Citations

Objective We sought to characterize factors associated with postoperative complications in patients undergoing primary cleft lip repair (CLR). Design The National Surgical Quality Improvement Program-Pediatric database was queried to identify patients under 12 months old undergoing CLR using CPT codes. Multivariable analysis was conducted to characterize complications and associated comorbidities. Setting A multicenter sample. Patients/Participants A total of 11 957 cases (81.9% unilateral CLR and 18.1% bilateral CLR) were identified. Interventions None. Main Outcomes/Measures The postoperative outcomes of significance were surgical site infection (SSI), wound dehiscence, and unplanned reintubation within 30 days of CLR. Results The cohort had a mean age of 4.7 ± 2.0 months and a median American Society of Anesthesiologists classification of 2. SSIs occurred in 0.6% of cases and were independently associated with bilateral cleft anatomy (OR 2.16, P = .003) and longer anesthesia time (OR per minute: 1.004, P = .009). Wound dehiscence occurred in 0.4% of patients and was independently associated with bilateral cleft anatomy (OR 4.03, P < .001) but was associated with shorter anesthesia duration (OR per minute: 0.991, P < .001). Unplanned reintubation occurred in 0.2% of cases, with these patients having significantly higher rates of multiple comorbidities. Conclusion Wound dehiscence, SSI, and unplanned reintubation were rare complications following CLR. Patients with a bilateral cleft lip had increased odds of both SSI and wound dehiscence.

Abstract In Alzheimer’s disease (AD), tau pathology arises in entorhinal cortex layer II (ECII) and advances through defined hippocampal circuits to CA1 and connected neocortical regions, yet the determinants of this hierarchical spread remain unclear. We previously established a circuit-defined propagation model by expressing Cre-inducible human P301L 2N4R tau selectively in Wolframin-1 (Wfs1) + ECII neurons using AAV-FLEX-Tau P301L in Wfs1-Cre mice. Here, to test how amyloid-β (Aβ) and human tau background shape propagation, we generated human MAPT knock-in Wfs1 mice and APP NL-G-F / MAPT double knock-in Wfs1 mice (T-Wfs1 and AT-Wfs1) and induced ECII-restricted Tau P301L expression. Three months after injection, phosphorylated or misfolded tau-positive neurons were enriched in proximal CA1 in Wfs1 and T-Wfs1 mice, resembling primary age-related tauopathy, whereas AT-Wfs1 mice showed preferential accumulation near the CA1/subiculum (Sub) boundary, consistent with an AD-like pattern. In T-Wfs1 and AT-Wfs1 mice, tau spread extended through Sub to neocortical regions, and phosphorylated tau accumulated predominantly in excitatory rather than inhibitory neurons. Electrophysiological analyses revealed increased spontaneous neuronal firing and impaired GABAergic transmission in the CA1/Sub boundary and neocortical areas in T-Wfs1 and AT-Wfs1 mice, indicative of impaired GABAergic input and enhanced neuronal excitability in these regions. Together, these data indicate that human MAPT and Aβ pathology shift the circuit topography of tau propagation and are associated with early network dysfunction, supporting a synergistic interaction that promotes AD-like spread and synaptic imbalance.

Background: Sodium–glucose cotransporter 2 inhibitors (SGLT2i) are nephroprotective but are associated with early eGFR decline, also termed “eGFR dip.” Despite elevated risk of kidney disease, this phenomenon is understudied among people with HIV (PWH). Methods: In a 1:1 propensity score–matched cohort study using data from 9 Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) sites, we compared new SGLT2i users with new users of other antihyperglycemic classes. We estimated adjusted hazard ratios (aHRs) for time to ≥10% and ≥30% eGFR decline using multivariable Cox proportional hazards models and analyzed eGFR change using multivariable linear mixed models. In addition, longer-term eGFR trends over 24 months were visualized using locally weighted scatterplot smoothing (LOWESS) curves. Results: Among 1554 eligible PWH, we obtained 295 matched pairs. Over 6 months, eGFR decline incidence of ≥10% and ≥30% was higher among users of SGLT2i versus other antihyperglycemic classes (58.2% vs. 37.4%; aHR: 1.79; 95% CI: 1.40%–2.28%; and 17.3% vs. 9.8%; aHR: 1.69; 95% CI: 1.05–2.73; respectively). The adjusted mean eGFR change at 6 months was −2.62 mL/min/1.73 m 2 for SGLT2i versus 0.05 mL/min/1.73 m 2 for other classes. Long-term eGFR trends revealed an expected initial decline after SGLT2i initiation, followed by stabilization and a slower subsequent decline compared with other classes. Conclusions: Acute eGFR dips were more common among PWH initiating SGLT2i relative to other antihyperglycemic classes, although overall declines were small, transient, and consistent with the general population. Further research is needed to explore the long-term effects of SGLT2i in PWH.

