds treated with STSGs were retrospectively reviewed. Patients were included in one of two groups: wound bed preparation with PXBD before STSG or no preparation. Patients were excluded if they received wound bed preparation via another method. Patient demographics, comorbidities, wound history, wound bed preparation, and 30- and 60-day outcomes were collected., Results: There was no difference in healing outcomes between the PXBD (n = 27) and no preparation (n = 39) groups. At 30- and 60-day follow-up, percentage of STSG take was not significantly different between groups (77.9% versus 79.0%, P30 = .818; 82.2% versus 80.9%, P60 = .422). Mean wound sizes at these follow-up periods were not different (4.4 cm2 versus 5.1 cm2, P30 = .902; 1.2 cm2 versus 1.1 cm2, P60 = .689). The PXBD group had a higher mean ± SD hemoglobin A1c level (8.3 ± 3.5 versus 6.9 ± 1.6; P = .074) and age (64.9 ± 12.8 years versus 56.3 ± 11.9 years; P = .007) versus the no preparation group., Conclusions: Application of PXBDs for wound bed preparation had no effect on wound healing compared with no wound bed preparation. The two groups varied only by mean age and hemoglobin A1c level. The PXBD may be beneficial, but these results call for randomized controlled trials to determine the true impact of PXBDs on wound healing. In addition, PXBDs may have utility outside of clinically oriented outcomes, and future work should address patient-reported outcomes and pain scores with this adjunct.

Ongoing activity in nociceptors, a driver of spontaneous pain, can be generated in dorsal root ganglion neurons in the absence of sensory generator potentials if one or more of three neurophysiological alterations occur - prolonged depolarization of resting membrane potential (RMP), hyperpolarization of action potential (AP) threshold, and/or increased amplitude of depolarizing spontaneous fluctuations of membrane potential (DSFs) to bridge the gap between RMP and AP threshold. Previous work showed that acute, sustained exposure to serotonin (5-HT) hyperpolarized AP threshold and potentiated DSFs, leading to ongoing activity if a separate source of maintained depolarization was present. Cellular signaling pathways that increase DSF amplitude and promote ongoing activity acutely in nociceptors are not known for any neuromodulator. Here, isolated DRG neurons from male rats were used to define the pathway by which low concentrations of 5-HT enhance DSFs, hyperpolarize AP threshold, and promote ongoing activity. A selective 5-HT 4 receptor antagonist blocked these 5-HT-induced hyperexcitable effects, while a selective 5-HT 4 agonist mimicked the effects of 5-HT. Inhibition of cAMP effectors, protein kinase A (PKA) and exchange protein activated by cAMP (EPAC), attenuated 5-HT's hyperexcitable effects, but a blocker of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels had no significant effect. 5-HT 4 -dependent PKA activation was specific to DRG neurons that bind isolectin B4 (a nonpeptidergic nociceptor marker). 5-HT's effects on AP threshold, DSFs, and ongoing activity were mimicked by a cAMP analog. Sustained exposure to 5-HT promotes ongoing activity in nonpeptidergic nociceptors through the G s -coupled 5-HT 4 receptor and downstream cAMP signaling involving both PKA and EPAC., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Successful free tissue transfer is critical for lower extremity salvage in the chronic wound population. The rates of lower extremity free tissue transfer success lag behind those for other anatomical sites. The aim of this study was to evaluate whether positive qualitative day-of-free tissue transfer cultures or pathogen virulence negatively impacts short- and long-term outcomes of lower extremity free tissue transfer., Methods: Between April of 2011 and January of 2018, 105 lower extremity free tissue transfer procedures were performed. Growth level and speciation were identified from qualitative cultures taken during free tissue transfer. The relationship between demographics, comorbidities, culture data, postoperative infection, free tissue transfer survival, and long-term limb salvage was examined using logistic regression., Results: The median Charlson Comorbidity Index was 3. Intraoperative free tissue transfer cultures were positive in 39.1 percent. Flap survival was 93.3 percent. Postoperative infection developed in 12.4 percent. The limb salvage rate was 81.0 percent. Positive culture was not significant for flap survival, postoperative infection, or amputation. Cultures positive for Enterococcus species had a significant relationship with flap success (OR, 0.08; p = 0.01) and amputation (OR, 7.32; p = 0.04). Insufficient antimicrobial coverage had a significant relationship with postoperative infection (OR, 6.56; p = 0.01) despite the lack of pathogen concordance. On multivariate analysis, postoperative infection (OR, 12.85; p < 0.01) and Charlson Comorbidity Index were predictive of eventual amputation (OR, 1.44; p = 0.01)., Conclusions: Positive day-of-free tissue transfer cultures, regardless of pathogen, had limited predictive value for short- and long-term outcomes of free tissue transfer in the authors' cohort. These findings call for a broader multicenter prospective analysis and consideration of health care-associated infections and their impact on limb salvage outcomes., Clinical Question/level of Evidence: Risk, III., Competing Interests: Disclosure:There are no financial disclosures, commercial associations, or any other conditions posing a conflict of interest to report for any of the authors., (Copyright © 2020 by the American Society of Plastic Surgeons.)

