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Introduction: Current guidelines for pain treatment recommend a personalized, multimodal and interdisciplinary approach as well as the use of a combination of drug and non-drug therapies. Risk factors for chronification should already be reduced in patients with acute pain, e.g., after surgery or trauma. Auricular vagus nerve stimulation (aVNS) could be an effective non-drug therapy in the multimodal treatment of chronic and acute pain. The aim of this systematic review and meta-analysis is to evaluate the clinical efficacy and safety of aVNS in treating chronic and acute pain conditions., Methods: A systematic literature search was performed regarding the application of auricular electrical stimulation in chronic and acute pain. Studies were classified according to their level of evidence (Jadad scale), scientific validity and risk of bias (RoB 2 tool) and analyzed regarding indication, method, stimulation parameters, duration of treatment and efficacy and safety. A meta-analysis on (randomized) controlled trials (using different comparators) was performed for chronic and acute pain conditions, respectively, including subgroup analysis for percutaneous (pVNS-needle electrodes) and transcutaneous (tVNS-surface electrodes) aVNS. The visual analog pain scale (VAS) was defined as primary efficacy endpoint., Results: A total of n = 1496 patients were treated with aVNS in 23 identified and analyzed studies in chronic pain, 12 studies in acute postoperative pain and 7 studies in experimental acute pain. Of these, seven studies for chronic pain and six studies for acute postoperative pain were included in the meta-analysis. In chronic pain conditions, including back pain, migraine and abdominal pain, a statistically significant reduction in VAS pain intensity for active compared to sham aVNS or control treatment with an effect size Hedges' g/mean difference of - 1.95 (95% confidence interval [CI]: - 3.94 to 0.04, p = 0.008) could be shown and a more favorable effect in pVNS compared to tVNS (- 5.40 [- 8.94; - 1.85] vs. - 1.00 [- 1.55; - 0.44]; p = 0.015). In acute pain conditions, single studies showed significant improvements with aVNS, e.g., in kidney donor surgery or tonsillectomy but, overall, a non-statistically significant reduction in VAS pain intensity for active compared to sham aVNS or control with - 0.70 [- 2.34; 0.93] (p = 0.15) could be observed in the meta-analysis. In acute pain results vary greatly between studies depending especially on co-medication and timepoints of assessment after surgery. A significant reduction in analgesics or opiate intake was documented in most studies evaluating this effect in chronic and acute pain. In 3 of the 12 randomized controlled trials in patients with chronic pain, a sustainable pain reduction over a period of up to 12 months was shown. Overall, aVNS was very well tolerated., Conclusion: This systematic review and meta-analysis indicate that aVNS can be an effective and safe non-drug treatment in patients with specific chronic and acute postoperative pain conditions. Further research is needed to identify the influence of simulation parameters and find optimal and standardized treatment protocols while considering quality-of-life outcome parameters and prolonged follow-up periods. A more standardized approach and harmonization in study designs would improve comparability and robustness of outcomes., (© 2024. The Author(s).)

