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Sayed E Wahezi,1 Ugur Yener,1 Tahereh Naeimi,1 Heejung Choi,2 Yashar Eshraghi,3 Scott G Pritzlaff,4 Trent Emerick,5 Corey W Hunter,6 Moorice Caparo,1 Michael E Schatman,7 Farshad Ahadian,8 Charles Argoff,9 Timothy Deer,10 Dawood Sayed,11 Miles Day,12 Alaa Abd-Elsayed,13 Giuliano Lo Bianco14 1Department of Physical Medicine & Rehabilitation, Montefiore Medical Center, Bronx, NY, USA; 2Department of Anesthesiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; 3Department of Anesthesia, Ochsner Medical Health Center, New Orleans, LA, USA; 4Department of Anesthesiology and Pain Medicine, University of California, Davis, CA, USA; 5Division of Chronic Pain, Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; 6Ainsworth Institute of Pain Management, Department of Rehabilitation & Human Performance, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 7Department of Anesthesiology, Perioperative Care and Pain Medicine, Department of Population Health - Division of Medical Ethics, NYU Grossman School of Medicine, New York, NY, USA; 8Department of Anesthesiology, Center for Pain and Palliative Medicine, University of California, San Diego Medical Center, San Diego, CA, USA; 9Department of Neurology, Albany Medical Center, Albany, NY, USA; 10The Spine and Nerve Center of the Virginias, West Virginia University Hospitals, Charleston, WV, USA; 11Department of Anesthesiology, University of Kansas Medical Center, Kansas City, KS, USA; 12Department of Anesthesiology, Texas Tech University Health Sciences Center, Lubbock, TX, USA; 13Department of Anesthesiology, University of Wisconsin, Madison, WI, USA; 14Anesthesiology and Pain Department, Fondazione Istituto G. Giglio Cefalù, Palermo, ItalyCorrespondence: Sayed E Wahezi, Department of Physical Medicine and Rehabilitation, Montefiore Medical Center, 1250 Waters Place, Tower #2 8th Floor, Bronx, NY, 10461, USA, Tel +1 718-920 7246, Fax +1 929-263-3950, Email swahezi@montefiore.orgBackground: Pain medicine care has expanded to encompass a wider range of conditions, necessitating updated education and training for pain specialists to utilize emerging technologies effectively. A national survey was conducted through several verified Pain organizations regarding pain physician employers’ perspectives on pain medicine fellowship training and education. The survey aimed to gather insights from a diverse range of geographic locations, practice types (academic and private practice), and practice settings. The findings emphasize the need for educational programs to adapt to the evolving landscape of pain medicine.Methods: A survey was disseminated through several national professional pain societies, including the AAPM, ASIPP, NANS, and ASPN, and Pain DocMatters forum, an online verified pain physician forum to ensure a wide reach among potential respondents. The survey received responses from 196 participants, 39 from the Pain DocMatters forum and 157 through pain societies’ channels.Results: Most survey respondents reported a need for additional training and experience beyond what is offered during the one-year ACGME-approved fellowship. Professionalism and basic interventional skills were identified as the highest valued attributes of pain physician candidates by potential employers. Employers rated spinal cord stimulator (SCS) trials as the most important advanced procedure for trainees to learn. Other advanced procedures such as SCS implants, PNS implants, interspinous spacers, and percutaneous procedures involving the vertebral body were also rated as either very important or somewhat important by most respondents. A significant gap in training has been identified, with only 7% of respondents feeling that fellows were adequately prepared to independently practice in the current educational model. A vast majority of respondents stated that fellows need additional training following graduation from fellowship to practice independently.Conclusion: Training programs should provide more robust education to prepare their graduates for independent practice.Keywords: graduate medical education, fellowship training, analysis, multidisciplinary, independence

Ryan S D’Souza,1 Yeng F Her,1 Nasir Hussain,2 Jay Karri,3 Michael E Schatman,4 Aaron K Calodney,5 Christopher Lam,6 Thomas Buchheit,7 Brennan J Boettcher,8 George C Chang Chien,9 Scott G Pritzlaff,10 Christopher Centeno,11 Shane A Shapiro,12 Johana Klasova,1 Jay S Grider,13 Ryan Hubbard,14 Eliana Ege,15 Shelby Johnson,8 Max H Epstein,16 Eva Kubrova,8 Mohamed Ehab Ramadan,17 Alexandra Michelle Moreira,18 Swarnima Vardhan,19 Yashar Eshraghi,20 Saba Javed,21 Newaj M Abdullah,22 Paul J Christo,17 Sudhir Diwan,23 Leslie C Hassett,24 Dawood Sayed,6 Timothy R Deer25 1Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, USA; 2Department of Anesthesiology, The Ohio State Wexner Medical Center, Columbus, OH, USA; 3Departments of Orthopedic Surgery and Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA; 4Department of Anesthesiology, Perioperative Care, & Pain Medicine, NYU Grossman School of Medicine, New York, NY, USA; 5Precision Spine Care, Tyler, TX, USA; 6Department of Anesthesiology and Pain Medicine, The University of Kansas Medical Center, Kansas City, KS, USA; 7Department of Anesthesiology, Duke University, Durham, NC, USA; 8Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN, USA; 9Department of Regenerative Medicine, GCC Institute, Torrance, CA, USA; 10Department of Anesthesiology and Pain Medicine, University of California, Davis, Sacramento, CA, USA; 11Centeno-Schultz Clinic, Broomfield, CO, USA; 12Department of Orthopedic Surgery, Mayo Clinic, Jacksonville, FL, USA; 13Department of Anesthesiology, University of Kentucky College of Medicine, Lexington, KY, USA; 14Department of Sports Medicine, Anderson Orthopedic Clinic, Arlington, VA, USA; 15Department of Physical Medicine & Rehabilitation, Baylor College of Medicine, Houston, TX, USA; 16Department of Physical Medicine & Rehabilitation, Harvard Medical School, Boston, MA, USA; 17Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Hospital, Baltimore, MD, USA; 18Department of Physical Medicine & Rehabilitation, University of Miami/Jackson Memorial Hospital, Miami, FL, USA; 19Department of Internal Medicine, Yale New Haven Health – Bridgeport Hospital, Bridgeport, CT, USA; 20Department of Anesthesiology & Critical Care Medicine, Ochsner Health System, New Orleans, LA, USA; 21Department of Pain Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA; 22Department of Anesthesiology, University of Utah, Salt Lake City, UT, USA; 23Department of Pain Medicine, Advanced Spine on Park Avenue, New York City, NY, USA; 24Mayo Clinic Libraries, Mayo Clinic, Rochester, MN, USA; 25Department of Anesthesiology and Pain Medicine, West Virginia University School of Medicine, Charleston, WV, USACorrespondence: Ryan S D’Souza, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA, Tel +1-(507)-284-9696, Fax +1-(507)-266-7732, Email dsouza.ryan@mayo.eduPurpose: Injectable biologics have not only been described and developed to treat dermal wounds, cardiovascular disease, and cancer, but have also been reported to treat chronic pain