Citations

Objective To evaluate the safety and efficacy of Grayson's presurgical nasoalveolar molding (PNAM) technique on nasal and alveolar morphology in infants with unilateral cleft lip and palate (UCLP). Design Systematic review and meta-analysis. Setting : Multicenter international literature across clinical and academic institutions. Patients, Participants Infants with UCLP reported in 21 eligible studies (n = 534), of whom 368 received PNAM. Interventions Presurgical nasoalveolar molding (PNAM) according to the Grayson protocol. Main Outcome Measure(s) : Changes in nasal symmetry (nostril width ratio, columellar angle) and alveolar morphology (alveolar gap dimensions, intertuberosity distance). Results PNAM was performed for an average duration of 96 days with 11 adjustments per patient. Pooled analyses demonstrated significant improvements in nasal symmetry: nostril width ratio decreased from 2.4 (95% CI, 1.7–3.1; I² = 98%) to 1.8 (95% CI, 0.9–2.6; I² = 97%), and the columellar angle increased from 52° (95% CI, 42.0–62.8; I² = 100%) to 70° (95% CI, 59.1–80.6; I² = 98%). Alveolar gap narrowed from 10.7 mm (95% CI, 9.5–11.9; I² = 92%) to 3.9 mm (95% CI, 3.1–4.8; I² = 93%). Intertuberosity distance increased slightly, from 31.3 mm (95% CI, 29.3–33.3; I² = 95%) to 31.8 mm (95% CI, 28.9–34.8; I² = 98%). Conclusions Grayson's PNAM appears to improve nasal and alveolar morphology in infants with UCLP prior to definitive surgery. Standardized outcome measures and long-term prospective studies are needed to confirm these findings and refine clinical protocols.

Abstract MGMT is primarily inactivated via promoter methylation, but MGMT homozygous deletion (hmzdel) has been rarely reported as an alternative inactivating mechanism. Although functionally similar to a methylated MGMT promoter, MGMT hmzdel is associated with an unmethylated MGMT promoter test result reflecting the MGMT promoter status of the non-neoplastic cells invariably present in any tumor specimen. Thus, patients whose tumors have MGMT hmzdel (and unmethylated MGMT promoter) would be inaccurately predicted to lack benefit from alkylating chemotherapy based on MGMT promoter methylation testing alone. To evaluate the impact of this clinical scenario, we estimated the frequency and distribution of MGMT hmzdel in routine clinical testing of CNS tumors. Among 12,424 CNS tumors (3,044 with provided diagnosis of glioblastoma) tested using Oncoscan chromosomal microarray (2015-2025), 10 tumors (0.08%) had MGMT hmzdel: 8 with entire gene hmzdel and 2 with partial gene hmzdel favored to be inactivating (RNA-sequencing underway to exclude possibility of activating rearrangements). All tumors were supratentorial and non-midline. Median age at diagnosis was 58.5 years (range, 34-81), with 3:2 male:female. Of the 10 cases, 9 (of 3,044; 0.3%) had integrated diagnosis of glioblastoma, IDH-wildtype; the remaining case was a recurrent astrocytoma, IDH-mutant, CNS WHO grade 4. All 10 cases had loss of chromosome 10q and a highly unmethylated MGMT promoter by droplet digital PCR testing of downstream CpG sites 75-80/84-87, with median fraction abundance of 0.19% (range, 0-0.85). In summary, MGMT hmzdel only occurred in high-grade adult-type diffuse astrocytic gliomas, and is a rare potential pitfall for MGMT promoter methylation testing leading to inaccurate patient stratification. It is critical that laboratories performing routine CNS tumor copy number testing include MGMT in the curated list of reportable genes, and that clinicians be aware of this rare clinical scenario to accurately stratify patients despite misleading MGMT promoter test results.

Background The Woven EndoBridge (WEB) device represents an innovative solution for cerebral aneurysm occlusion, particularly for challenging wide-neck bifurcation aneurysms. However, factors affecting sustained occlusion remain poorly understood. We utilized machine learning to attempt to identify predictors of favorable long-term outcomes following WEB treatment. Methods In this multicenter retrospective study, we collected patient demographics, aneurysm characteristics, procedural details, and clinical outcomes. The primary endpoint was improvement in occlusion status, defined as maintained Raymond-Roy Occlusion Classification (RROC) grade 1, or improvement from grade 2 to 1, or from grade 3 to either 2 or 1 on final angiographic follow up. The dataset was split into training (75%) and validation (25%) sets. The CatBoost algorithm was selected based on performance metrics, with Shapley Additive exPlanations (SHAP) values calculated to determine feature importance. Furthermore, a multivariable binomial logistic regression model was performed to validate machine learning findings. Results Among 720 aneurysms from 36 hospitals, 84% showed improvement in occlusion at follow up. Both machine learning and multivariable logistic regression identified aneurysm height as the most consistent correlate of nonimprovement (odds ratio (OR) 0.90 per mm, p = 0.022). In the CatBoost model, the highest-ranking features by SHAP included aneurysm height, patient age, treatment acuity, ACom location, WEB-SLS device, bifurcation anatomy, aneurysm multiplicity, baseline modified Rankin Scale, access route, and partial thrombosis. Conclusions Machine-learning and regression analyses identified consistent predictors of occlusion improvement after WEB treatment, with aneurysm height most strongly linked to nonimprovement. These insights may guide patient selection and follow up. Findings require cautious interpretation and external validation in larger cohorts.