Background: Surgical dehiscence can occur after lower extremity orthopedic procedures. Underlying vascular aberrancy and localized ischemia contribute to chronic wound development requiring advanced techniques such as free tissue transfer. Localized vascular abnormality is an underrecognized contributing factor to such dehiscence. The authors reviewed their lower extremity free tissue transfer experience in this population to analyze the incidence of arterial abnormality and outcomes., Methods: The authors conducted a retrospective review of 64 lower extremity free tissue transfers performed for chronic wounds after orthopedic procedures from 2011 to 2018. The primary outcome was major arterial abnormality as identified on angiography. Secondary outcomes were flap success, limb salvage, and ambulation status., Results: The median age was 58 years, and 44 were men (69 percent). Comorbidities included osteomyelitis (77 percent), diabetes (39 percent), and peripheral vascular disease (17 percent). The incidence of arterial abnormality on angiography was 47 percent. Defect location correlated with angiosome of arterial abnormality in 53 percent. The flap success rate was 92 percent. Limb salvage and ambulation rates were 89 and 89 percent, respectively, at an average follow-up of 17.6 months. Men demonstrated an increased rate of limb salvage (p = 0.026). Diabetes (p = 0.012), arterial abnormality (p = 0.044), and arterial flap complication (p = 0.010) correlated with amputation., Conclusions: The high incidence of arterial abnormality in this population highlights the importance of expedient multidisciplinary care, including vascular and plastic surgery. Diagnostic angiography is important for identifying major arterial abnormality and the need for free tissue transfer for definitive coverage.

Equinus contracture carries 3- and 4-fold associations with diabetes and plantar foot ulceration, respectively. Percutaneous tendo-Achilles lengthening is a useful method to alleviate peak plantar pressure resulting from equinus. We aimed to evaluate the effectiveness of percutaneous tendo-Achilles lengthening and estimate the relative longevity of the approach in reducing ulcer recurrence. The medical records of patients with equinus contracture who underwent percutaneous tendo-Achilles lengthening from 2010 to 2017 were reviewed. Included patients presented with plantar ulcers and a gastroc-soleus equinus of any angle <10° of ankle dorsiflexion with the affected knee extended and flexed. Patients who received concomitant tendon lengthening procedures (including anterior tibial tendon or flexor digitorum longus) were excluded. Outcome measures included time to wound healing, time to ulcer recurrence, and development of transfer lesion. Ninety-one patients underwent percutaneous tendo-Achilles lengthening with subsequent pedal ulceration without concomitant procedures. A total of 69 (75.8%) patients had a plantar forefoot ulcer, 7 (7.7%) had midfoot ulcers, 5 (5.5%) had hindfoot ulcers, and 3 (3.3%) had ulcers in multiple locations. Seven patients received prophylactic tendo-Achilles lengthening. At a mean follow-up of 31.6 months (±26), 66 (78.6%) wounds healed at a median 12.9 weeks. A total of 29 patients (43.9%) experienced ulcer recurrence at a mean of 12 months. Twelve patients (13%) experienced a transfer lesion at a mean of 16.6 months. Tendo-Achilles lengthening can be an effective adjunctive approach to achieve wound healing and reduce long-term ulcer recurrence in patients with equinus contracture and neuropathic plantar foot ulcers. A relengthening procedure may be needed within approximately 12 months from index surgery., (Copyright © 2020 the American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

