Publications by Year: 2026

Essential fatty acid deficiency (EFAD) is a rare but serious condition with significant consequences including delayed growth and development, decreased immune response and reproductive dysfunction, among others. EFAD is of particular concern in vulnerable populations such as preterm infants and those receiving long-term parenteral nutrition (PN). As essential fatty acids (EFAs) must be supplemented in the diet due to the inability to synthesize these endogenously, EFAD develops secondary to inadequate EFA intake. The Holman Index, defined by the ratio of Mead acid to arachidonic acid (triene: tetraene (T:T)) in the plasma, has historically served as the method for diagnosis, with the threshold diagnostic value at ≥0.20. This index is derived from the body's natural metabolic response to EFA deprivation, increasing synthesis of Mead acid, and thus remains broadly applicable across various populations. Concerns regarding the established ratio and alternative use of absolute fatty acid values and profiles have been raised that question the utility of the Holman Index. Although recent developments in fatty acid profiling have allowed for increased precision in measurement and development of population-specific reference ranges, reliability of this data in diagnosing EFAD is controversial given variability amongst different studies and population dietary confounders. Data from animal and human studies have demonstrated that the Holman index has continued to reliably detect EFAD even in the era of new lipid emulsions and technological advancements. The Holman Index remains a vital tool in the diagnosis and monitoring of EFAD, offering consistency and early detection capacity in at-risk populations.

Artificial intelligence (AI) can transform mental health care globally by improving the efficiency, consistency, effectiveness and accessibility of training and supervision in evidence-based psychotherapies, including cognitive and behavioral therapies. This paper describes the potential role of AI in the training and supervision of clinicians and the associated gains, challenges and risks. AI could revolutionize the process of training and supervision by simulating patients in assessment and therapy sessions, providing real-time personalized fidelity feedback, and helping trainees to develop cultural sensitivity. Key challenges remain, however, including the identification and curation of high-quality datasets and algorithms, ethical considerations, implementation in low-resource settings and lack of rigorous research. The paper concludes by outlining guidelines for the future development, evaluation, and implementation of AI in CBT training and supervision, with the goal of maximizing its potential benefits while mitigating associated risks.

The incidence of early onset breast cancers (BCs) has increased, paralleling rising trends in delayed childbearing. We hypothesize that a distinct postpartum BC subtype (PPBC), identifiable by time since last birth (TSLB) and biomarker expression, contributes to this trend. We applied GeoMx Digital Spatial Profiling (DSP) to measure associations between TSLB and 71 proteins in 640 BCs from women ages ≤40 years included in the Young Women's BC Study. We analyzed data using univariable linear regression and multivariable Sliced Inverse Regression to account for higher order interactions among biomarkers. In keratin-rich segments, PR (p = 1.00x10-4) and PTEN (p = 1.00x10-3) were associated with longer TSLB; multivariable analyses revealed positive associations for GZMB (p = 4.00X10-4), SMA (1.00X10-4) and NF-1 (p = 1.00X10-3). In keratin-poor segments, univariable significant positive associations were found for PR (p = 2.00x10-4) and PTEN (p = 1.00x10-3), whereas CD20 (p = 3.00x10-4) and CTLA4 (p = 4.00x10-5) were negatively associated; multivariable significant associations were found for fibronectin (p = 3.00x10-5) and pan-Akt (p = 1.00x10-3). Associations persisted after adjustment for multiple comparisons and BC molecular subtypes. Associations including for PR, PTEN and CD20 were strongest among women with shortest TSLB. OPAL multiplex immunofluorescence assays for PR, PTEN, CD20, SMA and CTLA4, replicated several DSP findings, particularly when stratified by subtype and with compartment matching. In TCGA, RNA species linked to proteins associated with TSLB correlated strongly with a T cell exhaustion signature previously linked to poor prognosis among premenopausal women. These data support PPBC as a biologically coherent phenotype defined by TSLB and biomarker profile, with potential implications for prevention and therapy.