Background: Ventricular tachycardia (VT) is a potentially life-threatening arrhythmia frequently observed in structural heart diseases, including cardiac laminopathy, a genetic cardiomyopathy associated with a high risk of sudden cardiac death (SCD) and progressive systolic dysfunction caused by pathogenic variants in LMNA -encoded lamin A/C. While catheter ablation is a key therapeutic strategy for VT management, its efficacy in cardiac laminopathy remains poorly defined. Objective: This systematic review and single-arm meta-analysis aims to synthesize the available evidence in the literature on the role of VT ablation for patients with cardiac laminopathy. Methods: A single-arm meta-analysis was conducted following PRISMA guidelines, systematically searching PubMed, Embase, and Cochrane databases for studies investigating VT ablation outcomes in patients with cardiac laminopathy. We applied an inverse variance random-effects model for a meta-analysis of proportions. Results: We included 6 cohort studies and 1 abstract comprising 62 patients with LMNA-related cardiomyopathy (mean age at 53.2 ± 9.7 years, 85% males, and 88% with an ICD). The predominant ablation strategy was endocardial/endo-epicardial in 93% of cases. Acute success rate following VT ablation was 37% (95% CI: 14 to 63%) and 28% of the patients required multiple procedures. Over a median follow-up of 26 (9-35) months, VT recurrence rate after ablation was 91% (95% CI: 76 to 100%; Figure A ). The all-cause mortality rate was 54% (95% CI: 39% to 70%; Figure B ), primarily driven by cardiac causes 51% (95% CI: 25 to 76%; Figure C ). There was an elevated rate of heart transplantation 14% (95% CI: 1 to 34%), highlighting overall poor outcomes in this patient population. Conclusion: Catheter ablation in cardiac laminopathy is associated with limited long-term efficacy, with high rates of VT recurrence, cardiovascular mortality and heart transplantation. These findings underscore the importance of ICD implantation for primary prevention and the pressing need to develop alternative treatment strategies. Further research is necessary to determine whether specific LMNA variants influence ablation outcomes and to explore emerging therapies targeting the underlying molecular mechanisms of cardiac laminopathy.

Background: Pathogenic variants in LMNA -encoded lamin A/C cause a genetic cardiomyopathy marked by conduction disease, atrial and ventricular arrhythmias, and systolic dysfunction. The mechanisms underlying phenotypic differences between Ig-like and coiled-coil domain missense variants remains unclear. Here, we developed a novel suppression-and-replacement disease modeling (SupRep-DM) platform to screen LMNA missense variant function and prioritize mechanistically informative phenotypes. Methods: LMNA-SupRep-DM is a dual-component lentiviral system that enables simultaneous knockdown of endogenous LMNA via an LMNA -targeted shRNA and replacement with an shRNA-immune mutant lamin A cDNA encoding the pathogenic variant of interest with HA-tag. HEK293T cells and iPSC-derived cardiomyocytes (iPSC-CMs) were transduced with 9 unique SupRep-DM constructs harboring variants in either the coiled-coil (E82K, K97E, R216C, H222P, T224I, R335W) or Ig-like (R471H, R541C, R541H) domains. Cells were stained using HA-specific antibodies, imaged by confocal microscopy, and analyzed for nuclear morphology, aggregate burden, and fluorescence intensity. Statistics: Dunnett’s test and one-way ANOVA. Results: In HEK293T cells, 8/9 LMNA variants significantly reduced nuclear circularity (p< 0.05), most notably in K97E (-11%, n=89), R471H (-12%, n=62), and R541C (-9%, n=104). Additionally, K97E increased nuclear area (+24%) and R541C decreased it (−29%) vs wild-type (WT, p<0.0001). Lamin A intensity was significantly reduced in K97E, R471H, and R541C, but increased in T224I and R335W vs WT. In iPSC-CMs, Ig-fold variants R541C and R541H significantly reduced nuclear circularity (−28%, –34%), increased elongation (+42%, +49%), and elevated lamin A aggregates ~4–5-fold vs WT (p≤0.0005). R471H and the coiled-coil variant E82K also increased aggregate burden, while the remaining variants (K97E, R216C, H222P, T224I, R335W) showed no significant effects in iPSC-CMs. Conclusions: LMNA missense variants cause domain-specific nuclear disruptions, with variants localizing to the Ig-like domain inducing nuclear deformities and consistent aggregation across both cellular models. Coiled-coil variants showed more variable, context-dependent effects. The more pronounced phenotypes in iPSC-CMs may reflect contraction-mediated stress absent in HEK293T cells. The SupRep-DM platform sensitively detects these structural changes, demonstrating its utility for mechanistic prioritization of LMNA variants.

