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Importance With the availability of multiple classes of advanced therapies for the treatment of Crohn disease (CD), understanding the comparative safety of different therapies can inform treatment positioning. Objective To compare the risk of serious infections, venous thromboembolism (VTE), and major adverse cardiovascular events (MACE) with different advanced therapies in patients with CD. Design, Setting, and Participants This retrospective comparative effectiveness research study was conducted between January 1, 2016, and December 31, 2022, with a mean (SD) follow-up of 26.9 (2.4) months until July 1, 2024. Using an administrative claims database (OptumLabs Data Warehouse), commercially insured patients with CD, who initiated treatment with tumor necrosis factor-α (TNF) antagonists, anti-integrin agents (vedolizumab), interleukin (IL)-12/23p40 antagonists (ustekinumab), IL-23p19 antagonists (primarily risankizumab), or Janus kinase inhibitors (upadacitinib) between 2016 and 2022 and had follow-up for at least 1 year before and after treatment initiation, were included. Exposure TNF antagonists vs anti-integrin agents (vedolizumab) vs IL-12/23p40 antagonists (ustekinumab) vs IL-23p19 antagonists (risankizumab) vs Janus kinase inhibitors (upadacitinib). Main Outcomes and Measures The risk of serious infections, VTE, and MACE was compared with various advanced therapies through multinomial propensity score-based inverse probability treatment weighting, with propensity scores estimated through generalized boosted models, accounting for disease characteristics, health care utilization, comorbidities, and prior and concomitant medications, and through competing risk of mortality. Cause-specific hazard ratios (HRs) and 95% CIs for multiple treatment comparisons were calculated. Results This study included 12 245 patients with CD (mean [SD] age, 46.5 [17.5] years; 6642 females [54.2%]), who were treated with TNF antagonists (n = 5274), vedolizumab (n = 2716), ustekinumab (n = 3544), risankizumab (n = 559), or upadacitinib (n = 152). Serious infection incidence rates ranged from 5.46 (95% CI, 4.86-6.07) to 9.02 (95% CI, 6.38-11.89) per 100 person-years across therapies. After adjusting for confounding variables, there were no statistically significant differences in the risk of serious infections across different agents, including between risankizumab and ustekinumab (HR, 1.14 [95% CI, 0.78-1.67]), risankizumab and TNF antagonists (HR, 1.00 [95% CI, 0.68-1.47]), or ustekinumab and TNF antagonists (HR, 0.88 [95% CI, 0.74-1.04]). The incidence of VTE (incidence rate, 0.90 [95% CI, 0.71-1.10] to 2.33 [95% CI, 1.06-3.82] per 100 person-years) and MACE (0.68 [95% CI, 0.51-0.85] to 1.49 [95% CI, 0.43-2.76] per 100 person-years) was low, without any significant differences across agents. Conclusions and Relevance In this comparative effectiveness research study of patients with CD, no significant differences in the risks of serious infections, VTE, or MACE across various advanced therapies were found. These findings support clinical decision-making on choice of advanced therapies for most individual patients with CD to be driven primarily by comparative treatment effectiveness rather than driven by concerns of serious adverse events.

Abstract Diffuse hemispheric glioma, H3 G34‐mutant (DHG‐H3 G34) has been primarily molecularly characterized by methylation profiling and sequencing studies. We describe an integrated histomolecular evaluation including high‐resolution copy number profiling of a series of 60 DHG‐H3 G34 to further our understanding of the spectrum of genetic changes associated with this tumor type. Cases were clinically tested using an 187‐gene mutation and fusion targeted neuro‐oncology next‐generation sequencing panel ( n = 60) and Oncoscan chromosomal microarray ( n = 26) by a single laboratory (2018–2022). A subset of cases had immunohistochemical results for OLIG2 ( n = 42), p53 ( n = 48), and ATRX ( n = 46), and methylation array data ( n = 8). Median age at testing was 21 years (range, 12–50). No significant difference was noted in clinical, histopathological, and mutational profile between pediatric and adult patients. H3‐3A G34 mutations included G34R ( n = 56; 94%), G34V ( n = 3), and a non‐canonical G34E ( n = 1). Concurrent mutations most often involved TP53 ( n = 55; 92%), ATRX ( n = 50; 83%), and PDGFRA ( n = 34; 57%). A reportedly primary tumor was confirmed to be hypermutant and had a PMS2 mutation. A single case also showed an FGFR3::FAM184B fusion. All cases with available chromosomal microarray data had unbalanced genomes, which were often complex (14/26; 54%). The most frequent recurrent copy number abnormalities were losses involving 3q, 4q, 10q, 13q, and 18q, and 17p copy‐neutral loss of heterozygosity (cnLOH) encompassing TP53 . This copy number profile was reminiscent of that seen in Grade 4 IDH‐mutant astrocytomas. Collectively, a TP53 abnormality at copy number (12/26, all cnLOH), sequence (55/60) and protein expression (46/48) level was detected in all 60 cases. In conclusion, integrated high‐resolution copy number and histomolecular analysis expanded the spectrum of genetic changes associated with DHG‐H3 G34, including the presence of universal TP53 abnormalities with frequent cnLOH—a copy number abnormality that has been largely unrecognized—for this new 2021 World Health Organization central nervous system tumor type.

