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Introduction: Loss-of-function (LOF) and gain-of-function (GOF) pathogenic variants in the KCNH2 -encoded Kv11.1 potassium channel cause type 2 long QT syndrome(LQT2) and type 1 short QT syndrome (SQT1), respectively. Given the prevalence of KCNH2- mediated heart disease (1 in 8000 for LQT2,1 in 100,000 for SQT1) and the reduced penetrance/variable expressivity seen in LQTS and SQTS, large databases such as the Genome Aggregation Database (gnomAD, n=141,352 individuals) might harbor subjects with unidentified LQT2/SQT1-causative mutations. Objective: To determine which “ultra-rare” KCNH2 missense variants (MVs) in gnomAD are most likely to be LQT2- or SQT1-causative. Methods: A list of gnomAD-derived MVs in KCNH2 was compiled. The frequency of each MV in gnomAD was assessed. Each MV was analyzed by 8 in silico pathogenicity prediction tools. MVs that were seen once in gnomAD and predicted damaging by all 8 tools were considered possible LQT2/SQT1-causative MVs worthy of functional validation via whole-cell patch clamp. Results: Overall, 233/474 (49%) of gnomAD KCNH2 MVs were seen in just 1 of >140,000 subjects. Of these, 2 (0.4%) MVs (S320W, S379Y) were predicted damaging by 8 in silico tools. Both S320W and S379Y localize to the N-terminus of the Kv11.1 potassium channel. There was no significant change in peak or tail current density between heterozygously expressed KCNH2-S320W (n=13, p=NS) and KCNH2-WT (n=13). However, heterozygous KCNH2-S379Y (n=12) produced a marked increase in peak current density across the range -30 mV to +20 mV and shifted the V 1/2 of activation by -17 mV (p < 0.001). Also, tail current density of S379Y channels significantly increased across the range -20 mV to +20 mV and the V 1/2 of deactivation shifted by -26 mV (p < 0.001). Conclusion: With this stringent requirement of ultra-rarity, universal prediction of damaging impact, and functionally abnormal electrophysiological properties, one SQT1-causative pathogenic variant in gnomAD was identified consistent with the predicted frequency of SQTS. The search continues among the remaining 32 ultra-rare MVs in KCNH2 where at least 75% of the in silico tools predicted deleterious impact of the MV to find the 15-20 subjects in gnomAD’s population who ought to have an LQT2-causative MV.

Introduction: Loss-of-function (LOF) variants in the KCNH2 -encoded Kv11.1 potassium channel cause type 2 long QT syndrome (LQT2). To date, hundreds of KCNH2 missense variants (MVs) have been published as “disease-causative”. However, it has been suggested that 10% of rare LQTS variants in the literature may be "false positives”. Objective: To determine previously published KCNH2 variants that are likely false positives and warrant demotion to at least likely benign status. Methods: A list of all case-derived LQT2-associated MVs from six large published compendia was compiled. The frequency of each MV within the Genome Aggregation Database (gnomAD, n = 141,352 individuals) was recorded. Eight in silico variant assessment tools were used to grade each MV. Variants (n=8) absent in gnomAD but predicted “benign” by all 8 tools were considered potential false positives, despite being ultra-rare, and were characterized functionally using whole-cell patch clamp. Results: Overall, 339 KCNH2 MVs were identified among LQTS cases. Of these, 13 (4%) were seen at a minor allele frequency (MAF) > 0.0004 in gnomAD. This MAF cut-off is derived from the frequency of R176W-KCNH2, a well-established albeit weakly penetrant (i.e. < 20%) LQT2-causative MV. Variants seen at MAF > R176W-KCNH2 are unlikely to be LQT2-contributing. However, 253 MVs (75%) were absent in gnomAD. Of these, 8 (4%) MVs (I96V, G187S, A203T, P241L, H254Q, G314S, P935S, and P963T) were predicted by all 8 in silico tools to be benign and had never been characterized functionally. Patch clamp studies did not demonstrate any LOF perturbation for these 8 MVs. Conclusion: This study offers compelling evidence for the demotion from LQT2-causative status to likely benign status for 21 (6%) of the 339 previously published LQT2 MVs based either on i) gnomAD MAF unacceptably high for a 1:8000 disorder (LQT2) for 13 MVs or ii) ultra-rarity (never seen in gnomAD) but in silico variant assessment tools predicting benign impact of the amino acid substitution and in vitro functional validation studies devoid of LOF for 8 additional MVs. This meticulous “pruning” exercise must be conducted for all published variants previously implicated as the monogenic cause for LQTS in particular and all genetic heart diseases in general.

