To Operate or Not to Operate? Reconstructive Surgical Burden and Quality of Life of Pediatric Patients with Facial Differences.

OBJECTIVE: The Craniofacial Condition Quality of Life Scale (CFC-QoL) was used to evaluate the relationship between surgical burden and quality of life (QoL). DESIGN: Patient-parent dyads completed the CFC-QoL which queries the following QoL domains: Bullying, Peer Problems, Psychological Impact, Family Support, Appearance Satisfaction, and Desire for Appearance Change. Stepwise multivariate linear regressions were performed for each QoL domain. SETTING: Urban tertiary care center. PATIENTS, PARTICIPANTS: Pediatric patients with facial differences, and their parents. INTERVENTION: Survey study. MAIN OUTCOME MEASURE(S): Demographic, diagnostic, and surgical characteristics were collected. Surgical burden was calculated as the standard deviation from the mean number of surgeries per diagnostic cohort. RESULT: Patients (N = 168) were majority female (57.1%) and Hispanic (64.3%). Diagnoses were cleft lip and/or palate (CLP,n = 99) or other craniofacial conditions (CFC,n = 69). Average patient age was 2.3 ± 5.6 years at first reconstructive surgery and 12.3 ± 3.4 years at study enrollment. Patients received an average of 4.3 ± 4.1 reconstructive surgeries.Worse Bullying was associated with higher surgical burden. Worse Peer Problems was associated with higher surgical burden, but only for children with non-CLP CFCs. Worse Family Support was associated with CFC diagnosis, female sex, and higher surgical burden. Worse Psychological Impact was associated with higher surgical burden. Worse Appearance Satisfaction was associated with younger age and with lower surgical burden. Greater Desire for Appearance Change was associated with older age, higher surgical burden, CLP diagnosis, female sex, and non-Hispanic ethnicity. Socioeconomic status did not predict QoL per patient self- or parent-proxy report. CONCLUSIONS: Higher surgical burden was associated with worse QoL outcomes in multiple domains.

Perioperative Comparison Between Open Cranial Vault Remodeling and Distraction Osteogenesis for Unilateral Lambdoid Craniosynostosis.

There are multiple treatment options for unilateral lambdoid craniosynostosis (ULS) including open posterior cranial vault remodeling (OCVR) and distraction osteogenesis (DO). There is a paucity of data comparing these techniques in the treatment of ULS. This study compared the perioperative characteristics of these interventions for patients with ULS. An IRB-approved chart review was performed from January 1999 to November 2018 at a single institution. Inclusion criteria included the diagnosis of ULS, treatment with either OCVR or DO using a posterior rotational flap technique, and a minimum 1-year follow-up. Seventeen patients met the inclusion criteria (12 OCVR and 5 DO). Patients in each cohort were found to have a similar distribution in sex, age at the time of surgery, synostosis laterality, weight, and length of follow-up. There was no significant difference in mean estimated blood loss/kg, surgical time, or transfusion requirements between cohorts. Distraction osteogenesis patients had a longer mean hospital length of stay (3.4 +/- 0.6 d versus 2.0 +/- 0.6 d, P = 0.0004). All patients were admitted to the surgical ward postoperatively. In the OCVR cohort, complications included 1 dural tear, 1 surgical site infection, and 2 reoperations. In the DO cohort, 1 patient had a distraction site infection, treated with antibiotics. There was no significant difference in estimated blood loss, volume of blood transfusion, or surgical time between OCVR and DO. Patients who underwent OCVR had a higher incidence of postoperative complications and the need for reoperation. This data provides insight into the perioperative differences between OCVR and DO in patients with ULS.

Virtual and In-Person Day Camps for the Craniofacial Community.

ABSTRACT: Children with congenital craniofacial conditions (CFCs) and their families may stand to benefit from day camps offering tailored psychosocial support and resources. Nonprofit ConnectMed International has held virtual and in-person day camps in San Diego for this community since 2018. We administered surveys before and after a series of day camps to understand the needs of this community and benefits perceived programming offered. Although studies have reported the psychosocial benefits of camps for children with rare diseases, few have examined the specific benefit for children with CFCs and their parents. Herein, we present the findings of our survey study as the first article to report a needs assessments and psychosocial benefits of day camps for children with CFCs and their parents.

