Minimal clinically important differences in patient reported outcomes after coronary artery bypass surgery in the arterial revascularization trial.

OBJECTIVES: This paper identifies minimal clinically important differences (MCIDs) in quality of life (QoL) measures among patients who had coronary artery bypass grafting (CABG) and were enrolled in the Arterial Revascularization Trial (ART). METHODS AND RESULTS: The European Quality of Life 5 Dimensions (EQ-5D) and the Short Form Health Survey 36-Item (SF-36) physical component (PC) and mental component (MC) scores were recorded at baseline, 5 and 10 years in ART. The MCIDs were calculated as changes in QoL scores anchored to 1-class improvement in the New York Heart Association Functional class (NYHA) and Canadian Cardiovascular Society scale (CCS) at 5 years. Cox proportional hazards models were used to evaluate associations between MCIDs and mortality. Patient cohorts were examined for the SF-36 PC (N = 2,671), SF-36 MC (N = 2,815) and EQ-5D (N = 2,943) measures, respectively. All QoL scores significantly improved after CABG compared to baseline. When anchored to NYHA, the MCID at 5 years was 17 (95% CI: 17-20) for SF-36 PC, 14 (14-17) for the SF-36 MC, and 0.12 (0.12-0.15) for EQ-5D. Using the CCS as anchor, the MCID at 5 years was 15 (15-17) for the SF-36 PC, 12 (13-15) for the SF-36 MC, and 0.12 (0.11-0.14) for the EQ-5D. The MCIDs for SF-36 PC and EQ-5D at 5 years were associated with lower risk of mortality at the 10-year follow-up point after surgery. CONCLUSIONS: MCIDs for CABG patients have been identified. These thresholds may have direct clinical applications in monitoring patients during follow-up and in designing new trials that include QoL as a primary study outcome.

Preparing interns for clinical practice through an institution-wide simulation-based mastery learning program for teaching central venous catheter placement.

Central venous catheter (CVC) placement is a challenging procedure with known iatrogenic risks. However, there are no residency program requirements to demonstrate baseline CVC procedural competency. Competency-based procedural education has been shown to decrease CVC-associated morbidity, but there has been limited literature about institution-wide efforts to ensure initial trainee competency for CVC placement. This study describes the implementation of a competency-based CVC curriculum for first-year interns across an institution before supervised clinical care. An institution-wide, simulation-based mastery training curriculum was designed to assess initial competency in CVC placement in first-year residents during 2021 and 2022. A checklist was internally developed with a multidisciplinary team. Using the Mastery-Angoff technique, minimum passing standards were derived to define competency levels considered appropriate for intern participation in supervised clinical care. Interns were trained through the competency-based program with faculty assessing intern performance using the CVC checklist to verify procedural competency. Over 2 academic cycles, 229 interns from 20 specialties/subspecialties participated. Overall, 83% of interns met performance standards on their first posttest attempt, 14% on the second attempt, and 3% on the third attempt. Interns from both cycles demonstrated significant improvement from baseline to posttest scores (P < .001). Overall, 10.5% of interns performed dangerous actions during assessment (malpositioning, retained guidewire, or carotid dilation). All interns ultimately achieved the passing standard to demonstrate initial competency in the simulation assessment. All participating interns demonstrated simulation-based competency allowing them to place CVCs under supervised clinical care. Dangerous actions, however, were not uncommon. Simulation-based teaching and learning frameworks were a feasible method to promote patient safety through an institutional-wide verification of preliminary procedural competency.

Fear of COVID-19 among oral health professionals in South Africa.

