BACKGROUND:Lumbar radicular pain is often treated with interlaminar epidural particulate corticosteroid injection (ILEPSI). However, little literature exists on epidural tissue changes post ILEPSI. Investigating these potential tissue changes is valuable because of their possible clinical implications. OBJECTIVE:To report gross and histological epidural tissue changes after ILEPSI following spinal decompression surgery and compare the observed changes to those previously reported in the literature. DESIGN:A retrospective case series and systematic literature review were conducted. Surgeons were blinded to the details of corticosteroid injections and the study's specific aims. PARTICIPANTS:Patients who underwent spinal decompression surgery and through retrospective chart review were found to have had ILEPSI prior to surgery. METHODS:Four consecutive patients undergoing spinal decompression surgery were included in a convenience sample, all exhibiting abnormal epidural tissue formation. A retrospective chart review showed that each patient had received ILEPSI at the same spinal level before surgery. A systematic literature review, registered in International Prospective Register of Systematic Reviews, was subsequently conducted based on this novel finding. RESULTS:Surgical biopsies from four patients undergoing spinal decompression after ILEPSI showed "granulomatous-like reactions" in the epidural space. A systematic literature review found no similar epidural reactions but did find comparable findings in dermatology literature. CONCLUSION:The epidural "granulomatous-like reactions" observed after ILEPSI are a novel finding, resembling tissue reactions from particulate corticosteroid administration. This suggests a potential link between ILEPSI and these reactions.

BACKGROUND:Residency choice is often influenced by experiences in medical school. It is unclear what potential factors contribute to medical schools producing higher numbers of physical medicine & rehabilitation (PM&R) residents. OBJECTIVE:To identify the medical schools producing the most PM&R residents from 2017 to 2021 and potential influencing factors toward this production. DESIGN:Descriptive, cross-sectional study. SETTING:Accreditation Council for Graduate Medical Education accredited PM&R programs; allopathic/osteopathic/international medical schools. INTERVENTIONS:REDCap Survey. PARTICIPANTS:Representatives from medical schools producing the most PM&R residents. METHODS:The medical schools that produced the most PM&R residents from 2017 to 2021 were identified using publicly available information on the internet. A subgroup of the highest producing schools were surveyed to determine potential factors that contributed to production of PM&R residents. MAIN OUTCOME MEASURE:Medical schools with the highest number of matriculated PM&R residents from 2017 to 2021; potential factors influencing matriculating PM&R residents. RESULTS:The medical school that produced the most PM&R residents from 2017 to 2021 was New York Institute of Technology College of Osteopathic Medicine. Nine of the 11 medical schools producing the most PM&R residents were osteopathic. Of osteopathic graduates applying to residency, 2.87% matriculated into PM&R residencies compared to 1.21% of allopathic graduates (p < .001), though a greater number of allopathic graduates overall were represented. Among survey respondents 93.3% (14/15) attributed exposure to PM&R faculty/residents and exposure to PM&R through medical school curriculum as perceived factors contributing to production of PM&R residents. CONCLUSION:Osteopathic medical schools accounted for most of the schools producing the highest number of PM&R residents. A statistically significant higher percentage of osteopathic graduates were found to pursue PM&R as a career compared to allopathic counterparts although the total number of students entering PM&R was greater from allopathic schools. Potential factors contributing to medical students pursuing PM&R included faculty/resident involvement with medical students, and PM&R exposure through curriculum or interest groups.

