Study protocol for measuring stigmatization in persistent tic disorders: development and validation of the Tourette discrimination-stigmatization scale.

Introduction: Persistent Tic Disorders such as Tourette Syndrome are common neurodevelopmental disorders that are highly stigmatized. Many individuals with Persistent Tic Disorders experience peer rejection, loneliness, and self-stigma. Experiencing stigmatization during childhood can influence the persistence of moderate-to-severe tics later in life. Additionally, these factors have been associated with increased suicidal ideation, suicide attempts, and psychiatric symptom severity. There is a need for interventions to reduce stigma and stigmatization in Persistent Tic Disorders. Before developing cost-effective interventions to mitigate stigma's profound downstream health impacts, a reliable measure of stigmatization must be created. The overarching goal of this research is to develop and validate the Tourette Discrimination-Stigmatization (TD-STIGMA) Scale. Methods: This paper presents the study protocol for developing and validating the TD-STIGMA Scale. The study is designed as a mixed methods study to develop the TD-STIGMA scale and evaluate its psychometric properties. The study uses a phased approach: (1) collection of narrative and thematic content data through in-depth qualitative interviews of stakeholders, (2) development of a novel TD-STIGMA self-report scale using the Delphi Method based on these results, and (3) completion of analyses to determine the scale's psychometric properties (confirmatory factor analysis, convergent, known-group, criterion validity, and test-retest reliability). Discussion: This project will result in a personalized approach to stigma measurement about youth and young adults with Persistent Tic Disorders, which to date does not exist. There are several limitations. Comorbidities or spiritual or cultural beliefs may affect perceptions of stigma and are not directly assessed in this study. We will utilize institutional resources for community outreach to purposefully sample underrepresented minorities who may be at disproportionate risk of adverse outcomes. However, this may not be fully representative of the generalized tic population. The study team will be purposeful in maintaining participant engagement for study retention. Lastly, participants from a tertiary referral center may not fully represent the generalized tic community. However, we hope our broad recruitment strategy and virtual study visits will facilitate a diverse and inclusive sampling of the patient population.

Response Rate and Molecular Correlates to Encorafenib and Binimetinib in BRAF-V600E Mutant High-Grade Glioma.

PURPOSE: Although fewer than 5% of high-grade gliomas (HGG) are BRAF-V600E mutated, these tumors are notable as BRAF-targeted therapy shows efficacy for some populations. The purpose of this study was to evaluate response to the combination of encorafenib with binimetinib in adults with recurrent BRAF-V600-mutated HGG. PATIENTS AND METHODS: In this phase 2, open-label, Adult Brain Tumor Consortium (ABTC) trial (NCT03973918), encorafenib and binimetinib were administered at their FDA-approved doses continuously in 28-day cycles. Eligible patients were required to have HGG or glioblastoma with a BRAF-V600E alteration that was recurrent following at least one line of therapy, including radiotherapy. RESULTS: Five patients enrolled between January 2020 and administrative termination in November 2021 (due to closure of the ABTC). Enrolled patients received treatment for 2 to 40 months; currently one patient remains on treatment. Centrally determined radiographic response rate was 60%, with one complete response and two partial responses. Methylation profiling revealed that all tumors cluster most closely with anaplastic pleomorphic xanthoastrocytoma (PXA). Transcriptional profile for MAPK-response signature was similar across all tumors at baseline and did not correlate with response in this small population. Circulating tumor DNA measured in plasma samples before treatment, during response, and upon progression showed feasibility of detection for the BRAF-V600E alteration. No new safety signal was detected. CONCLUSIONS: Encorafenib and binimetinib exhibit positive tumor responses in patients with recurrent BRAF-V600E mutant HGG in this small series, warranting therapeutic consideration. Although toxicity remains a concern for BRAF-targeted therapies, no new safety signal was observed in these patients.

A structured, journal-led peer-review mentoring program enhances peer review training.