Background: The coronavirus disease 2019 (COVID-19) pandemic caused widespread psychological morbidity, especially among frontline workers. Oral health professionals (OHPs) are at increased risk of contracting and dying from COVID-19 because pf their proximity to infected patients. The objective of this study was to measure the level of COVID-19 fear and its predictors among South African OHPs. Aim: To evaluate the severity of fear of COVID-19 among OHPs in South Africa. Setting: Online platforms. Methods: In this cross-sectional study, a Google Forms-based online survey was conducted. The fear scale of COVID-19 (FCV-19S) was used to assess the level of fear among OHPs. Statistical data analysis was performed using SPSS 28.0. The multivariate logistic regression model was developed to assess the predictors of COVID-19 fear. Results: A total of 462 OHPs participated in this study. Approximately half of the participants, 212 (45.6%), indicated having severe fear of COVID-19. The regression model showed a significant association between COVID-19 fear and increased age, clinical experience, employment sector, professional group, positive COVID-19 test and COVID-19 vaccination. Conclusion: The results indicate that South African OHPs had low levels of corona phobia. Females, older and vaccinated OHPs had the greatest odds of COVID-19 fear. Contribution: This study provides insights into the severity of fear and anxiety experienced by OHPs in the time of the pandemic. The findings will aid in the development of appropriate interventions and programmes to deal with similar outbreaks in the future.

Heat stress increases carbohydrate oxidation rates and oxygen uptake during prolonged load carriage exercise.

Military missions are conducted in a multitude of environments including heat and may involve walking under load following severe exertion, the metabolic demands of which may have nutritional implications for fueling and recovery planning. Ten males equipped a military pack loaded to 30% of their body mass and walked in 20°C/40% relative humidity (RH) (TEMP) or 37°C/20% RH (HOT) either continuously (CW) for 90 min at the first ventilatory threshold or mixed walking (MW) with unloaded running intervals above the second ventilatory threshold between min 35 and 55 of the 90 min bout. Pulmonary gas, thermoregulatory, and cardiovascular variables were analyzed following running intervals. Final rectal temperature (MW: p < 0.001, g = 3.81, CW: p < 0.001, g = 4.04), oxygen uptake, cardiovascular strain, and energy expenditure were higher during HOT trials (p ≤ 0.05) regardless of exercise type. Both HOT trials elicited higher final carbohydrate oxidation (CHOox) than TEMP CW at min 90 (HOT MW: p < 0.001, g = 1.45, HOT CW: p = 0.009, g = 0.67) and HOT MW CHOox exceeded TEMP MW at min 80 and 90 (p = 0.049, g = 0.60 and p = 0.024, g = 0.73, respectively). There were no within-environment differences in substrate oxidation indicating that severe exertion work cycles did not produce a carryover effect during subsequent loaded walking. The rate of CHOox during 90 minutes of load carriage in the heat appears to be primarily affected by accumulated thermal load.

Frailty in patients with IDH-mutant gliomas: experience from a high-volume tumor center.

PURPOSE: Gliomas are increasingly diagnosed in an aging population, with treatment outcomes influenced by factors like tumor genetics and patient frailty. This study focused on IDH-mutant gliomas and assessed how frailty affects 30-day readmission and overall survival (OS). We aimed to address a gap in understanding the impact of frailty on this specific glioma subtype. METHODS: 136 patients with an IDH-mutant glioma between 2007 and 2021 were identified at our institution. High frailty was classified by scores ≥ 1 on the 5-factor modified frailty index (mFI-5) and ≥ 3 on the Charlson Comorbidity Index (CCI). Patient and tumor characteristics including age, sex, race, Karnofsky Performance Status (KPS), Body Mass Index (BMI), tumor type and location, type of operation, and therapy course were recorded. Outcomes measured included 30-day readmission and overall survival (OS). Analysis was conducted utilizing logistic regression and Kaplan-Meier curves. RESULTS: Of the 136 patients, 52 (38%) had high frailty: 18 with CCI ≥ 3, 34 with mFI-5 ≥ 1. High frailty correlated with increased BMI (CCI: 30.2, mFI-5: 30.1 kg/m2), more neurological deficits (CCI: 61%, mFI-5: 56%), and older age at surgery (CCI: 63, mFI-5: 48 years). Hospital readmission within 30 days occurred in 8 (5.9%) patients. Logistic regression indicated no significant difference in 30-day readmission rates (CCI: p = 0.30, mFI-5: p = 0.62) or median OS between high and low frailty groups. However, patients treated at our institution with newly diagnosed tumors with high mFI-5 had a 6.79 times higher adjusted death hazard than those with low mFI-5 (p = .049). CONCLUSION: Our analysis revealed that CCI and mFI-5 were not significantly associated with 30-day nor OS. However, in patients with non-recurrent tumors, there was a significant association of mFI-5 with OS. Further study of frailty with larger cohorts is warranted to enhance prognostication of outcome after neurosurgical treatment.