Background: Blood-based biomarker panels, including GALAD, have been proposed as an alternative to abdominal ultrasound for hepatocellular carcinoma (HCC) surveillance. Studies suggest longitudinal evaluation of biomarkers can improve test performance; however, no large studies have validated these findings. Methods: We leveraged the HCC Early Detection Strategy (HEDS) study (n=1019 patients with cirrhosis; 99 incident HCC) and Texas HCC Consortium (THCCC) (n=2345 patients with cirrhosis; 126 incident HCC) to compare the performance of fixed-threshold GALAD (cutoff of −1.36), and 4 longitudinal algorithms: longitudinal GALAD, PALAD, mFB-ALAD, and mPEB-ALAD. The HEDS cohort was used to derive longitudinal algorithms, and external validation was performed in THCCC. Patient-level sensitivity and test-level false-positive rate (FPR) were examined overall and across subgroups by age, sex, and cirrhosis etiology. Results: In THCCC, fixed-threshold GALAD had higher sensitivity in the 6 months before HCC diagnosis (71.4%, 95% CI: 62.9%–81.7%) than longitudinal GALAD (55.1%, 95% CI: 49.3–66.4), PALAD (55.1%, 95% CI: 50.0%–70.5%), mPEB-ALAD (53.1%, 95% CI: 43.6%–62.0%), and mFB-ALAD (42.9%, 95% CI: 32.3–48.5). However, fixed-threshold GALAD had a higher FPR (25.4%, 95% CI: 23.7%–26.9%) compared with longitudinal GALAD (15.0%, 95% CI: 12.8%–15.8%), PALAD (13.0%, 95% CI: 10.2%–14.6%), and mFB-ALAD (11.2%, 95% CI: 9.6%–12.1%) but comparable to mPEB-ALAD (22.9%, 95% CI: 21.2%–23.8%). In subgroup analyses, fixed-threshold GALAD had the highest FPR in males (35.6%) and those aged ≥65 (43.5%); longitudinal algorithms had significantly lower FPRs in subgroups but with lower sensitivity for HCC. Conclusions: Improvements in FPRs with longitudinal GALAD algorithms, as compared with fixed-threshold GALAD, are offset by significantly decreased sensitivity for HCC detection.

Abstract Objective To assess the role of small‐molecule calcitonin gene–related peptide receptor antagonists (gepants) in the acute treatment of migraine, particularly in relation to triptan treatments. Background Triptans have established efficacy and are widely prescribed for the acute treatment of migraine. However, triptans may not be recommended for some individuals due to cardiovascular contraindications and precautions, as well as other comorbidities, and many may discontinue triptans because of inadequate or inconsistent symptom relief or poor tolerability. Several gepants are also indicated for the treatment of migraine (both acute and preventive), and their demonstrated efficacy and safety may address some challenges associated with triptans. Methods This narrative review addresses considerations for the acute treatment of migraine through summarizing literature and data from preclinical studies and clinical trials of triptans and gepants. Results We consider triptans and gepants, where available, first‐line treatment options for the acute treatment of migraine. Triptans may be prescribed in the absence of contraindications, significant risk of cardiovascular disease, or risk for or history of medication‐overuse headache. In those who have contraindications or precautions for triptans, those who do not have an adequate response to triptans, and those unable to tolerate them, gepants are often an appropriate option. The efficacy and safety of gepants for the acute treatment of migraine has been established through clinical trials and open‐label extension studies and based on real‐world evidence. Gepants have demonstrated efficacy and tolerability in triptan insufficient responders, perhaps because of their distinct mechanisms of action. Additionally, the safety of gepants, including relative cardiovascular safety, is supported in pivotal controlled trials and open‐label extension trials. In experimental settings and through their use as preventive treatment for migraine, gepants appear unlikely to produce medication‐overuse headache. In addition, one gepant (ubrogepant) has demonstrated efficacy in preventing headache onset when given during the prodrome, a finding that has not been demonstrated for triptans. A single‐arm, open‐label study of naratriptan given during the prodrome suggested fewer subsequent headaches, but interpretation is limited because there was no contemporaneous control group. Limited head‐to‐head clinical trials comparing gepants and triptans have not demonstrated significant differences. Prescribers of both triptans and gepants should be mindful of potential drug–drug interactions. Conclusions Key advantages of gepants include their favorable tolerability, efficacy for the acute treatment of both the prodromal/premonitory phase (ubrogepant) and the headache phase of migraine (ubrogepant, rimegepant, zavegepant), lack of cardiovascular contraindications, and lack of association with medication‐overuse headache. Disadvantages include limitations due to cost and access and CYP3A4 drug interactions for most gepants. Together, the advantages may help to optimize patient care and lead to better persistence and effectiveness in a real‐world setting. Head‐to‐head studies are needed to clarify the comparative effectiveness of triptans and gepants.