Background: The primary cardiac manifestations of the Marfan syndrome (MFS) include aortic root dilation and mitral valve prolapse (MVP). There are only scant data describing MV disease in MFS patients who undergo aortic root replacement. Methods: We retrospectively studied 239 patients (90 female; mean age 34 y) with MFS enrolled in a prospective multicenter registry. All patients were referred for repair of aortic root aneurysms with either composite graft aortic valve replacement (AVR, n=59) or an aortic valve-sparing procedure (AVS, n=180). MVP and mitral regurgitation (MR) severity was evaluated by echocardiography preoperatively and during follow-up (postoperatively, 6 months, and 1, 2, and 3 years after surgery). The severity of MR was graded as none, trivial (0), mild (1), moderate (2), moderate to severe (3), or severe (4). Preoperative echocardiography identified MVP in 166 (69%) patients without previous MV intervention. Results: Forty-one (25%) of 166 patients with MVP received AVR, and 125 (75%) received AVS, with similar proportions of patients with preoperative MR grade >2 in the two groups ( p =0.7). Thirty-three patients (20%) underwent concomitant MV intervention: 29 repairs and 4 replacements (15 patients (45%) had MR >2, 11 (33%) had MR=2, and 7 had MR ≤1). All patients with MR >2 underwent a MV procedure. One patient following MV repair required MV replacement on postoperative day 16 after developing grade 4 MR. No other patient required MV reintervention during follow-up (mean clinical follow-up, 30±9 months). Echocardiography performed 21±13 (±1 SD) months postoperatively revealed MR >2 in only 1 of 158 patients. There were 1 early death (bleeding) and 2 late deaths (multi-organ failure and unknown cause); all deaths occurred in patients with concomitant MV surgery. Conclusions: MVP is present in 69% of patients with MFS undergoing aortic root replacement; 20% of patients with MVP underwent a concomitant MV procedure. Short-term results suggest that a simultaneous MV procedure in patients with MR >2 is reasonable because operative risk was not increased and subsequent MV procedures were rare. More follow-up is needed to learn if prophylactic MV intervention at the time of aortic surgery might benefit patients with MR ≤2.

AbstractUse of magnetic resonance (MR) imaging in radiation therapy has increased substantially in recent years as more radiotherapy centers are having MR simulators installed, requesting more time on clinical diagnostic MR systems, or even treating with combination MR linear accelerator (MR‐linac) systems. With this increased use, to ensure the most accurate integration of images into radiotherapy (RT), RT immobilization devices and accessories must be able to be used safely in the MR environment and produce minimal perturbations. The determination of the safety profile and considerations often falls to the medical physicist or other support staff members who at a minimum should be a Level 2 personnel as per the ACR. The purpose of this guidance document will be to help guide the user in making determinations on MR Safety labeling (i.e., MR Safe, Conditional, or Unsafe) including standard testing, and verification of image quality, when using RT immobilization devices and accessories in an MR environment.