Understanding the mechanisms that drive transition from acute to chronic pain is essential to identify new therapeutic targets. The importance of endogenous resolution pathways acting as a "brake" to prevent development of chronic pain has been largely ignored. We examined the role of interleukin-10 (IL-10) in resolution of neuropathic pain induced by cisplatin. In search of an underlying mechanism, we studied the effect of cisplatin and IL-10 on spontaneous activity (SA) in dorsal root ganglia neurons. Cisplatin (2 mg/kg daily for 3 days) induced mechanical hypersensitivity that resolved within 3 weeks. In both sexes, resolution of mechanical hypersensitivity was delayed in Il10 mice, in WT mice treated intrathecally with neutralizing anti-IL-10 antibody, and in mice with cell-targeted deletion of IL-10R1 on advillin-positive sensory neurons. Electrophysiologically, small- to medium-sized dorsal root ganglia neurons from cisplatin-treated mice displayed an increase in the incidence of SA. Cisplatin treatment also depolarized the resting membrane potential, and decreased action potential voltage threshold and rheobase, while increasing ongoing activity at -45 mV and the amplitude of depolarizing spontaneous fluctuations. In vitro addition of IL-10 (10 ng/mL) reversed the effect of cisplatin on SA and on the depolarizing spontaneous fluctuation amplitudes, but unexpectedly had little effect on the other electrophysiological parameters affected by cisplatin. Collectively, our findings challenge the prevailing concept that IL-10 resolves pain solely by dampening neuroinflammation and demonstrate in a model of chemotherapy-induced neuropathic pain that endogenous IL-10 prevents transition to chronic pain by binding to IL-10 receptors on sensory neurons to regulate their activity.

Chronic pain caused by spinal cord injury (SCI) is notoriously resistant to treatment, particularly by opioids. After SCI, DRG neurons show hyperactivity and chronic depolarization of resting membrane potential (RMP) that is maintained by cAMP signaling through PKA and EPAC. Importantly, SCI also reduces the negative regulation by Gαi of adenylyl cyclase and its production of cAMP, independent of alterations in G protein-coupled receptors and/or G proteins. Opioid reduction of pain depends on coupling of opioid receptors to Gαi/o family members. Combining high-content imaging and cluster analysis, we show that in male rats SCI decreases opioid responsiveness in vitro within a specific subset of small-diameter nociceptors that bind isolectin B4. This SCI effect is mimicked in nociceptors from naive animals by a modest 5 min depolarization of RMP (15 mm K + ; -45 mV), reducing inhibition of cAMP signaling by μ-opioid receptor agonists DAMGO and morphine. Disinhibition and activation of C-Raf by depolarization-dependent phosphorylation are central to these effects. Expression of an activated C-Raf reduces sensitivity of adenylyl cyclase to opioids in nonexcitable HEK293 cells, whereas inhibition of C-Raf or treatment with the hyperpolarizing drug retigabine restores opioid responsiveness and blocks spontaneous activity of nociceptors after SCI. Inhibition of ERK downstream of C-Raf also blocks SCI-induced hyperexcitability and depolarization, without direct effects on opioid responsiveness. Thus, depolarization-dependent C-Raf and downstream ERK activity maintain a depolarized RMP and nociceptor hyperactivity after SCI, providing a self-reinforcing mechanism to persistently promote nociceptor hyperexcitability and limit the therapeutic effectiveness of opioids. SIGNIFICANCE STATEMENT Chronic pain induced by spinal cord injury (SCI) is often permanent and debilitating, and usually refractory to treatment with analgesics, including opioids. SCI-induced pain in a rat model has been shown to depend on persistent hyperactivity in primary nociceptors (injury-detecting sensory neurons), associated with a decrease in the sensitivity of adenylyl cyclase production of cAMP to inhibitory Gαi proteins in DRGs. This study shows that SCI and one consequence of SCI (chronic depolarization of resting membrane potential) decrease sensitivity to opioid-mediated inhibition of cAMP and promote hyperactivity of nociceptors by enhancing C-Raf activity. ERK activation downstream of C-Raf is necessary for maintaining ongoing depolarization and hyperactivity, demonstrating an unexpected positive feedback loop to persistently promote pain., (Copyright © 2020 the authors.)