Abstract Aims Type 2 myocardial infarction due to myocardial oxygen supply–demand imbalance is associated with poor outcomes. There are no guidelines to inform care for these patients. The consensus on the assessment and management of type 2 myocardial infarction is gained. Methods and results An international e-Delphi study including experts in type 2 myocardial infarction identified through systematic review was conducted. Participants were asked to describe their approach to (i) definition and diagnosis, (ii) risk stratification, (iii) assessment of coronary artery disease and cardiac function, (iv) specialty management, (v) treatment and secondary prevention, and (vi) communication and rehabilitation. Statements generated in round one were circulated, with consensus defined a priori as ≥70% agreement on a 5-point Likert scale. Where no consensus was reached, statements were amended and recirculated for a final round. The response rate was 56% (38/68), 54% (37/68), and 72% (49/68) in the first, second, and third rounds, respectively. Following the first round, 67 unique statements were generated across six domains. Overall, consensus was achieved on 64% (43/67) of statements. Consensus was achieved for 42% (5/12) of statements on the diagnosis of type 2 myocardial infarction, 75% (3/4) on risk stratification, 50% (9/18) on the assessment of coronary artery disease and cardiac function, 60% (6/10), on specialty management, 100% (9/9) on treatment and secondary prevention, and 79% (11/15) on communication and rehabilitation. Conclusion Consensus was obtained across a number of domains for the assessment and management of patients with type 2 myocardial infarction. However, there was limited agreement amongst experts on the diagnostic criteria, which may benefit from refinement.

Background: Ventricular tachycardia (VT) is a life-threatening arrhythmia frequently observed in structural heart diseases, including LMNA-related cardiomyopathy, a genetic disorder associated with high risk of sudden cardiac death and progressive systolic dysfunction. While catheter ablation is an established therapeutic option for VT, its efficacy in cardiac laminopathy remains poorly defined. Objectives: To synthesize available evidence on the role and outcomes of VT ablation in patients with cardiac laminopathy. Methods: A systematic review and single-arm meta-analysis was performed in accordance with PRISMA guidelines. PubMed, Embase, and Cochrane databases were searched for studies reporting VT ablation outcomes in LMNA-related cardiomyopathy. An inverse variance random-effects model was applied for meta-analysis of proportions. Results: Seven studies (six cohorts, one abstract) comprising 62 patients (mean age 53.2 ± 9.7 years; 85% male; 88% with implantable cardioverter-defibrillator) were included. An endocardial/endo-epicardial approach was used in 93% of cases. Acute procedural success was achieved in 37% (95% CI: 14–63%; I 2 = 27.4%), and 28% required multiple procedures. Over a median follow-up of 26 (9–35) months, VT recurrence occurred in 91% (95% CI: 76–100%; I 2 = 37.2%). All-cause mortality was 54% (95% CI: 39–70%; I 2 = 28%), predominantly from cardiac causes (51%, 95% CI: 25–76%; I 2 = 53%), and 14% (95% CI: 1–34%; I 2 = 42%) underwent heart transplantation. Conclusions: In LMNA-related cardiomyopathy, catheter ablation is associated with high VT recurrence, limited long-term success, and substantial cardiovascular mortality and transplantation rates, underscoring the importance of ICD implantation and the need for alternative strategies, including variant-specific and molecularly targeted therapies.

Abstract Columellar strut graft (CSG) and septal extension graft (SEG) are commonly used in septorhinoplasty for nasal tip support. We aimed to systematically review and compare CSG and SEG in achieving a desired nasolabial angle (NLA) and Goode's ratio (GR). Several databases were systematically searched from inception to August 2024. A two-arm meta-analysis of the pooled means was conducted with a random-effects model. This review was registered in PROSPERO (CRD42024574909). Eligible studies included primary septorhinoplasty patients (≥17 years) receiving CSG or SEG. Eight studies met eligibility criteria including 256 CSG and 371 SEG patients. Intergroup comparison of long-term postoperative NLA favored SEG (p < 0.05) while GR showed no differences. However, SEG patients had significant improvement in GR postoperatively (p < 0.05), unlike CSG patients. SEG may provide superior long-term nasal tip rotation and projection stability.