Faculty Bibliography

OBJECTIVE:To determine the test performance of cutaneous phosphorylated alpha-synuclein (P-SYN) in dementia with Lewy bodies (DLB), individuals with reduced Montreal Cognitive Assessment (MoCA) and healthy controls. METHODS:This is the first subgroup analysis of the Synuclein-One study, a prospective, blinded study evaluating P-SYN detection from skin biopsies in 218 subjects with a referral diagnosis of control (N = 151) and DLB (N = 67). All subjects completed detailed examinations, questionnaires, and had skin biopsies for detection of P-SYN. DLB patients were included if meeting the 4th DLB consensus probable criteria. Control subjects, aged 40-99, had no history, examination findings, or symptoms suggestive of a synucleinopathy or neurodegenerative disease. An expert review panel, blinded to pathological data, determined the final diagnosis. Controls with reduced MoCA (MoCA < 26, N = 26) at screening were analyzed separately. RESULTS:After expert panel review, only 50/67 patients met consensus criteria for DLB, 26/151 controls had a reduced MoCA, and 120/151 controls had a normal MoCA. The proportions of subjects with cutaneous P-SYN detected by skin biopsy were 96.0% (48 of 50) of the DLB group, 31% (8 of 26) of the controls with reduced MoCA, and 3.3% (4 of 120) of the controls with normal MoCA. INTERPRETATION/CONCLUSIONS:In this prospective, blinded, cross-sectional study, a high proportion of subjects meeting clinical consensus criteria for DLB had P-SYN detected in skin biopsies. Almost 1/3 of subjects with reduced MoCA testing also had P-SYN detected. These results support a role for skin biopsy detection of P-SYN in patients with DLB. TRIAL REGISTRATION/BACKGROUND:NCT04700722.

Recent advances in biological therapies, small molecules and allergen-specific immunotherapy are reshaping the management of immunoallergic diseases, progressively shifting therapeutic goals from short-term disease control toward the possibility of achieving sustained clinical remission. Despite increasing evidence across multiple conditions, a universally accepted and disease-transversal definition of clinical remission (CR) remains lacking. In this review we propose a comprehensive framework for defining clinical remission across a broad spectrum of immune-mediated diseases traditionally managed in Allergy and Clinical Immunology practice, including asthma, allergic rhinitis, chronic rhinosinusitis with nasal polyps, chronic urticaria, atopic dermatitis, mastocytosis, food allergy, and eosinophilic esophagitis. Clinical remission is defined as a sustained state of absence of clinically relevant disease manifestations, independently of underlying biological activity; suppression of inflammatory pathways and normalization of biomarkers define biological remission, which may coexist with, but is not required for, clinical remission. We introduce the 3D-CR model, a pragmatic, disease-adaptable framework integrating 3 complementary domains - clinical, biological, and functional - to characterize remission states as complete, partial, or absent. Building on this model, we propose the Allergic Disease Remission Score (ADReS) as a modular tool designed to support standardized assessment, longitudinal follow-up, and cross-disease comparison in clinical trials and real-world settings. These tools are intended as conceptual and research instruments rather than prescriptive algorithms for individual therapeutic decision-making. Finally, we outline a World Allergy Organization call to action advocating for a harmonized global approach to defining, measuring, and implementing clinical remission as a meaningful treatment target. Establishing standardized remission endpoints has the potential to improve patient outcomes, facilitate precision medicine strategies, enhance comparability across studies, and reduce heterogeneity in clinical research and practice worldwide.