BACKGROUND: Bicuspid aortic valve (BAV) is a frequent congenital heart defect with a high heritability. Despite this, only a limited number of genes have been associated with the disease, and the molecular mechanisms remain unexplained in most cases. This study aimed to further understand the genetic architecture of BAV. METHODS: A genome-wide association study meta-analysis including 9631 cases among 65 677 participants was performed. Genes were prioritized using transcriptomic analyses based on RNA sequencing in relevant tissues, including human fetal and adult aortic valves. The impact of the knockdown or knockout of 4 candidate genes on cardiac development was verified in zebrafish. A polygenic risk score was developed, its association with BAV was evaluated in an independent cohort, and its association with a wide range of phenotypes (n=976) was evaluated in UK Biobank (n=355 618 individuals). RESULTS: Thirty-six genomic loci were identified, including 32 that were not described previously. Among the prioritized genes, KANK2 and ERBB4 were identified as potentially causal through transcriptomic analyses, colocalization, and Mendelian randomization based on gene expression in human aortic valves (n=484), whereas PRDM6 and STRN were prioritized using similar analyses from aortic (n=326) and left ventricular tissues (n=326), respectively. Targeting 4 candidate genes ( WNT4 , LEF1 , STRN , and KANK2 ) in zebrafish led to disruption in cardiac development. A polygenic risk score was associated with an odds ratio of 2.07 (95% CI, 1.90–2.25; P =5.43×10 -62 ) per SD for BAV and significantly associated with thoracic aortic aneurysm and atrial fibrillation in UK Biobank. CONCLUSIONS: This study supports a significant polygenic contribution to BAV, where the combination of multiple common variants in genes involved in heart morphogenesis disrupts aortic valve development.

Abstract Background 99mTc-labelled cardiac scintigraphy enables noninvasive diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM). Guidelines recommend using planar semiquantitative (heart to contralateral ratio, H/CL) and single photon emission computed tomography (SPECT) qualitative visual grading for diagnostic interpretation. However, planar imaging has inherent limitations, and visual grading is prone to interobserver variability, underscoring the need for standardized quantitative assessment. We developed a 3D volumetric quantitative score (3D Score) and assessed its diagnostic performance compared to myocardial tissue, the gold standard for ATTR-CM diagnosis. Methods At a single, tertiary referral center, we retrospectively identified consecutive patients from 06/2017 to 06/2024 who underwent 3-hour 99mTc-pyrophosphate or 99mTc-hydroxymethylene diphosphonate planar and SPECT/CT for suspected ATTR-CM and had archived myocardial tissue (biopsy or myectomy). On planar imaging, H/CL was calculated. On SPECT/CT, volumes of interest were drawn around the entire left ventricle (LV), avoiding calcifications, and within the right atrium (RA) blood pool. Mean uptake values were used to calculate the 3D Score (LVmean:RAmean), Fig 1A. Myocardial tissue was stained via sulfated Alcian blue and/or Congo red histochemistry. Once histologically confirmed, amyloid deposits were subtyped by liquid chromatography tandem mass spectrometry. The diagnostic performance of H/CL and 3D Score was assessed using receiver operating characteristic (ROC) curve analysis and predictive characteristics were defined. ROC areas under the curve (AUC) were compared using Delong test. Optimal cutoffs were determined using Youden’s J statistic. Baseline characteristics (demographics, echocardiogram, biomarkers) and H/CL were compared between patients above and below 3D Score cutoff. Results 239 patients were identified (median age 72 [65-78], 78% male, 46% ATTR positive). Median time between cardiac scintigraphy and myocardial tissue collection was 22 (6-65) days. Distribution of the 3D Score stratified by ATTR-CM status is illustrated in Fig 1B-C. The discriminative ability of the 3D Score was excellent (AUC 0.92) and superior to H/CL (0.87, p =0.006, Fig 1D-E). The optimal 3D Score cutoff for identifying ATTR-CM was ≥1.0 with sensitivity of 86%, specificity of 92%, positive predictive value (PPV) 90%, and negative predictive value (NPV) 89%. The optimal H/CL ratio cutoff for identifying ATTR-CM was ≥1.4 with sensitivity of 72%, specificity of 86%, PPV 81%, NPV 78%. Baseline characteristics of the overall cohort stratified by 3D Score are displayed in Table 1. Conclusions The 3D Score demonstrated excellent diagnostic performance for detecting ATTR-CM and was superior to current quantitative metrics. Future studies are needed to externally validate its performance across diverse patient cohorts and imaging centers and to investigate correlation with myocardial amyloid burden. Figure 1

