Faculty Bibliography

BACKGROUND AND OBJECTIVES/OBJECTIVE:This systematic review (SR) provides updated evidence-based conclusions regarding the use of pharmacologic migraine prevention in adults to inform a new joint American Academy of Neurology (AAN) and American Headache Society practice guideline. METHODS:A multidisciplinary panel conducted an SR following the 2017 AAN Clinical Practice Guideline Process Manual. Randomized controlled trials evaluating pharmacologic preventive treatments for adults with episodic or chronic migraine were included. Searches encompassed MEDLINE, Embase, and ClinicalTrials.gov from database inception through June 6, 2024. Studies were screened in duplicate, with dual independent risk-of-bias assessment. Outcomes included change in monthly headache days, ≥50% responder rate, and validated patient-reported quality of life (QOL) measures. Raw mean differences, standardized mean differences, and risk ratios were calculated. A modified Grading of Recommendations Assessment, Development, and Evaluation process was used to classify certainty of evidence. RESULTS:A total of 217 studies met inclusion criteria. For episodic migraine, high-confidence evidence showed that galcanezumab and erenumab are more effective than placebo in reducing headache frequency. Moderate-confidence evidence supported benefit from atogepant, eptinezumab, fremanezumab, propranolol, topiramate, and valproate. Several additional oral agents including amitriptyline, bisoprolol, flunarizine, fluoxetine, levetiracetam, metoprolol, nifedipine, pizotifen, and telmisartan had low-confidence evidence suggesting possible benefit. For chronic migraine, high-confidence evidence supported reductions in headache frequency with fremanezumab, galcanezumab, and onabotulinumtoxinA. Moderate-confidence evidence supported benefit from atogepant, eptinezumab, erenumab, topiramate and valproate. Across both episodic and chronic migraine populations, erenumab, fremanezumab, galcanezumab, eptinezumab, rimegepant, atogepant, topiramate and onabotulinumtoxinA demonstrated improvements in patient-reported QOL outcomes on validated instruments. Evidence comparing active treatments was limited and generally of low or very low confidence, restricting conclusions about comparative effectiveness. DISCUSSION/CONCLUSIONS:This SR provides a comprehensive synthesis of evidence on pharmacologic migraine prevention in adults. High- and moderate-confidence findings confirm the efficacy of several established and newer preventive therapies and demonstrate improvements in patient-reported outcomes across multiple validated measures. These conclusions informed the development of evidence-based recommendations, presented in a companion publication, to guide clinicians in selecting preventive medications for adults with episodic and chronic migraine.

Chromatin-modifying complexes are critical in gene regulation, yet their proposed interactions with RNA remain poorly understood. Counter to prior models of specific recruitment, we find that WDR5, an essential subunit of the MLL1/KMT2A histone methyltransferase complex, binds RNA promiscuously. Using a stringent approach, we demonstrate that WDR5 directly engages a diverse pool of cellular RNAs, dictated primarily by RNA abundance rather than specific motifs. Equilibrium binding assays show that RNA length, rather than sequence, governs high affinity. WDR5 binds to RNA through multiple surfaces, some of which overlap with MLL1 complex subunit interfaces. Strikingly, we find that RNA binding disrupts the MLL1 complex by competitively displacing WDR5 from these critical protein-protein interactions, leading to a marked inhibition of MLL1 catalytic activity. Further experiments in human cell lines suggest that this disassembly mechanism may operate to homeostatically downregulate MLL1 complex activity, thereby integrating transcriptional activity with chromatin state.

The human sodium-citrate cotransporter NaCT imports various tri- and di-carboxylates into the cell as TCA cycle intermediates. This substrate uptake process is driven by an inward sodium gradient. The protein is a member of the divalent anion-sodium symporter (DASS) family. Whereas extensive biochemical and structural studies have been carried out for NaCT, how the substrate binding and translocation is coupled to the sodium gradient remains unclear. Here using single particle cryo-electron microscopy, we determined the structures of the human NaCT protein in three states: sodium-free, in the presence of sodium, and bound to sodium and a substrate mimicking inhibitor. These structures suggest a simultaneous binding mechanism for sodium-substrate coupling, distinct from the sequential binding, conformational selection mechanism previously observed for the bacterial DASS protein VcINDY.

Autistic individuals face an increased risk of experiencing traumatic events and of being significantly affected by them, whether these events are life-threatening or social in nature. Emotion regulation (ER) difficulties are central to both conditions, yet their role in this neuropsychiatric co-occurrence remains under-researched. This study examined ER's mediating role in the association between autism and posttraumatic stress symptoms (PTSS). Participants included 68 autistic and 101 nonautistic adults who completed the PCL-5 regarding life-threatening and social triggers, alongside the Difficulties in Emotion Regulation Scale (DERS) and a sociodemographic questionnaire. Autistic adults reported significantly higher PTSS following both event types and greater ER difficulties compared to controls. ER difficulties fully mediated the association between autism and PTSS for both life-threatening and social triggers. Specifically, the lack of emotional clarity subscale emerged as a distinct, significant mediator for both trauma types. These findings identify ER difficulties, particularly challenges understanding one's emotions, as a core mechanism linking autism and trauma-related distress. Trauma-focused interventions for autistic individuals should integrate modules enhancing emotional clarity to improve resilience and treatment outcomes.