Cystic fibrosis (CF) is caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, leading to abnormal anion transport and consequent airway dehydration and hyper-viscous mucus. Potential difference (PD) testing measures voltage across the epithelium and can be a sensitive marker for changes in ion transport reflective of CFTR activity. By the conventional method, agar gel salt-bridge-based probes in combination with calomel electrodes have been used to measure transepithelial PD across the respiratory mucosa, allowing discrimination between healthy controls and CF. This method is known to be cumbersome and subject to errors due to discontinuity in salt bridges as a result of entrained air that are difficult to detect and a lack of real time visual guidance for probe placement, adversely affecting quality control and data analysis. These limitations are particularly relevant to endobronchial PD, where visualization is less precise, and the chance of electrical discontinuity with extended salt bridges is greater. We developed a novel portable probe system with onboard silver-silver chloride electrodes, integrated gas removal to extract gas bubbles, and optical coherence tomography-mediated visual guidance to provide a platform for improved accuracy and sensitivity of CFTR functional testing that can be adapted for endobronchial PD testing. We also developed a bedside electrocell simulator for the validation of probe performance, ensuring real-time external validation and use of probes that exhibit optimal performance characteristics before human measurements. In a pilot nasal PD study in CF subjects and non-CF controls (n = 10), measurements with the new probe were feasible with discrimination between disease groups. Bland-Altman suggested limited agreement (mean difference: -2.44, SD 4.79; 95% limits of agreement -11.84 to 6.95), but the Deming regression demonstrated a consistent linear relationship despite proportional bias (b = 1.21, P < 0.001) and the Somers' D indicated moderate concordance in rank ordering (0.56; 95% CI: -0.24 to 0.90). These results establish proof of principle of the new device and support the need for further validation in a larger sample.NEW & NOTEWORTHY Cystic fibrosis (CF) impairs CFTR protein function, disrupting ion transport and airway hydration. Traditional potential difference (PD) testing uses salt-bridge probes and calomel electrodes, but is error-prone due to air bubbles and poor visual guidance, especially in endobronchial applications. A novel probe with integrated silver-silver chloride electrodes, gas removal, and OCT guidance improves accuracy and usability. Validation through benchtop and preliminary human nasal testing shows 55% concordance with conventional methods, supporting its clinical potential.

Study DesignNarrative Review.ObjectivesTo summarize the scientific contributions generated from the AO Spine Knowledge Forum Tumor (AOSKFT) databases, focusing on primary spine tumors, and highlight key findings, research trends, and future directions.MethodsData from the Primary Tumor Retrospective (PT-Retro) and Primary Tumor Research Outcome Network (PTRON) registries were analyzed. The nineteen studies included were peer-reviewed manuscripts focused on primary spine tumors, excluding abstracts, book chapters, systematic reviews, and metastatic studies.ResultsThe PT-Retro registry compiled data from 1495 patients across 18 primary tumor histologies, offering insights into recurrence, survival, and treatment paradigms. Key findings emphasize the importance of Enneking-appropriate (EA) resection in improving survival and reducing recurrence in tumors such as chordoma, chondrosarcoma, and osteosarcoma. Genetic markers, including hTERT promoter mutations and rs2305089 SNP, were linked to prognosis in specific histologies. Benign tumors, such as giant cell tumors and aneurysmal bone cysts, demonstrated variable outcomes with different surgical approaches and selective arterial embolization.ConclusionsThe AOSKFT registries have significantly advanced knowledge in primary spine tumor management, emphasizing preoperative staging, surgical margins, and multidisciplinary approaches. International, multicentric registries are essential for studying rare diseases like primary spine tumors, enabling robust data collection, improved statistical power, and broader applicability of findings across diverse clinical settings. Ongoing prospective data collection through PTRON will further refine evidence-based care for these rare and challenging conditions.

BACKGROUND AND OBJECTIVES: Epilepsy incidence peaks in childhood and again after age 55. Up to half of individuals with late-onset epilepsy lack an identifiable cause, but previous imaging studies suggest subtle mesiotemporal atrophy. In this study, we aimed to quantify whole-brain cortical and deep gray matter alterations in late-onset unexplained epilepsy (LOUE) and to examine their associations with cognitive and clinical measures.

METHODS: We prospectively recruited patients with LOUE through Brigham and Women's Hospital and its affiliated sites and compared them with sociodemographically matched healthy older adults from the Harvard Aging Brain Study. Inclusion criteria for LOUE were at least 1 unexplained seizure after age 55, onset within the past 5 years, and no identifiable cortical lesion on MRI. All participants underwent 3T structural MRI and neuropsychological testing. Cortical thickness and deep gray matter volumes were extracted, and linear models were used to compare patients with LOUE and controls. Correlations were computed between structural alterations and demographic, cognitive, and clinical measures.

RESULTS: We included 59 patients with LOUE (mean age 71.2 ± 7.0 years, 49% female) and 53 controls (mean age 70.7 ± 5.2 years, 53% female). Patients with LOUE showed reduced cortical thickness in sensory and mesiotemporal cortices (d = -0.75, 95% CI [-1.14 to -0.37], FDR-corrected p values [pFDR] < 0.05) and reduced deep gray matter volumes in the pallidum and putamen (d = -0.55, 95% CI [-0.93 to -0.17], pFDR < 0.05). These structural reductions correlated with lower performance on a category fluency task (r = 0.31, pFDR = 0.016) and the extended Preclinical Alzheimer's Cognitive Composite (r = 0.37, pFDR = 0.0041). Conversely, patients showed increased thickness in the left inferior frontal gyrus (d = 0.82, 95% CI [0.43-1.20], pFDR < 0.05) and increased thalamic volume (d = 1.13, 95% CI [0.73-1.53], pFDR < 0.05), which were more pronounced in those with focal seizures sparing consciousness (d = -0.62, puncorr = 0.021).