The most common consequence of neuropathy is a diabetic foot ulcer, which usually occurs on the plantar surface of the foot. Split-thickness skin grafting (STSG) has been shown in numerous studies to be an effective treatment for rapid coverage of diabetic ulcers. The purpose of this study is to retrospectively examine the outcomes of STSG to the plantar foot and determine the durability of this treatment compared to non-plantar surface STSG. This is a retrospective, single-center, institutional review board approved, case-control study of all patients who received STSG to their lower extremity for chronic ulcers from November 2013 to February 2017. Patients with ulcers on the plantar surface were considered cases, and non-plantar surface ulcers were considered controls. There were 182 patients who received STSG to the lower extremity, 52 to the plantar surface foot and 130 to non-plantar surface locations. Healing at 30 days was not significantly different between plantar and nonplantar ulcers (19% versus 28%, p = .199) but did become significant at 60, 90, and 365 days (21% versus 45%, p = .003; 33% versus 49%, p = .043; 38% versus 64%, p = .002, respectively). However, time to full healing was not significantly different between plantar and nonplantar groups (18.2 ± 19.5 versus 17.4 ± 21.6 weeks, mean ± standard deviation, p = .84). Recurrence was low for both groups (17% versus 10%, respectively), and there was no significant difference between groups (p = .17). Patients with plantar surface ulcers can achieve a durable coverage/closure of their wounds with STSG. When combined with appropriate patient selection and postoperative offloading, acceptable recurrence rates can be achieved., (Copyright © 2019 the American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Available treatments for neuropathic pain have modest efficacy and significant adverse effects, including abuse potential. Because oxidative stress is a key mechanistic node for neuropathic pain, the authors focused on the master regulator of the antioxidant response-nuclear factor erythroid 2-related factor 2 (NFE2L2; Nrf2)-as an alternative target for neuropathic pain. The authors tested whether dimethyl fumarate (U.S. Food and Drug Administration-approved treatment for multiple sclerosis) would activate NFE2L2 and promote antioxidant activity to reverse neuropathic pain behaviors and oxidative stress-dependent mechanisms., Methods: Male Sprague Dawley rats, and male and female wild type and Nfe2l2 mice were treated with oral dimethyl fumarate/vehicle for 5 days (300 mg/kg; daily) after spared nerve injury/sham surgery (n = 5 to 8 per group). Allodynia was measured in von Frey reflex tests and hyperalgesia in operant conflict-avoidance tests. Ipsilateral L4/5 dorsal root ganglia were assayed for antioxidant and cytokine/chemokine levels, and mitochondrial bioenergetic capacity., Results: Dimethyl fumarate treatment reversed mechanical allodynia (injury-vehicle, 0.45 ± 0.06 g [mean ± SD]; injury-dimethyl fumarate, 8.2 ± 0.16 g; P < 0.001) and hyperalgesia induced by nerve injury (injury-vehicle, 2 of 6 crossed noxious probes; injury-dimethyl fumarate, 6 of 6 crossed; P = 0.013). The antiallodynic effect of dimethyl fumarate was lost in nerve-injured Nfe2l2 mice, but retained in nerve-injured male and female wild type mice (wild type, 0.94 ± 0.25 g; Nfe2l2, 0.02 ± 0.01 g; P < 0.001). Superoxide dismutase activity was increased by dimethyl fumarate after nerve injury (injury-vehicle, 3.96 ± 1.28 mU/mg; injury-dimethyl fumarate, 7.97 ± 0.47 mU/mg; P < 0.001). Treatment reduced the injury-dependent increases in cytokines and chemokines, including interleukin-1β (injury-vehicle, 13.30 ± 2.95 pg/mg; injury-dimethyl fumarate, 6.33 ± 1.97 pg/mg; P = 0.022). Injury-impaired mitochondrial bioenergetics, including basal respiratory capacity, were restored by dimethyl fumarate treatment (P = 0.025)., Conclusions: Dimethyl fumarate, a nonopioid and orally-bioavailable drug, alleviated nociceptive hypersensitivity induced by peripheral nerve injury via activation of NFE2L2 antioxidant signaling. Dimethyl fumarate also resolved neuroinflammation and mitochondrial dysfunction-oxidative stress-dependent mechanisms that drive nociceptive hypersensitivity after nerve injury.