Introduction: The International Neuromodulation Society convened a multispecialty group of physicians and scientists based on expertise with international representation to establish evidence-based guidance on intrathecal drug delivery in treating chronic pain. This Polyanalgesic Consensus Conference (PACC)® project, created more than two decades ago, intends to provide evidence-based guidance for important safety and efficacy issues surrounding intrathecal drug delivery and its impact on the practice of neuromodulation., Materials and Methods: Authors were chosen on the basis of their clinical expertise, familiarity with the peer-reviewed literature, research productivity, and contributions to the neuromodulation literature. Section leaders supervised literature searches of MEDLINE, BioMed Central, Current Contents Connect, Embase, International Pharmaceutical Abstracts, Web of Science, Google Scholar, and PubMed from 2017 (when PACC® last published guidelines) to the present. Identified studies were graded using the United States Preventive Services Task Force criteria for evidence and certainty of net benefit. Recommendations are based on the strength of evidence or consensus when evidence is scant., Results: The PACC® examined the published literature and established evidence- and consensus-based recommendations to guide best practices. Additional guidance will occur as new evidence is developed in future iterations of this process., Conclusions: The PACC® recommends best practices regarding intrathecal drug delivery to improve safety and efficacy. The evidence- and consensus-based recommendations should be used as a guide to assist decision-making when clinically appropriate., Competing Interests: Conflict of Interest Alaa Abd-Elsayed is a consultant for Medtronic. Philip Kim reports consulting fees from Medtronic, personal fees from TerSera, outside the submitted work; personal fees from Biotronik and Medtronic on a medical board; reseach support from Biotronik, Medtronic, Boston, Nevro, Saluda, and Cornerloc; and participation in a data safety monitoring board on RTX on Morton neuroma study. Christophe Perruchoud reports consulting fees, honoraria, and participation on a data safety monitoring board or advisory board for Medtronic. Anjum Bux reports personal fees from Flowonix Corp, Boston Scientific, AIS, Medtronic, and Vertos, outside the submitted work. Rui Duarte reports personal fees from Saluda Medical, Boston Scientific, Medtronic, and Mainstay Medical, outside the submitted work. Michael Saulino reports research grants from Medtronic and Flowonix; fellowship support from Medtronic, Piramal, and Saol; Denis Dupoiron reports personal fees from Medtronic and Esteve, outside the submitted work. Dennis Patin consults for Medtronic, Abbott, Boston Scientific, and Nevro. Julie G. Pilitsis reports grants and other from Boston Scientific, Nevro, Abbott, TerSera, and Medtronic; other from Saluda, Aim Medical Robotics, and Karuna Labs; grants from National Institutes of Health (NIH) 2R01CA166379-06; and grants from NIH U44NS115111, outside the submitted work. Lawrence R. Poree reports personal fees from Medtronic and Nalu, and grants and personal fees from Saluda, outside the submitted work. Harry Sukumaran reports personal fees from Abbott, Boston Scientific, and Nevro, and personal fees and nonfinancial support from Vertos Medical, outside the submitted work. Erik Shaw reports support from Pfizer/Lilly for tanezumab articles; consulting fees and/or honoraria from TerSera, Boston Scientific, SPR Therapeutics; participation on a data safety monitoring board or advisory board for Pfizer/Lilly NGF blocker; and stock options from SpineThera and ROM Tech. Tony L. Yaksh reports grants from NIH-National Institute of Neurological Disorders and Stroke (NINDS), other from CODA, IONIS, and Medtronic during the conduct of the study; grants from NIH-NINDS, IONIS, and Medtronic, outside the submitted work. Robert M. Levy is an unpaid and uncompensated consultant for Abbott, Biotronik, Nalu, and Synergia. The remaining authors reported no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: The International Neuromodulation Society convened a multispecialty group of physicians based on expertise with international representation to establish evidence-based guidance on using intrathecal drug delivery in chronic pain treatment. This Polyanalgesic Consensus Conference (PACC)® project's scope is to provide evidence-based guidance for clinical pharmacology and best practices for intrathecal drug delivery for cancer pain., Materials and Methods: Authors were chosen on the basis of their clinical expertise, familiarity with the peer-reviewed literature, research productivity, and contributions to the neuromodulation literature. Section leaders supervised literature searches using Medline, EMBASE, Cochrane CENTRAL, BioMed Central, Web of Science, Google Scholar, PubMed, Current Contents Connect, Meeting Abstracts, and Scopus from 2017 (when the PACC last published guidelines) to the present. Identified studies were graded using the United States Preventive Services Task Force criteria for evidence and certainty of net benefit. Recommendations were based on the strength of evidence, and when evidence was scant, recommendations were based on expert consensus., Results: The PACC evaluated the published literature and established evidence- and consensus-based expert opinion recommendations to guide best practices in treating cancer pain. Additional guidance will occur as new evidence is developed in future iterations of this process., Conclusions: The PACC recommends best practices regarding the use of intrathecal drug delivery in cancer pain, with an emphasis on managing the unique disease and patient characteristics encountered in oncology. These evidence- and consensus-based expert opinion recommendations should be used as a guide to assist decision-making when clinically appropriate., Competing Interests: Conflict of Interest Shane E. Brogan acts as a paid consultant for Medtronic. Eric Buchser reports grants from the Swiss National Foundation and the Commission for Technology and Innovation; and grants, personal fees and nonfinancial support from Medtronic, during the conduct of the study. Timothy R. Deer reports no conflicts that pertain to intrathecal therapy; reports conflicts within the neuromodulation field that include consulting for Abbott, Saluda, Ethos, Nalu, PainTeq, and Cornorloc; he also holds a patent pending with Abbott; is on the advisory board of Abbott and Nalu; has stock options Saluda, Spinethera, and Nalu; and has institutional research grants from Abbott, Saluda, Vertiflex and Mainstay. Denis Dupoiron reports personal fees from Medtronic and Esteve during the conduct of the study. Amitabh Gulati reports personal fees from Medtronic, Flowonix, AIS HealthCare, SPR Therapeutics, Nalu Medical, Bausch Health, and Spark Medical, outside the submitted work. Jennifer Hah reports grants from NIH NIDA, outside the submitted work. Gladstone C. McDowell II reports personal fees and other from Medtronic Corporation; personal fees, nonfinancial support, and other from Flowonix Corporation and TerSera Therapeutics, outside the submitted work. Christophe Perruchoud reports grants and personal fees from Medtronic and Boston Scientific, during the conduct of the study; and personal fees from Medtronic and Boston Scientific, outside the submitted work. Fabian Piedimonte reports personal fees from Medtronic and Abbott, which stopped in June 2020. Julie G. Pilitsis reports grants and other from Boston Scientific, Nevro, Abbott, Medtronic, and TerSera; other from Saluda; grants from NIH 2R01CA166379-06, other from Aim Medical Robotics and Karuna Labs; and grants from NIH U44NS115111, outside the submitted work. Jason E. Pope reports other from Ethos Labs, Flowonix, Saluda, PainTeq, Aurora Spine, Thermaquil, Celeri Health, Spine Thera, AGR, NIS, Abbott, Medtronic, Biotronik, Mainstay, Muse, AIS, SPR Therapeutics, TerSera, Vertiflex, Boston Scientific, Vertos, SPARK, and WISE, outside the submitted work. Michael F. Saulino reports research grants from Medtronic and Flowonix; fellowship support from Medtronic, Piramal, and Saol. Peter S. Staats reports grants from Saluda, Nalu, AIS Therapeutics, Thermaquil, Biotronik, electroCore and Vertos, outside the scope of this work; royalties from the Averitas-Qutenza Patch, outside the scope of this work; payment or honoraria from Medtronic and SPR Therapeutics, outside the scope of this work; patents for vagus nerve and topical capsaicin products; participation in a Data Safety Monitoring or Advisory Board for Nalu and Saluda; a leadership role in the World Institute of Pain, American Society of Pain and Neuroscience, American Society of Interventional Pain Physicians, and the Florida Academy of Pain Management; and stock options in Saluda, Nalu and electroCore. Mark S. Wallace reports grants from NIH and is a consultant to TerSera. Tony L. Yaksh reports grants from NIH NINDS, other from CODA, IONIS, and Medtronic, during the conduct of the study; and grants from NIH-NINDS, IONIS, and Medtronic, outside the submitted work. The remaining authors reported no conflict of interest., (Copyright © 2024 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Introduction: The International Neuromodulation Society convened a multispecialty group of physicians based on expertise and international representation to establish evidence-based guidance on the mitigation of neuromodulation complications. This Neurostimulation Appropriateness Consensus Committee (NACC)® project intends to update evidence-based guidance and offer expert opinion that will improve efficacy and safety., Materials and Methods: Authors were chosen on the basis of their clinical expertise, familiarity with the peer-reviewed literature, research productivity, and contributions to the neuromodulation literature. Section leaders supervised literature searches of MEDLINE, BioMed Central, Current Contents Connect, Embase, International Pharmaceutical Abstracts, Web of Science, Google Scholar, and PubMed from 2017 (when NACC last published guidelines) to October 2023. Identified studies were graded using the United States Preventive Services Task Force criteria for evidence and certainty of net benefit. Recommendations are based on the strength of evidence or consensus when evidence was scant., Results: The NACC examined the published literature and established evidence- and consensus-based recommendations to guide best practices. Additional guidance will occur as new evidence is developed in future iterations of this process., Conclusions: The NACC recommends best practices regarding the mitigation of complications associated with neurostimulation to improve safety and efficacy. The evidence- and consensus-based recommendations should be used as a guide to assist decision-making when clinically appropriate., Competing Interests: Conflict of Interest Timothy R. Deer consults for Abbott, Saluda, Ethos, Nalu, PainTeq, and Cornorloc; holds a patent pending with Abbott; is on the advisory board of Abbott and Nalu; has stock options with Saluda, Spinethera, and Nalu; and has institutional research grants from Abbott, Saluda, Vertiflex, and Mainstay. Dawood Sayed consults for Abbott, Saluda, PainTeq, and Surgentec and holds stock in PainTeq, Surgentec, Neuralace, Vertos, SPR, and Mainstay. Jason E. Pope serves as a consultant, on the advisory board, and conducts research for Ethos Labs, Flowonix, Saluda, PainTeq, Aurora Spine, Mainstay, Thermaquil, Abbott, Vertiflex, Vertos, and SPR Therapeutics; owns stock in PainTeq, Aurora Spine, Thermaquil, Spine Thera, Saluda, Abbott, AGR, NIS, Vertos, Celeri Health, and SPARK; receives royalties from Aurora Spine; consults for Biotronik, Medtronic, Boston Scientific, and WISE; conducts research for Ethos, Celeri Health, and Boston Scientific; and serves on the advisory board of Spine Thera. Steven M. Falowski consults for Abbott, Medtronic, Boston Scientific, Vertos, and Saluda. Research is performed with Abbott, Medtronic, Biotronik, Saluda, and Vertiflex. Equity positions are held in Saluda, CornerLoc, SPR Therapeutics, Thermaquil, Stimgenics, SpineThera, Neural Integrative Solutions, and AGR. Konstantin V. Slavin reports grants from Medtronic, Abbott, and Boston Scientific; personal fees from Medtronic, Abbott, Boston Scientific, MSEI, Nuvectra, and Stimwave; and nonfinancial support from Neuramodix, Thermaquil, Higgs Boson, and Stimwave, outside the submitted work. Sean Li consults for Abbott, Avanos, Averitas Pharma, Biotronik, Nalu, NeuroOne, PainTeq, Saluda, SPR Therapeutics, and Vertos Medical; and has research grants from Avanos, Averitas Pharma, Biotronik, Nevro, PainTeq, Saluda, and SPR Therapeutics and equity in Nalu and NeuroOne. Lawrence R. Poree reports personal fees and other from Saluda Medical Inc, personal fees and other from Nalu Inc, personal fees from Medtronic, and personal fees from Gimer, outside the submitted work. Sam Eldabe reports personal fees from Medtronic, Mainstay Medical, Saluda Medical, and Boston Scientific; and grants from Medtronic, during the conduct of the study. Kaare Meier reports teaching fees from Abbott, outside the submitted work; his institution has received travel support from Abbott and Boston Scientific. Julie G. Pilitsis is a consultant for Boston Scientific, Nevro, TerSera, Medtronic, Saluda, and Abbott and receives grant support from Medtronic, Boston Scientific, Abbott, Nevro, TerSera, and National Institutes of Health (NIH) 2R01CA166379-06 and NIH U44NS115111. She is medical advisor for Aim Medical Robotics and Karuna and has stock equity. Alexios G. Carayannopoulos’ institution has received grant/research money in his name from Medtronic, Abbott, Nevro, Boston Scientific, Asahi, Aspen Medical, NIH, and the Defense Advanced Research Projects Agency. Christophe Perruchoud reports grants and personal fees from Medtronic and Boston Scientific during the conduct of the study; and advisory board membership for Medtronic and Boston Scientific. Amir Hadanny reports consulting fees and stock options from Aviv Scientific and EEG-Sense, and travel support from Aviv Scientific. Eric Lee consults with Abbott, Nalu and Boston Scientific. Mehul J. Desai consults for Medtronic, Nalu Medical, and SPR Therapeutics, and has stock options in SPR Therapeutics, SynerFuse, Virdio Health, and VRYSA Technologies. Ajay Antony consults for Saluda, Vertos, Abbott, Boston Scientific, and PainTeq. Fabian Piedimonte reports personal fees from Medtronic and Abbott outside the submitted work and divested as of June 2020. Robert M. Levy is an uncompensated consultant for Nalu, Saluda Medical, Mainstay Medical; and has stock options from Nalu and Saluda Medical obtained before 2019 and not exercisable through the duration of his terms as INS president and editor-in-chief of the journal, Neuromodulation: Technology at the Neural Interface. The remaining authors reported no conflict of interest., (Copyright © 2024 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Background: Current guidelines recommend a personalized, multimodal, and interdisciplinary approach for the treatment of chronic pain. Already in the acute treatment of postoperative pain, it can be useful to minimize risk factors for chronification. Auricular vagus nerve stimulation (aVNS) could be an effective non-drug therapy for the treatment of chronic and acute pain., Aim of the Work: The aim of this systematic review is to evaluate the clinical efficacy of aVNS in chronic and acute pain as well as its effect on medication intake., Materials and Methods: A systematic literature search was carried out on the application of auricular electrical stimulation in chronic and acute pain. Studies were classified according to their level of evidence and evaluated via the Jadad scale as well as their scientific validity, and then analyzed in terms of indication, method, stimulation parameters, duration of treatment, efficacy, and safety., Results: Twenty studies on chronic pain indications, ten studies on acute postoperative pain, as well as seven studies on experimental acute pain were identified and analyzed. The search revealed a total of n = 1105 aVNS-treated patients. The best evidence on the efficacy of aVNS is available for the indications chronic low back pain, chronic cervical syndrome, chronic abdominal pain, and chronic migraine as well as acute postoperative pain in oocyte aspiration, laparoscopic nephrectomy, and open colorectal surgery. Additionally a significant reduction in analgesic or opiate intake was evident in most studies. In three randomized controlled trials in chronic pain patients, a sustainable pain reduction over a period of up to 12 months was shown. Overall, aVNS was very well tolerated., Conclusion: This review indicates that aVNS can be a complementary and effective non-drug treatment for patients with chronic and acute postoperative pain. Future studies in these indications should focus on standardizing and optimizing treatment parameters, inclusion of quality-of-life outcome parameters, and longer follow-up periods to better understand the sustainable therapeutic effect of aVNS., (© 2023. The Author(s).)

