Faculty Bibliography

IMPORTANCE/UNASSIGNED:Lyme disease (LD) is the most common vector-borne illness in the US. Given the increasing prevalence and expanding geographic bounds of LD, in-depth, up-to-date understanding of costs associated with an LD diagnosis, including patient out-of-pocket (OOP) costs, is needed. OBJECTIVE/UNASSIGNED:To assess health care costs in a broad US population diagnosed with LD, overall and stratified by localized disease vs disseminated disease. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This retrospective cohort study identified patients from Optum's deidentified Market Clarity Data (Optum Market Clarity) between December 2, 2014, and January 30, 2023 (study period), with an LD diagnosis between January 1, 2016, and December 31, 2022 (identification period), having at least 14 months of continuous health plan enrollment. Optum Market Clarity is an integrated, multisource medical claims, pharmacy claims, and electronic health records data set. Outpatients had a claim with an LD diagnosis plus relevant antibiotics within 30 days, and inpatients had a claim with LD as the primary diagnosis or as a secondary diagnosis with an LD-associated condition as the primary diagnosis. Data were analyzed from February 27, 2023, to October 20, 2025. EXPOSURE/UNASSIGNED:The main exposure was LD diagnosis. Case patients were classified as having disseminated, localized, or indeterminate LD based on diagnosis codes for LD and LD-associated conditions, inpatient vs outpatient services, or antibiotic treatment type. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Health care costs (reported in US dollars) for LD cases overall and stratified by localized disease vs disseminated disease were assessed 4 ways: (1) LD-specific costs per episode, (2) all-cause 6-month baseline vs follow-up costs for case patients with LD, (3) all-cause 6-month follow-up costs for case patients with LD compared with the control group, and (4) multivariable case-control analysis. Costs are reported as estimated direct (standardized) costs and patient OOP costs. Wald 95% CIs were used for means of cost measures. RESULTS/UNASSIGNED:A total of 70 531 case patients with LD were included. Their mean (SD) age was 44.8 (21.3) years; 51.3% were female. Estimated direct costs of LD were substantial across assessment methods, including episode cost (mean, $2227 [95% CI, $2111-$2342]), case patients as self-controls analysis (difference, $3304 [95% CI, $3117-$3491] in mean 6-month costs between baseline and follow-up), case-control analysis (difference, $4098 [95% CI, $3888-$4307] in mean 6-month follow-up costs), and multivariable-adjusted analysis (case-control difference, $5571 in projected mean 6-month follow-up costs; cost ratio, 1.96 [95% CI, 1.90-2.02]). OOP costs were available for 10 962 patients (15.5%) with LD. Mean OOP costs attributed to LD ranged from $188 to $399. Extrapolating to the US population in high-incidence states, annual costs of LD could range between $591 million and $1.05 billion (2022 dollars), with $411 to $771 million attributable to disseminated disease. CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this retrospective cohort study, LD presented a large financial burden to the health care system and patients, especially for those with disseminated disease. These findings highlight the need for effective preventive measures to reduce costs for patients and the health care system.

IMPORTANCE/UNASSIGNED:Treatment for cognitive dysfunction due to postacute sequelae of long COVID (ie, symptoms of fatigue, malaise, weakness, confusion that persist beyond 12 weeks after an initial COVID infection) remains a significant unmet need. OBJECTIVE/UNASSIGNED:To test evidence-based rehabilitation strategies for improving cognitive symptoms in persons with long COVID. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This was a 5-arm, multicenter, randomized clinical trial of 3 remotely delivered interventions conducted between August 17, 2023, and June 10, 2024. The study took place at 22 trial sites and included the screening of individuals with cognitive long COVID. INTERVENTIONS/UNASSIGNED:Participants were randomized to 1 of 5 arms: adaptive computerized cognitive training (BrainHQ [Posit Science]), cognitive-behavioral rehabilitation involving both group and individual counseling sessions (PASC-Cognitive Recovery [PASC-CoRE]) paired with BrainHQ, and transcranial direct current stimulation (tDCS) paired with BrainHQ. Two comparator arms were included as follows: unstructured computer puzzles and games (active comparator) and sham tDCS paired with BrainHQ. The interventions occurred 5 times per week over 10 weeks. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Cognitive and behavioral in-person assessments were performed at baseline, midintervention, at the end of intervention, and 3 months after the end of the intervention. The primary outcome measure was the modified Everyday Cognition Scale 2 (ECog2) completed at the end of the intervention compared to the baseline visit based on participant self-report looking back over the prior 7 days. RESULTS/UNASSIGNED:A total of 378 individuals were screened, from which there were 328 participants (median [IQR] age, 48.0 [37.0-58.0] years; 241 female [73.5%]; race: 15 Asian [4.6%], 47 Black [14.3%], and 235 White [71.6%]; ethnicity: 52 Hispanic [15.9%]). None of the 3 active interventions demonstrated benefits on the modified ECog2 in the intention-to-treat population by the end of the intervention period. The adjusted differences in mean change were 0.0 (95% CI, -0.2 to 0.2) for BrainHQ vs active comparator, 0.1 (95% CI, -0.1 to 0.3) for PASC-CoRE + BrainHQ vs active comparator, 0.0 (95% CI, -0.2 to 0.2) for tDCS-active + BrainHQ vs tDCS-sham + BrainHQ, and 0.1 (95% CI, -0.1 to 0.3) for PASC-CoRE + BrainHQ vs BrainHQ alone. Secondary participant-reported outcomes and neuropsychological tests showed no differential benefits for any treatment arm. All 5 arms demonstrated some improvements over time on the modified ECog2 and on secondary outcomes. There were no serious adverse events attributable to the interventions. CONCLUSIONS AND RELEVANCE/UNASSIGNED:This phase 2 randomized clinical trial failed to demonstrate differential benefits for online cognitive training, a structured cognitive rehabilitation program, and tDCS for cognitive long COVID. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT05965739.