conditions. Despite emerging evidence supporting regenerative medicine therapy for pain, many aspects remain controversial.Methods: The American Society of Pain and Neuroscience (ASPN) identified the educational need for an evidence-based guideline on regenerative medicine therapy for chronic pain. The executive board nominated experts spanning multiple specialties including anesthesiology, physical medicine and rehabilitation, and sports medicine based on expertise, publications, research, and clinical practice. A steering committee selected preliminary questions, which were reviewed and refined. Evidence was appraised using the United States Preventive Services Task Force (USPSTF) criteria for evidence level and degree of recommendation. Using a modified Delphi approach, consensus points were distributed to all collaborators and each collaborator voted on each point. If collaborators provided a decision of “disagree” or “abstain”, they were invited to provide a rationale in a non-blinded fashion to the committee chair, who incorporated the respective comments and distributed revised versions to the committee until consensus was achieved.Results: Sixteen questions were selected for guideline development. Questions that were addressed included type of injectable biologics and mechanism, evidence in treating chronic pain indications (eg, tendinopathy, muscular pathology, osteoarthritis, intervertebral disc disease, neuropathic pain), role in surgical augmentation, dosing, comparative efficacy between injectable biologics, peri-procedural practices to optimize therapeutic response and quality of injectate, federal regulations, and complications with mitigating strategies.Conclusion: In well-selected individuals with certain chronic pain indications, use of injectable biologics may provide superior analgesia, functionality, and/or quality of life compared to conventional medical management or placebo. Future high-quality randomized clinical trials are warranted with implementation of minimum reporting standards, standardization of preparation protocols, investigation of dose–response associations, and comparative analysis between different injectable biologics.Keywords: regenerative medicine, injectable biologics, platelet-rich plasma, mesenchymal stem cell, bone marrow aspirate concentrate, pain medicine

Yashar Eshraghi,1– 3 Krishnan Chakravarthy,4,5 Natalie H Strand,6 Prasad Shirvalkar,7 Nathaniel M Schuster,4 Rany T Abdallah,8 Ricardo Vallejo,9,10 Dawood Sayed,11 David Kim,11 Chong Kim,12 Kathleen Meacham,13 Timothy Deer14,15 On Behalf of Translational Research Committee American Society of Pain and Neuroscience (ASPN)1Department of Anesthesia, Interventional Pain Management, Ochsner Health System, New Orleans, LA, USA; 2University of Queensland Ochsner Clinical School. Academics Department, Ochsner Health System, New Orleans, LA, USA; 3Louisiana State University School of Medicine, New Orleans, LA, USA; 4Division of Pain Medicine, Department of Anesthesiology, University of California San Diego, San Diego, CA, USA; 5VA San Diego Health Care, San Diego, CA, USA; 6Division of Pain Medicine, Department of Anesthesiology, Mayo Clinic, Phoenix, Arizona, USA; 7Department of Anesthesiology (Pain Management), Department of Neurology, UCSF School of Medicine, San Francisco, CA, USA; 8Center for Interventional Pain and Spine, Wilmington, DE, USA; 9National Spine and Pain Center, Bloomington, IL, USA; 10Psychology Department, Illinois Wesleyan University, Bloomington, IL, USA; 11University of Kansas Medical Center, Kansas City, KS, USA; 12Departments of Physical Medicine and Rehabilitation and Anesthesiology, Case Western Reserve University/MetroHealth, Cleveland, OH, USA; 13Division of Pain Management, Department of Anesthesiology, Washington University School of Medicine, St Louis, MO; 14The Spine and Nerve Center of the Virginias, Charleston, WV, USA; 15West Virginia University, School of Medicine, Charleston, WV, USACorrespondence: Yashar Eshraghi Email Yashar.Eshraghi@gmail.comBackground: Healthcare clinical and even policy decisions are progressively made based on research-based evidence. The process by which the appropriate trials are developed and well-written manuscripts by means of evidence-based medicine recommendations has resulted in unprecedented necessity in evidence-based medicine in neuromodulation.Methods: The essential considerations in the planning of neuromodulation research are discussed in the light of available scientific literature as well as the authors’ scientific expertise regarding research study design and scientific manuscript preparation.Conclusion: This article should enable the reader to understand how to appropriately design a clinical research study and prepare scientific manuscripts. The high-quality and well-designed studies, when performed and reported effectively, support evidence-based medicine and foster improved patient outcomes.Keywords: research, study design, neuromodulation, neurostimulation, clinical evidence review

Introduction: The Accreditation Council for Graduate Medical Education (ACGME) approved the first pain medicine fellowship programs over three decades ago, designed around a pharmacological philosophy. Following that, there has been a rise in the transition of pain medicine education toward a multidisciplinary interventional model based on a tremendous surge of contemporaneous literature in these areas. This trend has created variability in clinical experience and education amongst accredited pain medicine programs with minimal literature evaluating the differences and commonalities in education and experience of different pain medicine fellowships through Program Director (PD) experiences. This study aims to gather insight from pain medicine fellowship program directors across the country to assess clinical and interventional training, providing valuable perspectives on the future of pain medicine education., Methods: This study involved 56 PDs of ACGME-accredited pain fellowship programs in the United States. The recruitment process included three phases: advanced notification, invitation, and follow-up to maximize response rate. Participants completed a standard online questionnaire, covering various topics such as subcategory fields, online platforms for supplemental education, clinical experience, postgraduate practice success, and training adequacy., Results: Surveys were completed by 39/56 (69%) standing members of the Association of Pain Program Directors (APPD). All PDs allowed fellows to participate in industry-related and professional society-related procedural workshops, with 59% encouraging these workshops. PDs emphasized the importance of integrity, professionalism, and diligence for long-term success. Fifty-four percent of PDs expressed the need for extension of fellowship training to avoid supplemental education by industry or pain/spine societies., Conclusion: This study highlights the challenge of providing adequate training in all Pain Medicine subtopics within a 12-month pain medicine fellowship. PDs suggest the need for additional training for fellows and discuss the importance of curriculum standardization., (© 2024 World Institute of Pain.)