Therapeutic vaccines that elicit cytotoxic T cell responses targeting tumor-specific neoantigens hold promise for providing long-term clinical benefit to patients with cancer. Here we evaluated safety and tolerability of a therapeutic vaccine encoding 20 shared neoantigens derived from selected common oncogenic driver mutations as primary endpoints in an ongoing phase 1/2 study in patients with advanced/metastatic solid tumors. Secondary endpoints included immunogenicity, overall response rate, progression-free survival and overall survival. Eligible patients were selected if their tumors expressed one of the human leukocyte antigen-matched tumor mutations included in the vaccine, with the majority of patients (18/19) harboring a mutation in KRAS. The vaccine regimen, consisting of a chimp adenovirus (ChAd68) and self-amplifying mRNA (samRNA) in combination with the immune checkpoint inhibitors ipilimumab and nivolumab, was shown to be well tolerated, with observed treatment-related adverse events consistent with acute inflammation expected with viral vector-based vaccines and immune checkpoint blockade, the majority grade 1/2. Two patients experienced grade 3/4 serious treatment-related adverse events that were also dose-limiting toxicities. The overall response rate was 0%, and median progression-free survival and overall survival were 1.9 months and 7.9 months, respectively. T cell responses were biased toward human leukocyte antigen-matched TP53 neoantigens encoded in the vaccine relative to KRAS neoantigens expressed by the patients’ tumors, indicating a previously unknown hierarchy of neoantigen immunodominance that may impact the therapeutic efficacy of multiepitope shared neoantigen vaccines. These data led to the development of an optimized vaccine exclusively targeting KRAS-derived neoantigens that is being evaluated in a subset of patients in phase 2 of the clinical study. ClinicalTrials.gov registration: NCT03953235 . In an interim analysis of a phase 1/2 trial, a heterologous prime boost vaccine comprised of a chimpanzee adenovirus and self-amplifying mRNA that encodes neoantigens derived from common oncogenic driver mutations in combination with immune checkpoint blockade was safe and elicited neoantigen-specific T cell responses in patients with advanced solid tumors.

Instrumented lumbar spinal fusion is common and results in biomechanical changes at adjacent spinal segments that increase facet load bearing. This can cause facet-mediated pain at levels adjacent to the surgical construct. Medial branch nerve radiofrequency ablation (RFA) exists as a treatment for some cases. It is important to acknowledge that the approach and instrumentation used during some specific lumbar fusion approaches will disrupt the medial branch nerve(s). Thus, the proceduralist must consider the fusion approach when determining which medial branch nerves are necessary to anesthetize for diagnosis and then to potentially target with RFA. This article discusses the relevant technical considerations for preparing for RFA to denervate lumbosacral facet joints adjacent to fusion constructs.

Introduction: Cognitive Behavioral Immersion (CBI) is a novel cognitive-behavioral skills program delivered by lay coaches in the metaverse through immersive virtual reality technology. Objectives: The objective for this study was to run a feasibility and pilot study of CBI for individuals in recovery from a substance use disorder. Methods: Data from 48 participants were used and program usage was assessed. Participants were asked to complete questionnaires assessing affect, perceived online social support, and group therapy alliance throughout their participation in the program. Structured qualitative interviews were also conducted with a subset of participants (n = 11) to understand the feasibility of the novel program. Results: Participants experienced a significant increase in their positive affect and non-significant decrease in their negative affect during their most recently attended session. Participants also experienced a nonsignificant increase in online social support across their participation in the program. Structured qualitative interviews revealed eight primary themes, including both advantages (community, psychoeducational impact, immersion, comparability with other interventions, coping in the pandemic, and anonymity) and areas of improvement (challenges and technological usability) of the program. Conclusion: This study provides preliminary support for the feasibility and potential effects of CBI and its incorporation of lay coaches to lead cognitive-behavioral skills groups in the metaverse. Future research is encouraged to examine the feasibility and efficacy of this program for a broader array of clinical presentations.