Hydra head formation depends on an organizing center in which Wnt/β-catenin signaling, that plays an inductive role, positively regulates Sp5 and Zic4 , with Sp5 limiting Wnt3/β-catenin expression and Zic4 triggering tentacle formation. Using transgenic lines in which the HySp5 promoter drives eGFP expression in either the epidermis or gastrodermis, we show that Sp5 promoter activity is differentially regulated in each epithelial layer. In intact animals, epidermal HySp5: GFP activity is strong apically and weak along the body column, while in the gastrodermis, it is maximal in the tentacle ring region and maintained at a high level along the upper body column. During apical regeneration, HySp5 :GFP is activated early in the gastrodermis and later in the epidermis. Alsterpaullone treatment induces a shift in apical HySp5:GFP expression towards the body column where it forms transient circular figures in the epidermis. Upon β-catenin (RNAi), HySp5: GFP activity is down-regulated in the epidermis while bud-like structures expressing HySp5: GFP in the gastrodermis develop. Sp5 (RNAi) reveals a negative Sp5 autoregulation in the epidermis, but not in the gastrodermis. These differential regulations in the epidermis and gastrodermis highlight the distinct architectures of the Wnt/β-catenin/TCF/Sp5/Zic4 network in the hypostome, tentacle base and body column of intact animals, as well as in the buds and apical and basal regenerating tips.