Abstract Background Error analysis plays a crucial role in clinical concept extraction, a fundamental subtask within clinical natural language processing (NLP). The process typically involves a manual review of error types, such as contextual and linguistic factors contributing to their occurrence, and the identification of underlying causes to refine the NLP model and improve its performance. Conducting error analysis can be complex, requiring a combination of NLP expertise and domain-specific knowledge. Due to the high heterogeneity of electronic health record (EHR) settings across different institutions, challenges may arise when attempting to standardize and reproduce the error analysis process. Objectives This study aims to facilitate a collaborative effort to establish common definitions and taxonomies for capturing diverse error types, fostering community consensus on error analysis for clinical concept extraction tasks. Materials and Methods We iteratively developed and evaluated an error taxonomy based on existing literature, standards, real-world data, multisite case evaluations, and community feedback. The finalized taxonomy was released in both .dtd and .owl formats at the Open Health Natural Language Processing Consortium. The taxonomy is compatible with several different open-source annotation tools, including MAE, Brat, and MedTator. Results The resulting error taxonomy comprises 43 distinct error classes, organized into 6 error dimensions and 4 properties, including model type (symbolic and statistical machine learning), evaluation subject (model and human), evaluation level (patient, document, sentence, and concept), and annotation examples. Internal and external evaluations revealed strong variations in error types across methodological approaches, tasks, and EHR settings. Key points emerged from community feedback, including the need to enhancing clarity, generalizability, and usability of the taxonomy, along with dissemination strategies. Conclusion The proposed taxonomy can facilitate the acceleration and standardization of the error analysis process in multi-site settings, thus improving the provenance, interpretability, and portability of NLP models. Future researchers could explore the potential direction of developing automated or semi-automated methods to assist in the classification and standardization of error analysis.

OBJECTIVE The aim of this study was to compare outcomes of direct targeting in deep brain stimulation (DBS) for essential tremor using 7T MRI versus 3T MRI. The authors hypothesized that 7T MRI direct targeting would be noninferior to 3T MRI in early tremor outcomes. METHODS A retrospective study was conducted on patients undergoing unilateral thalamic DBS for essential tremor between 2021 and 2023. Two matched cohorts were assessed, one using 7T MRI and the other using 3T MRI for surgical planning. The primary endpoint was the percentage improvement in the Fahn-Tolosa-Marin Tremor Rating Scale (TRS) scores. Additionally, the authors assessed optimized programming settings and variance in electrode position on postoperative imaging. Demographic and clinical data were compared using the nonparametric Mann-Whitney U-test. The squared Euclidean distance of each contact from the group mean centroid was calculated and averaged across the entire cohort to provide the variance (i.e., the mean squared distance) of electrode contact position. RESULTS A total of 34 patients were analyzed, with 17 in each cohort. There were no significant differences in demographic information or mean surgical dates between the groups. There were no differences in intraoperative target repositioning or adverse events. The 7T group had a significantly greater TRS improvement than the 3T group (64.9% ± 11.4% vs 50.9% ± 16.4%, p = 0.004). Patients in the 7T cohort also had a lower mean stimulation current compared with those in the 3T cohort (2.0 ± 0.8 mA vs 2.7 ± 0.9 mA, p = 0.01). Image evaluation revealed that although the mean electrode position was comparable between 7T and 3T, the 7T electrode positioning was more clustered, indicating a lower variance in the final electrode location. The mean Euclidean distance between the individual electrode tips and the group centroid was significantly less at 7T than at 3T (1.82 ± 0.68 mm vs 2.75 ± 0.81 mm, p = 0.001). CONCLUSIONS Despite concerns for increased artifacts and distortions at 7T, the authors show that these effects can be mitigated with an appropriate workflow, leading to improved surgical outcomes with direct targeting using 7T MRI. Their results suggest similar accuracy but greater precision in targeting with 7T MRI compared with 3T MRI, resulting in lower stimulation currents and improved tremor reduction. Future studies are needed to assess outcomes related to 7T MRI in targeting other subcortical structures.

