Publications by Year: 2025

Background/Objectives: Although clinicopathologic correlation with integration of clinical and radiographic data is the gold standard in distinguishing primary extramammary Paget disease (EMPD) from secondary EMPD, immunoprofiling of EMPD tumors enables distinction between primary and secondary EMPD. Methods: We evaluated the immunoprofiles of previously published cases in the literature as well as 12 secondary EMPD cases from our archives in order to construct a diagnostic algorithm that enables the distinction between primary and secondary EMPD. Results: Immunoprofiles of 480 primary (published cases) and 132 secondary (120 published cases and 12 institutional cases) EMPD cases were compared. CK7, CK20, CDX2, GATA3, GCDFP15, TRPS1, and SATB2 expression was significantly different in primary EMPD versus colonic secondary EMPD (p < 0.001 for all except SATB2, p = 0.036). CK20, GCDFP15, TRPS1, p63 and uroplakin II/III expression was significantly different in primary EMPD versus urothelial secondary EMPD (p < 0.001). CK7, CDX2, SATB2, GATA3 and p63 expression was significantly different in colonic versus urothelial secondary EMPD. CK20, CDX2, and GCDFP15 expression was significantly different in colonic versus prostatic secondary EMPD. CK20 expression was significantly different in colonic versus prostatic secondary EMPD (p = 0.018). CK20, GCDFP15 and TRPS1 are helpful in the distinction of primary EMPD versus colonic and urothelial secondary EMPD (p < 0.001). Conclusions: We propose that the initial IHC panel should include TRPS1, CK7 and CK20. In TRPS1-negative cases, additional immunostains should be performed: CDX2 and SATB2 for colonic; p63, GATA3 and uroplakin II/III for urothelial; and PSA and NKX3.1 for prostatic secondary EMPD.

Background/Objectives: Anterior cruciate ligament (ACL) injuries frequently lead to long-term quadriceps impairments despite surgical repair. There is growing evidence that these deficits are caused in part by alterations in the central nervous system. Thus, transcranial neuromodulation (TNM) could be valuable in ACL rehabilitation. To systematically review randomized controlled trials (RCTs) assessing the effects of TNM on neurophysiological, functional, and safety outcomes in patients with ACL injury or reconstruction. Methods: We conducted searches on PubMed, Scopus, Web of Science, and Cochrane. We considered all original studies evaluating TNM, including transcranial current stimulation (tCS) and transcranial magnetic stimulation (TMS), in patients with ACL reconstruction or injury. Measures of corticospinal excitability, safety, balance, and muscle strength were assessed. We employed the Cochrane RoB 2 method to assess the risk of bias. Results: Seven studies comprising 129 participants (64 TNM, 65 controls) were included. Most studies applied transcranial direct current stimulation (tDCS) over the primary motor cortex contralateral to the ACL injury in conjunction with physical rehabilitation. Single-session protocols demonstrated minimal effects, whereas repeated sessions resulted in improvements in corticospinal excitability, quadriceps strength, and balance. No serious adverse events were reported; minor effects included transient headache or scalp tingling. The risk of bias was assessed as low to moderate across the studies. Conclusions: TNM appears to be safe and may enhance functional recovery in individuals with ACL injuries when administered in multiple sessions alongside standard rehabilitation. Further high-quality trials are necessary to determine optimal protocols and long-term outcomes.