Background: Despite increased attention paid to assessment and management, pain continues to be a prevalent and undertreated symptom in patients with cancer. Intrathecal drug delivery (IDD) is a therapeutic option that allows targeted delivery of analgesics to the intrathecal space., Objective: The aim of this review was to examine the efficacy of managing cancer-related pain with IDD. Secondary objectives included the effects of IDD on systemic opioid use and infection rates., Evidence Review: A systematic search of the literature published between 1990 and 2019 was performed to identify studies evaluating the efficacy and/or safety of IDD with external or implanted pumps in patients with cancer-related pain. Data were extracted and meta-analyses performed to determine the mean changes in pain levels at short-, mid-, and long-term intervals; changes in opioid (oral morphine equivalent [OME]) daily dose; and infection rates. Changes were assessed compared with baseline., Findings: Pain levels were decreased from baseline: On a 0 to 10 scale, mean differences were -4.34 (95% CI [-4.93 to -3.75], p < 0.001) at 4 to 5 weeks; -4.34 (95% CI [-5.07 to -3.62], p < 0.001) at 6 to 12 weeks; and -3.32 (95% CI [-4.60 to -2.04], p < 0.001) at >6 months. Weighted mean OME consumption was reduced by 308.24 (SE = 22.72) mg/d. Weighted mean infection rates were ∼3% for external and implanted pumps., Conclusions: Meta-analyses show a statistically significant and sustained decrease in cancer pain with IDD, compared with baseline. Systemic opioid consumption was reduced on average by >50% after IDD. Infection rates were comparable with other indications., (Copyright © 2021 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