Chronic pain following spinal cord injury (SCI) is associated with electrical hyperactivity (spontaneous and evoked) in primary nociceptors. Cyclic adenosine monophosphate (cAMP) signaling is an important contributor to nociceptor excitability, and knockdown of the cAMP effector, exchange protein activated by cAMP (EPAC), has been shown to relieve pain-like responses in several chronic pain models. To examine potentially distinct roles of each EPAC isoform (EPAC1 and 2) in maintaining chronic pain, we used rat and mouse models of contusive spinal cord injury (SCI). Pharmacological inhibition of EPAC1 or 2 in a rat SCI model was sufficient to reverse SCI-induced nociceptor hyperactivity, indicating that EPAC1 and 2 signaling activity are complementary, with both required to maintain hyperactivity. However, EPAC activation was not sufficient to induce similar hyperactivity in nociceptors from naïve rats, and we observed no change in EPAC protein expression after SCI. In the mouse SCI model, inhibition of both EPAC isoforms through a combination of pharmacological inhibition and genetic deletion was required to reverse SCI-induced nociceptor hyperactivity. This was consistent with our finding that neither EPAC1 -/- nor EPAC2 -/- mice were protected against SCI-induced chronic pain as assessed with an operant mechanical conflict test. Thus, EPAC1 and 2 activity may play a redundant role in mouse nociceptors, although no corresponding change in EPAC protein expression levels was detected after SCI. Despite some differences between these species, our data demonstrate a fundamental role for both EPAC1 and EPAC2 in mechanisms maintaining nociceptor hyperactivity and chronic pain after SCI., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2019 The Authors.)

Chronic pain is considered maladaptive by clinicians because it provides no apparent protective or recuperative benefits. Similarly, evolutionary speculations have assumed that chronic pain represents maladaptive or evolutionarily neutral dysregulation of acute pain mechanisms. By contrast, the present hypothesis proposes that chronic pain can be driven by mechanisms that evolved to reduce increased vulnerability to attack from predators and aggressive conspecifics, which often target prey showing physical impairment after severe injury. Ongoing pain and anxiety persisting long after severe injury continue to enhance vigilance and behavioural caution, decreasing the heightened vulnerability to attack that results from motor impairment and disfigurement, thereby increasing survival and reproduction (fitness). This hypothesis is supported by evidence of animals surviving and reproducing after traumatic amputations, and by complex specializations that enable primary nociceptors to detect local and systemic signs of injury and inflammation, and to maintain low-frequency discharge that can promote ongoing pain indefinitely. Ongoing activity in nociceptors involves intricate electrophysiological and anatomical specializations, including inducible alterations in the expression of ion channels and receptors that produce persistent hyperexcitability and hypersensitivity to chemical signals of injury. Clinically maladaptive chronic pain may sometimes result from the recruitment of this powerful evolutionary adaptation to severe bodily injury. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.

Our understanding of the biology of pain is limited by our ignorance about its evolution. We know little about how states in other species showing various degrees of apparent similarity to human pain states are related to human pain, or how the mechanisms essential for pain-related states evolved. Nevertheless, insights into the evolution of mechanisms and behaviour important for pain are beginning to emerge from wide-ranging investigations of cellular mechanisms and behavioural responses linked to nociceptor activation, tissue injury, inflammation and the environmental context of these responses in diverse species. In February 2019, an unprecedented meeting on the evolution of pain hosted by the Royal Society brought together scientists from disparate fields who investigate nociception and pain-related behaviour in crustaceans, insects, leeches, gastropod and cephalopod molluscs, fish and mammals (primarily rodents and humans). Here, we identify evolutionary themes that connect these research efforts, including adaptive and maladaptive features of pain-related behavioural and neuronal alterations-some of which are quite general, and some that may apply primarily to humans. We also highlight major questions, including how pain should be defined, that need to be answered as we seek to understand the evolution of pain. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.