Exposure to World Trade Center (WTC) dust following the September 11, 2001 attacks has been linked to numerous negative health outcomes in First Responders, including cognitive impairment disproportionately impacting First Responders with aging. However, the mechanisms underlying neurocognitive decline remain poorly characterized. This investigation examined the effects of WTC dust exposure on myelin integrity and neuroinflammatory signaling in twelve-week old male spontaneously hypertensive rats. To model Ground Zero exposure in First Responders, WTC dust was intratracheally administered for two consecutive days (2.43 [± 0.78] mg/day).  It was hypothesized that WTC dust exposure would enhance neuroinflammatory signaling and promote an earlier, progressive decline of myelin abundance. Rats were euthanized at 3 and 12 mo post-exposure. Changes in myelin abundance (Black-Gold II), myelin basic protein (MBP) and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase), and microglial responses (ionized calcium-binding protein; Iba1) were assessed through immunohistochemical staining, and cytokines were measured in brain homogenates. WTC dust exposure resulted in increased Black-Gold II staining at 3 mo despite no changes in MBP or CNPase. In contrast, microglial activation and IL-1β concentrations were elevated in dust-exposed rats at 12 mo. Collectively, these data suggest WTC dust exposure induces sustained neuroinflammatory signaling and may elicit a compensatory myelin response indicative of early neurodegeneration.

INTRODUCTION/BACKGROUND:The purpose of this case series is to investigate outcomes for repair of fractures of the scapular spine and acromial process following reverse total shoulder arthroplasty (RTSA). METHODS:All adult patients who were treated operatively for a stress scapular spine or acromial fracture following a RTSA at a single center between 2013 and 2024 were identified. All patients underwent operative repair with plate and screw fixation with or without adjunctive bone grafting. Data collected included patient demographics, injury characteristics, fracture classification, surgical details, radiographic findings, and clinical outcomes, which were based on chart review of follow-up visits and revision surgeries. RESULTS:Among 2006 RTSA procedures performed during the study period, 18 patients (0.9%) developed a scapular spine or acromial stress fracture, 16 (88.9%) of which required operative fixation. Mean follow-up after fixation was 23 months. The cohort included 11 women (68.8%) and 5 men (31.2%), with a mean age of 71.9 years. All fractures were attributed to an insufficiency mechanism. Bone graft or biologic augmentation was performed in 11 patients (68.8%). Following index fracture fixation, 10 patients (62.5%) developed a postoperative complication or adverse clinical outcome, including nonunion in 6 patients (37.5%), fracture-related infection in 2 patient (12.5%), subsequent secondary acromial stress fracture in 1 patient (6.2%), and glenoid component loosening with humeral component dislocation in 1 patient (6.2%). Nine patients (56.3%) underwent at least one additional surgical procedure, including 8 patients (50.0%) who required an unplanned reoperation; hardware removal was the most common subsequent procedure (7/16, 43.8%). At final follow-up, 5 patients (31.3%) reported chronic pain, 3 patients (18.8%) had persistent nonunion, and 3 patients (18.8%) had hardware failure managed nonoperatively. The number of plates used and implant positioning did not differ significantly between patients who achieved union and those who did not (p = 0.264). CONCLUSION/CONCLUSIONS:Scapular spine and acromial stress fractures following RTSA are uncommon but clinically consequential complications of reverse total shoulder arthroplasty. Standard operative fixation demonstrated a low rate of success after a single intervention, underscoring the need for alternative treatment strategies. LEVEL OF EVIDENCE/METHODS:Level IV.