Background: Successful treatments for intractable chronic low back pain (CLBP) in patients who are not eligible for surgical interventions are scarce. The superior efficacy of differential target multiplexed spinal cord stimulation (DTM SCS) to conventional SCS (Conv-SCS) on the treatment of CLBP in patients with persistent spinal pain syndrome (PSPS) who have failed surgical interventions (PSPS-T2) motivated the evaluation of DTM SCS versus Conv-SCS on PSPS patients who are non-surgical candidates (PSPS-T1)., Methods: This is a prospective, open label, crossover, post-market randomized controlled trial in 20 centers across the United States. Eligible patients were randomized to either DTM SCS or Conv-SCS in a 1:1 ratio. Primary endpoint was CLBP responder rate (percentage of subjects with ≥50% CLBP relief) at 3-month in randomized subjects who completed trialing (modified intention-to-treat population). Patients were followed up to 12 months. Secondary endpoints included change of CLBP and leg pain, responder rates, changes in disability, quality of life, patient satisfaction and global impression of change, and safety profile. An optional crossover was available at 6-month to all patients., Results: About 121 PSPS-T1 subjects with CLBP and leg pain mostly associated with degenerative disc disease and radiculopathy and who were not eligible for spine surgery were randomized. CLBP responder rate with DTM SCS (93.5%) was superior to Conv-SCS (36.4%) at the primary endpoint. Superior CLBP responder rates (88.1%-90.5%) were obtained with DTM SCS at all other timepoints. Mean CLBP reduction with DTM SCS (6.52 cm) was superior to that with Conv-SCS (3.01 cm) at the primary endpoint. Similar CLBP reductions (6.23-6.43 cm) were obtained with DTM SCS at other timepoints. DTM SCS provided significantly better leg pain reduction and responder rate, improvement of disability and quality of life, and better patient satisfaction and global impression of change. 90.9% of Conv-SCS subjects who crossed over were CLBP responders at completion of the study. Similar safety profiles were observed between the two groups., Conclusion: DTM SCS for chronic CLBP in nonsurgical candidates is superior to Conv-SCS. Improvements were sustained and provided significant benefits on the management of these patients., Competing Interests: One or more of the authors declare financial or professional relationships on ICMJE-NASSJ disclosure forms., (© 2024 The Author(s).)

Background: Since 1992, when the Accreditation Council of Graduate Medical Education (ACGME) acknowledged pain medicine as a subspecialty, the field has experienced significant growth in its number of programs, diversity of sponsoring specialties, treatment algorithms, and popularity among applicants. These shifts prompted changes to the educational model, overseen by program directors (PDs) and the ACGME. The pool of pain fellowship applicants also changed during that period., Objectives: This study aims to investigate trainees' reasons for applying to pain medicine fellowship programs as well as the applicants' specific expectations, interests, and motivations, thereby contributing to the remodeling and universal improvement of programs across the country., Study Design: Online survey via SurveyMonkey. The online questionnaire targeted pain fellowship applicants in 2023 and current fellows in the US., Methods: Our study was designed by board members of the Association of Pain Program Directors (APPD). The board disseminated a survey to those who applied to ACGME Pain Medicine fellowships in 2023 as well as to existing fellows. The survey was emailed to residency and fellowship PDs for dissemination to their trainees. The participants answered a 12-question survey on their reasons for pursuing pain medicine fellowships, expectations of and beyond those fellowships, and educational adjustments., Results: There were 283 survey participants (80% applicants in residency training and 20% fellows). Participants ranked basic interventional procedures and a strong desire to learn advanced procedures as the most significant factors in pursuing a pain fellowship. Most trainees (70%) did not wish to pursue a 2-year fellowship, and 50% desired to go into private practice., Limitations: The relatively small number of respondents is a limitation that could introduce sampling error. Since most of the respondents were from the fields of physical medicine and rehabilitation (PM&R) and anesthesia, the use of convenience sampling reduced our ability to generalize the results to the wider community. Furthermore, approximately 80% of the trainees were residents, who might have had less experience in or knowledge of the survey's particulars than did the fellows., Conclusion: This survey demonstrated that procedural volume and diversity were important factors in trainees' decisions to apply to the field of pain medicine; however, extending the duration of a pain fellowship was not an option survey participants favored. Therefore, PDs and educational stakeholders in pain fellowship training need to develop creative strategies to maintain competitive applicants' interest while they adapt to our evolving field.

