A Perspective on Electrical Stimulation and Sympathetic Regeneration in Peripheral Nerve Injuries.

Peripheral nerve injuries (PNIs) are common and devastating. The current standard of care relies on the slow and inefficient process of nerve regeneration after surgical intervention. Electrical stimulation (ES) has been shown to both experimentally and clinically result in improved regeneration and functional recovery after PNI for motor and sensory neurons; however, its effects on sympathetic regeneration have never been studied. Sympathetic neurons are responsible for a myriad of homeostatic processes that include, but are not limited to, blood pressure, immune response, sweating, and the structural integrity of the neuromuscular junction. Almost one quarter of the axons in the sciatic nerve are from sympathetic neurons, and their importance in bodily homeostasis and the pathogenesis of neuropathic pain should not be underestimated. Therefore, as ES continues to make its way into patient care, it is not only important to understand its impact on all neuron subtypes, but also to ensure that potential adverse effects are minimized. This piece gives an overview of the effects of ES in animals models and in humans while offering a perspective on the potential effects of ES on sympathetic axon regeneration.

Discrepancies in Financial Conflicts of Interest in Robotic Cardiothoracic Surgery Studies.

BACKGROUND: In academic surgery publications, self-reporting of conflicts of interest (COI) has often proved to be inaccurate. Here, we review the accuracy of COI disclosures for studies related to the use of robotic technology in cardiothoracic surgery and evaluate factors associated with increased discrepancies. METHODS: A literature search identified robotic surgery-related studies with at least 1 American author published between January 2015 and December 2020 from 3 major American cardiothoracic surgery journals (The Journal of Thoracic and Cardiovascular Surgery, The Annals of Thoracic Surgery, and Annals of Cardiothoracic Surgery). Industry payments from Intuitive Surgical (Intuitive) were collected with use of the Centers for Medicare and Medicaid Open Payments database. COI discrepancies were identified by comparing author declaration statements with payments found for the year of publication and the year prior (24-month period). RESULTS: A total of 144 studies (764 authors) were identified. At least 1 author of 112 studies (78%) had received payments from Intuitive. At least 1 author of 98 studies (68%) had received an undeclared payment from Intuitive. Authors who accurately disclosed payments received significantly higher median payments compared with authors who did not ($16,511 [interquartile range, $6389-$159,035] vs $1762 [interquartile range, $338-$7500]; P < .0001). Last authors were significantly more likely to have a COI discrepancy compared with middle and first authors (P = .018; P = .0015). CONCLUSIONS: Most studies investigating the use of robotic technology in cardiothoracic surgery did not accurately declare COI with Intuitive. This study highlights the need for improved accuracy of reporting industry sponsorship by publishing authors.

Interpretive Qualitative Evaluation Informs Research Participation and Advocacy Training Program for Seniors: A Pilot Study.

Background: An 8-week educational intervention co-taught by medical students and faculty was designed to foster communication between clinical researchers and populations of interest to ultimately increase participation in clinical research by older adults, including underrepresented groups. Weekly topics focused on age-related changes and health conditions, socio-contextual factors impacting aging populations, and wellness strategies. Objectives: To evaluate the successes and weaknesses of an educational intervention aimed at increasing the participation of older adults in clinical research. Design: A focus group was assembled after an 8-week educational intervention, titled DREAMS, to obtain participants' feedback on the program, following a pre-formulated interview guide. Settings: Participants were interviewed in a health center office environment in the United States of America in April of 2016. Participants: A post-intervention focus group was conducted with a group of eight older adults (mean age = 75.8 ± 11.4 years) from 51 total participants who completed the intervention. Methods: The focus group was interviewed loosely following a pre-formed question guide. Participants were encouraged to give honest feedback. The conversation was recorded, transcribed verbatim, and analyzed using thematic analyses. Results: While participants viewed most aspects of the study as a success and stated that it was a productive learning experience, most participants had suggestions for improvements in the program content and implementation. Specifically, the composition of and direction to small breakout groups should be carefully considered and planned in this population, and attention should be paid to the delivery of sensitive topic such as death and dementia. A clear main benefit of this programmatic approach is the development of a rapport amongst participants and between participants and clinical researchers. Conclusions: The results provide useful insights regarding improving participation among hard-to-reach and historically underrepresented groups of older adults in clinical research. Future iterations of this program and similar educational interventions can use these findings to better achieve the programmatic objectives.