Injury to sensory neurons causes an increase in the excitability of these cells leading to enhanced action potential generation and a lowering of spike threshold. This type of sensory neuron plasticity occurs across vertebrate and invertebrate species and has been linked to the development of both acute and persistent pain. Injury-induced plasticity in sensory neurons relies on localized changes in gene expression that occur at the level of mRNA translation. Many different translation regulation signalling events have been defined and these signalling events are thought to selectively target subsets of mRNAs. Recent evidence from mice suggests that the key signalling event for nociceptor plasticity is mitogen-activated protein kinase-interacting kinase (MNK) -mediated phosphorylation of eukaryotic translation initiation factor (eIF) 4E. To test the degree to which this is conserved in other species, we used a previously described sensory neuron plasticity model in Aplysia californica . We find, using a variety of pharmacological tools, that MNK signalling is crucial for axonal hyperexcitability in sensory neurons from Aplysia . We propose that MNK-eIF4E signalling is a core, evolutionarily conserved, signalling module that controls nociceptor plasticity. This finding has important implications for the therapeutic potential of this target, and it provides interesting clues about the evolutionary origins of mechanisms important for pain-related plasticity. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.

Introduction: Tissue ischemia resulting from arterial insufficiency is a major factor affecting lower extremity wound healing in patients with peripheral arterial disease (PAD). Accelerated wound closure with split-thickness skin grafting (STSG) provides a durable barrier to infection and can prevent limb loss. Published STSG outcomes data are minimal in the post endovascular intervention population., Objective: In this study, the authors examine factors predictive of STSG healing in patients with PAD following vascular intervention, including the effect of non-inline flow via arterial-arterial and non-arterial collateralization., Materials and Methods: Patients with PAD and wounds of the foot and ankle who underwent STSG between January 2014 and December 2016 were retrospectively reviewed. All patients received angiographic evaluation and endovascular or open revascularization where necessary. Effects of extremity revascularizations, STSG percent take, and amputation rate were evaluated., Results: Thirty-five patients with 47 wounds underwent STSG. There were 21 men and 14 women with a mean age of 64 ± 13 years. Revascularization was required in 23 patients (25 extremities) before STSG, with balloon angioplasty for tibial artery lesions as the most common revascularization. Patent pedal arch was present in 8 patients; 35 patients had an absent or incomplete pedal arch. Patients with a fully patent pedal arch healed at a significantly higher rate than those with an absent or incomplete pedal arch at 1 month (62.5% vs. 17.1%, P ⟨ .05). At 90-day follow-up, 9 of 35 (25.7%) patients with 9 of 47 (19.1%) wounds were lost to follow-up, leaving 18 of 38 (47.37%) wounds healed and 20 (52.63%) still open. Ultimately, 36 of 47 (76.60%) wounds healed and 6 major amputations in 6 patients were required at a mean 502 ± 342 days follow-up., Conclusions: These results suggest the importance of arterial-arterial connections such as the pedal arch to the healing potential of foot and ankle wounds after STSG in this high-risk patient population.