Objectives: Total knee arthroplasty (TKA) is an effective surgery for end-stage knee osteoarthritis, but chronic postoperative pain and reduced function affect up to 20% of patients who undergo such surgery. There are limited treatment options, but percutaneous peripheral nerve stimulation (PNS) is a promising nonopioid treatment option for chronic, persistent postoperative pain. The objective of the present study was to evaluate the effect of a 60-day percutaneous PNS treatment in a multicenter, randomized, double-blind, placebo-controlled trial for treating persistent postoperative pain after TKA., Materials and Methods: Patients with postoperative pain after knee replacement were screened for this postmarket, institutional review board-approved, prospectively registered (NCT04341948) trial. Subjects were randomized to receive either active PNS or placebo (sham) stimulation. Subjects and a designated evaluator were blinded to group assignments. Subjects in both groups underwent ultrasound-guided placement of percutaneous fine-wire coiled leads targeting the femoral and sciatic nerves on the leg with postoperative pain. Leads were indwelling for eight weeks, and the primary efficacy outcome compared the proportion of subjects in each group reporting ≥50% reduction in average pain relative to baseline during weeks five to eight. Functional outcomes (6-minute walk test; 6MWT and Western Ontario and McMaster Universities Osteoarthritis Index) and quality of life (Patient Global Impression of Change) also were evaluated at end of treatment (EOT)., Results: A greater proportion of subjects in the PNS groups (60%; 12/20) than in the placebo (sham) group (24%; 5/21) responded with ≥50% pain relief relative to baseline (p = 0.028) during the primary endpoint (weeks 5-8). Subjects in the PNS group also walked a significantly greater distance at EOT than did those in the placebo (sham) group (6MWT; +47% vs -9% change from baseline; p = 0.048, n = 18 vs n = 20 completed the test, respectively). Prospective follow-up to 12 months is ongoing., Conclusions: This study provides evidence that percutaneous PNS decreases persistent pain, which leads to improved functional outcomes after TKA at EOT., Competing Interests: Conflict of Interest Johnathan H. Goree serves as a consultant to Saluda Medical, Stratus Medical, and Abbott. David M. Dickerson serves as a consultant to Abbott, Vertos, Biotronik, and SPR Therapeutics, and has received honoraria for lectures from Nalu. Yashar Eshraghi serves as a consultant for Saluda Medical and SPR Therapeutics. Ali K. Valimahomed serves as a consultant for SPR Therapeutics, Nalu, Vertos, and Biotronik, and has received honoraria for lectures from the World Academy of Pain Medicine. Jarna R. Shah serves as a consultant for and has received honoraria from SPR Therapeutics. Maged N. Guirguis serves as a consultant for SPR Therapeutics, Nevro, Saluda, Boston Scientific, Abbott, Averitas Pharma, PainTeq, and Avanos. Maxim S. Eckmann serves as a consultant for Avanos and has participated on a data safety monitoring or advisory board for Abbott. Amorn Wongsarnpigoon is an inventor on >40 patents planned, issued, or pending related to peripheral nerve stimulation (PNS) and has stock/stock options with SPR Therapeutics. Joseph W. Boggs is an inventor on >100 patents planned, issued, or pending related to PNS and has stock/stock options with SPR Therapeutics. John E. Gilbert, Amorn Wongsarnpigoon, and Joseph W. Boggs are all employees of SPR Therapeutics as well in case that needs to be included. The remaining authors reported no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Low back pain is the leading cause of disability worldwide, with sacroiliac joint pain comprising up to 30% of cases of axial lower back pain. Conservative therapies provide only modest relief. Although placebo-controlled trials show efficacy for sacral lateral branch cooled radiofrequency ablation, there are no comparative effectiveness studies., Methods: In this randomized, multicenter comparative effectiveness study, 210 patients with clinically suspected sacroiliac joint pain who obtained short-term benefit from diagnostic sacroiliac joint injections and prognostic lateral branch blocks were randomly assigned to receive cooled radiofrequency ablation of the L5 dorsal ramus and S1-S3 lateral branches or standard medical management consisting of pharmacotherapy, injections and integrative therapies. The primary outcome measure was mean reduction in low back pain score on a 0-10 Numeric Rating Scale at 3 months. Secondary outcomes included measures of quality of life and function., Results: 3 months post-treatment, the mean Numeric Rating Scale pain score for the cooled radiofrequency ablation group was 3.8±2.4 (mean reduction 2.5±2.5) compared with 5.9±1.7 (mean reduction 0.4±1.7) in the standard medical management group (p<0.0001). 52.3% of subjects in the cooled radiofrequency ablation group experienced > 2 points or 30% pain relief and were deemed responders versus 4.3% of standard medical management patients (p<0.0001). Comparable improvements favoring cooled radiofrequency ablation were noted in Oswestry Disability Index score (mean 29.7±15.2 vs 41.5+13.6; p<0.0001) and quality of life (mean EuroQoL-5 score 0.68±0.22 vs 0.47±0.29; p<0.0001)., Conclusions: In patients with sacroiliac joint pain, cooled radiofrequency ablation provided statistically superior improvements across the spectrum of patient outcomes compared with standard medical management., Trial Registration Number: NCT03601949., Competing Interests: Competing interests: All authors received institutional research funding. SPC, LKa, LKo, SL, DPB and MJD are consultants for Avanos (which makes radiofrequency equipment). Currently, SPC is the editorial board member of RAPM., (© American Society of Regional Anesthesia & Pain Medicine 2024. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Background: Diabetic nephropathy (DN) which refers to the cases with biopsy proven kidney lesions, is one of the main complications of diabetes all around the world; however, the underlying biological changes causing DN remain to be understood. Studying the alterations in gene expression profiles could give a holistic view of the molecular pathogenicity of DN and aid to discover key molecules as potential therapeutic targets. Here, we performed a meta-analysis study that included microarray gene expression profiles coming from glomerular samples of DN patients in order to acquire a list of consensus Differentially Expressed Genes (meta-DEGs) correlated with DN., Methods: After quality control and normalization steps, five gene expression datasets (GES1009, GSE30528, GSE47183, GSE104948, and GSE93804) were entered into the meta-analysis. The meta-analysis was performed by random effect size method and the meta-DEGs were put through network analysis and different pathway enrichment analyses steps. MiRTarBase and TRRUST databases were utilized to predict the meta-DEGs related miRNAs and transcription factors. A co-regulatory network including DEGs, transcription factors and miRNAs was constructed by Cytoscape, and top molecules were identified based on centrality scores in the network., Results: The identified meta-DEGs were 1364 DEGs including 665 downregulated and 669 upregulated DEGs. The results of pathway enrichment analysis showed, "immune system", "extracellular matrix organization", "hemostasis", "signal transduction", and "platelet activation" to be the top enriched terms with involvement of the meta-DEGs. After construction of the multilayer regulatory network, several top DEGs (TP53, MYC, BTG2, VEGFA, PTEN, etc.), as well as top miRNAs (miR-335, miR-16, miR-17, miR-20a, and miR-93), and transcription factors (SP1, STAT3, NF-KB1, RELA, E2F1), were introduced as potential therapeutic targets in DN. Among the regulatory molecules, miR-335-5p and SP1 were the most interactive miRNA and transcription factor molecules with the highest degree scores in the constructed network., Conclusion: By performing a meta-analysis of available DN-related transcriptomics datasets, we reached a consensus list of DEGs for this complicated disorder. Further enrichment and network analyses steps revealed the involved pathways in the DN pathogenesis and marked the most potential therapeutic targets in this disease., (Copyright © 2022 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Peripheral nerve stimulation (PNS) is an effective neuromodulation therapy for chronic neuropathic and nociceptive pain. Although the total number of PNS implantations has increased over the last decade, no curriculum exists to guide training and learning of this therapy. The goal of the North American Neuromodulation Society (NANS) education committee is to develop a series of competency-based curriculums for neuromodulation therapies. The PNS curriculum is the latest part of such series, following the curriculums for spinal cord stimulation and intrathecal drug delivery system., Materials and Methods: A multidisciplinary task force (anesthesiology, physical medicine and rehabilitation, neurosurgery, preventive medicine and public health, and neurology) was created by the educational committee of NANS to develop a PNS curriculum in accordance with the Accreditation Council for Graduate Medical Education (ACGME) milestones. The curriculum was created based on the best available evidence and expert knowledge (from our task force members) of available PNS systems. The final PNS curriculum was approved by the NANS board., Results: A PNS curriculum was developed by the task force. Milestones included professionalism, practice-based learning, interpersonal communication, medical knowledge, systems-based practice, procedural skills, and patient care. Each milestone was defined into three categories: early learner, advanced learner, and practitioner., Conclusions: This manuscript provides a PNS training curriculum developed by a multidisciplinary task force of the NANS educational committee in accordance with the milestones described by ACGME for basic learners, advanced learners, and practitioners. This curriculum will help provide a structured training and evaluation process for obtaining proficiency in PNS treatment(s)., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Motivation: The recent availability of omics data allows the construction of holistic maps of interactions between numerous role-playing biomolecules. However, these networks are often static, ignoring the dynamic behavior of biological processes. On the other hand, dynamic models are commonly constructed on small scales. Hence, the construction of large-scale dynamic models that can quantitatively predict the time-course cellular behaviors remains a big challenge., Results: In this study, a pipeline is proposed for the automatic construction of large-scale dynamic models. The pipeline uses a list of biomolecules and their time-course trajectories in a given phenomenon as input. First, the interaction network of the biomolecules is constructed. To state the underlying molecular events of each interaction, it is translated into a map of biochemical reactions. Next, to define the kinetics of the reactions, an ordinary differential equation (ODE) is generated for each involved biomolecule. Finally, the parameters of the ODE system are estimated by a novel large-scale parameter approximation method. The high performance of the pipeline is demonstrated by modeling the response of a colorectal cancer cell line to different chemotherapy regimens. In conclusion, Systematic Protein Association Dynamic ANalyzer constructs genome-scale dynamic models, filling the gap between large-scale static and small-scale dynamic modeling strategies. This simulation approach allows for holistic quantitative predictions which are critical for the simulation of therapeutic interventions in precision medicine., Availability and Implementation: Detailed information about the constructed large-scale model of colorectal cancer is available in supplementary data. The SPADAN toolbox source code is also available on GitHub (https://github.com/PooyaBorzou/SPADAN)., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Hypertensive nephropathy (HN) is a high-burden disorder and a leading cause of end-stage renal disease. Despite huge investigations, the underlying mechanisms are yet largely unknown. Systems biology is a promising approach to providing a comprehensive insight into this complex disorder., Methods: Proteome profiles of kidney tubulointerstitium and outer and inner cortex from a rat model of HN were retrieved from the proteomics identification database, and the quality of the datasets was assessed. Proteins that exhibited differential expression were detected and their interactions were analyzed in the kidney sub-compartments. Furthermore, enzymes were linked to the attributed metabolites. Functional enrichment analyses were performed to identify key pathways and processes based on the differentially expressed