Retrospective operationalization of allostatic load in patients with cancer: A systematic review.

Allostatic load (AL) has been shown to impact cancer outcomes. At present, no gold standard exists surrounding AL computation. As such, a systematic review of the literature was performed to identify studies that retrospectively calculated AL in patients with cancer. The following variables were collected for each study: AL calculation method, including the biomarkers used and their cutoff values, number of biosystems represented, definition of high AL, and the use of proxy biomarkers. Thirteen articles were included for full-text review. The number of biomarkers used in the calculation of AL varied considerably, ranging from 6 to 16. Considerable variability was also observed in terms of utilized biomarkers and biosystem representation. This lack of standardization complicates retrospective AL calculation among patients with cancer. Nonetheless, determining AL in patients with cancer presents an important step in the optimization of patient care and outcomes.

Mobilizing Endogenous Progenitor Cells Using pSDF1α-Activated Scaffolds Accelerates Angiogenesis and Bone Repair in Critical-Sized Bone Defects.

Mobilizing endogenous progenitor cells to repair damaged tissue in situ has the potential to revolutionize the field of regenerative medicine, while the early establishment of a vascular network will ensure survival of newly generated tissue. In this study we describe a gene-activated scaffold containing a stromal derived factor 1α plasmid (pSDF1α), a pro-angiogenic gene that is also thought to be involved in the recruitment of mesenchymal stromal cells (MSCs) to sites of injury. We show that over-expression of SDF1α protein enhanced MSC recruitment and induced vessel-like structure formation by endothelial cells in vitro. When implanted subcutaneously, transcriptomic analysis revealed that endogenous MSCs were recruited and significant angiogenesis was stimulated. Just one-week after implantation into a calvarial critical-sized bone defect, pSDF1α-activated scaffolds had recruited MSCs and rapidly activated angiogenic and osteogenic programs, upregulating Runx2, Dlx5, and Sp7. At the same time-point, pVEGF-activated scaffolds had recruited a variety of cell types, activating endochondral ossification. The early response induced by both scaffolds led to complete bridging of the critical-sized bone defects within 4-weeks. The versatile cell-free gene-activated scaffold described in this study is capable of harnessing and enhancing the body's own regenerative capacity and has immense potential in a myriad of applications. This article is protected by copyright. All rights reserved.

Adjunctive Statistical Standardization of Adjuvant Estrogen Receptor and Progesterone Receptor in Canadian Cancer Trials Group MA.27 Postmenopausal Breast Cancer Trial of Exemestane Versus Anastrozole.