The 2025 World Allergy Organization (WAO) Guidelines for the Classification, Diagnosis, and Treatment of Hereditary Angioedema (HAE) with Consideration of Worldwide Disparities provide a comprehensive, evidence-informed, and globally applicable framework for the care of this rare and potentially life-threatening disorder. HAE is a genetic disease characterized by recurrent episodes of subcutaneous and submucosal swelling, most commonly mediated by bradykinin, and is associated with substantial morbidity, impaired quality of life, and a lifelong risk of fatal laryngeal edema. The Guidelines were developed by an international panel of 40 experts from 22 countries, with representation from all world regions, reflecting the commitment of WAO to geographic diversity, inclusiveness, and global relevance. The development process for these guidelines followed a structured and transparent methodology that integrated systematic literature review, appraisal of real-world evidence, and application of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework adapted for rare diseases, complemented by a formal Delphi consensus process. This approach was specifically designed to address the limitations of conventional evidence hierarchies in rare disorders, while ensuring clinical applicability across heterogeneous healthcare systems and resource settings. A central element of the guidelines is an updated classification of HAE based on underlying pathophysiology and disease endotypes. The traditional distinction between HAE types 1 and 2 is unified under the term HAE with C1 inhibitor deficiency (HAE-C1-INH), reflecting shared biological mechanisms and management principles. The guidelines also recognize an expanding spectrum of HAE with normal C1 inhibitor (HAE-nC1-INH), including forms associated with pathogenic variants in F12, PLG, ANGPT1, KNG1, MYOF, HS3ST6, CPN1, and DAB2IP, as well as cases with currently unidentified genetic causes. The diagnostic strategy emphasizes early clinical recognition based on characteristic features, including recurrent angioedema without urticaria, abdominal or laryngeal involvement, early symptom onset, and family history. A simplified diagnostic algorithm is proposed, prioritizing the C1 inhibitor functional assay as the preferred initial test when performed in a reliable specialized laboratory. Alternative diagnostic pathways are outlined for settings with limited access to specialized testing, including pragmatic combinations of biochemical assays and selective use of genetic testing, particularly relevant for HAE-nC1-INH and family screening. Management recommendations address on-demand treatment of acute attacks, short-term prophylaxis, and individualized long-term prophylaxis. Universal access to on-demand therapy is emphasized for all patients with confirmed HAE, including those who are asymptomatic, given the unpredictable nature of attacks and lifelong risk. Long-term prophylaxis is addressed within a treat-to-target framework aimed at achieving complete disease control and sustained improvement in health-related quality of life, with regular reassessment and shared decision-making. Empowering patients and caregivers through structured education, access to appropriate medications, and integration with specialized referral centers is associated with earlier treatment, reduced healthcare utilization, and improved equity of care and reduced avoidable morbidity and mortality worldwide. The 2025 WAO Guidelines for Hereditary Angioedema establish an evidence-informed, patient-centered, and forward-looking framework for the classification, diagnosis, and management of HAE. By integrating advances in pathophysiology, diagnostics, and therapeutics with global expert consensus and real-world considerations, the guidelines aim to support consistent, equitable, and high-quality care for patients with HAE across regions and healthcare systems.

Sepsis is a systemic inflammatory disorder marked by dysregulated inflammation and coagulopathy. Annexin A2 (A2), a profibrinolytic protein, assembles plasminogen and tissue plasminogen activator on cell surfaces, thereby maintaining vascular patency. However, its role in human sepsis has remained poorly defined. We investigated whether A2 undergoes qualitative or quantitative modification during human sepsis with associated end-organ dysfunction. Peripheral blood mononuclear cells and plasma were collected from 65 patients with sepsis and 27 healthy controls. A2 expression and integrity were evaluated with cell surface plasmin generation using immunoblot and fluorometric assays. Both A2 integrity and plasmin generation were significantly reduced in patients with sepsis and with septic shock. A2 underwent sepsis-related membrane-associated proteolysis mediated by a serine protease. A2 reduction correlated with interleukin-18 levels and was significantly associated with renal, pulmonary, cardiovascular, and neurologic dysfunction. A2 proteolysis may represent a novel biomarker and therapeutic target for sepsis-related microvasculopathy.

BACKGROUND:Nondiagnostic cytology for thyroid nodules, consistent with The Bethesda System for Reporting Thyroid Cytopathology category I (B1) poses a management dilemma for clinicians. The objective of this study was to define the malignancy risk of nodules with B1 cytology using American College of Radiology Thyroid Imaging Reporting & Data System (TI-RADS) and to assess whether TI-RADS can help guide the decision to perform a repeat biopsy of these nodules. MATERIALS AND METHODS/METHODS:This retrospective cohort study evaluated 139 B1 nodules that had a definitive diagnosis on repeat biopsy or surgical excision. Sonographic features were evaluated and classified according to TI-RADS. TI-RADS category and total points were compared to the final diagnosis to determine the malignancy risk of B1 thyroid nodules. RESULTS:Of the 139 nodules, 11 (7.9%) were malignant. The malignancy risk of nodules assigned TI-RADS category 1 and 2 were both 0%, TI-RADS 3 was 2.9%, whereas TI-RADS 4 and 5 were 5.9% and 46.2%, respectively. The optimal cutoff for TI-RADS points predicting malignancy was 5 points. CONCLUSION/CONCLUSIONS:B1 thyroid nodules in TI-RADS categories 1-3 may not require repeat biopsy given low malignancy risk. However, B1 nodules in TI-RADS categories 4 and 5 have a higher malignancy risk and thus should undergo repeat biopsy.