One size does not fit all: Sex bias in pharmacologic venous thromboembolism prophylaxis.

BACKGROUND: The optimal enoxaparin dosing strategy to achieve venous thromboembolism (VTE) prophylaxis in trauma patients remains unclear. Current dosing guidelines often include weight, age, and renal function but still fail to achieve appropriate prophylactic anti-Xa levels in many patients. We hypothesized that additional patient factors influence anti-Xa response to enoxaparin in trauma patients. METHODS: This is a retrospective review of patients admitted to a Level 1 trauma center for ≥4 days from July 2015 to September 2020, who received enoxaparin VTE prophylaxis per protocol (50-59 kg, 30 mg/dose; 60-99 kg, 40 mg/dose; ≥100 kg, 50 mg/dose; all doses every 12 hours) and had an appropriately timed peak anti-Xa level. Multivariate regression was performed to identify independent predictors of prophylactic anti-Xa levels (0.2-0.4 IU/mL) upon first measurement. RESULTS: The cohort (N = 1,435) was 76.4% male, with a mean ± SD age of 49.9 ± 20.0 years and a mean ± SD weight of 82.5 ± 20.2 kg (males, 85.2 kg; females, 73.7 kg; p <0.001). Overall, 68.6% of patients (n = 984) had a prophylactic anti-Xa level on first assessment (69.6% of males, 65.1% of females). Males were more likely to have a subprophylactic level than females (22.1% vs. 8.0%, p <0.001), whereas females were more likely to have supraprophylactic levels than males (26.9% vs. 8.3%, p < 0.001). When controlling for creatinine clearance, anti-Xa level was independently associated with dose-to-weight ratio (odds ratio, 0.191 for 0.5 mg/kg; p < 0.001; confidence interval, 0.151-0.230) and female sex (odds ratio, 0.060; p < 0.001; confidence interval, 0.047-0.072). Weight and age were not significant when controlling for the other factors. CONCLUSION: Male patients have a decreased anti-Xa response to enoxaparin when compared with female patients, leading to a greater incidence of subprophylactic anti-Xa levels in male patients at all dose-to-weight ratios. To improve the accuracy of VTE chemoprophylaxis, sex should be considered as a variable in enoxaparin dosing models. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

Intracranial Volumes of Healthy Children in the First 3 Years of Life: An Analysis of 270 Magnetic Resonance Imaging Scans.

BACKGROUND: There is a paucity of data on normal intracranial volumes for healthy children during the first few years of life, when cranial growth velocity is greatest. The aim of this study was to generate a normative predictive model of intracranial volumes based on brain magnetic resonance imaging from a large sample of healthy children to serve as a reference tool for future studies on craniosynostosis. METHODS: Structural magnetic resonance imaging data for healthy children up to 3 years of age was acquired from the National Institutes of Health Pediatric MRI Data Repository. Intracranial volumes were calculated using T1-weighted scans with FreeSurfer (version 6.0.0). Mean intracranial volumes were calculated and best-fit logarithmic curves were generated. Results were compared to previously published intracranial volume curves. RESULTS: Two-hundred seventy magnetic resonance imaging scans were available: 118 were collected in the first year of life, 97 were collected between years 1 and 2, and 55 were collected between years 2 and 3. A best-fit logarithmic growth curve was generated for male and female patients. The authors' regression models showed that male patients had significantly greater intracranial volumes than female patients after 1 month of age. Predicted intracranial volumes were also greater in male and female patients in the first 6 months of life as compared to previously published intracranial volume curves. CONCLUSIONS: To the authors' knowledge, this is the largest series of demographically representative magnetic resonance imaging-based intracranial volumes for children aged 3 years and younger. The model generated in this study can be used by investigators as a reference for evaluating craniosynostosis patients.

Delayed Presentation of Sagittal Suture Craniosynostosis.