BACKGROUND: Peer review is essential to the advancement of knowledge. However, training on how to conduct peer review is limited, unorganized, and not well studied. Thus, we sought to determine if a structured mentored peer-review program improved peer review training as measured by multiple quantitative and qualitative assessments. METHODS: This pre-post intervention study enrolled 55 mentees across 5 cohorts from 2020 to 2023. Each cohort completed pre-program evaluations, participated in 2 mentored reviews, and completed post-program evaluations over 6 months. Mentors and mentees completed pre-program demographic and review experience questionnaires. Outcome measures included (1) total and sub-scores on the modified Review Quality Index (mRQI) applied to the same pre-selected research manuscript reviewed by mentees both pre and post intervention, (2) mentee self-perceived comfort with and understanding of the review process using a custom questionnaire, and (3) mentor satisfaction surveys. Pre- and post-program measures were compared using the Wilcoxon signed-rank test. RESULTS: Post-program total modified RQI score (median (IQR) = 31 (26.3-35.8)) was higher than pre-program total score (26.6 (19.7-29.7)) for the 42 mentees who completed both pre- and post-program reviews. Mentees reported improved perception of review (median (IQR) pre = 4 (3-4), post = 5 (4-5)) and editorial processes (pre = 3 (2-4), post = 4 (4-5)) as well as self-perceived confidence in completing an independent review of both scientific (median (IQR) pre = 2 (2-3), post = 4 (4-4)) and non-scientific (pre = 3 (2-4), post = 4 (4-5)) manuscripts following program participation. p < 0.0001 for all scores noted. Mentors reported high scores for enjoyment (median (range) 5/5 (3-5)) and interest in repeat participation (5/5 (2-5)). CONCLUSIONS: A 6-month structured mentored-review program including 2 mentored reviews improves peer review training as measured by the modified RQI as well as participant self-perceived understanding of publication science with high mentor satisfaction.

Contributions of neuroimmune interactions to chemotherapy-induced peripheral neuropathy development and its prevention/therapy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating sequela that is difficult for both clinicians and cancer patients to manage. Precise mechanisms of CIPN remain elusive and current clinically prescribed therapies for CIPN have limited efficacy. Recent studies have begun investigating the interactions between the peripheral and central nervous systems and the immune system. Understanding these neuroimmune interactions may shift the paradigm of elucidating CIPN mechanisms. Although the contribution of immune cells to CIPN pathogenesis represents a promising area of research, its fully defined mechanisms have not yet been established. Therefore, in this review, we will discuss (i) current shortcoming of CIPN treatments, (ii) the roles of neuroimmune interactions in CIPN development and (iii) potential neuroimmune interaction-targeting treatment strategies for CIPN. Interestingly, monocytes/macrophages in dorsal root ganglia; microglia and astrocytes in spinal cord; mast cells in skin; and Schwann cell near peripheral nerves have been identified as inducers of CIPN behaviors, whereas T cells have been found to contribute to CIPN resolution. Additionally, nerve-resident immune cells have been targeted as prevention and/or therapy for CIPN using traditional herbal medicines, small molecule inhibitors, and intravenous immunoglobulins in a preclinical setting. Overall, unveiling neuroimmune interactions associated with CIPN may ultimately reduce cancer mortality and improve cancer patients' quality of life.

Interest and Satisfaction of Telemedicine Use Among Ambulatory Neurology Patients in Western North Carolina During the COVID-19 Pandemic.

Introduction: During the COVID-19 pandemic, care shifted from exclusively telemedicine to hybrid models with in-person, video, and telephone visits. We explored how patient satisfaction and visit preferences have changed by comparing in-person versus virtual visits (telephone and video) in an ambulatory neurology practice across three time points. Methods: Patients who completed a virtual visit in March 2020 (early-pandemic), May 2020 (mid-pandemic), and March 2021 (later-pandemic) were contacted. Patients were assessed for visit satisfaction and desire for future telemedicine. Univariate and multivariable logistic regression analysis was conducted to determine factors independently associated with video visit completion. Results: Four thousand seven hundred seventy-eight the number of ambulatory visits (n = 4,778) were performed (1,004 early; 1,265 mid; and 2,509 later); 1,724 patients (36%) assented to postvisit feedback; mean age 45.8 ± 24.4 years, 58% female, 79% white, and 56% with Medicare/Medicaid insurance. Patient satisfaction significantly increased (73% early, 79% mid, 81% later-pandemic, p = 0.008). Interest in telemedicine also increased for patients completing telephone visits (40% early, 50% mid, 59% later, p = 0.027) and video visits (52% early, 59% mid, 62% later, p = 0.035). Patients satisfied with telemedicine visits were younger (p < 0.001). White patients were more interested in future telemedicine (p = 0.037). Multivariable analysis showed that older patients (for each 1 year older), Black patients, and patients with Medicare/Medicaid were 2%, 45%, and 54% less likely to complete a video visit than telephone, respectively. Discussion: Patients, especially younger ones, have become more satisfied and more interested in hybrid care models during the COVID-19 pandemic. Barriers to conducting video visits persist for older, Black patients with Medicare or Medicaid insurance.