Abstract Background Vascular Ehlers-Danlos syndrome (VEDS) and Marfan’s syndrome are associated with cardiovascular complications, including arrhythmias. However, atrial fibrillation (AF) risk in these populations has not been frequently reported. This study assessed the AF risk in VEDS and Marfan's syndrome patients using propensity score-matched analysis from an international database. Methods The TriNetX Research Network, an international database with de-identified patient data from over 100 centers, was used to pull patients with a diagnosis of VEDS and Marfan's Syndrome. Baseline characteristics (e.g., demographics, cardiovascular comorbidities, etc.) were collected, and propensity score matching was performed to balance the cohorts. Rates of AF were collected across both cohorts, and risk analysis and Kaplan-Meier survival were used to assess outcomes. Results A total of 1,114 and 23,172 patients had VEDS and Marfan’s syndrome, respectively. After propensity score matching, each cohort included 1,091 balanced patients regarding demographics and clinical characteristics. When compared in the matched cohorts, AF incidence was lower in VEDS (4.6%) compared to Marfan’s syndrome (8.6%), with a risk difference of -0.040 (95% CI: -0.061, -0.020; z = -3.794; p < 0.001). The risk ratio was 0.532 (95% CI: 0.381, 0.742), and the odds ratio was 0.509 (95% CI: 0.358, 0.726), indicating a significantly lower risk of AF in VEDS. Kaplan-Meier analysis showed an AF survival probability of 84.23% in VEDS and 78.20% in Marfan’s syndrome (log-rank p = 0.071). The hazard ratio was 0.723 (95% CI: 0.508, 1.029), which didn’t reach statistical significance (p = 0.579). Conclusion Patients with VEDS have a significantly lower risk of developing AF compared to those with Marfan’s syndrome. However, no significant difference in AF survival probability was observed. These findings suggest significant differences in the arrhythmic burden between these connective tissue disorders, which can direct future risk stratification and management strategies.Figure 1

Abstract Background Common genetic variation has been linked to an increased risk of developing dilated cardiomyopathy (DCM) in case-control studies. However, the phenotypic profile and biological mechanisms by which genetic background may predispose individuals to DCM and outcomes in the general population remain unclear. Aim The primary objectives of this study were twofold: (1) to validate a DCM polygenic score (PRS-1) based on a prior meta-analysis of case–control genetic association studies [Tadros R et al. Nat Genet (2021)]; and (2) To apply this PRS, along with two recently developed PRSs for DCM [PRS-2 from Zheng SL et al. Nat Genet (2024) and PRS-3 from Jurgens SJ et al. Nat Genet (2024)] to a general population that underwent comprehensive longitudinal phenotypic assessments and had long-term outcomes available. Methods While the PRS-1 was derived from only 13 SNPs, PRS-2 and PRS-3 were generated from 709,534 and 1,072,247 SNPs, respectively with significant overlap between them. These DCM-PRSs were applied to an unselected community-based cohort (n=1897) aged >45 years, who underwent a physical examination, echocardiogram, and blood sample at baseline. Subsequent clinical outcomes were collected over a median 16 year follow-up (IQR: 15-17). Results No significant differences between the quartiles were present in terms of age, sex (48% male), and cardiovascular risk factors (CV-RF) (such as hypertension, diabetes, and coronary artery disease). However, linear regression models demonstrated a significant correlation between all DCM-PRSs and left ventricular (LV) parameters, including LV ejection fraction, LV end-systolic diameter, and LV end-diastolic diameter (Table). Multivariable regression analysis confirmed that these correlations were independent of age, sex, CV-RF, and population stratification (adjusted for the first 10 principal components [PCs]). During follow-up, 47 individuals developed DCM. A logistic regression analysis, using a 3:1 matched cohort of non-DCM vs. DCM individuals based on age and sex and adjusted for the same 10 PCs, found a significant correlation between DCM development and both PRS-1 [OR=2.27 (1.06–4.85), p=0.03] and