Publications by Year: 2026

Broadly neutralizing antibodies (bNAbs) targeting multiple sites of HIV-1 Env vulnerability can be induced by infection, but simultaneous elicitation of bNAbs against multiple epitopes has not been achieved by vaccination. In this study, we designed a dual-epitope vaccine targeting both the fusion peptide (FP) and the V2 apex and evaluated its capacity to induce bNAbs against both epitopes in rhesus macaques. This vaccine combined an FP conjugate with a cocktail of engineered Env trimers with enhanced V2 apex recognition and increased antigen retention in lymph nodes. Macaque immunization with the dual-epitope vaccine elicited >1,000-fold higher autologous tier 2-neutralizing titers than wild-type Env trimers and enhanced heterologous neutralization. Both FP- and V2 apex-monoclonal antibodies were isolated from immunized macaques and showed heterologous neutralization with genetic and structural signatures similar to well-characterized FP and V2 apex bNAbs. These results demonstrate proof of concept for simultaneous vaccine elicitation of neutralizing antibodies against multiple sites of Env vulnerability.

BACKGROUND: MECOM encodes a developmental and haematopoietic transcription factor associated with a rare early-onset syndrome including bone marrow failure, skeletal and other congenital anomalies. Heterozygous de novo variants are the primary cause. We previously identified MECOM as a candidate gene for paediatric pulmonary arterial hypertension (PAH) using trio exome sequencing.

METHODS: To test the role of MECOM in paediatric PAH and further define the clinical phenotype of MECOM-associated syndrome, we queried GeneMatcher and screened rare disease databases for individuals with predicted deleterious MECOM variants. We analysed the clinical spectrum of patients, performed protein modelling of genetic variants and assessed cardiopulmonary expression.

RESULTS: We identified 15 individuals with MECOM variants, including 11 unrelated probands and 8 de novo variants. 11 individuals had severe or mild thrombocytopenia, 9 had skeletal issues, 8 had cardiac anomalies, 6 had PAH and 10 had additional conditions. Three were diagnosed in utero and died in the neonatal period. All missense variants map to the zinc finger 6 or zinc finger 8/9 region, a known hotspot for MECOM-associated syndrome. Protein modelling predicted that both regions are DNA-binding, and that the variants may interfere with binding to a VEGFR2/KDR enhancer. Data from LungMAP showed that MECOM is primarily expressed in pulmonary arterial endothelial cells.

CONCLUSION: Rare MECOM variants are associated with early-onset syndromic PAH. PAH monitoring should be considered for all individuals with rare MECOM variants. We speculate that the pathogenetic mechanism for PAH and cardiac defects may be impaired VEGFR2/KDR signalling.

BACKGROUND AND OBJECTIVES: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of seizure-related deaths in people with epilepsy. Despite evidence that SUDEP counseling does not cause stress, improves treatment adherence, and empowers people with epilepsy and their caregivers, it remains underdiscussed. This study aimed to explore the in-depth perspectives of parents who have lost a child to SUDEP, focusing on their experiences, grief, and coping strategies, while factoring in their demographics, the clinical features of their deceased children, and their previous awareness of SUDEP, all aspects that have not been systematically investigated before.

METHODS: This qualitative phenomenological study involved in-depth semistructured interviews with 51 parents of 43 children who died of SUDEP. Transcripts were analyzed using immersion/crystallization qualitative methodology with Dedoose software, using an iterative consensus-building process. Thematic analysis revealed common perspectives, grief narratives, coping strategies, and perceived needs among parents after their child's SUDEP.

RESULTS: Of the 51 participating parents (mean age 54.1 ± 9.4 years, 71% female), 27 reported being unaware of SUDEP before it occurred, whereas 24 reported previous awareness of it. These groups shared similar demographics and clinical characteristics. However, "unaware" parents expressed more intense trauma and prolonged maladaptive grief, characterized by guilt, extreme anger, and medical distrust. By contrast, "aware" parents described mitigated trauma, with less guilt- and anger-ridden grief, and reduced reliance on specialized support groups. Previous SUDEP awareness provided emotional preparation, buffering the devastating reality and fostering agency and acceptance. Another theme highlighted the struggles parents faced immediately after SUDEP, particularly with law enforcement and treating physicians. Unanimously, parents emphasized the paramount importance of counseling about the known relationship between epilepsy and SUDEP.