Members of the CUGBP Elav-like family of RNA-binding proteins are expressed in distinct populations of primary sensory neurons.

Primary sensory dorsal root ganglia (DRG) neurons are diverse, with distinct populations that respond to specific stimuli. Previously, we observed that functionally distinct populations of DRG neurons express mRNA transcript variants with different 3' untranslated regions (3'UTRs). 3'UTRs harbor binding sites for interaction with RNA-binding proteins (RBPs) for transporting mRNAs to subcellular domains, modulating transcript stability, and regulating the rate of translation. In the current study, analysis of publicly available single-cell RNA-sequencing data generated from adult mice revealed that 17 3'UTR-binding RBPs were enriched in specific populations of DRG neurons. This included four members of the CUG triplet repeat (CUGBP) Elav-like family (CELF): CELF2 and CELF4 were enriched in peptidergic, CELF6 in both peptidergic and nonpeptidergic, and CELF3 in tyrosine hydroxylase-expressing neurons. Immunofluorescence studies confirmed that 60% of CELF4+ neurons are small-diameter C fibers and 33% medium-diameter myelinated (likely Aδ) fibers and showed that CELF4 is distributed to peripheral termini. Coexpression analyses using transcriptomic data and immunofluorescence revealed that CELF4 is enriched in nociceptive neurons that express GFRA3, CGRP, and the capsaicin receptor TRPV1. Reanalysis of published transcriptomic data from macaque DRG revealed a highly similar distribution of CELF members, and reanalysis of single-nucleus RNA-sequencing data derived from mouse and rat DRG after sciatic injury revealed differential expression of CELFs in specific populations of sensory neurons. We propose that CELF RBPs may regulate the fate of mRNAs in populations of nociceptors, and may play a role in pain and/or neuronal regeneration following nerve injury.

Conditioning electrical stimulation fails to enhance sympathetic axon regeneration.

Peripheral nerve injuries are common, and there is a critical need for the development of novel therapeutics to complement surgical repair. Conditioning electrical stimulation (CES) is a novel variation to the well-studied perioperative electrical stimulation, both of which have displayed success in enhancing the regeneration of motor and sensory axons in an injured peripheral nerve. CES is a clinically attractive alternative not only because of its ability to be performed at the bedside prior to a scheduled nerve repair surgery, but it has also been shown to be superior to perioperative electrical stimulation in the enhancement of motor and sensory regeneration. However, the effects of CES on sympathetic regeneration are unknown. Therefore, we tested the effects of two clinically relevant CES paradigms on sympathetic axon regeneration and distal target reinnervation. Because of the long history of evidence for the enhancement of motor and sensory axons in response to electrical stimulation, we hypothesize that CES will also enhance sympathetic axon regeneration. Our results indicate that the growth of sympathetic axons is acutely inhibited by CES; however, at a longer survival time point post-injury, there is no difference between sham CES and the CES groups. There has been evidence to suggest that the growth of sympathetic axons is inhibited by a conditioning lesion, and that sympathetic axons may respond to electrical stimulation by sprouting rather than elongation. Our data indicate that sympathetic axons may retain some regenerative ability after CES, but no enhancement is exhibited, which may be accounted for by the inability of the current clinically relevant electrical stimulation paradigm to recruit the small-caliber sympathetic axons into activity. Further studies will be needed to optimize electrical stimulation parameters in order to enhance the regeneration of all neuron types.

A Cost-Utility Analysis of the Use of Closed-Incision Negative Pressure System in Vascular Surgery Groin Incisions.