Be in the Digital Room Where it Happens, Part II: Social Media for Neurology Educators.

Social media has changed the way we communicate and interact. Unsurprisingly, it has also changed how we teach and learn. Younger generations of learners have transitioned from traditional educational sources to digital ones. Medical educators need to adapt to trends in medical education and develop fluency in the digital methods used by medical learners today. This is part two of a two-part series on social media and digital education in neurology. This article provides an overview of how social media can be used as a teaching tool in medical education and provides an overview in which it is grounded. We offer practical strategies on how social media can promote lifelong learning, educator development, educator support, and foster educator identity with accompanying neurology-specific examples. We also review considerations for incorporating social media into teaching and learning practices and future directions for integrating these tools in neurology education.

Pearls & Oy-sters: Case of Atypical Peripheral Nerve Findings Following Paclitaxel for Breast Cancer.

Neuromuscular ultrasound (NMUS) is a valuable tool in establishing a diagnosis of carpal tunnel syndrome (CTS) and can be particularly helpful in patients with clinical CTS but normal nerve conduction studies (NCSs). This case involves the uncommon presentation of enlarged median nerves on NMUS with normal NCS in a patient with breast cancer who developed chemotherapy-induced peripheral neuropathy and CTS after taxane treatment. This case demonstrates that CTS should not be excluded based on electrodiagnostic studies alone, and comorbid CTS should be considered in patients receiving neurotoxic chemotherapy, even in the setting of normal NCS.

Collagen deposition within brain metastases is associated with leptomeningeal failure after cavity-directed radiosurgery.

Background: Leptomeningeal failure (LMF) represents a devastating progression of disease following resection of brain metastases (BrM). We sought to identify a biomarker at time of BrM resection that predicts for LMF using mass spectrometry-based proteomic analysis of resected BrM and to translate this finding with histochemical assays. Methods: We retrospectively reviewed 39 patients with proteomic data available from resected BrM. We performed an unsupervised analysis with false discovery rate adjustment (FDR) to compare proteomic signature of BrM from patients that developed LMF versus those that did not. Based on proteomic analysis, we applied trichrome stain to a total of 55 patients who specifically underwent resection and adjuvant radiosurgery. We used competing risks regression to assess predictors of LMF. Results: Of 39 patients with proteomic data, FDR revealed type I collagen-alpha-1 (COL1A1, P = .045) was associated with LMF. The degree of trichrome stain in each block correlated with COL1A1 expression (ß = 1.849, P = .001). In a cohort of 55 patients, a higher degree of trichrome staining was associated with an increased hazard of LMF in resected BrM (Hazard Ratio 1.58, 95% CI 1.11-2.26, P = .01). Conclusion: The degree of trichrome staining correlated with COL1A1 and portended a higher risk of LMF in patients with resected brain metastases treated with adjuvant radiosurgery. Collagen deposition and degree of fibrosis may be able to serve as a biomarker for LMF.

Comparative effectiveness study of flipped classroom versus online-only instruction of clinical reasoning for medical students.