Postreconstructive outcomes were compared in diabetic patients with Charcot neuroarthropathy (CN) who had peripheral arterial disease (PAD) diagnosed with angiography versus patients who were diagnosed clinically. A retrospective review was performed of patients with diabetic CN requiring reconstruction secondary to ulceration and/or acute infection. Of the 284 patients in the CN osseous reconstruction cohort, after accounting for exclusion criteria, 59 (20.8%) patients with PAD were included in the analyses. Forty (67.8%) of these 59 patients were diagnosed with PAD clinically and 19 (32.2%) were diagnosed with the use of angiography. Bivariate analysis was used to compare outcomes between those diagnosed with PAD via angiography versus those diagnosed clinically for the following postreconstruction outcomes: wound healing, delayed healing, surgical site infection, pin tract infection, osteomyelitis, dehiscence, transfer ulcer, new site of Charcot collapse, contralateral Charcot event, nonunion, major lower extremity amputation, and return to ambulation. Bivariate analysis found return to ambulation postreconstruction (p = .0054) to be the only statistically significant factor. There was a trend toward significance for major lower extremity amputation, with higher rates of amputation in the clinically diagnosed PAD arm. Return to ambulation indicates improved functional outcomes. The main goal of limb salvage should be focused on improving the patient's functional performance. With significantly faster rates of return to ambulation and a trend toward decreased rates of major amputation, angiography was found to be a better assessor of PAD than clinical evaluations., (Copyright © 2019 the American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

Studies using rodent models of neuropathic pain use sham surgery control procedures that cause deep tissue damage. Sham surgeries would thus be expected to induce potentially long-lasting postsurgical pain, but little evidence for such pain has been reported. Operant tests of voluntary behavior can reveal negative motivational and cognitive aspects of pain that may provide sensitive tools for detecting pain-related alterations. In a previously described operant mechanical conflict test involving lengthy familiarization and training, rodents freely choose to either escape from a brightly lit chamber by crossing sharp probes or refuse to cross. Here, we describe a brief (2-day) mechanical conflict protocol that exploits rats' innate exploratory response to a novel environment to detect persistently enhanced pain-avoidance behavior after sham surgeries for 2 neural injury models: thoracic spinal cord injury and chronic constriction injury of the sciatic nerve. Pitting the combined motivations to avoid the bright light and to explore the novel device against pain from crossing noxious probes disclosed a conflicting, hyperalgesia-related reluctance to repeatedly cross the probes after injury. Rats receiving standard sham surgeries demonstrated enhanced pain-like avoidance behavior compared with naive controls, and this behavior was similar to that of corresponding chronic constriction injury or spinal cord injury rats weeks or months after injury. In the case of sham surgery for spinal cord injury, video analysis of voluntary exploratory behavior directed at the probes revealed enhanced forepaw withdrawal responses. These findings have important implications for preclinical investigations into behavioral alterations and physiological mechanisms associated with postsurgical and neuropathic pain.

Background: Incisional hernia is a common complication following visceral organ transplantation. Transplant patients are at increased risk of primary and recurrent hernias due to chronic immune suppression and large incisions. We conducted a retrospective review of patients with a history of liver or kidney transplantation who underwent hernia repair to analyze outcomes and hernia recurrence., Methods: This is a single center, retrospective review of 19 patients who received kidney and/or liver transplantation prior to presenting with an incisional hernia from 2011 to 2017. All hernias were repaired with open component separation technique (CST) with biologic mesh underlay., Results: The mean age of patients was 61.0±8.3 years old, with a mean body mass index of 28.4±4.8 kg/m2, 15 males (78.9%), and four females (21.1%). There were seven kidney, 11 liver, and one combined liver and kidney transplant patients. The most common comorbidities were hypertension (16 patients, 84.2%), diabetes (9 patients, 47.4%), and tobacco use (8 patients, 42.1%). Complications occurred in six patients (31.6%) including hematoma (1/19), abscess (1/19), seroma (2/19), and hernia recurrence (3/19) at mean follow-up of 28.7±22.8 months. With the exception of two patients with incomplete follow-up, all patients healed at a median time of 27 days., Conclusions: This small, retrospective series of complex open CST in transplant patients shows acceptable rates of long-term hernia recurrence and healing. By using a multidisciplinary approach for abdominal wall reconstruction, we believe that modified open CST with biologic mesh is a safe and effective technique in the transplant population with complex abdominal hernias.