OBJECTIVE: Closed-incision negative pressure therapy (CINPT) with the Prevena system has been used and clinically evaluated in high-risk groin incisions to reduce the risk of postoperative complications. We performed a cost-effectiveness analysis evaluating CINPT in femoral-popliteal bypass with prosthetic graft. METHODS: A literature review looking at prospective randomized trials determined the probabilities and outcomes for femoral-popliteal bypass with and without CINPT. Reported utility scores were used to estimate the quality adjusted life years (QALYs) associated with a successful procedure and postoperative complications. Medicare current procedure terminology and diagnosis-related group codes were used to assess the costs for a successful surgery and associated complications. A decision analysis tree was constructed with rollback analysis to highlight the more cost-effective strategy. An incremental cost-effectiveness ratio (ICER) analysis was performed with a willingness to pay at $50,000. Deterministic and probabilistic sensitivity analyses were performed to validate the robustness of the results, and to accommodate for the uncertainty in the literature. RESULTS: Femoral-popliteal bypass with CINPT is less costly ($40,138 vs $41,774) and more effective (6.14 vs 6.13) compared to without CINPT. This resulted in a negative ICER of -234,764.03, which favored CINPT, indicating a dominant strategy. In one-way sensitivity analysis, surgery without CINPT was more cost-effective if the probability of successful surgery falls below 84.9% or if the cost of CINPT exceeds $3139. Monte Carlo analysis showed a confidence of 99.07% that CINPT is more cost-effective. CONCLUSIONS: Despite the added device cost of CINPT, it is cost-effective in vascular surgical operations using groin incisions.

Disruption of Endosomal Sorting in Schwann Cells Leads to Defective Myelination and Endosomal Abnormalities Observed in Charcot-Marie-Tooth Disease.

Endosomal sorting plays a fundamental role in directing neural development. By altering the temporal and spatial distribution of membrane receptors, endosomes regulate signaling pathways that control the differentiation and function of neural cells. Several genes linked to inherited demyelinating peripheral neuropathies, known as Charcot-Marie-Tooth (CMT) disease, encode proteins that directly interact with components of the endosomal sorting complex required for transport (ESCRT). Our previous studies demonstrated that a point mutation in the ESCRT component hepatocyte growth-factor-regulated tyrosine kinase substrate (HGS), an endosomal scaffolding protein that identifies internalized cargo to be sorted by the endosome, causes a peripheral neuropathy in the neurodevelopmentally impaired teetering mice. Here, we constructed a Schwann cell-specific deletion of Hgs to determine the role of endosomal sorting during myelination. Inactivation of HGS in Schwann cells resulted in motor and sensory deficits, slowed nerve conduction velocities, delayed myelination and hypomyelinated axons, all of which occur in demyelinating forms of CMT. Consistent with a delay in Schwann cell maturation, HGS-deficient sciatic nerves displayed increased mRNA levels for several promyelinating genes and decreased mRNA levels for genes that serve as markers of myelinating Schwann cells. Loss of HGS also altered the abundance and activation of the ERBB2/3 receptors, which are essential for Schwann cell development. We therefore hypothesize that HGS plays a critical role in endosomal sorting of the ERBB2/3 receptors during Schwann cell maturation, which further implicates endosomal dysfunction in inherited peripheral neuropathies.SIGNIFICANCE STATEMENT Schwann cells myelinate peripheral axons, and defects in Schwann cell function cause inherited demyelinating peripheral neuropathies known as CMT. Although many CMT-linked mutations are in genes that encode putative endosomal proteins, little is known about the requirements of endosomal sorting during myelination. In this study, we demonstrate that loss of HGS disrupts the endosomal sorting pathway in Schwann cells, resulting in hypomyelination, aberrant myelin sheaths, and impairment of the ERBB2/3 receptor pathway. These findings suggest that defective endosomal trafficking of internalized cell surface receptors may be a common mechanism contributing to demyelinating CMT.

Angiogenesis is critical for the exercise-mediated enhancement of axon regeneration following peripheral nerve injury.