PURPOSE: ASCO/College of American Pathologists guidelines recommend reporting estrogen receptor (ER) and progesterone receptor (PgR) as positive with (1%-100%) staining. Statistically standardized quantitated positivity could indicate differential associations of positivity with breast cancer outcomes. METHODS: MA.27 (ClinicalTrials.gov identifier: NCT00066573) was a phase III adjuvant trial of exemestane versus anastrozole in postmenopausal women with early-stage breast cancer. Immunochemistry ER and PgR HSCORE and % positivity (%+) were centrally assessed by machine image quantitation and statistically standardized to mean 0 and standard deviation (SD) 1 after Box-Cox variance stabilization transformations of square for ER; for PgR, (1) natural logarithm (0.1 added to 0 HSCOREs and 0%+) and (2) square root. Our primary end point was MA.27 distant disease-free survival (DDFS) at a median 4.1-year follow-up, and secondary end point was event-free survival (EFS). Univariate survival with cut points at SDs about a mean of 0 (≤-1; (-1, 0]; (0, 1]; >1) was described with Kaplan-Meier plots and examined with Wilcoxon (Peto-Prentice) test statistic. Adjusted Cox multivariable regressions had two-sided Wald tests and nominal significance P < .05. RESULTS: Of 7,576 women accrued, 3,048 women's tumors had machine-quantitated image analysis results: 2,900 (95%) for ER, 2,726 (89%) for PgR, and 2,582 (85% of 3,048) with both ER and PgR. Higher statistically standardized ER and PgR HSCORE and %+ were associated with better univariate DDFS and EFS (P < .001). In multivariable assessments, ER HSCORE and %+ were not significantly associated (P = .52-.88) with DDFS in models with PgR, whereas higher PgR HSCORE and %+ were significantly associated with better DDFS (P = .001) in models with ER. CONCLUSION: Adjunctive statistical standardization differentiated quantitated levels of ER and PgR. Patients with higher ER- and PgR-standardized units had superior DDFS compared with those with HSCOREs and %+ ≤-1.

An in vivo "turning model" reveals new RanBP9 interactions in lung macrophages.

The biological functions of the scaffold protein Ran Binding Protein 9 (RanBP9) remain elusive in macrophages or any other cell type where this protein is expressed together with its CTLH (C-terminal to LisH) complex partners. We have engineered a new mouse model, named RanBP9-TurnX, where RanBP9 fused to three copies of the HA tag (RanBP9-3xHA) can be turned into RanBP9-V5 tagged upon Cre-mediated recombination. We created this model to enable stringent biochemical studies at cell type specific level throughout the entire organism. Here, we have used this tool crossed with LysM-Cre transgenic mice to identify RanBP9 interactions in lung macrophages. We show that RanBP9-V5 and RanBP9-3xHA can be both co-immunoprecipitated with the known members of the CTLH complex from the same whole lung lysates. However, more than ninety percent of the proteins pulled down by RanBP9-V5 differ from those pulled-down by RanBP9-HA. The lung RanBP9-V5 associated proteome includes previously unknown interactions with macrophage-specific proteins as well as with players of the innate immune response, DNA damage response, metabolism, and mitochondrial function. This work provides the first lung specific RanBP9-associated interactome in physiological conditions and reveals that RanBP9 and the CTLH complex could be key regulators of macrophage bioenergetics and immune functions.

Nodal Metastases in Stage 3 Head and Neck Melanoma: Patterns of Metastases and Patterns of Failure.

OBJECTIVE: Stage 3 patients with clinically positive nodal metastasis are treated with therapeutic neck dissection and adjuvant systemic therapy. The aim of our study was to examined the predictability of pre-operative CT as a nodal drainage assessment tool. METHODS: Retrospective review of all patients with clinically positive head and neck cutaneous melanoma between 2010 and 2019. Clinical disease was diagnosed as radiological suspicious, biopsy-proven node. A pre-operative CT evaluation for nodal metastasis was compared to pathology report. RESULTS: A total of 53 patients were included. Forty patients (75.5%) were males with a mean age of 59 (SD 15.52). The majority of patients (26.4%) had an unknown primary site. The most common sites for primary were the cheek in eight patients (15.1%) followed by forehead (9.4%) and lateral neck (9.4%). Preoperative CT predicted nodal disease in 84.6% of cases. The primary region that mainly failed from the previously described clinical prediction was the upper anterior neck with 83.3% parotid involvement. A total of 10 patients (18.9%) were diagnosis with non-clinical nodes on pathology with a median non-clinical node of 1 (range 1-2). Of them, 9 (90%) were in the same clinical levels detected by CT. Pre-operative CT was associated with a neck level accuracy of 98.1%. CONCLUSION: Stage 3 head and neck melanoma with clinically positive nodal metastasis that are eligible for an adjuvant systemic treatment, may benefit from a highly selective neck dissection according to their pre-operative imaging studies. This should be further evaluated in a large-scale clinical trial. LEVEL OF EVIDENCE: 3 Laryngoscope, 2024.