proteins and predicted metabolites., Results: Proteasome-mediated protein degradation, actin cytoskeleton organization, and Rho GTPase signaling pathway are involved in the pathogenesis of HN. Furthermore, tissue hypoxia and dysregulated energy homeostasis are among the key underlying events. The metabolism of purine and amino acids is also affected in HN., Conclusion: Although the proposed pathogenic mechanisms remain to be further validated in experimental studies, this study contributes to the understanding of the molecular mechanisms of HN through a systematic unsupervised approach. Considering the significant alterations of metabolic pathways, HN can be viewed as an "acquired error of metabolism.", (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: The COVID-19 pandemic resulted in a novel challenge for healthcare delivery and implementation in the United States (US) in 2020 and beyond. Telemedicine arose as a significant and effective medium for safe and efficacious physician-patient interactions. Prior to the COVID-19 pandemic, telemedicine while available, had infrequently been utilized in pain medicine practices due to difficulties with reimbursement, the learning curve associated with new technology usage, and the need for new logistical systems in place to implement telemedicine effectively. Given the unique constraints on the healthcare system during the COVID-19 pandemic, the ubiquitous utilization of telemedicine among pain medicine physicians increased, giving insight into potential future roles for the technology beyond the pandemic., Objectives: To survey and understand the state of implementation of telemedicine into pain medicine practices across practice settings and geographical areas; to identify potential barriers to the implementation of telemedicine in pain medicine practice; and to identify the likelihood of telemedicine continuing beyond the pandemic in pain medicine practice., Study Design: Online questionnaire targeting Pain Medicine physicians in the US. Participants were asked questions related to the use of telemedicine during the first peak of the COVID-19 pandemic., Setting: Online-based questionnaire distributed to academic and private practice pain medicine physicians nationally in the United States., Methods: A 34 web-based questionnaires were distributed by the American Society of Regional Anesthesia and Pain Medicine and the Spine Intervention Society to all active members. Data were analyzed using SAS v9.4., Results: Between December 3, 2020, and February 18, 2021, 164 participants accessed the survey with a response rate of 14.3%. Overall, academic physicians were more likely to implement telemedicine than private practice physicians. Telemedicine was also more frequently utilized for follow-up appointments rather than initial visits., Limitations: Although our n = 164, the overall low response rate of 14.3% warrants further investigation into the utilization of telemedicine throughout the COVID-19 pandemic., Conclusions: Telemedicine as an emerging technology for efficient communication played a key role in mitigating the adverse effects of the COVID -19 pandemic on chronic pain patients. The utilization of telemedicine remarkably increased after the start of the pandemic within 1 to 2 weeks. Overall, private hospital-based centers were significantly less likely to implement telemedicine than academic centers, possibly due to limited access to secure telemedicine platforms and high start-up costs. Telemedicine was used more frequently for follow-up visits than initial visit encounters at most centers. In spite of the unforeseen consequences to the healthcare system and chronic pain practices in the US from COVID-19, telehealth has emerged as a unique model of care for patients with chronic pain. Although it has flaws, telehealth has the ability to increase access to care beyond the end of the pandemic. Further identification of barriers to the use of telemedicine platforms in private practices should be addressed from a policy perspective to facilitate increased care access.

This article comprehensively covers 3 major novel technologies and techniques in the management of chronic lower back pain. The first 2 procedures, percutaneous interspinous spacer implantation, and minimally invasive lumbar decompression have shown significant impact in the management of lumbar spinal stenosis (LSS), especially in patients who are not great surgical candidates or are otherwise not amenable to open spinal surgery. The wealth of data for these procedures continues to increase, with up to 4 to 6-year follow-up data recently being made available. A novel solution for vertebrogenic back pain is also discussed as follow-up data emphasizes the safety and sustainability of the procedure. This article also establishes a framework for evaluating novel technologies in interventional pain management., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Declined immune response is the main cause of decreased potency of the influenza vaccine in the elderly, regardless of virus mutations. Herein, we hypothesized that the addition of α -tocopherol to the influenza vaccine formulation might increase vaccine potency and efficacy. Hemagglutinin of the H1N1 virus was formulated in Alum and α -tocopherol, and then aged (16-20-month-old) and young (6-8-week-old) mice were immunized subcutaneously two times with 2-week intervals with 5  μ g of different vaccine formulations. Two weeks after the final boosting, IFN- γ and IL-4 cytokines were assessed by using ELISA. Humoral immune responses were assessed by hemagglutination inhibition (HI). In addition, vaccine efficacy was determined by intranasal viral challenge of mice using mouse-adapted H1N1 virus. Our results showed that the new vaccine formulation improved IFN- γ and IL-4 responses in the experimental mice. However, the increase was evident mainly in the aged group and, to some extent, in the young group. Results from the HI assay showed that α -tocopherol in the vaccine formulation could increase HI activity in both young and aged mice. Furthermore, α -tocopherol, as an adjuvant, increased the protectivity of the influenza vaccine in both aged and young groups through the decreased lung viral load and increased survival rate of the experimental mice. In conclusion, it seems that α -tocopherol can not only be used as an appropriate adjuvant for aged people, but also empower old and worn out cells to increase the effectiveness of the vaccine in the elderly.