DISCUSSION: Previous awareness of SUDEP (or lack thereof) has complex and far-reaching effects on the subsequent parental perceived trauma, grief, and coping processes. Furthermore, emergency responders, official personnel, and treating physicians may mishandle the aftermath of SUDEP. This study's findings strongly advocate for a paradigm shift in SUDEP-related practices across multiple disciplines, including legislation. Emphasis should be placed on increasing proactive SUDEP counseling to mitigate the traumatic effect and subsequent grieving process when SUDEP occurs.

OBJECTIVE: Cerebral cavernous malformations (CCMs) are groups of blood vessels that develop abnormally in both the brain and/or spinal cord. Currently, MRI and/or CT are the primary methods for assessing CCMs. Plasma-based biomarkers could serve as a complement to standard imaging techniques by providing a quantitative and molecular-based technique to detect disease at lower cost. Therefore, the authors evaluated cell division cycle 42 binding protein beta (CDC42BPB) as a potential novel plasma biomarker for CCMs.

METHODS: Plasma samples were obtained from patients with pathological analysis-confirmed CCM (n = 10, age 1-16 years) and compared to controls (n = 24, age 1-19 years). The protein levels were measured using the Olink Proximity Extension Assay. Findings were confirmed with ELISA. CDC42BPB expression was further analyzed with Western blot and immunohistochemistry analysis in patient-derived primary cells and CCM tissues, respectively.

RESULTS: CCM patients exhibited significantly higher CDC42BPB plasma levels compared to controls (approximately 6-fold greater expression, p = 0.004). Furthermore, the high CDC42BPB plasma expression was concordant with the protein levels in CCM tissues and patient-derived primary cells.

CONCLUSIONS: The authors present data supporting the measurement of CDC42BPB plasma level as a putative biomarker for CCMs. These findings have implications relevant to improving diagnosis, follow-up, and molecular pathophysiological analysis.

INTRODUCTION: Children with hip pain, limp and inability to bear weight often present a diagnostic clinical challenge. Sonography is an ideal first-line imaging modality to assess for effusion, and recent literature suggests that point-of-care ultrasound (POCUS) performed by emergency providers can be safely and accurately performed at the bedside. This systematic review and meta-analysis aims to summarize the diagnostic accuracy of POCUS for pediatric hip effusion.

METHODS: MEDLINE, Embase, Web of Science, CINAHL, and Cochrane Central databases were searched through July 2025, with no date limits, using pre-defined criteria for articles assessing the diagnostic accuracy of POCUS for pediatric hip effusion. Data were extracted and quality assessment was performed using the QUADAS-2 tool. Test characteristics were pooled using a bivariate mixed effects model for meta-analysis.

RESULTS: Four studies, with a total of 526 hips scanned, met our inclusion criteria. The reference standard for all included studies was radiology-performed ultrasonography. POCUS demonstrated a pooled sensitivity of 88% (95% CI, 82%-92%), specificity of 97% (95% CI, 93%-99%), positive likelihood ratio of 35 (95% CI, 12.0-100.8), and negative likelihood ratio of 0.13 (0.08-0.19).

CONCLUSIONS: POCUS has high specificity and moderate sensitivity for hip effusion in children and is a valuable first-line diagnostic tool for evaluating children with hip pain, limp and inability to bear weight in emergency and acute care settings.

BACKGROUND: Cognitive deficits are cardinal features of schizophrenia-spectrum disorders (SSD) and bipolar disorder (BD). However, their heterogeneous and overlapping characteristics require a dimensional approach to better understand the neurobiological basis of cognition in the psychosis spectrum. To date, only a few studies have examined the neuroanatomical features of cognitive subgroups in transdiagnostic samples, and white matter microstructural characteristics of these subgroups have not been elucidated. This study aimed to investigate white matter and cortical thickness alterations in cognitive subgroups in the schizophrenia-bipolar spectrum.

