Faculty Bibliography

This practice guideline provides updated evidence-based recommendations regarding the use of pharmacologic migraine prevention in adults. A multidisciplinary panel conducted a systematic review and developed practice recommendations following the process outlined in the 2017 edition of the American Academy of Neurology Clinical Practice Guideline Process Manual. The systematic review includes studies published through June 6, 2024, and is available in a companion publication. Recommendations are supported by structured rationales that integrate evidence from the systematic review, related evidence, principles of care, and inferences from evidence. Recommendations are provided on how to decide when it is appropriate to start a pharmacologic migraine preventive medication and how to decide which migraine preventive medication to start. Recommendations address decision making on appropriate choices of migraine preventive medications in specific situations and populations, including patients with fibromyalgia, obesity, or hypertension; considerations for older adults; treatment during pregnancy and lactation; sex-related factors in choosing medications; and treatment for patients with medication overuse. Recommendations on assessment of treatment efficacy, adverse effects, and discontinuing migraine preventive medications are provided.

BACKGROUND/AIM/OBJECTIVE:-defined 32-gene Ewing Sarcoma Specific Signature (ESS32) into a practical target atlas by integrating tumor RNA expression with normal-tissue context, protein evidence, subcellular localization, and therapeutic accessibility. MATERIALS AND METHODS/METHODS:-skeletal-muscle comparison, broad normal-organ context, EWSR1::FLI1 perturbation, tumor-only support cohorts, cell-line models, and cross-sarcoma comparison. Results were overlaid with Human Protein Atlas and published proteomic/surfaceome evidence. RESULTS:In GSE17674, the strongest tumor-enriched transcripts included NKX2-2, NPY1R, STEAP1, RBM11, RNF182, LIPI, CD99, STEAP2, LOXHD1, and DCDC2. Normal-tissue and compartment data substantially reordered RNA-only ranking. NKX2-2 showed the strongest Ewing-associated signal but encodes a nuclear transcription factor, favoring peptide-HLA/T-cell receptor (TCR) or vaccine development. RBM11 and LIPI emerged as high-interest intracellular/secretome-associated candidates, with an explicit epididymal/male reproductive caveat for LIPI. CD99 and NPY1R illustrated normal-cell reservoir and receptor-distribution constraints. CONCLUSION/CONCLUSIONS:ESS32 should be interpreted as an EWSR1::FLI1-associated RNA discovery set, not as a pre-validated target panel. Practical nomination requires integration of RNA enrichment, normal-tissue distribution, protein evidence, cellular compartment, and modality compatibility before nomination of TCR, vaccine, antibody-drug conjugate (ADC), chimeric antigen receptor (CAR), radioligand, or validation-first candidates.

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.

Ketogenic diet (KGD) combined with ketamine (KET) suppresses food restriction-evoked hyperactivity in activity-based anorexia (ABA) mouse model of anorexia nervosa (AN) for more than 28 days, thereby improving weight retention and reducing anxiety, even after mice return to standard diet (SD) and are re-challenged with ABA (KGD + KET → SD, "KET + KGD group"). Suppression of these AN-like behavior is not sustained in mice fed KGD without KET (KGD → SD, "KGD-only group"). We hypothesized that the sustained efficacy of KET + KGD is associated with altered prevalence of certain synapses in the dorsal hippocampus that influence behavior. We compared the prevalence of excitatory and inhibitory synapses between KET + KGD (N = 7) versus KGD-only (N = 7) groups, using electron microscopy and GAD immunolabeling to distinguish GABAergic inhibitory synapses from non-GABAergic excitatory synapses. Pyramidal cell layer (PCL) was analyzed to assess the contribution by parvalbumin + subtype of GABAergic neurons known to reside there, while stratum lacunosum-molecular (SLM) was analyzed to assess inhibition by non-PV + GABAergic neurons known to reside there. In both PCL and SLM, the KET + KGD group exhibited greater correlation between GABAergic inhibition of PNs and weight retention. In SLM of the KET + KGD group, the areal density of excitatory synapses was less. Inhibitory synapses onto GABAergic dendrites (disinhibition which may also augment excitability) correlated negatively with hyperactivity for the KET + KGD group only. KET + KGD, but not KGD-only, may sustain ABA resilience by enhancing plasticity of both glutamatergic and GABAergic synapses. This jointly sustained plasticity underlying hippocampal excitability may be the cellular bases for KET + KGD treatment's suppression of AN relapses.

OBJECTIVE:To quantify general population prevalence, and differences by sex and BMI, in ultrasound (US) features of knee osteoarthritis (KOA), patient-reported knee symptoms (Ksx), radiographic KOA (rKOA), and symptomatic KOA (sxKOA). METHODS:Participants from the Johnston County Health Study (2019-2024; n=902) provided demographic, clinical, and imaging data. Ksx was defined as self-reported pain, aching or stiffness on most days of any one month in the past 12 months. rKOA was defined as Kellgren-Lawrence grade ≥2 (or total knee replacement (TKR)), severe rKOA as grades 3-4 (or TKR), and sxKOA as rKOA and Ksx in the same knee. Standardized US scoring was performed as previously reported. Weighted prevalence estimates and 95% confidence intervals (CI) for Ksx, rKOA, sxKOA, severe rKOA, and US features were calculated overall and by sex and BMI category. RESULTS:Among 902 participants (67% female; 66% non-Hispanic white, mean age 55 years, and BMI 33 kg/m²), the weighted prevalence of Ksx, rKOA, sxKOA, and severe rKOA were 61%, 36%, 27%, and 21%, respectively, all higher (based on non-overlapping CIs) than baseline estimates from the Johnston County Osteoarthritis Project and other cohorts. Ksx, rKOA, sxKOA, and severe rKOA were higher among females and those with obesity. Compared to females with obesity, those with severe obesity had higher prevalence of all radiographic outcomes at moderate and severe grades with non-overlapping CI. US effusion and synovitis were more prevalent in males, whereas medial and lateral cartilage damage were more common in females. With increasing obesity, osteophytes and medial cartilage damage were more prevalent, while gryescale effusion was actually less frequent. CONCLUSION/CONCLUSIONS:KOA prevalence continues to increase in the population. Sex and BMI differences in KOA prevalence and US features were most pronounced among females with severe obesity. Distinguishing between sexes and by obesity levels may improve understanding of KOA mechanisms and guide tailored prevention and treatment strategies.