The molecular mechanisms that maintain cellular identities and prevent dedifferentiation or transdifferentiation remain mysterious. However, both processes are transiently used during animal regeneration. Therefore, organisms that regenerate their organs, appendages, or even their whole body offer a fruitful paradigm to investigate the regulation of cell fate stability. Here, we used Hydra as a model system and show that Zic4, whose expression is controlled by Wnt3/β-catenin signaling and the Sp5 transcription factor, plays a key role in tentacle formation and tentacle maintenance. Reducing Zic4 expression suffices to induce transdifferentiation of tentacle epithelial cells into foot epithelial cells. This switch requires the reentry of tentacle battery cells into the cell cycle without cell division and is accompanied by degeneration of nematocytes embedded in these cells. These results indicate that maintenance of cell fate by a Wnt-controlled mechanism is a key process both during homeostasis and during regeneration.

Intrathecal drug delivery appeared in the early eighties and allows to administer high concentrate analgesic medications in the cerebrospinal fluid with higher efficacy and a limited incidence of systemic side effects. Opioids are still the first line treatment with high-quality evidence for chronic cancer pain, and limited evidence for chronic non-cancer pain, being often considered as a last resort therapy. Device implantation requires a strict patient's selection with a close follow-up in order to adapt therapy, refill the reservoir and detect and prevent potential severe complications., Competing Interests: Christophe Perruchoud est consultant pour Medtronic (advisory board). L’autre auteur n’a déclaré aucun conflit d’intérêts en relation avec cet article.

Advances in our understanding of the biology of spinal systems in organizing and defining the content of exteroceptive information upon which higher centers define the state of the organism and its role in the regulation of somatic and automatic output, defining the motor response of the organism, along with the unique biology and spatial organization of this space, have resulted in an increased focus on therapeutics targeted at this extracranial neuraxial space. Intrathecal (IT) drug delivery systems (IDDS) are well-established as an effective therapeutic approach to patients with chronic non-malignant or malignant pain and as a tool for management of patients with severe spasticity and to deliver therapeutics that address a myriad of spinal pathologies. The risk to benefit ratio of IDD makes it a useful interventional approach. While not without risks, this approach has a significant therapeutic safety margin when employed using drugs with a validated safety profile and by skilled practioners. The present review addresses current advances in our understanding of the biology and dynamics of the intrathecal space, therapeutic platforms, novel therapeutics, delivery technology, issues of safety and rational implementation of its therapy, with a particular emphasis upon the management of pain., Competing Interests: CP is a consultant for Medtronic (honoraria for scientific advisory board and consultation fees). TY holds consulting agreements with Medtronic and Sorrento and is on the SAB for Raft and Navega. TY and MH hold a patent for an intrathecal catheter described herein. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 De Andres, Hayek, Perruchoud, Lawrence, Reina, De Andres-Serrano, Rubio-Haro, Hunt and Yaksh.)