BACKGROUND AND IMPORTANCE/BACKGROUND:Rhino-orbital cerebral mucormycosis (ROCM) is an aggressive fungal infection involving the paranasal sinuses, orbit, and intracranial cavity, with a propensity for vascular invasion. This can lead to complications such as internal carotid artery (ICA) thrombosis and occlusion, presenting major neurosurgical challenges. Although surgical debridement and antifungal therapy are the mainstays of treatment, cases with significant neurovascular involvement require specialized intervention. We report a case of ROCM with severe flow-limiting ICA stenosis treated by direct extracranial-intracranial bypass. CLINICAL PRESENTATION/METHODS:tA 65-year-old man with diabetes presented with progressive left-sided blindness and facial numbness. Imaging revealed a left orbital mass extending into the paranasal sinuses and intracranially. Empiric antifungal therapy was started. Pathology confirmed Rhizopus species. Despite extensive surgical debridement and antifungal therapy, the patient developed progressive severe cavernous ICA stenosis, leading to watershed territory strokes. To restore cerebral perfusion, protect from distal emboli, and prepare for potential aggressive debridement, a flow-replacing direct (superficial temporal artery-middle cerebral artery (M2)) bypass was performed, and the supraclinoid carotid was trapped. Intraoperative angiography confirmed robust flow through the bypass. The patient was discharged on antifungal therapy and aspirin. At 6-month follow-up, the patient was neurologically intact with an modified Rankin Scale score of 1. Computed tomography angiography and transcranioplasty Doppler ultrasonography confirmed good flow through the bypass. CONCLUSION/CONCLUSIONS:In addition to antifungal therapy and surgical debridement, superficial temporal artery-middle cerebral artery bypass can be a lifesaving intervention in the management of ROCM with severe cerebrovascular compromise. This case highlights the critical role of cranial bypass in preserving cerebral perfusion in patients with flow-limiting ROCM-associated ICA invasion.

OBJECTIVE:This study aims to better characterize the long-term neurological quality of life (QOL) outcomes (using the Neuro-QOL scale) in survivors of new onset refractory status epilepticus (NORSE), including its subtype febrile infection-related epilepsy syndrome (FIRES), and provide guidance for psychological and social support strategies. METHODS:Utilizing data from a multicenter prospective study of NORSE/FIRES led by Yale University, we enrolled patients who completed the validated, patient-reported Neuro-QOL scale at least once at 3-6 months (n = 37), 12 months (n = 29), 24 months (n = 23), or ≥36 months (n = 9) following discharge. The Neuro-QOL scale assesses physical, mental, and social health in patients with neurological disorders. QOL impairment (QOL-I) scores were calculated, with higher scores indicating greater impairment. T-scores enabled comparisons with reference populations. RESULTS:In adults, median QOL-I improved from 44.1% at 3-6 months to 37.6% at 36+ months. Paired analysis showed significant improvement in QOL-I between 3-6 and 24 months (p = .016), with specific improvements in communication, satisfaction with social roles, fatigue, and mobility. Greater improvement was also observed for participation in social roles (5.5-point T-score gain) compared to the reference population, suggesting meaningful change. A gradual improvement in overall QOL-I scores was also observed in pediatric participants, despite a modest sample size (n = 5 with data at 3-6 and 12 months). Measures of fatigue and anxiety persisted in adults, and cognitive difficulties persisted in both adults and children. In adults, longer status epilepticus duration and intensive care unit stay were associated with poorer QOL. Additionally, a higher number of antiseizure medications was associated with more depression, cognitive impairments, and perceived stigma. SIGNIFICANCE/CONCLUSIONS:These findings highlight the potential for recovery following an acute episode of NORSE, although many patients continue to face challenges requiring ongoing support, and the clinical meaning of the reported QOL improvement remains unclear. Furthermore, the findings underscore the importance of strategic multidisciplinary support systems in the years following discharge.