Background: Opioid-induced androgen deficiency (OPIAD) related to chronic, long-acting opioid use can be a significant detriment to patient quality of life. The aim of this study was to investigate the association between chronic opioid use and hypogonadism. Methods: A single-center, retrospective, matched case-control analysis of 357 males (94 cases, 263 controls, aiming for 1:4 matching) was performed. Study subjects were ages 18 to 80 years and had a diagnosis of chronic opioid use. Patients with a hypogonadism diagnosis were matched to patients without a hypogonadism diagnosis by age, ethnicity, and body mass index. The maximum morphine equivalent daily dose (MEDD) was compared in each group. Results: A significant linear association between MEDD and the odds of developing hypogonadism ( P <0.001) in males with chronic use of opioids was observed, with an odds ratio of 1.44 (95% CI 1.16-1.78) by 100-unit difference in maximum MEDD. Conclusion: Results showed a significant, positive linear association between chronic opioid dose and the odds of developing hypogonadism in males. This higher index of suspicion of OPIAD could lead to earlier recognition of symptoms and increase the positive predictive value of diagnostic laboratory tests., (©2021 by the author(s); Creative Commons Attribution License (CC BY).)

Competing Interests: Competing interests: None declared.

Today's, vaccination is the most cost-effective approaches for preventing infectious diseases. In this strategy, adjuvants play an important role. Propolis from honey bee can stimulate the immune system and several studies have shown the modulating effects of Propolis on the immune responses. Here, the adjuvant effects of aqueous and alcoholic extracts of Propolis were studied on the multi-epitope vaccines against HIV-1. A recombinant vaccine against HIV-1 was prepared and BALB/c mice were immunized. subcutaneously on day 0 with 100 μl of candidate vaccine (10 μg) formulated in an alcoholic extract of Propolis. The second group of mice was immunized with the vaccine (10 μg) formulated in aqueous extract of Propolis. Also, candidate vaccine was formulated in Freund's and Alum adjuvants in the third and fourth groups. Experimental mice were immunized three times with two week intervals under the same conditions and suitable control groups. After final injection, lymphocyte proliferation was measured by BrdU method, IL-4 and IFN-γ cytokines, specific total IgG antibodies, IgG1 and IgG2a isotypes were evaluated using ELISA. The results show that the aqueous and alcoholic extracts were able to enhance lymphocyte proliferation, IL-4 and IFN-γ cytokines and antibody responses with dominant IgG1 pattern and comparable to Freund's and Alum adjuvants. It seems that aqueous and alcoholic extracts of Propolis show adjuvant activity and may be useful for vaccine formulation., Competing Interests: Declaration of competing interest The authors of this research article have no financial conflict of interest statement., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Lumbar synovial cysts can result from spondylosis of facet joints. These cysts can encroach on adjacent nerve roots, causing symptoms of radiculopathy. Currently the only definitive treatment for these symptoms is surgery, which may involve laminectomy or laminotomy, with or without spinal fusion. Surgery has been reported to successfully relieve radicular pain in 83.5% of patients by Zhenbo et al. Little information is available concerning the efficacy and outcome of percutaneous fluoroscopic synovial cyst rupture for treatment of facet joint synovial cysts., Objective: The goal of this investigation was to assess the efficacy of fluoroscopically guided lumbar synovial cyst rupture, in particular for its relief of radicular symptoms and its potential to reduce the need for surgical intervention., Study Design: Retrospective evaluation of a case series., Setting: University hospital and urban public health care system., Methods: With approval from the Institutional Review Board of Case Western Reserve University/ MetroHealth Medical Center, we reviewed the medical charts of patients with lumbar radiculopathy who underwent percutaneous lumbar synovial cyst rupture. The 30 patients in the cohort were treated by one pain specialist between 2006 and 2013. These patients were diagnosed with moderate to severe lower back pain, radiculopathy, and ranged in age from 42 to 80 years. Patients were followed up for a minimum of 6 months and up to 24 months. Pre- and post-procedure pain assessments were reviewed by clinical chart review. In addition post-procedure pain assessments and duration of pain relief were obtained with telephone interviews. Pain had been reported by the patients using a numeric rating scale of 0 - 10 (0 = no pain; 10 = worst possible pain). Charts were reviewed to determine if surgery was eventually performed to correct radicular symptoms., Results: More than 6 months of pain relief was achieved in 14/30 patients (46%) and between one and 6 months of pain relief was achieved in 7/30 patients (23.3%). Nine patients (30.0%) had recurrence of the synovial cyst requiring repeat rupture and 6 patients (20.0%) required surgical intervention for cyst removal. A Wilcoxon signed-rank test demonstrated that the difference in numeric pain rating scale scores before and after the procedure was statistically significant (P < 0.0001). The average pain reduction was 71.2%. No complications were reported., Limitations: The results are limited by the retrospective nature of the data collection and the lack of detailed information regarding patients' functional improvement., Conclusions: Rupture of percutaneous lumbar synovial cysts in patients with lumbar radiculopathy was associated with immediate relief of radicular symptoms. In 80% of the patients, synovial cyst rupture eliminated the need for surgical interventions over the measured term. This minimally invasive procedure helps relieve pain in a subset of a patient population associated with these characteristics and is useful for management of this condition. Cyst expansion and failure to rupture with possible neuronal compression are the potential complications of this procedure. This complication did not occur in the study population., Key Words: Fluoroscopically guided lumbar synovial cyst rupture, lumbar synovial cyst, lumbar zygapophyseal joint cyst, nonsurgical intervention, radiculopathy, spondylosis.