Introduction: Mastectomy skin flap necrosis represents a significant complication of breast reconstructive procedures and is reported to occur in 30%-52% of patients undergoing breast reconstruction. Early identification of ischemia and early initiation of hyperbaric oxygen (HBO2) therapy can mitigate the effects of ischemia and rescue otherwise non-viable breast flap tissue., Methods: We retrospectively examined the outcomes of HBO2 therapy in eight breasts with compromised mastectomy skin flaps between September 2015 and January 2017. Indocyanine green angiography (ICGA) was used to assess perfusion intraoperatively and post-HBO2 administration., Results: Seven patients were referred for HBO2 within 24 hours of mastectomy. One patient failed to improve despite starting hyperbaric treatment within 24 hours. All other patients manifested successful healing of their mastectomy skin flaps with acceptable cosmesis after 10 HBO2 treatments. The mean relative perfusion of the at-risk area was 13.8% (±3.7%) pre-HBO2 and 101.6% (±37.3%) post-HBO2. The average area at-risk pre-HBO2 was 17.1 cm2 and reduced to zero post-HBO2. Relative perfusion values after HBO2 were found to be 6.8 (±3.4) times greater than those measured prior to HBO2., Conclusions: A short course of HBO2 may be sufficient to successfully rescue at risk post-mastectomy breast flaps. ICGA is a useful adjunct for evaluating post-mastectomy breast flap perfusion before and after HBO2 therapy., Competing Interests: The authors of this paper declare no conflicts of interest exist with this submission., (Copyright© Undersea and Hyperbaric Medical Society.)

Ongoing pain has been linked to ongoing activity (OA) in human C-fiber nociceptors, but rodent models of pain-related OA have concentrated on allodynia rather than ongoing pain, and on OA generated in non-nociceptive Aβ fibers rather than C-fiber nociceptors. Little is known about how ongoing pain or nociceptor OA is generated. To define neurophysiological alterations underlying nociceptor OA, we have used isolated dorsal root ganglion neurons that continue to generate OA after removal from animals displaying ongoing pain. We subclassify OA as either spontaneous activity generated solely by alterations intrinsic to the active neuron or as extrinsically driven OA. Both types of OA were implicated previously in nociceptors in vivo and after isolation following spinal cord injury, which produces chronic ongoing pain. Using novel automated algorithms to analyze irregular changes in membrane potential, we have found, in a distinctive, nonaccommodating type of probable nociceptor, induction by spinal cord injury of 3 alterations that promote OA: (1) prolonged depolarization of resting membrane potential, (2) a hyperpolarizing shift in the voltage threshold for action potential generation, and (3) an increase in the incidence of large depolarizing spontaneous fluctuations (DSFs). Can DSFs also be enhanced acutely to promote OA in neurons from uninjured animals? A low dose of serotonin failed to change resting membrane potential but lowered action potential threshold. When combined with artificial depolarization to model inflammation, serotonin also strongly potentiated DSFs and OA. These findings reveal nociceptor specializations for generating OA that may promote ongoing pain in chronic and acute conditions.

Background: Lower-extremity free flap reconstruction is a growing trend in the management of lower extremity wounds. Heparin-induced thrombocytopenia (HIT) is a significant risk to free flap reconstruction. The purpose of this study was to investigate the incidence of HIT in patients receiving lower-extremity free flap surgery., Methods: We conducted a retrospective, single center, IRB approved cohort study in which we reviewed all patients who received lower-extremity free flap surgeries between 2011 and 2016. The 4T and HIT Expert Probability (HEP) scores were calculated to assess the likelihood of HIT., Results: One hundred patient charts revealed three patients with HIT. One patient was excluded due to a prior diagnosis of HIT. HIT incidence in patients receiving lower-extremity free flaps was between 1% and 3%, which is consistent with the national average. 4T scores indicated that two of three HIT-positive patients had a high probability of HIT (approximately 64%), and one of three HIT-positive patients had an intermediate probability (approximately 14%). HEP scoring indicated that all the three (100%) patients had HIT., Conclusions: These data suggest that the incidence of HIT in patients receiving lower-extremity free flaps correlates with the incidence of HIT nationally. The use of available scoring methods and other algorithms, combined with patient history helps to assess the immediate perioperative risks of HIT in the absence of rapid immunologic confirmatory tests. This knowledge can allow for successful free flap salvage or for performance of free flaps in patients with a history of HIT., (Copyright © 2018. Published by Elsevier Ltd.)