Enhancing axon regeneration is a major focus of nerve injury research, and the quality of the surgical nerve repair plays a large role in the aggregate success of nerve regeneration. Additionally, exercise is known to promote successful axon regeneration after surgical nerve repair. In this study, we asked how exercise-induced nerve regeneration is affected when a transected nerve is repaired with or without fibrin glue. Fibrin glue repaired nerves exhibited greater vasculature within the tissue bridge compared to nerves that were intrinsically repaired. Fibrin glue repaired nerves also exhibited more robust axon regeneration after exercise compared to nerves that were not repaired with fibrin glue. When angiogenesis of the tissue bridge was prevented, exercise was unable to enhance regeneration despite the presence of fibrin glue. These findings suggest that the biological properties of fibrin glue enhance angiogenesis within the repair site, and a vascularized bridge is required for enhanced axon elongation with exercise. The combination of fibrin glue repair and exercise resulted in notable differences in vascular growth, axon elongation, neuromuscular junction reinnervation, and functional recovery. Fibrin glue should be considered as an adjuvant for nerve repair to enhance the subsequent efficacy of activity- and physical therapy-based treatment interventions.

Assessment of Financial Conflicts of Interest Related to the Use of Dermal Substitutes in Burn Management.

This study aims to systematically review the accuracy of the self-reporting of conflicts of interest (COIs) among studies related to the use of dermal substitute products in burn management and evaluate factors associated with increased discrepancies. To do so, a literature search was done to identify studies investigating the use of dermal substitutes in burn management published between 2015 and 2019. Industry payments were collected using the Centers for Medicare and Medicaid Services Open Payments database. Declared COIs were then compared with the listed payments. Studies and authors were considered to have a COI if they received payments totaling more than $100 for each company. A total of 51 studies (322 authors) were included for analysis. Forty studies and 104 authors received at least one payment from the industry. Of these studies, 38 (95%) studies and 91 (88%) authors were found to have a COI discrepancy. From 2015 to 2019, 1391 general payments (totaling $1,696,848) and 108 research payments (totaling $1,849,537) were made by 82 companies. When increasing the threshold on what would be considered an undisclosed payment, the proportion of authors with discrepancies gradually decreased, from 88% of authors with undisclosed payments more than $100 to 27% of authors with undisclosed payments more than $10,000. Author order, journal impact factor, and study type were not significantly associated with increased risk of discrepancy. We found that the majority of studies investigating the use of dermal substitute products for burn management did not accurately declare COI, highlighting the need for a uniform declaration process and greater transparency of industry sponsorship by authors when publishing peer-reviewed burn surgery research papers.

Conflicts of Interest in Studies Related to Mesh Use in Ventral Hernia Repair and Abdominal Wall Reconstruction.

OBJECTIVE: To examine the accuracy of the reporting of conflicts of interest (COI) among studies related to mesh use in ventral hernia repair and abdominal wall reconstruction. SUMMARY BACKGROUND DATA: Accurate declaration of COI is integral to ensuring transparency of study results. Multiple studies have demonstrated undeclared COI are prevalent in surgical literature. METHODS: Studies with at least 1 American author accepted between 2014 and 2018 in 12 major, peer-reviewed general surgery and plastic surgery journals were included. Declared COI were compared with payments listed in the "Open Payments" database [maintained by the Centers for Medicare & Medicaid Services (CMS)] during the year of acceptance and 1 year prior. Studies and authors were considered to have a COI if they received payments from any of 8 major mesh companies totaling >$100.00 from each company. Risk factors for undeclared COI were determined at the study and author levels. RESULTS: One hundred twenty-six studies (553 authors) were included. One hundred two studies (81.0%) had one or more authors who received payments from industry and inaccurately declared their COI. Two hundred forty-eight authors (44.8%) did not declare their COI accurately. On multivariate analysis, last authors were found to be at highest risk for undeclared payments (OR 3.59, 95%CI 2.02-6.20), whereas middle authors were at significantly higher risk for undeclared payments than first authors (OR 1.64, 95%CI 1.04-2.56). CONCLUSIONS: The majority of studies investigating the use of mesh in ventral hernia repairs and abdominal wall reconstructions did not accurately declare COI. Last authors are at highest risk of undisclosed payments. Current policies on disclosing COI seem to be insufficient to ensure transparency of publications.