DISCUSSION: Structural brain changes in LOUE are more extensive than previously recognized and are associated with cognitive vulnerability. Although the cross-sectional design and use of independent cohorts limit conclusions about disease progression, the findings suggest that LOUE may fall along a continuum between epilepsy and neurodegenerative disease.

Hereditary hemorrhagic telangiectasia (HHT) causes severe recurrent epistaxis, chronic gastrointestinal bleeding, solid organ arteriovenous malformations, and significant anemia. Although it is the second most common inherited bleeding disorder worldwide, no approved therapies exist. The multicenter, US randomized, controlled PATH-HHT trial demonstrated efficacy of short-term pomalidomide treatment of epistaxis in HHT. However, questions regarding long-term safety, effectiveness, and utility for HHT-associated gastrointestinal bleeding remain. The PATH-HHT ATLAS (after trial longitudinal assessment study) was a multicenter US longitudinal observational study evaluating patients enrolled in PATH-HHT who continued pomalidomide after PATH-HHT through a poststudy drug access program, with ongoing close monitoring per PATH-HHT protocol and as mandated by the US Food and Drug Administration. Sixty-two patients treated with pomalidomide for HHT for up to 4.4 years were included. Significant, durable improvements in mean epistaxis severity score (5.55 points [baseline] to 2.80 points [month 12]; P< .0001) and mean hematologic support score (9.11 red cell unit equivalents [RUEs] during 6 months pretreatment to 5.73 RUEs [months 7-12]; P = .0056) were observed. Pomalidomide was less effective for gastrointestinal bleeding than for epistaxis, particularly in patients with high red blood cell transfusion requirements. Thirty-one patients (50%) underwent dose reduction from 4 mg daily, primarily due to neutropenia, but most maintained effectiveness at 2 or 3 mg daily. Over 105.2 patient-years of pomalidomide treatment, 0 patients developed peripheral neuropathy, 1 developed venous thromboembolism, and 5 developed serious infections. In conclusion, pomalidomide was effective for HHT-associated epistaxis over extended durations, albeit with nontrivial potential toxicities, and may be considered for certain patients with HHT. This trial was registered at www.clinicaltrials.gov as NCT07018401.

Noninvasive measurement of the human brain's angioarchitecture is essential for understanding functional neuroimaging signals, diagnosing cerebrovascular diseases, and tracking neurodegeneration. Ultrahigh-field MRI now enables mesoscopic (<0.5 millimeters) imaging, revealing vascular details previously inaccessible in vivo. Yet current approaches face two barriers: Scan times often exceed 40 minutes, and the conventional visualization methods remain limited for navigating the vasculature. Here, we present a fast whole-brain MRI protocol that resolves the venous network at 0.35 millimeters in under 7 minutes. We also introduce processing and visualization techniques that distinguish vessel types and more intuitively navigate the vasculature. These advances allow in vivo reproduction of the seminal vasculature images of Henri M. Duvernoy and provide whole-brain intracortical meso-vein maps in humans. Our methods lay the groundwork for detailed examination of vascular organization across individuals, brain regions, and cortical layers. More generally, these methods make mesoscopic imaging of angioarchitecture viable for broad neuroscientific and clinical applications.

Sphingosine 1-phosphate (S1P) is a bioactive lipid that circulates in plasma bound to high-density lipoproteins (HDL) and albumin. Circulating S1P levels correlate positively with systolic blood pressure (BP) in hypertension and negatively with severity in septic shock and with left ventricular function in heart disease. In mice, isolated deficiency in HDL-S1P and endothelial cell S1P receptor (R)-1 both trigger hypertension, supporting an essential role for HDL-S1P in endothelial function. Physiological roles of albumin-S1P and myocyte S1PRs in the cardiovascular system remain incompletely defined. We report that mice lacking all circulating S1P pools display hypotension and lack of BP increase with age, which contrasts with HDL-S1P deficiency and suggests an essential role for albumin-S1P in cardiovascular homeostasis. Although cardiac output was preserved in a basal state, left ventricular systolic function and contractile reserve were reduced in the absence of circulating S1P. Cardiac function and BP were partially or fully normalized by transfusion of erythrocytes capable of S1P production. Hypotension was accompanied by reduced peripheral resistance, and albumin-S1P, but not S1P complexed to an HDL-like chaperone, dose-dependently increased vascular resistance in isolated perfused kidneys via S1PR3 and S1PR2. Epistatic analysis supported a critical role for S1PR3 in S1P-dependent BP maintenance and pointed to a distinct origin of the cardiac phenotype. We thus uncover an essential role for circulating S1P in maintaining BP and left ventricular systolic function in mice. Our results also highlight distinct functions for the pools of S1P bound to HDL and to albumin, carrying both diagnostic and therapeutic implications.