Background: The US Food and Drug Administration (FDA) authorized over 690 machine learning (ML)-enabled medical devices between 1995 and 2023. In 2024, new guidance enabled the inclusion of Predetermined Change Control Plans (PCCPs), raising expectations for transparency, equity, and safety under the Good Machine Learning Practice (GMLP) framework. Objective: The objective was to assess regulatory pathways, predicate lineage, demographic transparency, performance reporting, and PCCP uptake among ML-enabled devices approved by the FDA in 2024. Methods: We conducted a cross-sectional analysis of all FDA-authorized ML-enabled devices in 2024. Data extracted from FDA summaries included regulatory pathway, predicate genealogy, performance metrics, demographic disclosures, PCCPs, and cybersecurity statements. Descriptive and nonparametric statistics were used. Results: The FDA authorized 168 ML-enabled Class II devices in 2024. Most (94.6%) were cleared via 510(k); 5.4% were cleared via De Novo. Radiology dominated (74.4%), followed by cardiovascular (6.5%) and neurology (6.0%). Non-US sponsors accounted for 57.7% of clearances. Among 159 510(k) devices, 97.5% cited an identifiable predicate; the median predicate age was 2.2 years (IQR 1.2-4.1), and 64.5% ML-enabled. Predicate reuse remained uncommon (9.9%). Median review time was 162 days (151 days for 510(k) vs. 372 days De Novo; p < 0.001). A total of 49 devices (29.2%) reported both sensitivity and specificity; 15.5% provided demographic data. PCCPs appeared in 16.7% of summaries, and cybersecurity considerations appeared in 54.2%. Conclusions: While 2024 marked a record year for ML-enabled device approvals and internationalization, uptake of PCCPs and transparent performance and demographic reporting remained limited. Policy efforts to standardize disclosures and strengthen post market oversight are critical for realizing the promises of GMLP.

Background: Circulating sphingolipids have been implicated in central nervous system degenerative disorders, but their relationship with peripheral neuropathy remains unclear. Objectives: To evaluate associations between plasma sphingolipid levels and subsequent loss of vibration and light pressure sensation in the lower limbs of older adults. Methods: Plasma concentrations of 11 ceramide (Cer) and sphingomyelin (SM) species were measured in stored samples from 4612 participants in the Cardiovascular Health Study. Vibration sensation was assessed 4-6 years later in 2208 individuals using tuning fork testing, and light pressure sensation was evaluated 11-13 years later in 815 participants using monofilament testing. Sensory impairment was graded on a 3-point scale, with higher scores indicating greater loss. Ordinal logistic regression models examined associations between a doubling of sphingolipid levels and sensory decline, with stratification by diabetes status. Results: In primary models, no sphingolipid species showed significant associations with sensory outcomes. However, after adjusting for inflammatory markers, higher SM-16 levels were linked to increased odds of vibration sensation loss (OR 2.08; 95% CI: 1.11-3.90), while higher SM-24 levels were associated with reduced odds (OR 0.68; 95% CI: 0.46-0.998). Significant interactions with diabetes status were observed for light pressure sensation: SM-14 was associated with increased odds of sensory loss in participants with incident diabetes (OR 5.22; 95% CI: 1.58-17.29), and Cer-18 was associated with increased odds in those with prevalent diabetes (OR 2.38; 95% CI: 1.18-4.78). Conclusions: Elevated levels of specific ceramide and sphingomyelin species may be predictive of future peripheral sensory loss in older adults, with diabetes status influencing these associations.

Background/Objectives: Hemodynamic stressors, including abnormal wall shear stress (low or high) or oscillatory shear index are recognized as contributors to the pathogenesis, growth, and rupture of intracranial aneurysms (IAs). Computational fluid dynamics (CFD) has therefore become an essential tool for their quantitative assessment. This systematic review aimed to identify the most frequently analyzed hemodynamic and morphological parameters in recent CFD studies and summarize the methodological strategies employed. Methods: A systematic review was conducted following the PRISMA guidelines, including original studies published between 2019 and 2024 in PubMed, Scopus, Web of Science, and Embase databases. Eligible studies applied CFD to human saccular aneurysms addressing rupture or growth. Exclusion criteria comprised stent-assisted treatments, idealized or phantom models, and non-human or in vitro analyses. Extracted data included study characteristics, CFD software, meshing and solver approaches, and reported parameters. Results: Thirty-five studies met the eligibility criteria. Commercial software predominated across the segmentation, meshing, and solver stages. The most frequently evaluated wall shear stress metrics were the oscillatory shear index (OSI, 91.43%), time-averaged wall shear stress (TAWSS, 71.43%), low shear area ratio (LSAR, 60.00%), normalized wall shear stress (NWSS, 51.43%), and relative residence time (RRT, 45.71%). Morphological parameters such as the aspect ratio (AR, 74.29%), size ratio (SR, 68.57%), and volume (42.86%), reflecting aneurysm shape and relative size, were the most consistently evaluated and demonstrated strong associations with rupture and growth. Conclusions: A core set of morphological and hemodynamic parameters (AR, SR, TAWSS, OSI, RRT, and LSAR) was consistently identified as potential discriminators for the rupture and growth of intracranial aneurysms. However, substantial methodological heterogeneity and the absence of unified standards hinder reproducibility and clinical translation. Future research must urgently standardize computational frameworks, parameter definitions, and boundary conditions to enhance the consistency, comparability, and clinical applicability of CFD in aneurysm risk assessment.