Background: Cervical transforaminal epidural steroid injections (CTFESIs) may help decrease pain and restore function in patients with cervical radiculopathy. Evidence of the injections' effectiveness, however, remains controversial, and multiple case reports have identified potential complications. Such reports have led to diminished interest in including the procedure in patient care algorithms., Objectives: Our retrospective analysis aims to evaluate the CTFESI-associated pain relief and possible decreased need for spine surgery, along with its potential predictive role in determining cervical surgical outcomes. Finally, our study intends to estimate associated complications., Methods: A pain management database registry was used to identify patients who were referred by spine surgeons for diagnostic CTFESIs in preparation for possible surgery between January 2001 and December 2009. Outcomes were defined as the incidence of cervical surgery after diagnostic injection and the associated pain relief. A Poisson distribution was used to obtain a 95% confidence interval for the incidence of complications., Results: Sixty-four patients met the inclusion and exclusion criteria. After diagnostic CTFESIs, 45 (70.3%) of the observed 64 patients did not require cervical spine surgery whereas 19 (29.7%) still did. The mean pain reduction was 4.4 units on the numeric rating scale, with no observed complications., Conclusions: This retrospective analysis further demonstrates the safety, diagnostic value, and possible therapeutic role of CTFESIs. A larger, controlled, randomized study is needed to assess definitively the procedure's efficacy and safety.

Objective: The present study was performed to identify factors that lead to a favorable outcome of postpalatoplasty velopharyngeal incompetence using the double-opposing Z-palatoplasty., Design: A retrospective analysis was performed on 23 consecutive nonsyndromic patients who underwent secondary surgical management of velopharyngeal incompetence using a double-opposing Z-palatoplasty technique following primary, non-Furlow palatoplasty for overt cleft palate., Main Outcome Measures: All subjects were evaluated preoperatively using a perceptual speech assessment scale, nasendoscopy, and videofluoroscopy. Inclusion criteria consisted of a velopharyngeal gap of 9 mm or less on phonation. Patients were followed with perceptual speech assessment for at least 1 year following secondary surgery., Results: The perceptual speech assessment score for all patients decreased from 6.48 ± 2.26 (mean ± standard deviation; range, 3 to 11) to 1.90 ± 1.51 (range, 0 to 6) at 6 months or more postoperatively (P < .0001). Of the 21 patients with follow-up data 1 year or more post-op, 16 (76%) achieved velopharyngeal competence and five (24%) had borderline competence. Preoperative assessment factors associated with compromised outcome included a large velopharyngeal gap of 7 to 9 mm, poor lateral wall motion of 40% or less, and an elevated perceptual speech assessment score., Conclusion: Double-opposing Z-palatoplasty is a surgical technique that can be used successfully to correct velopharyngeal incompetence in selected secondary palatoplasty patients. This technique permits correction of velopharyngeal incompetence and restoration of the velopharyngeal mechanism irrespective of prior intravelar veloplasty and without accompanying loss in the nasal airway. Preoperative assessment can better identify those patients who are less likely to achieve velopharyngeal competence following double-opposing Z-palatoplasty alone.

Background: Evidence suggests that recurrent nocturnal hypoxemia may affect pain response and/or the sensitivity to opioid analgesia. We tested the hypothesis that nocturnal hypoxemia, quantified by sleep time spent at an arterial saturation (SaO2) < 90% and minimum nocturnal SaO2 on polysomnography, are associated with decreased pain and reduced opioid consumption during the initial 72 postoperative hours in patients having laparoscopic bariatric surgery., Methods: With Institutional Review Board approval, we examined the records of all patients who underwent laparoscopic bariatric surgery between 2004 and 2010 and had an available nocturnal polysomnography study. We assessed the relationships between the time-weighted average of pain score and total opioid consumption during the initial 72 postoperative hours, and: (a) the percentage of total sleep time spent at SaO2 < 90%, (b) the minimum nocturnal SaO2, and (c) the number of apnea/hypopnea episodes per hour of sleep. We used multivariable regression models to adjust for both clinical and sleep-related confounders., Results: Two hundred eighteen patients were included in the analysis. Percentage of total sleep time spent at SaO2 < 90% was inversely associated with total postoperative opioid consumption; a 5-%- absolute increase in the former would relatively decrease median opioid consumption by 16% (98.75% CI: 2% to 28%, P = 0.006). However, the percentage of total sleep time spent at SaO2 < 90% was not associated with pain. The minimum nocturnal SaO2 was associated neither with total postoperative opioid consumption nor with pain. In addition, neither pain nor total opioid consumption was significantly associated with the number of apnea/hypopnea episodes per hour of sleep., Conclusions: Preoperative nocturnal intermittent hypoxia may enhance sensitivity to opioids.

Background: Recurrent nocturnal hypoxemia in obstructive sleep apnea enhances sympathetic function, decreases baroreceptor sensitivity, and weakens peripheral vascular responses to adrenergic signals. The authors hypothesized that the percentage of total sleep time spent at oxyhemoglobin saturation (SaO2) less than 90% and minimum nocturnal SaO2 on preoperative polysomnography are associated with decreased intraoperative mean arterial pressure., Methods: The authors examined the records of all patients who had laparoscopic bariatric surgery at Cleveland Clinic between 2005 and 2009 and an available polysomnography study. The authors assessed the relationships between the percentage of total sleep time spent at SaO2 less than 90% and minimum nocturnal SaO2, and the time-weighted average of mean arterial pressure. The authors used multivariable regression models to adjust for prespecified clinical confounders., Results: Two hundred eighty-one patients were included in the analysis. The average change in the time-weighted average of mean arterial pressure was -0.02 (97.5% CI, -0.08, 0.04) mmHg for each 1% absolute increase in the percentage of sleep time spent at SaO2 less than 90% (P = 0.50). The average change was -0.13 (97.5% CI, -0.27, 0.01) mmHg, for each 1% absolute decrease in the minimum SaO2 (P = 0.04 > significance criterion of 0.025, Bonferroni correction). An unplanned analysis estimated 1% absolute decrease in minimum SaO2 was associated with -0.22 (98.75% CI, -0.39, -0.04) mmHg, change in mean arterial pressure (P = 0.002) in the time period between endotracheal intubation and trocar insertion., Conclusion: Recurrent nocturnal hypoxemia in obstructive sleep apnea is not a risk marker for intraoperative hypotension.