Reporting of Financial Conflicts of Interest in Studies of Placental Membrane Allografts.

Objective: To systematically review the accuracy of self-reported financial conflicts of interest (COI) by authors of placental membrane allograft product studies. Approach: A PubMed search identified placental membrane allograft studies published between 2015 and 2019. Industry payments were collected using the Centers for Medicare & Medicaid Services Open Payments database. Self-declared COI were compared with recorded payments. Risk factors for positive product recommendation were determined at study and author levels. Results: Eighty-nine studies (417 authors) were identified. Seventy-five studies (84%) had at least one author receive undisclosed payments. From 2015 to 2019, 5,841 general payments (totaling $15,558,026) and 1,234 research payments (totaling $18,290,062) were made by 46 companies. Travel/lodging was the most commonly reported transaction (34%). Authors were comprised mostly of podiatrists (27%), plastic surgeons (15%), and orthopedic surgeons (15%). Comparative studies were less likely to have a positive product recommendation compared to noncomparative studies (odds ratio [OR] 0.204, 95% confidence interval 0.06-0.066, p = 0.02). Multivariate analysis showed no association between COI discrepancy and product recommendation. Innovation: The accuracy of self-reported financial COI in placental membrane studies is evaluated for the first time. Conclusion: The majority of placental membrane product studies did not declare all industry payments. Whether these payments represent "relevant COI" remains unclear. In addition, not all placental product companies report to the Open Payments database, suggesting that the issue may be even more significant. This study highlights the need for improved definitions of "relevant COI," a standardized reporting system across journals, and the uniform participation of all medical product vendors.

Assessment of self-reported financial conflicts of interest in vascular surgery studies.

OBJECTIVE/BACKGROUND: With increased collaboration between surgeons and industry, there has been a push towards improving transparency of conflicts of interest (COIs). This study aims to determine the accuracy of reporting of COIs among studies in major vascular surgery journals. METHODS: A literature search identified all comparative studies published from January 2018 through December 2018 from three major United States vascular surgery journals (Journal of Vascular Surgery, Vascular and Endovascular Surgery, and Annals of Vascular Surgery). Industry payments were collected using the Centers for Medicare and Medicaid Services Open Payments database. COI discrepancies were identified by comparing author declaration statements with payments found for the year of publication and year prior. RESULTS: A total of 239 studies (1642 authors) were identified. Two hundred twenty-one studies (92%) and 669 authors (63%) received undisclosed payments when utilizing a cut-off payment amount of $250. In 2018, 10,778 payments (totaling $22,174,578) were made by 145 companies. Food and beverage payments were the most commonly reported transaction (42%), but accounted for only 3% of total reported monetary values. Authors who accurately disclosed payments received significantly higher median general payments compared with authors who did not accurately disclose payments ($56,581 [interquartile range, $2441-$100,551] vs $2361 [interquartile range, $525-$9,699]; P < .001). When stratifying by dollar-amount discrepancy, the proportions of authors receiving undisclosed payments decreased with increasing payment thresholds. Multivariate analysis demonstrated that first and senior authors were both significantly more likely to have undisclosed payments (odds ratio, 2.0; 95% confidence interval, 1.1-3.6 and odds ratio, 2.9; 95% confidence interval, 1.6-5.2, respectively). CONCLUSIONS: There is a significant discordance between self-reported COI in vascular surgery studies compared with payments received in the Centers for Medicare and Medicaid Services Open Payments database. This study highlights the need for increased efforts to both improve definitions of what constitutes a relevant COI and encourage a standardized reporting process for vascular surgery studies.