Severity of effect considerations regarding the use of mutation as a toxicological endpoint for risk assessment: A report from the 8th International Workshop on Genotoxicity Testing (IWGT).

Exposure levels without appreciable human health risk may be determined by dividing a point of departure on a dose-response curve (e.g., benchmark dose) by a composite adjustment factor (AF). An "effect severity" AF (ESAF) is employed in some regulatory contexts. An ESAF of 10 may be incorporated in the derivation of a health-based guidance value (HBGV) when a "severe" toxicological endpoint, such as teratogenicity, irreversible reproductive effects, neurotoxicity, or cancer was observed in the reference study. Although mutation data have been used historically for hazard identification, this endpoint is suitable for quantitative dose-response modeling and risk assessment. As part of the 8th International Workshops on Genotoxicity Testing, a sub-group of the Quantitative Analysis Work Group (WG) explored how the concept of effect severity could be applied to mutation. To approach this question, the WG reviewed the prevailing regulatory guidance on how an ESAF is incorporated into risk assessments, evaluated current knowledge of associations between germline or somatic mutation and severe disease risk, and mined available data on the fraction of human germline mutations expected to cause severe disease. Based on this review and given that mutations are irreversible and some cause severe human disease, in regulatory settings where an ESAF is used, a majority of the WG recommends applying an ESAF value between 2 and 10 when deriving a HBGV from mutation data. This recommendation may need to be revisited in the future if direct measurement of disease-causing mutations by error-corrected next generation sequencing clarifies selection of ESAF values.

The brain microvasculature is a primary mediator of interferon-α neurotoxicity in human cerebral interferonopathies.

Aicardi-Goutières syndrome (AGS) is an autoinflammatory disease characterized by aberrant interferon (IFN)-α production. The major cause of morbidity in AGS is brain disease, yet the primary source and target of neurotoxic IFN-α remain unclear. Here, we demonstrated that the brain was the primary source of neurotoxic IFN-α in AGS and confirmed the neurotoxicity of intracerebral IFN-α using astrocyte-driven Ifna1 misexpression in mice. Using single-cell RNA sequencing, we demonstrated that intracerebral IFN-α-activated receptor (IFNAR) signaling within cerebral endothelial cells caused a distinctive cerebral small vessel disease similar to that observed in individuals with AGS. Magnetic resonance imaging (MRI) and single-molecule ELISA revealed that central and not peripheral IFN-α was the primary determinant of microvascular disease in humans. Ablation of endothelial Ifnar1 in mice rescued microvascular disease, stopped the development of diffuse brain disease, and prolonged lifespan. These results identify the cerebral microvasculature as a primary mediator of IFN-α neurotoxicity in AGS, representing an accessible target for therapeutic intervention.

PD-L1 promotes oncolytic virus infection via a metabolic shift that inhibits the type I IFN pathway.

While conventional wisdom initially postulated that PD-L1 serves as the inert ligand for PD-1, an emerging body of literature suggests that PD-L1 has cell-intrinsic functions in immune and cancer cells. In line with these studies, here we show that engagement of PD-L1 via cellular ligands or agonistic antibodies, including those used in the clinic, potently inhibits the type I interferon pathway in cancer cells. Hampered type I interferon responses in PD-L1-expressing cancer cells resulted in enhanced efficacy of oncolytic viruses in vitro and in vivo. Consistently, PD-L1 expression marked tumor explants from cancer patients that were best infected by oncolytic viruses. Mechanistically, PD-L1 promoted a metabolic shift characterized by enhanced glycolysis rate that resulted in increased lactate production. In turn, lactate inhibited type I IFN responses. In addition to adding mechanistic insight into PD-L1 intrinsic function, our results will also help guide the numerous ongoing efforts to combine PD-L1 antibodies with oncolytic virotherapy in clinical trials.