While spinal cord stimulation (SCS) is a well-established therapy to address refractory persistent spinal pain syndrome after spinal surgery (PSPS-T2), its lack of spatial selectivity and reported discomfort due to positional effects can be considered as significant limitations. As alternatives, new waveforms, such as burst stimulation and different spatial neural targets, such as dorsal root ganglion stimulation (DRGS), have shown promising results. Comparisons between DRGS and standard SCS, or their combination, have never been studied on the same patients. "BOOST DRG" is the first prospective, randomized, double-blinded, crossover study to compare SCS vs. DRGS vs. SCS+DRGS. Sixty-six PSPS-T2 patients will be recruited internationally in three centers. Before crossing over, patients will receive each stimulation modality for 1 month, using tonic conventional stimulation. After 3 months, stimulation will consist in switching to burst for 1 month, and patients will choose which modality/waveform they receive and will then be reassessed at 6 and 12 months. In addition to our primary outcome based on pain rating, this study is designed to assess quality of life, functional disability, psychological distress, pain surface coverage, global impression of change, medication quantification, adverse events, brain functional imaging and electroencephalography, with the objective being to provide a multidimensional insight based on composite pain assessment.

Given the differing mechanisms thought to underlie therapeutic sub- and supra-perception-based neurostimulative modalities, Spinal Cord Stimulation (SCS) systems designed for combined delivery of these approaches may help improve analgesic outcomes and quality of life, and reduce treatment failures. This multicenter, observational case-series evaluated 188 patients with chronic back and/or leg pain implanted with an SCS device capable of sequential or simultaneous delivery of sub-perception and supra-perception stimulation programming (i.e., combination therapy) at 16 in Europe. Following implantation, patients were provided with an array of advanced supra-perception programs (e.g., paresthesia-based SCS using multiple independent current sources), and a custom set of sub-perception programs optimized with specific waveforms and/or field shapes. A mean overall pain score of 7.9 ± 1.7 (Standard Deviation (SD)) was reported pre-trial (Baseline). Overall pain was reduced by 4.4 ± 2.8 points (NRS) at 3-months ( n = 117) and at 12 months post-implant ( n = 90), respectively ( p < 0.0001). Substantial quality-of-life (EQ-5D-5L) improvement as assessed at last follow-up was also observed ( n = 60). These results suggest that an implanted SCS device capable of combination therapy, while also enabled with patient-specific waveform optimization and stimulation field targeting capabilities, can enable highly effective pain relief and improve quality of life in patients suffering with chronic pain.

Hydra vulgaris (Hv) has a high regenerative potential and negligible senescence, as its stem cell populations divide continuously. In contrast, the cold-sensitive H. oligactis (Ho&#95;CS) rapidly develop an aging phenotype under stress, with epithelial stem cells deficient for autophagy, unable to maintain their self-renewal. Here we tested in aging, non-aging and regenerating Hydra the activity and regulation of the ULK1 kinase involved in autophagosome formation. In vitro kinase assays show that human ULK1 activity is activated by Hv extracts but repressed by Ho&#95;CS extracts, reflecting the ability or inability of their respective epithelial cells to initiate autophagosome formation. The factors that keep ULK1 inactive in Ho&#95;CS remain uncharacterized. Hv&#95;Basel1 animals exposed to the ULK1 inhibitor SBI-0206965 no longer regenerate their head, indicating that the sustained autophagy flux recorded in regenerating Hv&#95;AEP2 transgenic animals expressing the DsRed-GFP-LC3A autophagy tandem sensor is necessary. The SBI-0206965 treatment also alters the contractility of intact Hv&#95;Basel1 animals, and leads to a progressive reduction of animal size in Hv&#95;AEP2, similarly to what is observed in ULK1(RNAi) animals. We conclude that the evolutionarily-conserved role of ULK1 in autophagy initiation is crucial to maintain a dynamic homeostasis in Hydra, which supports regeneration efficiency and prevents aging., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Precise localization of the center of the reservoir access port (RAP) of intrathecal pump is a crucial step to ensure a safe refill procedure. In difficult refill cases, ultrasound guidance has been reported useful. Being more expensive and time-consuming, the purpose of the study was therefore to identify situations in which sonographic localization is more accurate than the template method, in order to restrict its use to these defined conditions., Materials and Methods: The RAP was localized using the template provided by the manufacturer and by ultrasound guidance. The distance between the two points was measured. A distance superior to 3.5 mm, corresponding to the radius of the silicone septum of the RAP, was considered a clinically significant deviation., Results: During the study period, 22 patients underwent a total of 81 refill procedures. No significant correlation was found between the distance between the two points and age, height, weight, body mass index (BMI) or abdominal perimeter. The correlation was significant between distance and pump's depth. According to the ROC curve, the sensitivity of ultrasound identification of the RAP was 69.2% and the specificity 83.3% when the pump was implanted at a depth of 10 mm., Discussion: Our results are comparable to these published in the literature, pointing the usefulness of ultrasound for refill of deeply implanted pumps. Our study provides an additional element by specifying the depth from which the ultrasound seems to be superior to template., Conclusion: Poor accuracy in RAP identification of intrathecal pump can lead to life-threatening complications. The results of our study suggest that the localization of recessed-RAP can be improved by ultrasound in cases of pump implanted deeper than 10 mm. For more superficially implanted devices, the template method seems to be as accurate as ultrasound., (© 2019 International Neuromodulation Society.)