PRS-3 [OR=2.63 (1.20–5.75), p=0.02], while PRS-2 did not show a significant association [OR=1.85 (0.84–4.06), p=0.12]. No association was found between the DCM-PRSs and heart failure (HF) biomarkers (aldosterone, natriuretic peptides, ST2, Galectin-3) or HF outcomes (all-cause mortality/HF hospitalization). Conclusion PRS-1 for DCM despite being derived from only 13 risk alleles, performs at least as well as the newer and more extensive PRSs, in its correlation with LV function, dimensions, and DCM development (except for PRS-2) in a general population. The absence of correlation between these DCM-PRSs and the renin-angiotensin-aldosterone system or natriuretic peptides suggests that genetic background influences LV traits through mechanisms independent of these biological pathways.

Since its introduction into medical terminology by Lord Henry Cohen in 1941, the term “neurapraxia” has become established in the neurological and neurosurgical lexicon, although it is often misused or misspelled. It denotes a transient dysfunction of a peripheral nerve, as distinct from axonotmesis and neurotmesis, which describe more significant structural injuries to a peripheral nerve. To expand our understanding of neurapraxia, it is necessary to examine the phenomenon in both temporal and spatial contexts. This study examines neurapraxia in: (A) Time—(1) the origins of the term neurapraxia and (2) the time-course of a neurapraxic injury and its recovery, and (B) Space—(3) the microstructure of a neurapraxic injury and (4) the locations of neurapraxic injuries within the peripheral nervous system. We demonstrate that the term neurapraxia encompasses both a temporal and a spatial definition. In time, it applies to transient peripheral nerve palsy, from which recovery occurs before there is sufficient time for axonal regeneration, typically within a few weeks. In space, there is a histopathological change limited to localized demyelination in nerves lined by epineurium and myelinated by Schwann cells. Nerves distal to the spine qualify as nerves to which the term neurapraxia can apply; however, cranial nerves and spinal nerve roots (including cauda equina) are inconsistent with this owing to the variability in myelinating cells along their course (oligodendroglia proximally, i.e., central glial segment), the absence of an epineurial covering, and exposure to cerebrospinal fluid.

BACKGROUND AND OBJECTIVES: Myelomeningocele is defined by the presence of a fluid-filled sac that contains the neural placode and cerebrospinal fluid (CSF) at the level of the spinal defect. Alternatively, the term myeloschisis is used when the neural placode is not contained within a CSF-filled sac. While both are eligible for prenatal closure, few studies have characterized the impact of the type of lesion on postnatal outcomes. This study compares the outcomes of these 2 types of open spinal dysraphism using data from the Fetal Myelomeningocele Consortium registry sponsored by the North American Fetal Therapy Network. METHODS: The prospective observational Fetal Myelomeningocele Consortium registry was used to extract deidentified data corresponding to patients who underwent fetal closure of myelomeningocele vs myeloschisis. Demographics, operative characteristics, perioperative complications, and postnatal outcomes were collected. RESULTS: A total of 1327 patients were identified, including 991 (74.7%) with myelomeningocele and 336 (25.3%) with myeloschisis. Compared with myelomeningocele, myeloschisis was associated with lower rates of prenatal talipes (11% vs 24%, P < .001) and higher rates of favorable prenatal movement (94% vs 86%, P < .001). Postnatally, myeloschisis conferred higher rates of leg movement (97% vs 90%, P = .002) and an increased likelihood of ambulation in the household (10.4% vs 4.1%, P = .009) and outside (7.2% vs 1.9%, P = .004) at 1 year. However, myeloschisis was also linked to greater use of skin patches during closure (49% vs 27%, P < .001), higher CSF leak rates among those with wound dehiscence (26% vs 8%, P = .014), and more frequent CSF diversion and tethered cord surgeries at follow-up. CONCLUSION: Myeloschisis and myelomeningocele demonstrate distinct clinical profiles. Although patients with myeloschisis may have favorable motor outcomes, they are also characterized by higher rates of CSF leakage, CSF diversion, and tethered cord surgery. These findings highlight the need for lesion-specific prognostication and may inform surgical planning and parental counseling in the context of prenatal spina bifida closure.