Two-dimensional perovskite templates for durable, efficient formamidinium perovskite solar cells.

We present a design strategy for fabricating ultrastable phase-pure films of formamidinium lead iodide (FAPbI3) by lattice templating using specific two-dimensional (2D) perovskites with FA as the cage cation. When a pure FAPbI3 precursor solution is brought in contact with the 2D perovskite, the black phase forms preferentially at 100°C, much lower than the standard FAPbI3 annealing temperature of 150°C. X-ray diffraction and optical spectroscopy suggest that the resulting FAPbI3 film compresses slightly to acquire the (011) interplanar distances of the 2D perovskite seed. The 2D-templated bulk FAPbI3 films exhibited an efficiency of 24.1% in a p-i-n architecture with 0.5-square centimeter active area and an exceptional durability, retaining 97% of their initial efficiency after 1000 hours under 85°C and maximum power point tracking.

Health Disparities in the Neurosurgical Care of Patients with Trigeminal Neuralgia.

INTRODUCTION: There has been limited investigation into how social determinants of health (SDOH) impact treatment outcomes in patients with trigeminal neuralgia (TN). We aimed to investigate how SDOH may alter the course of clinical care for patients with TN. METHODS: The electronic medical record was queried for patients with a diagnosis of TN co-managed by neurosurgeons and other facial pain specialists at our medical center. Area Deprivation Index (ADI) served as a proxy for socioeconomic status. Multivariable linear regression models were performed using RStudio to assess the impact of social determinants on the time to neurosurgical referral and surgical intervention. RESULTS: 229 patients (mean age 50 years, 74% female) were included. 135 (60%) patients underwent a neurosurgical procedure after referral, the most common being microvascular decompression (n=84, 62%) (Table 1). Most of the patients were white (76.3%) and insured by Medicare (51.8%), followed by private insurance (38.6%). Age and sex were significant predictors of time to neurosurgical referral after symptom onset, as older patients (p<0.01, Figure 3) and females (p=0.02) tended to have a greater delay between symptom onset and specialist referral. Race, socioeconomic status, and insurance status were not significantly associated with time-to-referral or time-to-treatment. DISCUSSION: This study found that older and female patients with TN had a longer time from symptom onset to specialist referral. Based on these data, there is no association between race, socioeconomic status, and insurance status with time-to-referral or time-to-treatment in patients with TN.

Vectorial drivers of malaria transmission in Jabi Tehnan district, Amhara Regional State, Ethiopia.

Among the factors affecting the effectiveness of malaria control is poor knowledge of the entomologic drivers of the disease. We investigated anopheline populations as part of a baseline study to implement house screening of windows and doors as a supplementary malaria control tool towards elimination in Jabi Tehnan district, Amhara Regional State of Ethiopia. The samples were surveyed monthly using CDC light traps between June 2020 and May 2021. Mosquito trap density (< 3 mosquitoes/trap) was low, however, with a high overall Plasmodium sporozoite rate (9%; indoor = 4.3%, outdoor = 13.1%) comprising P. falciparum (88.9%) and P. vivax (11.1%). Anopheles gambiae s.l., mostly An. arabiensis, comprised > 80% of total anopheline captures and contributed ~ 42% of Plasmodium-infected mosquitoes. On the other hand, morphologically scored Anopheles funestus s.l., constituting about 6% of anopheline collections, accounted for 50% of sporozoite-infected mosquitoes. Most of the infected An. funestus s.l. specimens (86.7%) were grouped with previously unknown or undescribed Anopheles species previously implicated as a cryptic malaria vector in the western Kenyan highlands, confirming its wider geographic distribution in eastern Africa. Other species with Plasmodium infection included An. longipalpis C, An. theileri, An. demillioni, and An. nili. Cumulatively, 77.8% of the infected mosquitoes occurred outdoors. These results suggest efficient malaria parasite transmission despite the low vector densities, which has implications for effective endpoint indicators to monitor malaria control progress. Additionally, the largely outdoor infection and discovery of previously unknown and cryptic vectors suggest an increased risk of residual malaria transmission and, thus, a constraint on effective malaria prevention and control.