Hydra are freshwater polyps widely studied for their amazing regenerative capacity, adult stem cell populations, low senescence and value as ecotoxicological marker. Many wild-type strains of H. vulgaris have been collected worldwide and maintained effectively under laboratory conditions by asexual reproduction, while stable transgenic lines have been continuously produced since 2006. Efforts are now needed to ensure the genetic characterization of all these strains, which despite similar morphologies, show significant variability in their response to gene expression silencing procedures, pharmacological treatments or environmental conditions. Here, we established a rapid and reliable procedure at the single polyp level to produce via PCR amplification of three distinct microsatellite sequences molecular signatures that distinguish between Hydra strains and species. The TG-rich region of an uncharacterized gene (ms-c25145) helps to distinguish between Eurasian H. vulgaris-Pallas strains (Hm-105, Basel1, Basel2 and reg-16), between Eurasian and North American H. vulgaris strains (H. carnea, AEP), and between the H. vulgaris and H. oligactis species. The AT-rich microsatellite sequences located in the AIP gene (Aryl Hydrocarbon Receptor Interaction Protein, ms-AIP) also differ between Eurasian and North American H. vulgaris strains. Finally, the AT-rich microsatellite located in the Myb-Like cyclin D-binding transcription factor1 gene (ms-DMTF1) gene helps to distinguish certain transgenic AEP lines. This study shows that the analysis of microsatellite sequences, which is capable of tracing genomic variations between closely related lineages of Hydra, provides a sensitive and robust tool for characterizing the Hydra strains., Competing Interests: The authors have declared that no competing interests exist.

Background: The safety and efficacy of intrathecal drug delivery systems (IDDSs) for the treatment of cancer-related pain have been demonstrated in randomized controlled clinical trials (RCTs). Despite positive evidence for this therapy, IDDS remains underutilized to treat cancer pain. Real-world registry data augment existing safety and effectiveness data and are presented here to broaden awareness of this therapeutic option, needed for adequate cancer-related pain treatment, and as a viable tool addressing concerns with systemic opioid use., Methods: This prospective, long-term, multicenter (United States, Western Europe, and Latin America) registry started in 2003 to monitor the performance of SynchroMed Infusion Systems. Patient-reported outcomes were added in 2013. Before data acquisition, all sites obtained Ethics Committee/Institutional Review Board approval and written patient consent. The study was registered (NCT01524276 at clinicaltrials.gov) before patients were enrolled. Patients who provided informed consent were enrolled in the registry at initial IDDS implant or replacement., Results: Through July 2017, 1403 patients with cancer pain were enrolled and implanted. The average (minimum/maximum) age of patients was 59 years (13/93 years), with 56.6% female. The most frequent cancer types were lung, breast, colon/rectal, pancreatic, and prostate. The majority of patients whose registry follow-up ended (87%; 1141/1311) were followed through death, with 4.3% (n = 57) exiting due to device explant or therapy discontinuation; the remaining 113 (8.6%) discontinued for reasons such as transfer of care, lost to follow-up, and site closure. Pain scores within the cohort of patients providing baseline and follow-up data improved significantly at 6 (P = .0007; n = 103) and 12 (P = .0026; n = 55) months compared to baseline, with EuroQol with 5 dimensions (EuroQol-5D) scores showing significant improvement at 6 months (P = .0016; n = 41). Infection requiring surgical intervention (IDDS explant, replacement, pocket revision, irrigation and debridement, etc) was reported in 3.2% of patients., Conclusions: Adequate and improved pain control in patients with cancer, even in advanced stages, with concurrent quality of life maintenance is attainable. Results from this large-scale, multicenter, single-group cohort supplement existing RCT data that support IDDS as a safe and effective therapeutic option with a positive benefit-risk ratio in the treatment of cancer pain.