Background: The best treatment for children with KD who fail to respond to the first dose of IVIG (refractory KD) is currently unknown. The purpose of this study was to determine treatment practices of pediatric rheumatologists in North America who manage IVIG-refractory KD. Methods: A 34-item web-based survey was sent to 102 randomly selected members of the Childhood Arthritis and Rheumatology Research Alliance (CARRA). The anonymous survey addressed the use of primary intensification as well as the treatment of IVIG-refractory KD. Results: The response rate was 82%; 56% (all pediatric rheumatologists) completed the survey. Primary intensification was used for macrophage activation syndrome (MAS), KD shock, and those at high risk for coronary artery aneurysms (CAAs) by 84%, 76% and 52% of responders, respectively, with corticosteroids (CSs) used most frequently. For IVIG-refractory KD without CAA, a second dose of IVIG was used most often (63% alone; 23% plus CS). With non-giant CAAs, only 15% used a second IVIG alone, 40% used IVIG plus CS, and 35% took infliximab, usually with CS/IVIG. With giant CAA, treatments used most frequently were CS, a second IVIG, and infliximab (91%, 69%, and 58%, respectively), usually as combinations of two or more medications. Conclusions: Treatment of IVIG-refractory KD varies significantly among North American pediatric rheumatologists, particularly in the presence of CAAs. Our findings emphasize the need for research to identify the most effective therapy for this KD subgroup. The current use of primary intensification and the presence and size of the CAA will need to be considered as consensus treatment plans are developed.

Background: Autism spectrum disorder (ASD) and related neurodevelopmental conditions are a significant public health concern, with diagnostic delays hindering timely intervention. Traditional assessments often lead to waiting times exceeding a year. Advances in artificial intelligence (AI) and biomarker-based screening offer objective, efficient alternatives for early identification. Objective: This review synthesizes the latest evidence for AI-enabled technologies aimed at improving early ASD identification. Modalities covered include eye-tracking, acoustic analysis, video- and sensor-based behavioral screening, neuroimaging, molecular/genetic assays, electronic health record prediction, and home-based digital applications or apps. This manuscript critically evaluates their diagnostic accuracy, clinical feasibility, scalability, and implementation hurdles, while highlighting regulatory and ethical considerations. Findings: Across modalities, machine learning approaches demonstrate strong accuracy and specificity in ASD detection. Eye-tracking and voice-acoustic classifiers reliably differentiate for autistic children, while home-video analysis and Electronic Health Record (EHR)-based algorithms show promise for scalable screening. Multimodal integration significantly enhances predictive power. Several tools have received Food and Drug Administration clearance, signaling momentum for wider clinical deployment. Issues persist regarding equity, data privacy, algorithmic bias, and real-world performance. Conclusions: AI-enabled screeners and diagnostic aids have the potential to transform ASD detection and access to early intervention. Integrating these technologies into clinical workflows must safeguard equity, privacy, and clinician oversight. Ongoing longitudinal research and robust regulatory frameworks are essential to ensure these advances benefit diverse populations and deliver meaningful outcomes for children and families.

BACKGROUND: Medical education is becoming a more structured and recognized field of medicine. Beyond working at an academic medical center or doing occasional didactic or clinical teaching, some physicians dedicate significant time and effort to becoming medical educators. Little is known about the ways in which these physicians enter the field of medical education.

METHODS: This qualitative study utilized purposeful sampling to identify medical educators from different institutions and geographical areas, categorized by gender and career stage. Semi-structured interviews were conducted. Data related specifically to participants’ initial interest in medical education and foundational work in this area were identified and evaluated. Reflexive thematic analysis was used to develop themes across items and participants.