INTRODUCTION/UNASSIGNED:Older adults with chronic kidney disease (CKD) likely face higher dementia risk because of vascular injury and chronic inflammation, potentially intensified among racially minoritized groups and those in rural or deprived neighborhoods. We quantified this association and examined variation by race and ethnicity, urbanicity, and neighborhood deprivation. METHODS/UNASSIGNED:We identified 211,321 older adults with CKD stages 3 to 5 from the Medicare 5% sample (2010-2022) using International Classification of Diseases (ICD)-9 and/or ICD-10 codes. Zone Improvement Plan (ZIP)-code level urbanicity was defined using Rural-Urban Commuting Area Codes, and neighborhood deprivation was derived from the American Community Survey. We used cause-specific hazard models with time-varying CKD stage (reference = stage 3) to quantify the adjusted hazard ratio (aHR) of dementia and included interaction terms to test the differential effect of these associations by race and/or ethnicity, urbanicity, and neighborhood deprivation. RESULTS/UNASSIGNED:= 0.04). Among older Black (stage 4 aHR: 1.38, 95% CI: 1.28-1.48; stage 5 aHR: 2.01, 95% CI: 1.88-2.15) and Hispanic adults (stage 4 aHR: 1.33, 95% CI: 1.10-1.62; stage 5 aHR: 1.98, 95% CI: 1.67-2.34), stages 4 and 5 were associated with a higher risk of dementia. Among older adults in high-deprivation neighborhoods, stage 5 was associated with a higher risk of dementia (aHR: 1.89, 95% CI: 1.80-1.99). CONCLUSION/UNASSIGNED:CKD stages 4 and 5 were associated with a higher dementia risk, particularly among older Black adults and those in high-deprivation neighborhoods. These findings may inform targeted interventions for early detection and management of cognitive decline in advanced CKD.

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.

The outcomes of patients transferred to receiving centers who subsequently undergo robotic EGS remain uncharacterized at a national level. We aimed to quantify the association between transfer and outcomes among adults undergoing robotic EGS. We performed a retrospective cohort study of the Nationwide Readmissions Database (2016-2019) including adult nonelective admissions undergoing robotic EGS. Interhospital transfer versus direct admission was the exposure. Survey-weighted logistic regression estimated adjusted odds ratios (aOR) for clinical outcomes; generalized linear models with gamma family and log link estimated adjusted mean ratios (aMR) for length of stay (LOS) and cost. Average marginal effects provided adjusted risks/means and absolute differences. Among 26,869 unweighted robotic EGS admissions, representing an estimated 46,517 admissions nationally, 246 unweighted admissions were interhospital transfers, representing an estimated 444 transfers (1.0%) nationally. Transfers were older, more comorbid, and more severely ill and were treated predominantly at large, teaching hospitals. After adjustment, transfer was associated with a higher risk of postprocedural complications (8.0% vs. 3.5%; aRR 2.26, 95% CI 1.25-3.27), non-home discharge (31.2% vs. 18.9%; aRR 1.65, 95% CI 1.38-1.92), longer LOS (11.49 vs. 5.53 days; AMR 2.08, 95% CI 1.78-2.42), and higher cost ($43,340 vs. $21,821; AMR 1.99, 95% CI 1.68-2.35). The association with postprocedural complications was attenuated after additional adjustment for APR-DRG Severity of Illness, whereas associations with non-home discharge, LOS, and cost persisted. Among patients undergoing robotic EGS, interhospital transfer is independently associated with higher complication burden and greater resource use. Transferred patients represent a small but distinctly high-risk subgroup whose worse outcomes may reflect drivers that extend beyond the choice of surgical approach.

BACKGROUND:Epstein-Barr virus (EBV) is a key environmental risk factor for multiple sclerosis (MS), and tonsils and adenoids serve as a primary viral reservoir. This study investigates the potential role of adenotonsillectomy in pediatric-onset multiple sclerosis (POMS) risk and relapse rate. OBJECTIVES/OBJECTIVE:status, were collected. Multivariable logistic regression assessed the association between adenotonsillectomy and MS risk. In addition, negative binomial regression offset by follow-up time was used to assess the relationship between adenotonsillectomy and relapse rate in POMS participants with available follow-up data. RESULTS: = 0.013). CONCLUSIONS:Prior adenotonsillectomy was associated with increased risk of MS and greater relapse rate in pediatric patients, suggesting a potential interplay between EBV, immune regulation, and MS pathogenesis.