Abstract Neuroblastoma (NB) accounts for approximately 10% of pediatric cancer-related deaths. High-risk NB is often metastatic at diagnosis with a poor 5-year survival rate (&lt;50%) despite intensive multimodal therapy. GD2, a disialoganglioside glycolipid expressed in nearly all NBs, is a well-validated immunotherapy target. Although GD2-CAR-T cells have been clinically evaluated, their efficacy remains limited due to poor tumor infiltration and the immunosuppressive tumor microenvironment (TME), underscoring the need for alternative immune-based approaches. Given the inherent capacity of macrophages to infiltrate solid tumors, phagocytose cancer cells, and modulate the TME, we engineered the GD2-CAR macrophage (GD2-CAR-M) as a novel therapeutic platform for NB. GD2-specific CAR constructs containing the Hu3F8 single-chain variable fragment (scFv) were designed, validated, and introduced into multiple human and murine monocyte/macrophage cell lines via lentiviral transduction. Fluorescence microscopy and flow cytometry demonstrated a significant enhancement in the phagocytosis of GD2-high NB cells and the phagocytic efficiency correlating positively with GD2 expression levels, suggesting antigen-specific phagocytosis by GD2-CAR-M. Our further in vivo studies using an immunocompetent MYCN-driven NB non-genetically engineered mouse model (MYCN-NGEMM) showed that treatment with GD2-CAR-M markedly reduced tumor burden and prolonged survival compared with controls. Notably, mice bearing GD2-high-tumors exhibited significantly improved survival, including one complete remission among ten treated animals. Histological analyses revealed increased connective tissue deposition and decreased tumor cell density, suggesting TME remodeling. Single-cell RNA sequencing and immunohistochemistry further demonstrated enhanced infiltration of macrophages, neutrophils, and T cells, indicating a shift from a “cold” to a “hot” immune TME following GD2-CAR-M treatment. Consistent antitumor effects were also observed in our dbh-MYCN transgenic zebrafish with spontaneous development of NB following GD2-CAR-M administration. Taken together, GD2-CAR-M exhibits potent antigen-specific antitumor activity and promotes favorable TME remodeling in NB models. These findings highlight GD2-CAR-M as a promising translational immunotherapy strategy for high-risk NB. Citation Format: Shizhen (Jane) Zhu, Ke-En Tan, Kok Siong Yeo, Cheng Zhang, Caleb T. Baker, Alexis M. Sosic, Eddie Lim . Yat Yuen, Choong Yong Ung, Stephanie F. Polites, Yi Lin, William A. Weiss, Hu Li. Harnessing GD2-CAR macrophages to target high-risk neuroblastoma [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr B005.

BACKGROUND AND OBJECTIVES: Ventriculoperitoneal shunt (VPS) placement is a common treatment for idiopathic normal pressure hydrocephalus (iNPH), but patients may require VPS revision. This study aims to evaluate the effectiveness of a standardized VPS placement protocol by comparing indications and rates of shunt revision compared with a historical institutional cohort. METHODS: All patients treated with VPS for “suspected” iNPH at a tertiary care center between January 2000 and January 2023 were retrospectively reviewed and divided into temporally distinct historical (before 2017) and standardized (after 2017) cohorts. Cumulative incidence and timing of VPS revision were compared using competing risks analyses. RESULTS: A total of 561 patients (median age 75.0 years) were identified with 324 (57.8%) in the historical and 237 (42.2%) in the standardized cohorts. Significant variations in surgical technique and shunt hardware were noted between the cohorts. With a median follow-up of 11.4 months for historical and 12.4 months for standardized cohort, shunt revisions occurred in 19.4% and 8.4% of patients in the historical and standardized cohorts, respectively ( P < .001). Revision indications also varied significantly with lower rates of overdrainage ( P < .001), infection ( P < .001), and proximal malfunction ( P = .042) but higher rate of distal malfunction ( P = .03) in the standardized cohort. Notably, no infections were noted in the standardized cohort. CONCLUSION: Risk of shunt revision among iNPH patients may be associated with modifiable factors related to surgical technique and shunt hardware selection. Importantly, no short-term complications such as hemorrhage, infection, or catheter malposition were observed with the standardized protocol. Development and refinement of standardized shunt protocols for iNPH patients should be commonplace to facilitate tracking, identification, and modification of modifiable technical risk factors.