Table 2 sgRNA genes and sequences

Background Cancer immunotherapy has revolutionized treatment options for patients. However, many patients do not respond to immunotherapy, requiring a better understanding of the T cell response to cancer.1 Immunotherapy functions in part by improving CD8 TIL (Tumor Infiltrating Lymphocytes) functionality. CD8 TIL progress from a progenitor state into a more terminal state of dysfunction termed exhaustion, with diminished cytolytic capacity and an inability to clear tumors.2 Understanding the mechanisms regulating the development of exhausted T cells has clinical implications for improving current and development of new immunotherapies. Terminally exhausted CD8 TIL are transcriptionally distinct from progenitor exhausted CD8 TIL and our previous study identified epigenetic mechanisms that contributed to T cell dysfunction.3 We found that terminally exhausted CD8 TIL had an increased proportion of histone modifications corresponding to active enhancers and active promoters that did not correspond with expected gene transcription. Intriguingly, we also found decreased expression of AP-1 family members in exhausted CD8 TIL, which are key transcription factors that play roles in transcriptional regulation by mediating enhancer-promoter looping. Intriguingly, enhancers in terminally exhausted CD8 TIL were enriched for AP-1 (bZIP) binding motifs. The physical interaction of enhancers to promoters are essential to their function to promote optimal transcription and recruitment of key transcription factors to these genes. Recent work has shown the importance of chromatin structure for T cell activation and differentiation from naïve states to effector states, highlighting the importance of chromatin interactions in T cell fate and function.4 5 However, the role of 3D chromatin structure in the development of T cell exhaustion has not been explored. Methods We hypothesized that exhausted CD8 T cells may have alterations in 3D chromatin looping due to a loss of AP-1 factor expression that regulates their transcriptional potential and decreases their functionality. To investigate changes in chromatin interactions, we performed low-input Hi-C on terminally exhausted and progenitor CD8 T cells from B16 melanoma. We performed CUT&Tag for CCCTC-binding factor (CTCF) which regulates chromatin looping. Results We observed a loss of long-range chromatin interactions in terminally exhausted CD8 TIL compared to progenitor CD8 TIL and differential topological associating domains (TADs). We found loss of CTCF binding between precursor and terminally exhausted CD8 T cells at TAD boundaries. Conclusions Our findings indicate that chromatin conformation changes may be associated with T cell exhaustion and poor tumor control. Immunotherapies that aim to restore enhancer-promoter looping via AP-1 family binding may promote anti-tumor immunity. References Wei SC, Duffy CR, Allison JP. Fundamental Mechanisms of Immune Checkpoint Blockade Therapy. Cancer Discov. 2018;8(9):1069–86. Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol. 2015;15(8):486–99. Ford BR, Vignali PDA, Rittenhouse NL, Scharping NE, Peralta R, Lontos K, Frisch AT, Delgoffe GM, Poholek AC. Tumor microenvironmental signals reshape chromatin landscapes to limit the functional potential of exhausted T cells. Sci Immunol. 2022 Aug 5;7(74) Bediaga NG, Coughlan HD, Johanson TM, Garnham AL, Naselli G, Schröder J, Fearnley LG, Bandala-Sanchez E, Allan RS, Smyth GK, Harrison LC. Multi-level remodelling of chromatin underlying activation of human T cells. Sci Rep. 2021 Jan 12;11(1):528. Quon S, Yu B, Russ BE, Tsyganov K, Nguyen H, Toma C, Heeg M, Hocker JD, Milner JJ, Crotty S, Pipkin ME, Turner SJ, Goldrath AW. DNA architectural protein CTCF facilitates subset-specific chromatin interactions to limit the formation of memory CD8+ T cells. Immunity. 2023 May 9;56(5):959–978.e10.

Table 3 SCCHN clinical info

ABSTRACT:There is no standardized curriculum for teaching interventional spine procedures during residency. The objective of this protocol was to share a curriculum using a cadaver laboratory for teaching Physical Medicine and Rehabilitation residents interventional spine procedures, which can be an effective and safe medium to train residents. This protocol provides a checklist that can guide the residents while they are in the cadaver laboratory with a focus on some of the most common lumbar procedures. Twelve physical medicine and rehabilitation resident's confidence in their ability to maneuver the x-ray image intensifier (C-arm), identify spine anatomy under fluoroscopy, and drive the needle improved after the training curriculum (P < 0.005). Although the cadaver laboratory curriculum is not a replacement for the required Accreditation Council for Graduate Medical Education training, it may serve as a tool to improve resident preparedness for spine procedures.

Checkpoint inhibitor (CPI) therapies provide limited benefit to patients with tumors of low immune reactivity. T cell-inducing vaccines hold promise to exert long-lasting disease control in combination with CPI therapy. Safety, tolerability and recommended phase 2 dose (RP2D) of an individualized, heterologous chimpanzee adenovirus (ChAd68) and self-amplifying mRNA (samRNA)-based neoantigen vaccine in combination with nivolumab and ipilimumab were assessed as primary endpoints in an ongoing phase 1/2 study in patients with advanced metastatic solid tumors (NCT03639714). The individualized vaccine regimen was safe and well tolerated, with no dose-limiting toxicities. Treatment-related adverse events (TRAEs) >10% included pyrexia, fatigue, musculoskeletal and injection site pain and diarrhea. Serious TRAEs included one count each of pyrexia, duodenitis, increased transaminases and hyperthyroidism. The RP2D was 10 12 viral particles (VP) ChAd68 and 30 µg samRNA. Secondary endpoints included immunogenicity, feasibility of manufacturing and overall survival (OS). Vaccine manufacturing was feasible, with vaccination inducing long-lasting neoantigen-specific CD8 T cell responses. Several patients with microsatellite-stable colorectal cancer (MSS-CRC) had improved OS. Exploratory biomarker analyses showed decreased circulating tumor DNA (ctDNA) in patients with prolonged OS. Although small study size limits statistical and translational analyses, the increased OS observed in MSS-CRC warrants further exploration in larger randomized studies.