Labetalol and nifedipine are first-line antihypertensives for hypertensive disorders of pregnancy. However, there is limited research comparing their effectiveness based on hemodynamic profiles seen in preeclampsia, such as high cardiac output (CO) and high systemic vascular resistance (SVR). This study assesses whether concordance of antihypertensive treatment with the hemodynamic status on echocardiogram reduces time to achieve target postpartum blood pressure (BP) before discharge.This retrospective cohort study included patients with preeclampsia with severe features who received a postpartum echocardiography, excluding patients with cardiac etiology. Antihypertensive choices were provider-dependent. The CO and SVR were calculated retrospectively from the echocardiogram in collaboration with cardiology. Concordance was defined as patients with high CO (>6 L/min) started on labetalol and high SVR (>1,200 dynes·sec·cm⁵) started on nifedipine; opposite pairings were discordant. The primary outcome was time to achieve target BP, defined as the period from the start of antihypertensive therapy to when no titration was needed to sustain BPs of less than 140/90 mm Hg. Chi-square and Fisher's tests were used for categorical variables, and Mann-Whitney U test for continuous variables.Of 298 patients, 155 (52%) received concordant therapy and 143 (48%) discordant. Of the cohort, 229 (76.8%) had high SVR and 69 (23.2%) had high CO. Median time to target BP was not significantly different (concordant: 32 hours [interquartile range, IQR: 0-61], discordant: 41 hours [IQR: 4-75], p = 0.13). The concordant group needed fewer titrations to achieve target BP (1 [IQR: 0-2] vs. 2 [IQR: 1-3]; p = 0.008) and were less likely to be discharged home on multiple antihypertensive medications compared with the discordant group (28.9 vs. 42.7%, p = 0.014). Maternal demographics were similar between groups.While time to target BP did not differ, concordance of antihypertensive therapy to postpartum hemodynamics in patients with severe preeclampsia reduced medication adjustments and increased the likelihood of discharge on a single-agent regimen. · Echocardiography can be used to assess maternal hemodynamics.. · Aligning BP meds to hemodynamics cuts the need for a second agent.. · Aligning BP meds to hemodynamics reduces dose adjustments..

BACKGROUND:Glioblastoma intramedullary spinal cord metastasis (GISCM) is a rare sequela of high-grade astrocytoma and glioblastoma multiforme (GBM). Discrete intramedullary spinal cord metastases are less common than spinal leptomeningeal spread and may follow a more indolent course. Once identified as GISCM, palliative maximal safe resection of the tumor may be considered to alleviate neurological symptoms. Reports describing the surgical management of these rare lesions, including the use of emerging technologies that may aid in maximal safe resection, are sparse. A further understanding is also required regarding the course of disease and factors contributing to mortality in GISCM. METHODS:We reviewed the intraoperative management and clinical course of three patients treated for GISCM at our institution between 2015 and 2024. We additionally conducted a PRISMA-guided systematic literature review of PubMed Central, MEDLINE, and Bookshelf databases through May 26th, 2025, including original patient reports of GISCM from cranial astrocytoma or GBM. The disease course, management strategies, and causes of mortality in previously reported cases were analyzed. RESULTS:Our institutional cohort had a mean time to spinal metastasis of 26.2 months from diagnosis of cranial disease (range 17.5-40.5 months), with a mean survival of 9.2 months following maximal safe resection of extramedullary components (range 7-12 months). In two cases, intraoperative Stimulated Raman Histology (SRH) was employed to facilitate the rapid identification of metastatic GBM, thereby influencing surgical strategy. In one case, 5-aminolevulinic acid (5-ALA) was used to differentiate between tumor and spinal cord parenchyma, facilitating maximal safe debulking without neurological injury. Literature review identified 38 prior reported cases of GISCM, with a median time to spinal diagnosis of 11.0 months and a median survival of 3.5 months thereafter. The cause of death in the review cohort often involved multiple factors, and when analyzed for contributing factors to death, 38.7% involved cranial progression, 38.7% involved progression of spinal disease, and 29.0% involved medical complications. Gait ataxia at presentation was associated with shorter survival in review patients, potentially reflecting advanced disease with extramedullary cord compression. CONCLUSION/CONCLUSIONS:GISCM represents an entity distinct from leptomeningeal disease and may be managed in conjunction with recurrent cranial disease. Surgical debulking is a technically feasible strategy that can be safely facilitated using tools employed in the management of intracranial GBM, facilitating maximal safe resection without compromising survival.

Strain imaging, performed with echocardiography and cardiovascular magnetic resonance (CMR), is a noninvasive technique for detecting subclinical myocardial dysfunction across the heart failure spectrum, in various cardiomyopathies, and within the field of cardio-oncology. By quantifying myocardial deformation, strain enhances diagnosis, risk stratification, and treatment monitoring beyond traditional measures such as ejection fraction. While echocardiography remains the most accessible modality, ongoing advances in CMR techniques-including incorporation of artificial intelligence-promise to improve standardization, reproducibility, and clinical integration of strain imaging in the management of heart failure and cardiovascular care.