BACKGROUND AND OBJECTIVES/OBJECTIVE:This systematic review (SR) provides updated evidence-based conclusions regarding the use of pharmacologic migraine prevention in adults to inform a new joint American Academy of Neurology (AAN) and American Headache Society practice guideline. METHODS:A multidisciplinary panel conducted an SR following the 2017 AAN Clinical Practice Guideline Process Manual. Randomized controlled trials evaluating pharmacologic preventive treatments for adults with episodic or chronic migraine were included. Searches encompassed MEDLINE, Embase, and ClinicalTrials.gov from database inception through June 6, 2024. Studies were screened in duplicate, with dual independent risk-of-bias assessment. Outcomes included change in monthly headache days, ≥50% responder rate, and validated patient-reported quality of life (QOL) measures. Raw mean differences, standardized mean differences, and risk ratios were calculated. A modified Grading of Recommendations Assessment, Development, and Evaluation process was used to classify certainty of evidence. RESULTS:A total of 217 studies met inclusion criteria. For episodic migraine, high-confidence evidence showed that galcanezumab and erenumab are more effective than placebo in reducing headache frequency. Moderate-confidence evidence supported benefit from atogepant, eptinezumab, fremanezumab, propranolol, topiramate, and valproate. Several additional oral agents including amitriptyline, bisoprolol, flunarizine, fluoxetine, levetiracetam, metoprolol, nifedipine, pizotifen, and telmisartan had low-confidence evidence suggesting possible benefit. For chronic migraine, high-confidence evidence supported reductions in headache frequency with fremanezumab, galcanezumab, and onabotulinumtoxinA. Moderate-confidence evidence supported benefit from atogepant, eptinezumab, erenumab, topiramate and valproate. Across both episodic and chronic migraine populations, erenumab, fremanezumab, galcanezumab, eptinezumab, rimegepant, atogepant, topiramate and onabotulinumtoxinA demonstrated improvements in patient-reported QOL outcomes on validated instruments. Evidence comparing active treatments was limited and generally of low or very low confidence, restricting conclusions about comparative effectiveness. DISCUSSION/CONCLUSIONS:This SR provides a comprehensive synthesis of evidence on pharmacologic migraine prevention in adults. High- and moderate-confidence findings confirm the efficacy of several established and newer preventive therapies and demonstrate improvements in patient-reported outcomes across multiple validated measures. These conclusions informed the development of evidence-based recommendations, presented in a companion publication, to guide clinicians in selecting preventive medications for adults with episodic and chronic migraine.

OBJECTIVE:To compare characteristics between men and women as they seek medical care for their urinary incontinence (UI), examining patients' experience both with primary care (PCP) and UI specialists. METHODS:This is a cross-sectional study utilizing the National Association for Continence (NAFC)-sponsored adult patient-reported survey data from March 2020 to April 2020. Descriptive statistics were calculated as percentages, and comparisons were performed using a chi-squared test for categorical variables. The statistical significance level was set at p < 0.05. RESULTS:Two hundred sixty-six individuals with UI who had sought medical care completed the survey during the study period. One hundred twenty-four (47%) were women (W) and 142 (53%) were men (M). The study population was older, with the majority of respondents either 45-64 (35%) or 65+ (48%). Most participants sought care for their UI within 2 years of UI onset (59%) and first spoke to their PCP about their UI (64.7%). Women were more likely to endorse a severe emotional impact (OR 1.63, CI 1.04-2.56, p = 0.04) and physical impact (OR 1.90, CI 1.19-3.04, p = 0.01) of their UI on their life. In patients who spoke to their PCP about their UI, women were more likely to bring it up at a routine checkup, while men were more likely to make an appointment to discuss their UI. Men were more likely to endorse that their PCP had spoken to them about a wide range of treatment options and were more likely to have been started on a treatment plan. Men were also more likely to be started on a medication for their UI by their PCP compared to women. PCP referral rates to specialty care were higher amongst men. For those who received a referral, there was a high rate of specialist follow-up (94.0% vs. 98.5% p = 0.19). Men were mostly referred to urology (W 47% vs. 94% M, p < 0.01), with women more frequently referred to gynecology (W 15.9% vs. 0% M, p < 0.01) and urogynecology (W 25.0% vs. 0.9% M, p < 0.01). Specialists were more likely to speak about absorbent products with men compared to women (M 52.5% vs. W 30.7%, p = 0.002). CONCLUSIONS:Though women endorsed more severe impact of UI on their life, men were more likely to be counseled on a wide range of treatment options, started on a treatment plan, prescribed medication for their UI, and be referred to specialty care for treatment of their UI. TRIAL REGISTRATION/BACKGROUND:This study was not registered with clinicaltrials.gov because it used previously collected, deidentified data. CLINICALTRIALS/RESULTS:gov indicates that observational studies should be registered as a Patient Registry for prospective data collection, which does not apply to this study as the patients included in this survey are not followed.

Primary elbow osteoarthritis is a functionally limiting condition, predominantly affecting middle-aged men engaged in repetitive manual labor, and is characterized by pain, stiffness, and mechanical symptoms. Evaluation involves a detailed history focusing on pain, loss of motion, and mechanical symptoms, followed by clinical examination for range of motion deficits, crepitus, and instability. Radiographic assessment, including standard radiographs and, when indicated, computed tomography imaging, is essential for staging disease severity, identifying osteophytes, capsular contracture, and joint space narrowing. Initial management is nonsurgical, emphasizing activity modification, NSAIDs, physical therapy, and intra-articular corticosteroid injections. When conservative measures fail, surgical options include arthroscopic or open débridement, osteocapsular arthroplasty, and procedures such as the Outerbridge-Kashiwagi technique. Both arthroscopic and open approaches reliably improve pain, range of motion, and functional scores, with low complication rates. However, open procedures may yield greater flexion gains in select cases. Nonarthroplasty options for primary elbow arthritis encompass a spectrum from conservative management to arthroscopic and open surgical débridement, with treatment tailored to disease severity, patient age, and functional demands.