CONTEXT: Bedside clinical teaching is the backbone of clerkship education. Data-driven methods for supplementing bedside encounters with standardized content from vetted resources are needed. OBJECTIVE: To compare a flipped-classroom versus an interactive online-only instruction for improving knowledge, skills, self-directed learning (SDL) behaviors, and satisfaction in a medical school clerkship. METHODS: An IRB-approved prospective study employing a peer-reviewed clinical reasoning curriculum in neurology was conducted; 2nd-4th year medical students rotating through a required clerkship were enrolled. Students were randomized to flipped-classroom (i.e., flipped) or interactive asynchronous online instruction (i.e., online-only), which supplemented existing bedside teaching. Baseline and end-of-course knowledge, skill development, SDL behaviors, satisfaction, and long-term retention were assessed by peer-reviewed clinical reasoning exam, NBME scores, faculty/resident clinical evaluations, non-compulsory assignment completion, end-of-clerkship surveys, and objective structured clinical exam (OSCE). RESULTS: 104 students (49 flipped, 55 online-only) were enrolled. Age, gender, and training level did not differ by group (all p > 0.43); baseline knowledge was higher in the flipped group (p = 0.003). Knowledge-based exam scores did not differ by group even after adjusting for differences in baseline knowledge (2.3-points higher in flipped group, 95%CI -0.4-4.8, p = 0.07). Clinical skills were significantly higher in the flipped group, including examination skills (4.2 ± 0.5 vs. 3.9 ± 0.7, p = 0.03) and future housestaff potential (4.8 ± 0.3 vs 4.5 ± 0.6, p = 0.03). Students in the online-only group were more likely to engage in SDL (42 vs. 12%, p = 0.001) and reported more hours studying (6.1 vs. 3.8 hours, p = 0.03). Satisfaction (p = 0.51) and OSCE scores (p = 0.28) were not different by group. CONCLUSIONS: In this comparative study of two evidence-based curricular delivery approaches, we observed no difference in knowledge acquired. Greater clinical skills were observed with flipped instruction, while more SDL was observed with online-only instruction. Supplementing bedside teaching with blended instruction that balances live skill development with vetted online resources is optimal for clerkship education.

Characterizing the Impact of Clinical Exposure to Patients with Opioid Use Disorder on Medical Students' Perceptions of Stigma and Patient Care.

PHENOMENON: Opioid use disorder (OUD) is a growing public health crisis. Many residents and physicians do not feel comfortable working with patients with OUD. Social stigma promotes negative attitudes toward these patients and is a roadblock to delivering equitable and effective care. This study sought to (1) characterize medical students' experiences with patients with OUD, (2) understand the features that make a patient encounter memorable, (3) explore factors that influence future practice, and (4) describe the influence on stigma toward patients with OUD. Approach: A study was conducted using qualitative descriptive theory and purposive sampling of fourth-year medical students (M4s) enrolled at Wake Forest School of Medicine (WFSOM). Data collection consisted of a free-text question as a part of a larger survey to M4s in the Class of 2019 and 2020, followed by semi-structured interviews. The goal of the survey was to gain a broad understanding of student encounters with patients with OUD. The goal of the interviews was to gain a deeper understanding of the impact of these encounters on future practice and stigma. Thematic analysis was used to analyze all data. Findings: One-hundred-seventy out of 237 students (RR = 71.7%) completed the free text question describing a memorable encounter with a patient with OUD. Twelve students then completed interviews. Patient encounters occurred in three primary settings: Emergency department, inpatient clerkship, or Intensive Outpatient Program (IOP) meetings during psychiatry clerkship. Clinical encounters were memorable when there was: (1) conflict with patients or teams, (2) complicated care, (3) inadequate care, and (4) relevance to the student's future career. Memorable encounters influenced future practice by changing students' approaches to: (1) future treatment, (2) future communication, or (3) allowing students to practice professionalism. Regarding opioid stigma, students reported that these encounters made them: (1) more aware of stereotypes in medicine, (2) stereotypes in their personal lives, and (3) generated actions that students want to take in the future. Insights: A single, influential clinical encounter has the potential to substantially influence medical students' approach to patients with OUD, including both clinical management and attitudes toward care. Affecting encounters increased knowledge of OUD and fostered empathy and perspective-taking. Not all encounters had a defining impact on students' stigma toward OUD. Medical schools need to create opportunities that will have lasting impact by encouraging students to fully engage with patients with OUD.Supplemental data for this article is available online at https://doi.org/10.1080/10401334.2022.2038175 .

A Review on the Surgical Management of Insular Gliomas.

The surgical treatment of insular gliomas requires specialized knowledge. Over the last three decades, increased momentum in surgical resection of insular gliomas shifted the focus from one of expectant management to maximal safe resection to establish a diagnosis, characterize tumor genetics, treat preoperative symptoms (i.e., seizures), and delay malignant transformation through tumor cytoreduction. A comprehensive review of the literature was performed regarding insular glioma classification/genetics, insular anatomy, surgical approaches, and patient outcomes. Modern large, published series of insular resections have reported a median 80% resection, 80% improvement in preoperative seizures, and postsurgical permanent neurologic deficits of less than 10%. Major complication avoidance includes recognition and preservation of eloquent cortex for language and respecting the lateral lenticulostriate arteries.