The nervous system is produced and maintained in adult Hydra through the continuous production of nerve cells and mechanosensory cells (nematocytes or cnidocytes). De novo neurogenesis occurs slowly in intact animals that replace their dying nerve cells, at a faster rate in animals regenerating their head as a complete apical nervous system is built in few days. To dissect the molecular mechanisms that underlie these properties, a precise monitoring of the markers of neurogenesis and nematogenesis is required. Here we describe the conditions for an efficient BrdU-labeling coupled to an immunodetection of neuronal markers, either regulators of neurogenesis, here the homeoprotein prdl-a, or neuropeptides such as RFamide or Hym-355. This method can be performed on whole-mount animals as well as on macerated tissues when cells retain their morphology. Moreover, when antibodies are not available, BrdU-labeling can be combined with the analysis of gene expression by whole-mount in situ hybridization. This co-immunodetection procedure is well adapted to visualize and quantify the dynamics of de novo neurogenesis. Upon continuous BrdU labeling, the repeated measurements of BrdU-labeling indexes in specific cellular populations provide a precise monitoring of nematogenesis as well as neurogenesis, in homeostatic or developmental conditions.

In Hydra the nervous system is composed of neurons and mechanosensory cells that differentiate from interstitial stem cells (ISCs), which also provide gland cells and germ cells. The adult nervous system is actively maintained through continuous de novo neurogenesis that occurs at two distinct paces, slow in intact animals and fast in regenerating ones. Surprisingly Hydra vulgaris survive the elimination of cycling interstitial cells and the subsequent loss of neurogenesis if force-fed. By contrast, H. oligactis animals exposed to cold temperature undergo gametogenesis and a concomitant progressive loss of neurogenesis. In the cold-sensitive strain Ho&#95;CS, this loss irreversibly leads to aging and animal death. Within four weeks, Ho&#95;CS animals lose their contractility, feeding response, and reaction to light. Meanwhile, two positive regulators of neurogenesis, the homeoprotein prdl-a and the neuropeptide Hym-355, are no longer expressed, while the "old" RFamide-expressing neurons persist. A comparative transcriptomic analysis performed in cold-sensitive and cold-resistant strains confirms the downregulation of classical neuronal markers during aging but also shows the upregulation of putative regulators of neurotransmission and neurogenesis such as AHR, FGFR, FoxJ3, Fral2, Jagged, Meis1, Notch, Otx1, and TCF15. The switch of Fral2 expression from neurons to germ cells suggests that in aging animals, the neurogenic program active in ISCs is re-routed to germ cells, preventing de novo neurogenesis and impacting animal survival., (© 2019 The Authors. Developmental Neurobiology Published by Wiley Periodicals, Inc.)

Polyps of the cnidarian Hydra maintain their adult anatomy through two developmental organizers, the head organizer located apically and the foot organizer basally. The head organizer is made of two antagonistic cross-reacting components, an activator, driving apical differentiation and an inhibitor, preventing ectopic head formation. Here we characterize the head inhibitor by comparing planarian genes down-regulated when β-catenin is silenced to Hydra genes displaying a graded apical-to-basal expression and an up-regulation during head regeneration. We identify Sp5 as a transcription factor that fulfills the head inhibitor properties: leading to a robust multiheaded phenotype when knocked-down in Hydra, acting as a transcriptional repressor of Wnt3 and positively regulated by Wnt/β-catenin signaling. Hydra and zebrafish Sp5 repress Wnt3 promoter activity while Hydra Sp5 also activates its own expression, likely via β-catenin/TCF interaction. This work identifies Sp5 as a potent feedback loop inhibitor of Wnt/β-catenin signaling, a function conserved across eumetazoan evolution.

Purpose: Management of patients with persisting pain after spine surgery (PPSS) shows significant variability, and there is limited evidence from clinical studies to support treatment choice in daily practice. This study aimed to develop patient-specific recommendations on the management of PPSS., Methods: Using the RAND/UCLA appropriateness method (RUAM), an international panel of 6 neurosurgeons, 6 pain specialists, and 6 orthopaedic surgeons assessed the appropriateness of 4 treatment options (conservative, minimally invasive, neurostimulation, and re-operation) for 210 clinical scenarios. These scenarios were unique combinations of patient characteristics considered relevant to treatment choice. Appropriateness had to be expressed on a 9-point scale (1 = extremely inappropriate, 9 = extremely appropriate). A treatment was considered appropriate if the median score was ≥ 7 in the absence of disagreement (≥ 1/3 of ratings in each of the opposite sections 1-3 and 7-9)., Results: Appropriateness outcomes showed clear and specific patterns. In 48% of the scenarios, exclusively one of the 4 treatments was appropriate. Conservative treatment was usually considered appropriate for patients without clear anatomic abnormalities and for those with new pain differing from the original symptoms. Neurostimulation was considered appropriate in the case of (predominant) neuropathic leg pain in the absence of conditions that may require surgical intervention. Re-operation could be considered for patients with recurrent disc, spinal/foraminal stenosis, or spinal instability., Conclusions: Using the RUAM, an international multidisciplinary panel established criteria for appropriate treatment choice in patients with PPSS. These may be helpful to educate physicians and to improve consistency and quality of care. These slides can be retrieved under Electronic Supplementary Material.