Abstract Febrile infection‐related epilepsy syndrome (FIRES) is a subset of new onset refractory status epilepticus (NORSE) that involves a febrile infection prior to the onset of the refractory status epilepticus. It is unclear whether FIRES and non‐FIRES NORSE are distinct conditions. Here, we compare 34 patients with FIRES to 30 patients with non‐FIRES NORSE for demographics, clinical features, neuroimaging, and outcomes. Because patients with FIRES were younger than patients with non‐FIRES NORSE (median = 28 vs. 48 years old, p = .048) and more likely cryptogenic (odds ratio = 6.89), we next ran a regression analysis using age or etiology as a covariate. Respiratory and gastrointestinal prodromes occurred more frequently in FIRES patients, but no difference was found for non‐infection‐related prodromes. Status epilepticus subtype, cerebrospinal fluid (CSF) and magnetic resonance imaging findings, and outcomes were similar. However, FIRES cases were more frequently cryptogenic; had higher CSF interleukin 6, CSF macrophage inflammatory protein‐1 alpha (MIP‐1a), and serum chemokine ligand 2 (CCL2) levels; and received more antiseizure medications and immunotherapy. After controlling for age or etiology, no differences were observed in presenting symptoms and signs or inflammatory biomarkers, suggesting that FIRES and non‐FIRES NORSE are very similar conditions.

Endothelial cell (EC) injury is a crucial contributor to the progression of diabetic kidney disease (DKD), but the specific EC populations and mechanisms involved remain elusive. Kidney ECs (n = 5464) were collected at three timepoints from diabetic BTBRob/ob mice and non-diabetic littermates. Their heterogeneity, transcriptional changes, and alternative splicing during DKD progression were mapped using SmartSeq2 single-cell RNA sequencing (scRNAseq) and elucidated through pathway, network, and gene ontology enrichment analyses. We identified 13 distinct transcriptional EC phenotypes corresponding to different kidney vessel subtypes, confirmed through in situ hybridization and immunofluorescence. EC subtypes along nephrons displayed extensive zonation related to their functions. Differential gene expression analyses in peritubular and glomerular ECs in DKD underlined the regulation of DKD-relevant pathways including EIF2 signaling, oxidative phosphorylation, and IGF1 signaling. Importantly, this revealed the differential alteration of these pathways between the two EC subtypes and changes during disease progression. Furthermore, glomerular and peritubular ECs also displayed aberrant and dynamic alterations in alternative splicing (AS), which is strongly associated with DNA repair. Strikingly, genes displaying differential transcription or alternative splicing participate in divergent biological processes. Our study reveals the spatiotemporal regulation of gene transcription and AS linked to DKD progression, providing insight into pathomechanisms and clues to novel therapeutic targets for DKD treatment.

Microglia help limit the progression of Alzheimer’s disease (AD) by constraining amyloid-β (Aβ) pathology, effected through a balance of activating and inhibitory intracellular signals delivered by distinct cell surface receptors. Human leukocyte Ig-like receptor B4 (LILRB4) is an inhibitory receptor of the immunoglobulin (Ig) superfamily that is expressed on myeloid cells and recognizes apolipoprotein E (ApoE) among other ligands. Here, we find that LILRB4 is highly expressed in the microglia of patients with AD. Using mice that accumulate Aβ and carry a transgene encompassing a portion of the LILR region that includes LILRB4 , we corroborated abundant LILRB4 expression in microglia wrapping around Aβ plaques. Systemic treatment of these mice with an anti-human LILRB4 monoclonal antibody (mAb) reduced Aβ load, mitigated some Aβ-related behavioral abnormalities, enhanced microglia activity, and attenuated expression of interferon-induced genes. In vitro binding experiments established that human LILRB4 binds both human and mouse ApoE and that anti-human LILRB4 mAb blocks such interaction. In silico modeling, biochemical, and mutagenesis analyses identified a loop between the two extracellular Ig domains of LILRB4 required for interaction with mouse ApoE and further indicated that anti-LILRB4 mAb may block LILRB4-mApoE by directly binding this loop. Thus, targeting LILRB4 may be a potential therapeutic avenue for AD.