A transformer-based deep-learning approach for classifying brain metastases into primary organ sites using clinical whole-brain MRI images.

Treatment decisions for brain metastatic disease rely on knowledge of the primary organ site and are currently made with biopsy and histology. Here, we develop a deep-learning approach for accurate non-invasive digital histology with whole-brain magnetic resonance imaging (MRI) data. Contrast-enhanced T1-weighted and fast spoiled gradient echo brain MRI exams (n = 1,582) were preprocessed and input to the proposed deep-learning workflow for tumor segmentation, modality transfer, and primary site classification into one of five classes. Tenfold cross-validation generated an overall area under the receiver operating characteristic curve (AUC) of 0.878 (95% confidence interval [CI]: 0.873,0.883). These data establish that whole-brain imaging features are discriminative enough to allow accurate diagnosis of the primary organ site of malignancy. Our end-to-end deep radiomic approach has great potential for classifying metastatic tumor types from whole-brain MRI images. Further refinement may offer an invaluable clinical tool to expedite primary cancer site identification for precision treatment and improved outcomes.

Immersion bioprinting of hyaluronan and collagen bioink-supported 3D patient-derived brain tumor organoids.

Organoids, and in particular patient-derived organoids, have emerged as crucial tools for cancer research. Our organoid platform, which has supported patient-derived tumor organoids (PTOs) from a variety of tumor types, has been based on the use of hyaluronic acid (HA) and collagen, or gelatin, hydrogel bioinks. One hurdle to high throughput PTO biofabrication is that as high-throughput multi-well plates, bioprinted volumes have increased risk of contacting the sides of wells. When this happens, surface tension causes bioinks to fall flat, resulting in 2D cultures. To address this problem, we developed an organoid immersion bioprinting method-inspired by the FRESH printing method-in which organoids are bioprinted into support baths in well plates. The bath-in this case an HA solution-shields organoids from the well walls, preventing deformation. Here we describe an improvement to our approach, based on rheological assessment of previous gelatin baths versus newer HA support baths, combined with morphological assessment of immersion bioprinted organoids. HA print baths enabled more consistent organoid volumes and geometries. We optimized the printing parameters of this approach using a cell line. Finally, we deployed our optimized immersion bioprinting approach into a drug screening application, using PTOs derived from glioma biospecimens, and a lung adenocarcinoma brain metastasis. In these studies, we showed a general dose dependent response to an experimental p53 activator compound and temozolomide (TMZ), the drug most commonly given to brain tumor patients. Responses to the p53 activator compound were effective across all PTO sets, while TMZ responses were observed, but less pronounced, potentially explained by genetic and epigenetic states of the originating tumors. The studies presented herein showcase a bioprinting methodology that we hope can be used in increased throughput settings to help automate biofabrication of PTOs for drug development-based screening studies and precision medicine applications.

Be in the Digital Room Where it Happens, Part I: Tweeting & Technology for Career Development.

Social media has become a part of everyday life. It has changed the way we obtain and distribute information, connect, and interact with others. As the number of platforms and users grow, medical professionals have learned the value social media can have in education, research, advocacy, and clinical care initiatives. Platforms provide opportunities to network, build collaborations, and develop a reputation. This is part one of a two-part series. This article provides an overview on how social media can benefit professional career development for clinicians and researchers, as well as for advocacy to raise awareness against biases, disparities, and for patient benefit. We review challenges, limitations, and best practices for social media use by medical professionals with neurology-specific examples.

Efficacy of laser interstitial thermal therapy (LITT) for newly diagnosed and recurrent IDH wild-type glioblastoma.