BACKGROUND: Sagittal craniosynostosis typically presents as dolichocephaly or less frequently as clinocephaly, a "saddle-shaped" phenotype. This project aimed to characterize clinically relevant differences between sagittal synostosis phenotypes and examine the etiology of the delay in presentation. METHODS: An institutional review board-approved retrospective review was performed from January 1999 to November 2018 at a single institution. Analyses examined correlations between subphenotype, time of presentation, minor suture fusion, developmental delay, and operative technique. RESULTS: One hundred sixty patients diagnosed with single-suture sagittal craniosynostosis were identified. A total of 30.6% had a saddle phenotype (n = 49) and 69.4% had dolichocephaly (n = 111). Patients with the saddle phenotype were more likely to present with a developmental delay and to have at least 1 minor suture fused than patients with dolichocephaly were. Patients with the saddle phenotype presented for surgery at an older age and were more likely to undergo open cranial vault repair, with increased blood loss, higher transfusion volume, and longer time. CONCLUSIONS: This study highlights clinical differences in sagittal craniosynostosis phenotypes and shows that developmental delay is an initial presentation of the saddle phenotype. The saddle phenotype also correlated with fusion of the minor squamous and sphenoid sutures. The link between developmental delay and minor suture fusion was notable and should be explored with a larger sample size. Patients with saddle synostosis present for surgery at an older age than patients with dolichocephaly and therefore are more likely to receive open cranial vault repair, with a taxing intraoperative experience characterized by increased blood loss, increased transfusions, and longer operation time.

Role of t-tubule remodeling on mechanisms of abnormal calcium release during heart failure development in canine ventricle.

The goal of this work was to investigate the role of t-tubule (TT) remodeling in abnormal Ca2+ cycling in ventricular myocytes of failing dog hearts. Heart failure (HF) was induced using rapid right ventricular pacing. Extensive changes in echocardiographic parameters, including left and right ventricular dilation and systolic dysfunction, diastolic dysfunction, elevated left ventricular filling pressures, and abnormal cardiac mechanics, indicated that severe HF developed. TT loss was extensive when measured as the density of total cell volume, derived from three-dimensional confocal image analysis, and significantly increased the distances in the cell interior to closest cell membrane. Changes in Ca2+ transients indicated increases in heterogeneity of Ca2+ release along the cell length. When critical properties of Ca2+ release variability were plotted as a function of TT organization, there was a complex, nonlinear relationship between impaired calcium release and decreasing TT organization below a certain threshold of TT organization leading to increased sensitivity in Ca2+ release below a TT density threshold of 1.5%. The loss of TTs was also associated with a greater incidence of triggered Ca2+ waves during rapid pacing. Finally, virtually all of these observations were replicated by acute detubulation by formamide treatment, indicating an important role of TT remodeling in impaired Ca2+ cycling. We conclude that TT remodeling itself is a major contributor to abnormal Ca2+ cycling in HF, reducing myocardial performance. The loss of TTs is also responsible for a greater incidence of triggered Ca2+ waves that may play a role in ventricular arrhythmias arising in HF.NEW & NOTEWORTHY Three-dimensional analysis of t-tubule density showed t-tubule disruption throughout the whole myocyte in failing dog ventricle. A double-linear relationship between Ca2+ release and t-tubule density displays a steeper slope at t-tubule densities below a threshold value (∼1.5%) above which there is little effect on Ca2+ release (T-tubule reserve). T-tubule loss increases incidence of triggered Ca2+ waves. Chemically induced t-tubule disruption suggests that t-tubule loss alone is a critical component of abnormal Ca2+ cycling in heart failure.

A Posterior Rotational Flap Technique Using Distraction Osteogenesis for Unilateral Lambdoid Craniosynostosis.