The sacroiliac joint complex (SIJC) is composed of complex anatomy of numerous potential pain generators that demonstrate varying pathophysiology and differing innervations. This heterogeneity has been a challenge to advancing research and clinical care. Moving forward, individualized approaches taking these factors into account may be a path forward to improved outcomes. Thus, as we move toward precision medicine in interventional spine care, it is imperative to investigate more targeted diagnostic and therapeutic approaches to the SIJC.

ABSTRACT There is no standardized curriculum for teaching interventional spine procedures during residency. The objective of this protocol was to share a curriculum utilizing a cadaver lab for teaching PM&R residents interventional spine procedures which can be an effective and safe medium to train residents. This protocol provides a checklist that can guide the residents while they are in the cadaver lab with a focus on some of the most common lumbar procedures. Twelve PM&R resident's confidence in their ability to maneuver the x-ray image intensifier (C-arm), identify spine anatomy under fluoroscopy and drive the needle improved after the training curriculum (p < 0.005). While the cadaver lab curriculum is not a replacement for the required ACGME training, it may serve as a tool to improve resident preparedness for spine procedures.

Radiofrequency ablation (RFA) of the sacral lateral branches targets the innervation of the posterior sacroiliac ligaments and posterior portion of the sacroiliac joint, also referred to as the posterior sacroiliac joint complex. This review assesses the published evidence on local anesthetic blocks for the diagnosis of posterior sacroiliac joint complex pain and the efficacy of RFA of the sacral lateral branches as a treatment. The current evidence suggests that RFA can provide relief of pain that originates from the posterior sacroiliac joint complex, but interpretation of this literature is limited by variability in patient selection criteria, the specific nerves targeted for ablation, and the types of RFA technology and technique utilized.

Objectives The aims of the study were to systematically review the available literature concerning complications due to electromyography and to review those associated with nerve conduction studies. Design A systematic review was undertaken of Medline and Cochrane Central Register of Controlled Trials. Any complication related to clinical electromyography written in English was included, and all bibliographies were scanned for missed articles. Results A total of 27 articles fit the inclusion criteria, with two observational studies, and the rest case series or case studies; 42 patients were reported. Of these, 28 patients required hospitalization and 22 required surgery or a procedure, with zero deaths reported. Needle-related complications were the most prevalent (18 patients reported), with 17 related to pneumothoraces. Disorders of hemostasis were identified in 13 patients (many were asymptomatic) and cutaneous disorders were identified in 11 patients. Only one complication was identified in the narrative review related to nerve conduction studies. Conclusions This systematic review identified a variety of complications related to electromyography. Although the incidence of these occurrences cannot be elucidated from the case series and case study-predominant literature, adverse events seem to be rare but can cause significant morbidity. Electromyographers should be aware of all reported complications; this review outlines all reported occurrences that fit the inclusion criteria.

Ultrasound is gaining traction as a neuromodulation method due to its ability to remotely and non-invasively modulate neuronal activity with millimeter precision. However, there is little consensus about optimal ultrasound parameters required to elicit neuromodulation and how specific parameters drive mechanisms that underlie ultrasound neuromodulation. We address these questions in this work by performing a study to determine effective ultrasound parameters in a transgenic mouse brain slice model that enables calcium imaging as a quantitative readout of neuronal activity for ultrasound neuromodulation. We report that (1) calcium signaling increases with the application of ultrasound; (2) the neuronal response rate to ultrasound is dependent on pulse repetition frequency (PRF); and (3) ultrasound can reversibly alter the inhibitory effects of tetrodotoxin (TTX) in pharmacological studies. This study offers mechanistic insight into the PRF dependence of ultrasound neuromodulation and the nature of ultrasound/ion channel interaction.