Background: Treatment options for unresectable new and recurrent glioblastoma remain limited. Laser ablation has demonstrated safety as a surgical approach to treating primary brain tumors. The LAANTERN prospective multicenter registry (NCT02392078) data were analyzed to determine clinical outcomes for patients with new and recurrent IDH wild-type glioblastoma. Methods: Demographics, intraprocedural data, adverse events, KPS, health economics, and survival data were prospectively collected and then analyzed on IDH wild-type newly diagnosed and recurrent glioblastoma patients who were treated with laser ablation at 14 US centers between January 2016 and May 2019. Data were monitored for accuracy. Statistical analysis included individual variable summaries, multivariable differences in survival, and median survival numbers. Results: A total of 29 new and 60 recurrent IDH wild-type WHO grade 4 glioblastoma patients were treated. Positive MGMT promoter methylation status was present in 5/29 of new and 23/60 of recurrent patients. Median physician-estimated extent of ablation was 91%-99%. Median overall survival (OS) was 9.73 months (95% confidence interval: 5.16, 15.91) for newly diagnosed patients and median post-procedure survival was 8.97 months (6.94, 12.36) for recurrent patients. Median OS for newly diagnosed patients receiving post-LITT chemo/radiation was 16.14 months (6.11, not reached). Factors associated with improved survival were MGMT promoter methylation, adjuvant chemotherapy within 12 weeks, and tumor volume <3 cc. Conclusions: Laser ablation is a viable option for patients with new and recurrent glioblastoma. Median OS for IDH wild-type newly diagnosed glioblastoma is comparable to outcomes observed in other tumor resection studies when those patients undergo radiation and chemotherapy following LITT.

A comparison of telemedicine and in-person neurology visits: what are the factors that patients consider when selecting future visit type?

OBJECTIVE: To identify factors that patients consider when choosing between future in-person, video, or telephone visits. BACKGROUND: Telemedicine has been rapidly integrated into ambulatory neurology in response to the COVID-19 pandemic. METHODS: Ambulatory neurology patients at a single center were contacted via telephone to complete: (1) a survey quantifying likelihood of scheduling a future telemedicine visit, and (2) a semi-structured qualitative interview following their visit in March 2021. Data were processed using the principles of thematic analysis. RESULTS: Of 2493 visits, 39% assented to post-visit feedback; 74% were in-person visits and 13% video and telephone. Patients with in-person visits were less likely than those with video and telephone visits to "definitely" consider a future telemedicine visit (36 vs. 59 and 62%, respectively; p < 0.001). Patients considered five key factors when scheduling future visits: "Pros of Visit Type," "Barriers to Telemedicine," "Situational Context," "Inherent Beliefs," and "Extrinsic Variables." Patients with telemedicine visits considered convenience as a pro, while those with in-person visits cited improved quality of care. Accessibility and user familiarity were considered barriers to telemedicine by patients with in-person and telephone visits, whereas system limitations were prevalent among patients with video visits. Patients agreed that stable conditions can be monitored via telemedicine, whereas physical examination warrants an in-person visit. Telemedicine was inherently considered equivalent to in-person care by patients with telephone visits. Awareness of telemedicine must be improved for patients with in-person visits. CONCLUSION: Across visit types, patients agree that telemedicine is convenient and effective in many circumstances. Future care delivery models should incorporate the patient perspective to implement hybrid models where telemedicine is an adjunct to in-person visits in ambulatory neurology.

Methods and protocols for chemotherapy-induced peripheral neuropathy (CIPN) mouse models using paclitaxel.

While cancer patients may have chemotherapeutics to thank for being cured of their malignancy, they are often left to suffer a disabling neuropathy induced by that same cancer treatment. This neuropathy, known as chemotherapy-induced peripheral neuropathy, or CIPN, is one of the most debilitating survivorship concerns for patients, with many citing hallmark symptoms of hyperalgesia, allodynia, and numbness, and subsequently reducing their dose or even ceasing treatment altogether. Investigations into this interplay between the antineoplastic activity of chemotherapeutic agents and the preservation of peripheral nerve health are therefore crucial for the development of CIPN treatment and prevention methods. Responding to need, current literature is inundated with varying preclinical models of CIPN. This chapter thus seeks to provide a detailed and reliable methodology for the induction and assessment of CIPN in mice, using a preclinical model that is both reproducible and translatable to several aspects of the clinical phenotype. Specifically, this chapter lays out a model for intermittent low-dose paclitaxel induction of CIPN in C57BL/6J mice, and a testing of this induction via von Frey filament mechanical hypersensitivity assays, a mechanical hyposensitivity (numbness) assay, and a cold-thermal allodynia assay (acetone test). These protocols can easily be adjusted to fit the needs of individual CIPN experiments, as stated throughout the chapter.