METHODS: Globally Impaired (n = 31) and Near-Normal (n = 28) cognitive subgroups, comprising individuals diagnosed with schizophrenia (SZ), schizoaffective disorder (SAD) or BD, and healthy controls (HCs, n = 29), underwent 3T T1-weighted structural magnetic resonance imaging and diffusion tensor imaging scanning. Fractional anisotropy and cortical thickness measures were compared between the cognitive subgroups and healthy controls.

RESULTS: Abnormalities in white matter microstructure were only observed in patients with global cognitive impairment compared to HCs. The Near-Normal subgroup did not differ from HCs in white matter integrity. A bilateral reduction in cortical thickness was observed in both the Globally Impaired and Near-Normal subgroups when compared to HCs. Cortical thickness measures did not differentiate between the cognitive subgroups.

CONCLUSIONS: While reductions in cortical thickness in frontal and temporal regions appear to be a common feature of SZ and BD, abnormalities in white matter microstructure are associated with global cognitive impairment in the schizophrenia-bipolar spectrum. These original findings may be important in identifying more biologically valid clinical syndromes within the schizophrenia-bipolar spectrum.

BACKGROUND: Abdominal aortic calcification (AAC) is a subclinical measure of atherosclerotic cardiovascular disease (ASCVD). AAC can be captured on lateral spine images obtained from bone density machines during routine osteoporosis screening. Identifying individuals with AAC provides a new opportunity to prevent disease progression.

OBJECTIVES: The aim of the study was to externally validate a machine learning-derived AAC 24-point algorithm (ML-AAC24) with incident ASCVD.

METHODS: Middle-aged individuals from the UK Biobank Imaging Study with lateral spine images, obtained via dual-energy x-ray absorptiometry, were included. ML-AAC24 scores were grouped as low (<2), moderate (2 to <6), and high (≥6). Linked health records were used to identify ASCVD-associated events, including hospitalizations and death.

RESULTS: Among 53,611 participants (52% female; mean age 65 years), 78.2% had low, 16.4% had moderate, and 5.4% had high ML-AAC24. After excluding people with prevalent ASCVD or missing data, 1,163 (2.3%) of 50,923 people had an incident ASCVD event over a median follow-up of 4.1 [3.0-5.5] years. In age- and sex-adjusted analysis, compared to those with low ML-AAC24, those with moderate (HR: 1.80 [95% CI: 1.57-2.08]) and high ML-AAC24 (HR: 2.87 [95% CI: 2.39-3.44]) had a higher HR for incident ASCVD. Results remained comparable after adjustment for established ASCVD risk factors. Consistent patterns were observed when considering incident coronary artery disease, myocardial infarction, and stroke.

CONCLUSIONS: Assessing ML-AAC24 on lateral spine images offers a new and promising screening method to identify people with higher risk of incident ASVD events.

Patients who receive hematopoietic stem cell transplantation (HSCT) undergo complex treatment regimens often accompanied by significant physical and psychological symptom burdens. However, patient access to psychosocial care is limited, likely in the context of persistent shortages of supportive care clinicians and services. Clinicians can offer valuable insights into psychosocial needs, barriers to accessing psychosocial support, and recommendations to improve psychosocial care for the HSCT population. This qualitative study aimed to explore the perspectives of HSCT clinicians to better understand the challenges HSCT recipients face accessing psychosocial support and how these barriers can inform strategies to enhance psychosocial care. Unlike existing literature that largely focuses on unmet needs in the HSCT population from patient perspectives and patient-reported outcomes, this study delves into the unique insights of HSCT clinicians. A purposive sampling strategy was employed to recruit clinicians across specialties in the United States, including mental health and oncology, involved in HSCT care. Semistructured individual interviews were conducted to explore psychosocial care within HSCT programs. Using a framework-guided rapid analysis, 2 coders analyzed the interviews for emergent themes. Participants (N = 21) shared perspectives on multiple emerging themes, including (1) patient psychosocial challenges (eg, isolation, psychological distress); (2) barriers to psychosocial care (eg, workforce shortage, gaps in integration and continuity of care); and (3) recommendations to improve care delivery (eg, adopting a holistic, team-based model that is proactive and tailored to the needs of HSCT patients throughout their treatment and recovery). Findings highlight critical gaps in psychosocial care for HSCT recipients and offer actionable clinician recommendations to improve psychosocial care delivery for the HSCT population.