RESULTS: Twenty-two medical educators (11 male, 11 female) were interviewed. The average age of the participants was 51 (range: 31–72). Time from completion of training averaged 18 years (range: <1–41 years). Their paths to medical education were evaluated as part of a larger study examining the motivations of medical educators. The participants described varied ways of entering the field of medical education: by chance, through the influence and direction of others, or via self-advocacy.

CONCLUSIONS: Physicians become medical educators along different pathways, and their stories reflect varied perspectives and interpretations of career influences. Informal channels provide opportunities for some. However, offering positions to known contacts severely limits the number of potential applicants. This process may hinder efforts to create a diverse workforce in medical education.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12909-025-08014-9.

UNLABELLED: Nociceptors are primary afferent neurons that sense noxious stimuli. They can be activated by tissue injury as well as the accompanying local immune response. We have shown that following nerve injury in mice, cytotoxic Natural Killer (NK) cells infiltrate the peripheral nerve where they interact with stress-induced ligands of the activating receptor NKG2D (Klrk1). However, the diversity and specificity of NKG2D receptor ligands among sensory neuron subtypes, and translation of this mechanism to human cells, remains unknown. We used dorsal root ganglion (DRG) neurons cultured from C57BL/6J mice of both sexes with fluorescently labelled sensory neuron lines (Scn10a, Mrgprd, Calca, Trpv1, Th, Thy1), as well as human induced pluripotent stem cell-derived (hiPSCd)-sensory neurons after laser ablation, as in vitro models of axonal injury. We assessed the expression of NKG2D ligands by quantitative polymerase chain reaction (PCR) corroborated by publicly available RNA sequencing datasets and validated with single-cell PCR. Recombinant NKG2D receptor proteins were used in live cell-based assays to reveal the subcellular membrane localisation of NKG2D ligands with quantification by semi-automated image analysis. Functional interactions between human NK cells and sensory neurons were confirmed with co-cultures in microfluidic devices. We show that NKG2D ligands are expressed exclusively in unmyelinated DRG neurons after injury. Soluble mouse NKG2D receptors bound to puncta along distal neurites of injured axons enriched predominantly in Mrgprd-expressing non-peptidergic nociceptors. We observed low-level binding of soluble human NKG2D receptors to neurites of hiPSCd sensory neurons that increased after axonal laser ablation. Degeneration of hiPSCd sensory neurites by interleukin (IL-2) primed human NK cells was prevented by an NKG2D blocking antibody. The induction and enrichment of functional NKG2D receptor ligands selectively on pathological nerve fibres could aid the diagnosis of peripheral neuropathy in chronic pain conditions, and sheds new light on the potential role of nociceptive neurons in regulating the local tissue immune microenvironment.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-025-03675-1.

Weight stigma in healthcare contributes to poor patient outcomes, emotional harm, and avoidance of care. Healthcare systems are often perceived as hostile environments for many larger-bodied people who often report feeling judged, dismissed or denied appropriate treatment. Despite growing awareness, most medical educational programs and healthcare systems do not address weight bias directly. Persuading clinicians and staff to disrupt the traditional medical paradigm and instead adopt a size-inclusive perspective requires educational materials that push the envelope without pushing learners off a cliff. This paper describes the development of a weight-inclusive e-course designed to raise awareness of the impact of anti-fat bias in medicine. Grounded in the philosophical frameworks of Health at Every Size™ (HAES™) and Trauma-Informed Care (TIC), the course was co-created by a multidisciplinary team including clinicians, educators, activists, and individuals with lived experience. The collaborative process emphasized shared leadership, inclusive design, and emotional safety. We detail the course's development over six months of weekly virtual meetings, including content creation, conflict resolution, accessibility planning, and evaluation design. The course includes three tracks tailored to clinicians, staff, and patients, and integrates practical tools for weight-neutral care. Lessons learned from this process offer a replicable model for inclusive curriculum design. Our aim is for learners to engage deeply with this work in order to fully reap the benefits for themselves and their patients. Institutions seeking to address weight stigma can use this framework to foster respectful, equitable care for people in all bodies.