Panoply of P: An Array of Rhenium-Phosphorus Complexes Generated from a Transition Metal Anion.

We expand upon the synthetic utility of anionic rhenium complex Na[(BDI)ReCp] (1, BDI = N,N'-bis(2,6-diisopropylphenyl)-3,5-dimethyl-ß-diketiminate) to generate several rhenium-phosphorus complexes. Complex 1 reacts in a metathetical manner with chlorophosphines Ph2PCl, MeNHP-Cl, and OHP-Cl to generate XL-type phosphido complexes 2, 3, and 4, respectively (MeNHP-Cl = 2-chloro-1,3-dimethyl-1,3,2-diazaphospholidine; OHP-Cl = 2-chloro-1,3,2-dioxaphospholane). Crystallographic and computational investigations of phosphido triad 2, 3, and 4 reveal that increasing the electronegativity of the phosphorus substituent (C < N < O) results in a shortening and strengthening of the rhenium-phosphorus bond. Complex 1 reacts with iminophosphane Mes*NPCl (Mes* = 2,4,6-tritert-butylphenyl) to generate linear iminophosphanyl complex 5. In the presence of a suitable halide abstraction reagent, 1 reacts with the dichlorophosphine iPr2NPCl2 to afford cationic phosphinidene complex 6+. Complex 6+ may be reduced by one electron to form 6•, a rare example of a stable, paramagnetic phosphinidene complex. Spectroscopic and structural investigations, as well as computational analyses, are employed to elucidate the influence of the phosphorus substituent on the nature of the rhenium-phosphorus bond in 2 through 6. Furthermore, we examine several common analogies employed to understand metal phosphido, phosphinidene, and iminophosphanyl complexes.

The role of genetics on behavioral outcomes in nonsyndromic sagittal synostosis.

OBJECTIVE: Previous work identified an association between genetics and neurodevelopmental delays in patients with nonsyndromic craniosynostosis. The authors investigated the role of genetic mutations on behavioral outcomes of patients with treated sagittal synostosis. METHODS: Parents of children aged 6-18 years with surgically corrected sagittal synostosis were recruited to complete the Child Behavioral Checklist (overall behavioral problems), Conners 3rd Edition-Parent (attention-deficit/hyperactivity disorder), Social Responsiveness Scale 2nd Edition (autism spectrum disorder [ASD]), and Behavior Rating Inventory of Executive Function 2nd Edition (executive function). Genomic analysis was completed, and patients were identified if they had mutations in high probability of loss of function intolerant (pLI) genes (high pLI vs nonhigh pLI). Genetic burden was assessed relative to controls. Multivariate linear regression determined the association of mutations in high pLI genes with behavioral scores, while controlling for sociodemographic factors, age at surgery, surgery type, and IQ. RESULTS: Sixteen of 45 patients were in the high pLI group. There were no differences between the groups in terms of sociodemographic factors. A greater proportion of children in the high pLI group scored at or above borderline clinical levels for aggression (18.8% vs 0.0%, p = 0.05) and externalizing problems (31.3% vs 3.7%, p = 0.02). Among children in the nonhigh pLI group, older age at surgery was associated with worse scores on the rule-breaking, aggression, and externalizing problems domains and four out of five ASD domains. CONCLUSIONS: Children with treated nonsyndromic sagittal synostosis and mutations in high pLI genes had worse behavioral problems in externalizing behaviors and aggression, whereas older age at surgery was a significant predictor of worse behavioral outcomes in patients without mutations in high pLI genes.