Abstract Background Treatment with immune-checkpoint inhibitors (ICI) may be associated with adverse cardiac events. Troponin elevation is part of the diagnostic criteria for ICI related myocarditis (ICIrM) and myocardial infarction (MI), however there is limited data for causes of troponin elevation independent of MI and ICIrM and their clinical outcomes with ICI therapy. Purpose To assess the diagnostic and prognostic value of high-sensitivity troponin T (hs-TnT) in patients treated with ICI based on different etiologies and association with cardiac events. Methods All patients treated with ICI who had hs-TnT measured at a multi-center institution from 2011 to 2022 were included. Medical records were reviewed for baseline characteristics and long-term outcomes, including cardiac death and MACE (MI, stroke, heart failure [HF]), and cause of hs-TnT elevation. Risk of cardiac events and mortality were compared for the different etiologies of hs-TnT elevation. Results Of 5,423 patients treated with ICI, 1669 had post-ICI hs-TnT measurement. Mean age was 68.7±11.3 years, 58.3% were male, with follow-up through one year from ICI first administration. Elevated hs-TnT was seen in 1136 patients, with the different causes for elevation depicted in Figure 1, panel A. ICIrM patients exhibited the highest median hs-TnT value of 364 ng/L (IQR 1096), followed by a median of 98 ng/L for MI/Type 2 ischemia, 61 ng/L for infection/sepsis, 51 ng/L for pulmonary embolus, 50 ng/L for HF and 27 ng/L for indeterminate causes, Figure 1, panel B. Additionally, median time from first ICI dose to hs-TnT elevation according to each of the diagnoses are depicted in Figure 1, panel C, with ICIrM showing the shortest median time of 44 days (IQR 74). Hs-TnT elevation in patients with ICIrM had the highest risk for cardiac death (HR 52.7, 95% CI 11.7-238.0, p&lt;0.001), followed by hs-TnT elevation due to HF (HR 15.9, 95% CI 2.9-87.0, p=0.001), MI/type 2 ischemia (HR 11.6, 95% CI 2.4-56.1, p=0.002), and infection/sepsis (HR 5.7, 95% CI 1.0-31.0, p=0.045) compared to those with no hs-TnT elevation, Figure 2, panel A. Similarly, patients with ICIrM had highest risk for MACE (HR 8.2, 95% CI 4.4-15.3, p&lt;0.001), followed by increased hs-TnT due to MI/type 2 ischemia (HR 8.1, 95% CI 5.0-13.1, p&lt;0.001), HF (HR 7.6, 95% CI 4.2-13.7, p&lt;0.001), pulmonary embolism (HR 5.1, 95% CI 2.5-10.8, p&lt;0.001), infection/sepsis (HR 4.1, 95% CI 2.4-7.0, p&lt;0.001), and indeterminate cause (HR 2.4, 95% CI 1.5-3.8, p&lt;0.001), Figure 2, panel B. Conclusions Hs-TnT measurements have prognostic value for cardiac events in cancer patients receiving ICI therapy, including in those without ICIrM. Patients with ICIrM demonstrated the highest median hs-TnT levels and the poorest outcomes, with a graded response observed; the worst prognosis was seen in patients with hs-TnT elevation due to ICIrM, followed by other causes, and those without hs-TnT elevation had the best prognosis.Figure 1 Figure 2