OBJECTIVE:To update the 2016 American Headache Society (AHS) guideline on parenteral pharmacologic therapies for the management of migraine attacks in the emergency department (ED). METHODS:We conducted a systematic review and meta-analysis using the same methodology as the 2016 guideline. The original search strategy was repeated and expanded to include studies of nerve blocks and sphenopalatine ganglion (SPG) blocks. We searched Medline, Embase, Cochrane, clinicaltrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform through February 10, 2025. Eligible studies were randomized controlled trials (RCTs) involving adults diagnosed with migraine, treated in the ED with intravenous (IV), intramuscular (IM), subcutaneous (SC), or nerve block (including SPG block) interventions. Two reviewers independently screened titles/abstracts and full texts; a third reviewer resolved disagreements. Data were extracted using a standardized form and verified by a second reviewer. Risk of bias was assessed using the American Academy of Neurology (AAN) criteria. Where applicable, meta-analyses were performed. Efficacy was categorized as highly likely, likely, or possibly effective or ineffective. Clinical recommendations were developed using the AAN guideline development process. RESULTS:The search identified 26 new RCTs evaluating 20 injectable treatments. Of these, 12 were rated class I (low risk of bias), 9 class II, and 4 class III. Prochlorperazine IV, dexketoprofen IV, sumatriptan SC, and greater occipital nerve blocks (GONB) were considered highly likely to be effective based on multiple class I studies. Chlorpromazine IV, metoclopramide IV, eptinezumab IV, ketorolac IV, and supraorbital nerve blocks (SONB) were considered likely effective based on one class I or multiple class II studies. Hydromorphone IV, propofol IV, and paracetamol IV were considered likely ineffective based on class I or multiple class II studies. After review of the evidence and a consensus process, recommendations were made for each intervention. CONCLUSIONS:Prochlorperazine IV and GONB must be offered to eligible adults presenting to the ED with a migraine attack for treatment of headache requiring parenteral therapy (level A - must offer) in those without contraindications, while hydromorphone IV must not be offered (level A - must not offer). Treatments that should be offered when appropriate (level B - should offer) include dexketoprofen IV, ketorolac IV, metoclopramide IV, sumatriptan SC, and SONB. Chlorpromazine IV, dexamethasone IV, and valproate IV may be offered (level C - may offer). Paracetamol IV may not be offered (level C - should not offer). Eptinezumab should be offered (level B) only for patients matching the clinical trial population but is rated level U - no recommendation for an ED-specific population. Additional evidence is needed for caffeine, granisetron, ibuprofen, ketamine, lidocaine, normal saline, propofol, and SPG blocks, all currently rated level U - no recommendation.

BACKGROUND:Obstructive sleep apnea (OSA) is associated with Alzheimer's disease (AD) risk. Racial-, ethnic-, and sex-specific mechanisms of OSA and AD risk were examined. METHODS:We analyzed data from 3978 polysomnography patients without cognitive decline aged ≥ 60 including 663 OSA+ patients (284 non-Hispanic White, 207 Black, 172 Hispanic) matched to OSA- cohorts (1:1, n = 663; 1:4, n = 2652) and followed for AD through 2013. RESULTS:During the 8.5 (standard deviation 1.4) year period, 358 patients developed AD. AD risk was higher for Black (adjusted hazard ratio [aHR] 2.24 [1.24-2.71]), Hispanic (aHR 1.73, [1.38-3.51]), White (aHR 1.83, [1.21-3.37]), male (aHR 2.38, [1.31-3.47]), and female (aHR 1.37, [1.14-2.41]) patients. Hypoxia, sleep fragmentation, and sleep duration (p < 0.01) were associated with increased risk. Black and Hispanic, and female patients showed stronger effects for hypoxia and duration, and fragmentation, respectively. DISCUSSION/CONCLUSIONS:Hypoxia, fragmentation, and duration may underlie racial-, ethnic-, and sex-specific effects of AD risk.