INTRODUCTION: The craniofacial asymmetry seen in unilateral lambdoid craniosynostosis may not be effectively treated by posterior cranial vault remodeling, endoscopic suturectomy, and helmet therapy, or suturectomy and distraction osteogenesis alone due to limitations in soft-tissue envelope expansion and relapse of the deformity. The authors report a series of unilateral lambdoid craniosynostosis patients treated with a posterior rotational cranial-flap technique using internal distraction osteogenesis. METHODS: Posterior cranial vault reconstruction combined with internal distraction was used, aided by preoperative virtual surgical planning. An in situ posterior rotational flap osteotomy was utilized to maximize dural preservation. Primary outcome measures included age-adjusted volume change and age-adjusted percent volume change per mm distraction. Distraction characteristics and perioperative characteristics were also assessed. RESULTS: A total of 5 patients were identified. Mean predistraction intracranial volume was 1087.5 cc (SD  = 202.3 cc) and mean postdistraction included intracranial volume was 1266.1cc (SD  = 131.8cc). Mean age-adjusted percent included intracranial volume change was 14.1% (SD  = 9.6%), and mean percent intracranial volume change per mm distraction was 0.43%/mm distraction (SD  = 0.37%/mm distraction). One patient developed a distractor site infection postoperatively that was treated successfully with oral antibiotics. All patients had a Whitaker score of 1 at one year follow up. CONCLUSIONS: Posterior cranial vault remodeling using osteogenesis and a rotational cranial flap technique with dural preservation can be effectively used to maximize bone flap viability and limit postoperative relapse in patients with unilateral lambdoid craniosynostosis. Long term analysis as well as comparison to open techniques will need to be interrogated.

Triggered Ca2+ Waves Induce Depolarization of Maximum Diastolic Potential and Action Potential Prolongation in Dog Atrial Myocytes.

BACKGROUND: We have identified a novel form of abnormal Ca2+ wave activity in normal and failing dog atrial myocytes which occurs during the action potential (AP) and is absent during diastole. The goal of this study was to determine if triggered Ca2+ waves affect cellular electrophysiological properties. METHODS: Simultaneous recordings of intracellular Ca2+ and APs allowed measurements of maximum diastolic potential and AP duration during triggered calcium waves (TCWs) in isolated dog atrial myocytes. Computer simulations then explored electrophysiological behavior arising from TCWs at the tissue scale. RESULTS: At 3.3 to 5 Hz, TCWs occurred during the AP and often outlasted several AP cycles. Maximum diastolic potential was reduced, and AP duration was significantly prolonged during TCWs. All electrophysiological responses to TCWs were abolished by SEA0400 and ORM10103, indicating that Na-Ca exchange current caused depolarization. The time constant of recovery from inactivation of Ca2+ current was 40 to 70 ms in atrial myocytes (depending on holding potential) so this current could be responsible for AP activation during depolarization induced by TCWs. Modeling studies demonstrated that the characteristic properties of TCWs are potentially arrhythmogenic by promoting both conduction block and reentry arising from the depolarization induced by TCWs. CONCLUSIONS: Triggered Ca2+ waves activate inward NCX and dramatically reduce atrial maximum diastolic potential and prolong AP duration, establishing the substrate for reentry which could contribute to the initiation and maintenance of atrial arrhythmias.

3D collagen architecture regulates cell adhesion through degradability, thereby controlling metabolic and oxidative stress.

The collagen-rich tumor microenvironment plays a critical role in directing the migration behavior of cancer cells. 3D collagen architectures with small pores have been shown to confine cells and induce aggressive collective migration, irrespective of matrix stiffness and density. However, it remains unclear how cells sense collagen architecture and transduce this information to initiate collective migration. Here, we tune collagen architecture and analyze its effect on four core cell-ECM interactions: cytoskeletal polymerization, adhesion, contractility, and matrix degradation. From this comprehensive analysis, we deduce that matrix architecture initially modulates cancer cell adhesion strength, and that this results from architecture-induced changes to matrix degradability. That is, architectures with smaller pores are less degradable, and degradability is required for cancer cell adhesion to 3D fibrilar collagen. The biochemical consequences of this 3D low-attachment state are similar to those induced by suspension culture, including metabolic and oxidative stress. One distinction from suspension culture is the induction of collagen catabolism that occurs in 3D low-attachment conditions. Cells also upregulate Snail1 and Notch signaling in response to 3D low-attachment, which suggests a mechanism for the emergence of collective behaviors.