The Stroke Treatment Academic Industry Roundtable convened a workshop regarding artificial intelligence (AI) and innovative clinical trial designs during the Stroke Treatment Academic Industry Roundtable XIII meeting on March 28, 2025. This forum brought together stroke physicians and researchers, and industry representatives to discuss the current use and future opportunities for AI and novel trial designs in acute stroke trials. AI already plays a substantial role in the treatment of acute stroke with regards to imaging but is poised to have a much larger impact in clinical care and research trials over the coming years. The quality and understanding of the data are used to train the AI, the human element needed to ensure training is successful, and the clinician and trialist at the bedside, the humans "in the loop," will be necessary to maximize AI's effectiveness in clinical practice and trials. Platform trials address multiple scientific questions in an area of medicine simultaneously within the same trial structure by sharing controls across multiple interventions. While platform trials increase efficiency and potentially decrease the time needed to answer important clinical scientific questions, they also can introduce complexity to standard workflows. Future acute ischemic stroke clinical trials should incorporate elements of pragmatic and patient-centered trial design when possible. Pragmatic trials aim to assess the effectiveness of treatments when they are implemented into routine clinical care rather than under idealized conditions. AI models and platform, pragmatic, and patient-centered trial designs are new tools to answer important clinical questions, but understanding how they work, their best uses, and their limitations is critical for accelerating successful new treatments for stroke.

BACKGROUND:Identifying early neuropathological changes in Alzheimer's disease (AD) is important for improving treatment efficacy. Among quantitative MRI measures, transverse relaxation time (T2) has been shown to reflect tissue microstructure relevant in aging and neurodegeneration; however, findings regarding T2 changes in both normal aging and AD have been inconsistent. The association between T2 and amyloid-beta (Aβ) accumulation, a hallmark of AD pathology, is also unclear, particularly in cognitively normal individuals who may be in preclinical stages of the disease. PURPOSE/OBJECTIVE:To investigate longitudinal hippocampal T2 changes in a cognitively normal cohort of older adults and their association with global Aβ accumulation. STUDY TYPE/METHODS:Retrospective, longitudinal. SUBJECTS/METHODS:56 cognitively normal adults between 55 and 90 years of age (17 males and 39 females). FIELD STRENGTH/SEQUENCE/UNASSIGNED:3 Tesla; multi-echo spin echo sequence for T2 mapping; 18F-florbetaben positron emission tomography for Aβ measurement. ASSESSMENT/RESULTS:Bilateral hippocampal T2 and volume were extracted to relate to Aβ PET measurements. To understand variations in AD risk, participants were separated into Aβ-high and Aβ-low subgroups using a predetermined threshold. STATISTICAL TESTS/METHODS:Linear mixed-effect models and general linear models were used. A p-value < 0.025 was considered significant to account for bilateral comparisons. RESULTS:Older age was associated with increased T2 in the bilateral hippocampus (left: β = 0.30, right: β = 0.25) and smaller hippocampal volume on the left (β = -0.12). In the Aβ-low subgroup, both longitudinal T2 increase rates (β = 0.65) in the left hippocampus and bilateral cross-sectional T2 (left: β = 0.64, right: β = 0.46) were positively correlated with Aβ PET, independent of hippocampal volume. DATA CONCLUSION/CONCLUSIONS:This study provided in vivo evidence linking hippocampal T2 to Aβ accumulation in cognitively normal aging individuals, suggesting that quantitative T2 may be sensitive to microstructural changes accompanying early Aβ pathology, such as neuroinflammation, demyelination, and reduced tissue integrity. EVIDENCE LEVEL/METHODS:3. TECHNICAL EFFICACY/UNASSIGNED:Stage 2.

This manuscript explores the myriad ethical controversies associated with declaration of brain death/death by neurologic criteria (BD/DNC) during pregnancy raised by the case of Ms. Adriana Smith, a 30-year-old Georgia nurse, who came to international attention in May 2025. We will discuss: (1) the factors that may have impacted the decision not to perform neuroimaging when she first presented to medical attention; (2) the significance of identifying and deferring performance of futile interventions to decrease intracranial pressure relative to BD/DNC declaration; (3) the medical, ethical and legal complexities associated with BD/DNC declaration and continuation of maternal organ support in pregnancy; (4) the impact of continuing maternal organ support after BD/DNC declaration on the fetus, the family, Ms. Smith and the treatment team; and (5) the effects of media coverage of this case. This case's influence on future BD/DNC declarations during pregnancy, both in Georgia and elsewhere, remains to be seen.